The extremely rare chronic neutrophilic leukemia characterized by unrelieved abdominal distention and swollen painful limbs

The extremely rare chronic neutrophilic leukemia characterized by unrelieved abdominal distention and swollen painful limbs | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The extremely rare chronic neutrophilic leukemia characterized by unrelieved abdominal distention and swollen painful limbs Yanquan Liu, Huanwen Tang, Yuting Chen, Weidan Lun, Zhimin Yan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1776640/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Backgroud: Although the pathogenesis of hematological tumors has not been fully elucidated, the academic community believes that genetic mutation abnormalities caused by a wide range of environmental factors play a crucial role in the occurrence and development of hematological malignancies. Chronic neutrophilic leukemia (CNL) is a rare hematological tumor in the world. It is characterized by a Philadelphia chromosome BCR-ABL1-negative myeloproliferative tumor. In addition, it can be accompanied by mutations in various genes. Among them, Colony-stimulating factor 3 receptor (CSF3R) is a classic mutation in CNL and is included in the diagnostic criteria for CNL. Case presentation: This article describes a 46-year-old male patient who came to the hospital with non-specific clinical manifestations such as unrelieved abdominal distension and edema of both lower extremities as the first symptoms. The middle-aged male patient was given a peripheral blood routine test and biochemical tests revealed abnormalities, and was then given a bone marrow biopsy to complete various tests such as bone marrow morphology, immunology, molecular biology, cytogenetics, and imaging. Finally, he was diagnosed as a rare chronic neutrophilic leukemia. After the diagnosis, the patient took ruxolitinib orally targeted therapy as prescribed by the doctor and regularly reviewed the peripheral blood examination and bone marrow status. The current condition is well controlled. Conclusion: CNL is extremely rare, and the disease usually has non-specific clinical features and manifestations as the first symptoms, which can easily lead to missed or misdiagnosed by clinicians. It is necessary to increase the awareness and vigilance of CNL. Chronic neutrophilic leukemia CSF3R ruxolitinib diagnostic biomarker targeted therapy prognosis Figures Figure 1 Figure 2 Figure 3 Introduction CNL is a highly heterogeneous myeloproliferative disease that is rare worldwide. Although most patients have splenomegaly and some non-specific symptoms, CNL is different from chronic myeloid leukemia (CML) in that it does not have the Ph chromosome and BCR-ABL fusion gene [ 1 ]. Unfortunately, it is difficult to diagnose CNL in the absence of specific typical symptoms and bone marrow examination. The typical feature of CNL is the continuous proliferation of mature neutrophils in the bone marrow and the activating mutation of CSF3R gene, which is different from CML and myeloproliferative neoplasms (MPN) [ 2 ]. This article provides the clinical data of a CNL patient, and reviews the relevant international academic literatures in recent years. This article is expected to provide a certain understanding and reference for the diagnosis and treatment of CNL in the global hematology community. Case Presentation A 46-year-old male patient was admitted to the First Affiliated Hospital of Gannan Medical University for the first time on January 25, 2021 with the main complaint of “repeated abdominal distension for more than five months and abnormal white blood cells for one month”. The patient had abdominal distension and anorexia for no obvious cause since August 2020, but no nausea, vomiting, no abdominal pain, diarrhea, no bloody or black stools, no chills, fever, night sweats, no dizziness, fatigue, no chest tightness, shortness of breath and other symptoms. The patient did not pay attention to the symptoms, later, he developed waist, hip and left leg pain around December 2020, accompanied by limited movement, so he went to a local private hospital. The routine blood test in the private hospital indicated: white blood cells 21.89×10 9 /L, neutrophils 19.87×10 9 /L, hemoglobin 98g/L, platelets 62×10 9 /L, so the patient was provided with anti-infection and other treatments (specifically unknown) and was discharged from the hospital. Subsequently, the patient’s symptoms of abdominal distension, anorexia, and pain in the waist, buttocks and left leg gradually increased, accompanied by mild swelling of the left foot and severe limitation of activities. After that, the patient went to the local municipal hospital for treatment. The routine blood test of the hospital showed: white blood cells 56.01×10 9 /L, neutrophils 50.24×10 9 /L, platelets 86×10 9 /L, hemoglobin 101g/L, considering that the patient is in critical condition, the municipal hospital has not carried out any clinical diagnosis and treatment plan, and the patient was recommended to transfer to a higher-level hospital for diagnosis and treatment. Subsequently, the patient was referred to our hospital (the First Affiliated Hospital of Gannan Medical University) for further treatment. The outpatient department of hematology in our hospital plans to diagnose the cause of “leukocytosis: chronic myelogenous leukemia?” and then the patient was admitted to the department of hematology for further diagnosis and treatment. After detailed medical history inquiries by the resident physician in the department of Hematology, we knowed that this middle-aged patient has been in normal physical and mental state since onset, poor diet, normal sleep, normal stool and urination, and no significant change in his weight recently. While the patient had a history of gout for more than 5 years, and the spleen had enlarged for more than 20 years (no attention or clinical diagnosis and treatment measures were taken), and he denied the history of chronic diseases such as hypertension, coronary heart disease, diabetes, hepatitis, tuberculosis and other infectious diseases. The patient also denied the history of trauma, denial of blood transfusion, history of drug allergy, and history of food allergy. But the patient had a history of smoking and drinking for more than 10 years. The patient’s job is farming, long-term exposure to pollutants such as chemical fertilizers and dust, and due to outdoor farming, there is a long-term exposure to the sun’s ultraviolet rays. The patient’s parents are healthy, denying the history of similar diseases in the sibling family, and denying the family history of infectious diseases / psychiatry and genetic diseases. Physical examination revealed: Body temperature: 36.6°C, Pulse: 120 beats/min, Breathing: 20 beats/min, Blood pressure: 117/73mmHg. Consciousness, malnutrition, anemic appearance, pale skin and mucous membranes, no rash, no subcutaneous hemorrhage and ecchymosis, and no palpable enlargement of superficial lymph nodes. The physical examination of the head, neck, chest and other parts showed no obvious abnormality. The physical examination of the abdomen showed that the shape of the abdomen was bulging, the abdominal muscles were slightly tense, but there was no tenderness and rebound tenderness, no abdominal mass was touched, and liver was not palpated below rib edge, the spleen with hard texture can be palpated, and the spleen is enlarged to below the level of the umbilicus, with Ⅲ°+1cm swelling and tenderness (+). And shifting dullness was negative, bowel sounds were normal, there was no percussion pain in the bilateral kidneys, and moderate edema of both lower extremities. Physical examination of the remaining organ systems was unremarkable. After admission, we provided patients with complete examination items: reexamination of blood routine showed white blood cells 26.36×10 9 /L, hemoglobin 84g/L, platelets 61×10 9 /L, neutrophil ratio 91%, and other indicators were normal; coagulation function analysis showed that the prothrombin time was 13.6s, the fibrinogen was 3.11g/L, the activated partial thromboplastin time was 29.5s, and other indicators were normal. Blood biochemical examination showed albumin 36.8g/L, globulin 19.9g/L, lactate dehydrogenase 235U/L, uric acid 828µmol/L, C-reactive protein 6.93mg/L, and other indicators were normal; anemia test showed iron Protein 425ng/ml, vitamin B12 > 2000.00pg/ml, folic acid 1.89ng/ml; ANA, ENA and ds-DNA were all negative. Routine electrocardiogram showed sinus tachycardia. The chest and whole abdomen CT scan ( Fig. 1 ) showed that 1. large spleen; 2. multiple small stones in both kidneys; 3. bilateral pleural thickening; 4. a small amount of pelvic fluid. Importantly, we performed a bone marrow aspirate biopsy for the patient, and the bone marrow results ( Fig. 2 ) indicated: 1. Increased neutrophil ratio; 2. Poor megakaryocyte maturation and thrombocytopenia; 3. Myeloproliferative disease: CML?. At the same time, we tested the bone marrow specimens of this patient by molecular biology techniques, and the results showed that CSF3R gene exon 14 mutation (+), CSF3R gene exon 17 mutation (+), while BCR-ABL, CALR, MPL-w515 gene were all negative. Cytogenetic test results ( Fig. 3 ) suggest that the chromosome is 46,XY [ 7 ]. Therefore, based on the clinical manifestations and related examination results of the patient, we made a clear diagnosis for him: 1. chronic neutrophilic leukemia; 2. gout; 3. renal insufficiency; 4. gallstones. After treatment with sodium bicarbonate to alkalize the internal environment, hydroxyurea to reduce tumor burden, furosemide to reduce swelling, febuxostat to reduce uric acid, and oxycodone hydrochloride to relieve pain, symptoms of the the patient improved significantly, and then he was discharged from the hospital. Unfortunately, due to family economic factors and other reasons, the patient was not given CNL treatment drugs for the first treatment, only symptomatic and supportive treatment, and the patient did not return to our hospital for treatment on time after discharge. It was not until the patient developed symptoms such as increased abdominal pain and joint swelling and pain throughout the body that he returned to the hospital for the second time on September 24, 2021. After admission, we provided relevant examinations for the patient: routine blood test showed white blood cells 15.68×10 9 /L, hemoglobin 72g/L, platelets 62×10 9 /L, and other indicators were normal; coagulation function test showed prothrombin time 13.9s, fibrinogen 3.05g/L, activated partial thromboplastin time 31.7s, prothrombin activity 68%, D-dimer 1.33mg/L; blood biochemical tests showed albumin 31.7g/L, globulin 19.5g/L L, lactate dehydrogenase 266 U/L, C-reactive protein 7.63 mg/L, fasting blood glucose 2.31 mmol/L, potassium 3.91 mmol/L, calcium 2.03 mmol/L, other indicators were normal; chest CT scan showed: 1. A small amount of bilateral pleural effusion, partial insufflation of the lower lobes of both lungs; 2. Enlarged heart, pericardial effusion; 3. Decreased cardiac cavity density, possible anemia; hepatosplenomegaly; 4. Thyroid nodules. Ultrasound of the digestive system, urinary system, and para-aortic lymph nodes showed that 1. The intrahepatic echo was denser and thicker; the portal vein was widened; 2. Gallbladder polyps; 3. Double renal cysts; 4. Splenomegaly (spleen long diameter 330mm, thickness diameter 88mm, 85mm beyond the rib); 5. No obvious abnormality was found in the sonography of pancreas, bladder and prostate; 6. There was no dilation of the upper and lower segments of the bilateral ureters; 7. No obvious enlarged lymph nodes were found in the explorable range beside the abdominal aorta. In addition, we performed bone marrow biopsy on the patient for the second time, and the results showed that the bone marrow hyperplasia was extremely active, the myeloid lineage was significantly proliferated, blasts + promyelocytes accounted for 3.5%, teardrop-shaped red blood cells were seen, consider chronic neutrophilic leukemia. After the second admission, we gave the patient ruxolitinib targeted therapy for the primary disease of CNL, and at the same time, we gave the patient cefotaxime, levofloxacin anti-infection, as well as pain relief, diuresis and other treatments, the patient’s symptoms of general discomfort improved significantly, so the patient was discharged from our hospital. Then, we provided ruxolitinib 5 mg bid; etoricoxib 60 mg qd, febuxostat 40 mg qd and other oral treatments for the patients. And this patient was instructed to regularly review blood routine and blood biochemical tests after discharge. After the second discharge of the patient, follow-up work was carried out in an orderly manner. Subsequently, the patient returned to the hospital for the third time on January 8, 2022. He was re-examined for some tests: blood routine showed white blood cells 41.07×10 9 /L, hemoglobin 85g/L, platelets 46×10 9 /L, neutrophils 39.58×10 9 /L, the monocyte count was 0.03×10 9 /L, and other indicators were normal; no abnormality was found in coagulation analysis, blood biochemical examination. Re-examination of enhanced CT of the upper abdomen showed: 1. Megasplenomegaly, portal hypertension; low-density nodules in the spleen, consider cysts; 2. A little effusion in the abdominal cavity; 3. Multiple cysts in both kidneys, small stones in both kidneys. After admission, the patient was given a series of treatments such as hydroxyurea to reduce white blood cells, treatment of anti-inflammatory and pain relief, Interleukin-11 promotes platelet production, and ruxolitinib to treat the primary disease of CNL. After the above series of treatments, the patient’s symptoms of abdominal pain and bloating improved significantly. After discharge, we prescribed oral medicines for the patient (febuxostat 40 mg qd, etoricoxib 60 mg qd, ruxolitinib 5 mg bid). Since the follow-up work so far, the patient’s physical condition is acceptable, and the condition of CNL is well controlled. Discussion As early as one hundred years ago in 1920, Tuohy reported a case of an elderly woman with splenomegaly and polymorphonuclear neutropenia, which may be the “rudimentary” of CNL [ 3 ]. Then, Tanzer creatively proposed the term of “chronic neutrophilic leukemia” in The Lancet in 1964 [ 4 ]. Interestingly, chronic neutrophilic leukemia (CNL) is indeed an extremely rare and highly heterogeneous myeloproliferative neoplasm (MPN) in clinical practice. The disease is still dominated by case reports and a small number of case series studies, so the incidence and epidemiological characteristics of CNL remain a mystery. However, at least the existing clinical studies believe that CNL is more common in middle-aged and elderly men, and there is no significant regional and racial difference. The global incidence of CNL has been very low and has not shown an increasing trend [ 5 ]. CNL usually manifests as persistent mature neutrophils and leukocytosis in peripheral blood, bone marrow granulocyte hyperplasia, and significant liver and spleen enlargement [ 6 ]. Other non-specific clinical symptoms of CNL include anemia, fatigue, bleeding tendency, gout and metabolic arthritis, and patients with CNL may even experience B symptoms of lymphoma, such as cutaneous pruritus, night sweats, and weight loss [ 7 ]. Nevertheless, some patients with CNL can be completely asymptomatic at the time of diagnosis, and the only presentation may be an incidental finding of neutropenia [ 6 ]. The patient in this article was admitted to the hospital with the main symptoms of splenomegaly and abdominal distension, followed by pain and swelling in the waist, hip, and left leg, and limited mobility, indicating that the clinical manifestations of CNL are highly heterogeneous. On the other hand, due to the variable and non-specific clinical course of CNL patients, the causes of disease progression in CNL patients are usually refractory neutropenia, transformation to acute myeloid leukemia (AML), and progressively increase in organ enlargement (such as megalosplenia) [ 8 ]. Sudden intracranial hemorrhage, blast cell transformation in CNL patients, and side effects from clinical treatment strategies (such as chemotherapy or bone marrow transplantation) are the most common causes of death in CNL, and the median time for CNL to transform into AML is 21 months, and the median survival time is only 23.5 months [ 6 – 7 ]. Although the clinical manifestations and characteristics of most patients are difficult to distinguish CNL from other malignant diseases, it is worth noting that the positive mutation of colony-stimulating factor 3 receptor (CSF3R) gene is a typical and key molecular marker of the disease, while BCR-ABL negative, and nearly 90% of CNL patients carry CSF3R mutations [ 9 ]. What is thought-provoking is that the protagonist of this rare clinical case is a middle-aged male farmer, in addition to a history of smoking and drinking for more than ten years, the job of this patient is farming, and he has been exposed to chemical fertilizers and dust for a long time, and due to outdoor farming, there is a long-term exposure to the sun’s ultraviolet rays. Therefore, the history of smoking and drinking, and more importantly, whether the above environmental risk factors can lead to the appearance and mutation of oncogenes including CSF3R are issues worthy of in-depth research in the academic community. Moreover, it is worth mentioning that although CSF3R mutations are of great significance in CNL, mutant variants of CSF3R include point mutations of T618A and T618I, membrane-proximal mutations, and nonsense or frameshift mutations observed in the cytoplasmic tail of CSF3R [ 8 , 10 ]. And there are two different types of CSF3R mutations have been discovered: one is truncating mutations caused by Src family-TNK2 kinase dysregulation, while the other is a membrane-proximal mutation that results in JAK family kinase dysregulation [ 11 – 12 ], the two different types of CSF3R mutations described above have distinct clinical responses to tyrosine kinase inhibitors [ 12 ]. The former is sensitive to dasatinib, while the latter appears to respond well to ruxolitinib [ 13 ]. Fleischman used a bone marrow transplant mouse model to determine the ability of CSF3R T618I (the most common CSF3R mutation) to drive leukemia in CNL, and found that the CSF3R T618I mutation acts through the JAK-STAT signaling pathway [ 14 ]. Therefore, splenomegaly and agranulocytosis respond to treatment with the JAK inhibitor ruxolitinib [ 8 , 15 ]. In addition, some studies suggest that CNL may be associated with genes such as SETBP1, ASXL1, TET2, and CALR [ 6 – 7 ], however, the specific regulatory network and mechanism of action have not yet been unveiled, and further research is still required [ 11 ]. In 2016, the WHO issued the diagnostic criteria for CNL, but it is frustrating that there is no international standard treatment plan and standard of care for the treatment of CNL. Many researchers have used hydroxyurea, interferon-α or splenectomy as first-line treatments for the CNL patients, while the clinical effectiveness and remission rate are worrying [ 16 – 17 ]. Although CNL is a hematological malignancies, whether CNL patients can benefit from hematopoietic stem cell transplantation lacks sufficient data and consensus among hematologists [ 5 , 8 , 18 ]. In conclusion, CNL is indeed a unique myeloproliferative tumor, and as the driving oncogenic mutation gene of the disease, CSF3R deepens our understanding of the molecular pathogenesis of CNL and provides diagnostic biomarkers, and gives scientific and prospective significance to novel targeted therapies for CNL. Declarations Acknowledgements The authors express their gratitude to the patient which sharing the clinical data in the study. Besides, thanks for the approval from the patient for the publication of the case. Authors’ contributions All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave fnal approval of the version to be published; and agree to be accountable for all aspects of the work. All authors read and approved the fnal manuscript. Funding The study was supported by the National Natural Science Foundation of China (No.82073582), Special Innovation Project of Guangdong Provincial Department of Education (No.2020KTSCX048), Discipline Construction Project of Guangdong Medical University (No.4SG22003G, No.4SG21209G), Science and Technology Innovation Special Project of Guangdong Medical University (No.4SG22046G), and the Science and Technology Foundation of Jiangxi Provincial Health Commission (SKJP520201086-202130697). Availability of data and materials Not applicable. Ethics approval and consent to participate This study obtained with the ethical standards of the Ethics committee of the First Affiliated Hospital of Gannan Medical University. The data were obtained with the informed consent of the participant. Consent for publication Written informed consent was obtained from the patient for publication of this report and any accompanying images. Competing interests The authors have no conficts of interest to declare. Author details 1 Department of Hematology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China. 2 Department of Hematology, Institute of Environmental and Occupational Health, Dongguan Key Laboratory of Environmental Medicine, Graduate School of Guangdong Medical University, Dongguan, Guangdong, China References Li YP, Chen N, Ye XM, et al. Eighty-year-old man with rare chronic neutrophilic leukemia caused by CSF3R T618I mutation: A case report and review of literature. World J Clin Cases. 2020;8(24):6337–6345. doi: 10.12998/wjcc.v8.i24.6337 . Elliott MA, Tefferi A. Chronic neutrophilic leukemia: 2018 update on diagnosis, molecular genetics and management. Am J Hematol. 2018 Aug;93(4):578–587. doi: 10.1002/ajh.24983 . Tuohy E.L. A case of splenomegaly with polymorphonuclear neutrophil hyperleukocytosis. Am J Med Sci. 1920; 160: 18–25. [ https://www.semanticscholar.org/paper/A-CASE-OF-SPLENOMEGALY-WITH-POLYMORPHONUCLEAR-Tuohy/0705461eb49285d45bcea 00c822fa98bf75eb25e] Tanzer J, Harel P, Boiron M, et al. Cytochemical and cytogenetic findings in a case of chronic neutrophilic leukaemia of mature cell type. Lancet. 1964 Feb 15;1(7329):387–388. doi: 10.1016/s0140-6736(64)92142-7 . Ruan GJ, Smith CJ, Day C, et al. A population-based study of chronic neutrophilic leukemia in the United States. Blood Cancer J. 2020 Jun 15;10(6):68. doi: 10.1038/s41408-020-0334-1 . Szuber N, Tefferi A. Chronic neutrophilic leukemia: new science and new diagnostic criteria. Blood Cancer J. 2018 Feb 13;8(2):19. doi: 10.1038/s41408-018-0049-8 . Menezes J, Cigudosa JC. Chronic neutrophilic leukemia: a clinical perspective. Onco Targets Ther. 2015 Sep 1;8:2383–2390. doi: 10.2147/OTT.S49688 . Szuber N, Elliott M, Tefferi A. Chronic neutrophilic leukemia: 2020 update on diagnosis, molecular genetics, prognosis, and management. Am J Hematol. 2020 Feb;95(2):212–224. doi: 10.1002/ajh.25688 . Yin B, Chen X, Gao F, et al. Analysis of gene mutation characteristics in patients with chronic neutrophilic leukaemia. Hematology. 2019 Dec;24(1):538–543. doi: 10.1080/16078454.2019.1642554 . Spiciarich DR, Oh ST, Foley A, et al. A Novel Germline Variant in CSF3R Reduces N-Glycosylation and Exerts Potent Oncogenic Effects in Leukemia. Cancer Res. 2018 Dec 15;78(24):6762–6770. doi: 10.1158/0008-5472.CAN-18-1638 . Dwivedi P, Greis KD. Granulocyte colony-stimulating factor receptor signaling in severe congenital neutropenia, chronic neutrophilic leukemia, and related malignancies. Exp Hematol. 2017 Feb;46:9–20. doi: 10.1016/j.exphem.2016.10.008 . Maxson JE, Gotlib J, Pollyea DA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med. 2013 May 9;368(19):1781–1790. doi: 10.1056/NEJMoa1214514 . Mak KY, Au CH, Chan TL, et al. Next-generation sequencing panel for diagnosis and management of chronic neutrophilic leukaemia: a case report. Hong Kong Med J. 2019 Jun;25(3):248–250. doi: 10.12809/hkmj176959 . Fleischman AG, Maxson JE, Luty SB, et al. The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibition. Blood. 2013 Nov 21;122(22):3628–3631. doi: 10.1182/blood-2013-06-509976 . Hinze A, Rinke J, Hochhaus A, et al. Durable remission with ruxolitinib in a chronic neutrophilic leukemia patient harboring a truncation and membrane proximal CSF3R compound mutation. Ann Hematol. 2021 Feb;100(2):581–584. doi: 10.1007/s00277-020-04152-w . Yassin MA, Kohla S, Al-Sabbagh A, et al. A case of chronic neutrophilic leukemia successfully treated with pegylated interferon alpha-2a. Clin Med Insights Case Rep. 2015 Apr 19;8:33–6. doi: 10.4137/CCRep.S22820 . Shi J, Ni Y, Li J, et al. Concurrent chronic neutrophilic leukemia blast crisis and multiple myeloma: A case report and literature review. Oncol Lett. 2015 May;9(5):2208–2210. doi: 10.3892/ol.2015.3043 . Itonaga H, Ota S, Ikeda T, et al. Allogeneic hematopoietic stem cell transplantation for the treatment of BCR-ABL1-negative atypical chronic myeloid leukemia and chronic neutrophil leukemia: A retrospective nationwide study in Japan. Leuk Res. 2018 Dec;75:50–57. doi: 10.1016/j.leukres.2018.11.003 . Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1776640","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":116288266,"identity":"5bdacad8-5736-4ecd-9830-df29b70829eb","order_by":0,"name":"Yanquan Liu","email":"","orcid":"","institution":"The First Affiliated Hospital of Gannan Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yanquan","middleName":"","lastName":"Liu","suffix":""},{"id":116288267,"identity":"b9776c7c-a18b-4d67-b5db-82206dcdc808","order_by":1,"name":"Huanwen Tang","email":"","orcid":"","institution":"Guangdong Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Huanwen","middleName":"","lastName":"Tang","suffix":""},{"id":116288268,"identity":"10d5fad5-08a9-4989-b1c4-b25e9401e432","order_by":2,"name":"Yuting Chen","email":"","orcid":"","institution":"Guangdong Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuting","middleName":"","lastName":"Chen","suffix":""},{"id":116288269,"identity":"ca20b1df-0acd-454a-b1ce-5e08e3b34368","order_by":3,"name":"Weidan Lun","email":"","orcid":"","institution":"The First Affiliated Hospital of Gannan Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Weidan","middleName":"","lastName":"Lun","suffix":""},{"id":116288270,"identity":"934c693c-c9a9-4353-8031-b3ce93565841","order_by":4,"name":"Zhimin Yan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIiWNgGAWjYJACZgYDBh4G9sbGBxB+ArFaeA43GxwgXgsISKS3SRClxeD42cOfCwq2yZjzHGyr/phzmIGfPceA4ecOPFrO5CUYzzC4zWPZ3th24+C2wwySPW8MGHvP4NFyIMcgmQeoxeDMQYgWgxs5BsyMbXi0nH9jcBis5UZiWwFIiz1BLTdyDJthWhjAtkgQ0CJ5440xM9RhzRJnt6XzSJx5VnCwF48WvvM5xp95/ty2Nzje/vBD5TZrOf725I0PfuLRonAATYAHRKALogD5Bnyyo2AUjIJRMApAAACViFialway4QAAAABJRU5ErkJggg==","orcid":"","institution":"The First Affiliated Hospital of Gannan Medical University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Zhimin","middleName":"","lastName":"Yan","suffix":""}],"badges":[],"createdAt":"2022-06-20 12:29:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1776640/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1776640/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":23346709,"identity":"98749194-f0ca-4297-ad2e-31d163a559d6","added_by":"auto","created_at":"2022-07-01 20:22:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":150796,"visible":true,"origin":"","legend":"\u003cp\u003eAbdominal CT showed megalosplenia (Note: abdominal CT performed on the first admission of the patient).\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-1776640/v1/8c615566d7ca7de2e051a5a1.png"},{"id":23347330,"identity":"75514f44-3140-4425-b7f5-d535f4715de6","added_by":"auto","created_at":"2022-07-01 20:27:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":627229,"visible":true,"origin":"","legend":"\u003cp\u003eBone marrow morphology (a. Wright-Giemsa staining ×1000; b. Wright-Giemsa ×1000; c. neutrophil alkaline phosphatase (NAP) staining ×1000)\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-1776640/v1/c7d10e7076c550176b4d003c.png"},{"id":23346710,"identity":"2904c267-0018-4c56-9d25-c5a966dc434d","added_by":"auto","created_at":"2022-07-01 20:22:02","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":168298,"visible":true,"origin":"","legend":"\u003cp\u003eThe result of bone marrow cytogenetic test (chromosome) is 46, XY[7].\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-1776640/v1/88787d63fb991f0dd6944af8.png"},{"id":23347332,"identity":"fce66caf-c037-40b2-b7e2-9da2d81d0aaf","added_by":"auto","created_at":"2022-07-01 20:27:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":581224,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1776640/v1/362810f9-f875-459c-85f5-ba67b9df21fe.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The extremely rare chronic neutrophilic leukemia characterized by unrelieved abdominal distention and swollen painful limbs","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCNL is a highly heterogeneous myeloproliferative disease that is rare worldwide. Although most patients have splenomegaly and some non-specific symptoms, CNL is different from chronic myeloid leukemia (CML) in that it does not have the Ph chromosome and BCR-ABL fusion gene [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Unfortunately, it is difficult to diagnose CNL in the absence of specific typical symptoms and bone marrow examination. The typical feature of CNL is the continuous proliferation of mature neutrophils in the bone marrow and the activating mutation of CSF3R gene, which is different from CML and myeloproliferative neoplasms (MPN) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This article provides the clinical data of a CNL patient, and reviews the relevant international academic literatures in recent years. This article is expected to provide a certain understanding and reference for the diagnosis and treatment of CNL in the global hematology community.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 46-year-old male patient was admitted to the First Affiliated Hospital of Gannan Medical University for the first time on January 25, 2021 with the main complaint of \u0026ldquo;repeated abdominal distension for more than five months and abnormal white blood cells for one month\u0026rdquo;. The patient had abdominal distension and anorexia for no obvious cause since August 2020, but no nausea, vomiting, no abdominal pain, diarrhea, no bloody or black stools, no chills, fever, night sweats, no dizziness, fatigue, no chest tightness, shortness of breath and other symptoms. The patient did not pay attention to the symptoms, later, he developed waist, hip and left leg pain around December 2020, accompanied by limited movement, so he went to a local private hospital. The routine blood test in the private hospital indicated: white blood cells 21.89\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, neutrophils 19.87\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, hemoglobin 98g/L, platelets 62\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, so the patient was provided with anti-infection and other treatments (specifically unknown) and was discharged from the hospital. Subsequently, the patient\u0026rsquo;s symptoms of abdominal distension, anorexia, and pain in the waist, buttocks and left leg gradually increased, accompanied by mild swelling of the left foot and severe limitation of activities. After that, the patient went to the local municipal hospital for treatment. The routine blood test of the hospital showed: white blood cells 56.01\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, neutrophils 50.24\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, platelets 86\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, hemoglobin 101g/L, considering that the patient is in critical condition, the municipal hospital has not carried out any clinical diagnosis and treatment plan, and the patient was recommended to transfer to a higher-level hospital for diagnosis and treatment. Subsequently, the patient was referred to our hospital (the First Affiliated Hospital of Gannan Medical University) for further treatment. The outpatient department of hematology in our hospital plans to diagnose the cause of \u0026ldquo;leukocytosis: chronic myelogenous leukemia?\u0026rdquo; and then the patient was admitted to the department of hematology for further diagnosis and treatment.\u003c/p\u003e \u003cp\u003eAfter detailed medical history inquiries by the resident physician in the department of Hematology, we knowed that this middle-aged patient has been in normal physical and mental state since onset, poor diet, normal sleep, normal stool and urination, and no significant change in his weight recently. While the patient had a history of gout for more than 5 years, and the spleen had enlarged for more than 20 years (no attention or clinical diagnosis and treatment measures were taken), and he denied the history of chronic diseases such as hypertension, coronary heart disease, diabetes, hepatitis, tuberculosis and other infectious diseases. The patient also denied the history of trauma, denial of blood transfusion, history of drug allergy, and history of food allergy. But the patient had a history of smoking and drinking for more than 10 years. The patient\u0026rsquo;s job is farming, long-term exposure to pollutants such as chemical fertilizers and dust, and due to outdoor farming, there is a long-term exposure to the sun\u0026rsquo;s ultraviolet rays. The patient\u0026rsquo;s parents are healthy, denying the history of similar diseases in the sibling family, and denying the family history of infectious diseases / psychiatry and genetic diseases.\u003c/p\u003e \u003cp\u003ePhysical examination revealed: Body temperature: 36.6\u0026deg;C, Pulse: 120 beats/min, Breathing: 20 beats/min, Blood pressure: 117/73mmHg. Consciousness, malnutrition, anemic appearance, pale skin and mucous membranes, no rash, no subcutaneous hemorrhage and ecchymosis, and no palpable enlargement of superficial lymph nodes. The physical examination of the head, neck, chest and other parts showed no obvious abnormality. The physical examination of the abdomen showed that the shape of the abdomen was bulging, the abdominal muscles were slightly tense, but there was no tenderness and rebound tenderness, no abdominal mass was touched, and liver was not palpated below rib edge, the spleen with hard texture can be palpated, and the spleen is enlarged to below the level of the umbilicus, with Ⅲ\u0026deg;+1cm swelling and tenderness (+). And shifting dullness was negative, bowel sounds were normal, there was no percussion pain in the bilateral kidneys, and moderate edema of both lower extremities. Physical examination of the remaining organ systems was unremarkable.\u003c/p\u003e \u003cp\u003eAfter admission, we provided patients with complete examination items: reexamination of blood routine showed white blood cells 26.36\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, hemoglobin 84g/L, platelets 61\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, neutrophil ratio 91%, and other indicators were normal; coagulation function analysis showed that the prothrombin time was 13.6s, the fibrinogen was 3.11g/L, the activated partial thromboplastin time was 29.5s, and other indicators were normal. Blood biochemical examination showed albumin 36.8g/L, globulin 19.9g/L, lactate dehydrogenase 235U/L, uric acid 828\u0026micro;mol/L, C-reactive protein 6.93mg/L, and other indicators were normal; anemia test showed iron Protein 425ng/ml, vitamin B12\u0026thinsp;\u0026gt;\u0026thinsp;2000.00pg/ml, folic acid 1.89ng/ml; ANA, ENA and ds-DNA were all negative. Routine electrocardiogram showed sinus tachycardia. The chest and whole abdomen CT scan \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e showed that 1. large spleen; 2. multiple small stones in both kidneys; 3. bilateral pleural thickening; 4. a small amount of pelvic fluid. Importantly, we performed a bone marrow aspirate biopsy for the patient, and the bone marrow results \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e indicated: 1. Increased neutrophil ratio; 2. Poor megakaryocyte maturation and thrombocytopenia; 3. Myeloproliferative disease: CML?. At the same time, we tested the bone marrow specimens of this patient by molecular biology techniques, and the results showed that CSF3R gene exon 14 mutation (+), CSF3R gene exon 17 mutation (+), while BCR-ABL, CALR, MPL-w515 gene were all negative. Cytogenetic test results \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e suggest that the chromosome is 46,XY [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTherefore, based on the clinical manifestations and related examination results of the patient, we made a clear diagnosis for him: 1. chronic neutrophilic leukemia; 2. gout; 3. renal insufficiency; 4. gallstones. After treatment with sodium bicarbonate to alkalize the internal environment, hydroxyurea to reduce tumor burden, furosemide to reduce swelling, febuxostat to reduce uric acid, and oxycodone hydrochloride to relieve pain, symptoms of the the patient improved significantly, and then he was discharged from the hospital. Unfortunately, due to family economic factors and other reasons, the patient was not given CNL treatment drugs for the first treatment, only symptomatic and supportive treatment, and the patient did not return to our hospital for treatment on time after discharge.\u003c/p\u003e \u003cp\u003eIt was not until the patient developed symptoms such as increased abdominal pain and joint swelling and pain throughout the body that he returned to the hospital for the second time on September 24, 2021. After admission, we provided relevant examinations for the patient: routine blood test showed white blood cells 15.68\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, hemoglobin 72g/L, platelets 62\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, and other indicators were normal; coagulation function test showed prothrombin time 13.9s, fibrinogen 3.05g/L, activated partial thromboplastin time 31.7s, prothrombin activity 68%, D-dimer 1.33mg/L; blood biochemical tests showed albumin 31.7g/L, globulin 19.5g/L L, lactate dehydrogenase 266 U/L, C-reactive protein 7.63 mg/L, fasting blood glucose 2.31 mmol/L, potassium 3.91 mmol/L, calcium 2.03 mmol/L, other indicators were normal; chest CT scan showed: 1. A small amount of bilateral pleural effusion, partial insufflation of the lower lobes of both lungs; 2. Enlarged heart, pericardial effusion; 3. Decreased cardiac cavity density, possible anemia; hepatosplenomegaly; 4. Thyroid nodules. Ultrasound of the digestive system, urinary system, and para-aortic lymph nodes showed that 1. The intrahepatic echo was denser and thicker; the portal vein was widened; 2. Gallbladder polyps; 3. Double renal cysts; 4. Splenomegaly (spleen long diameter 330mm, thickness diameter 88mm, 85mm beyond the rib); 5. No obvious abnormality was found in the sonography of pancreas, bladder and prostate; 6. There was no dilation of the upper and lower segments of the bilateral ureters; 7. No obvious enlarged lymph nodes were found in the explorable range beside the abdominal aorta. In addition, we performed bone marrow biopsy on the patient for the second time, and the results showed that the bone marrow hyperplasia was extremely active, the myeloid lineage was significantly proliferated, blasts\u0026thinsp;+\u0026thinsp;promyelocytes accounted for 3.5%, teardrop-shaped red blood cells were seen, consider chronic neutrophilic leukemia. After the second admission, we gave the patient ruxolitinib targeted therapy for the primary disease of CNL, and at the same time, we gave the patient cefotaxime, levofloxacin anti-infection, as well as pain relief, diuresis and other treatments, the patient\u0026rsquo;s symptoms of general discomfort improved significantly, so the patient was discharged from our hospital. Then, we provided ruxolitinib 5 mg bid; etoricoxib 60 mg qd, febuxostat 40 mg qd and other oral treatments for the patients. And this patient was instructed to regularly review blood routine and blood biochemical tests after discharge. After the second discharge of the patient, follow-up work was carried out in an orderly manner.\u003c/p\u003e \u003cp\u003eSubsequently, the patient returned to the hospital for the third time on January 8, 2022. He was re-examined for some tests: blood routine showed white blood cells 41.07\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, hemoglobin 85g/L, platelets 46\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, neutrophils 39.58\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, the monocyte count was 0.03\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, and other indicators were normal; no abnormality was found in coagulation analysis, blood biochemical examination. Re-examination of enhanced CT of the upper abdomen showed: 1. Megasplenomegaly, portal hypertension; low-density nodules in the spleen, consider cysts; 2. A little effusion in the abdominal cavity; 3. Multiple cysts in both kidneys, small stones in both kidneys. After admission, the patient was given a series of treatments such as hydroxyurea to reduce white blood cells, treatment of anti-inflammatory and pain relief, Interleukin-11 promotes platelet production, and ruxolitinib to treat the primary disease of CNL. After the above series of treatments, the patient\u0026rsquo;s symptoms of abdominal pain and bloating improved significantly. After discharge, we prescribed oral medicines for the patient (febuxostat 40 mg qd, etoricoxib 60 mg qd, ruxolitinib 5 mg bid). Since the follow-up work so far, the patient\u0026rsquo;s physical condition is acceptable, and the condition of CNL is well controlled.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs early as one hundred years ago in 1920, Tuohy reported a case of an elderly woman with splenomegaly and polymorphonuclear neutropenia, which may be the \u0026ldquo;rudimentary\u0026rdquo; of CNL [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Then, Tanzer creatively proposed the term of \u0026ldquo;chronic neutrophilic leukemia\u0026rdquo; in \u003cem\u003eThe Lancet\u003c/em\u003e in 1964 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Interestingly, chronic neutrophilic leukemia (CNL) is indeed an extremely rare and highly heterogeneous myeloproliferative neoplasm (MPN) in clinical practice. The disease is still dominated by case reports and a small number of case series studies, so the incidence and epidemiological characteristics of CNL remain a mystery. However, at least the existing clinical studies believe that CNL is more common in middle-aged and elderly men, and there is no significant regional and racial difference. The global incidence of CNL has been very low and has not shown an increasing trend [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCNL usually manifests as persistent mature neutrophils and leukocytosis in peripheral blood, bone marrow granulocyte hyperplasia, and significant liver and spleen enlargement [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Other non-specific clinical symptoms of CNL include anemia, fatigue, bleeding tendency, gout and metabolic arthritis, and patients with CNL may even experience B symptoms of lymphoma, such as cutaneous pruritus, night sweats, and weight loss [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Nevertheless, some patients with CNL can be completely asymptomatic at the time of diagnosis, and the only presentation may be an incidental finding of neutropenia [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The patient in this article was admitted to the hospital with the main symptoms of splenomegaly and abdominal distension, followed by pain and swelling in the waist, hip, and left leg, and limited mobility, indicating that the clinical manifestations of CNL are highly heterogeneous.\u003c/p\u003e \u003cp\u003eOn the other hand, due to the variable and non-specific clinical course of CNL patients, the causes of disease progression in CNL patients are usually refractory neutropenia, transformation to acute myeloid leukemia (AML), and progressively increase in organ enlargement (such as megalosplenia) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Sudden intracranial hemorrhage, blast cell transformation in CNL patients, and side effects from clinical treatment strategies (such as chemotherapy or bone marrow transplantation) are the most common causes of death in CNL, and the median time for CNL to transform into AML is 21 months, and the median survival time is only 23.5 months [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough the clinical manifestations and characteristics of most patients are difficult to distinguish CNL from other malignant diseases, it is worth noting that the positive mutation of colony-stimulating factor 3 receptor (CSF3R) gene is a typical and key molecular marker of the disease, while BCR-ABL negative, and nearly 90% of CNL patients carry CSF3R mutations [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. What is thought-provoking is that the protagonist of this rare clinical case is a middle-aged male farmer, in addition to a history of smoking and drinking for more than ten years, the job of this patient is farming, and he has been exposed to chemical fertilizers and dust for a long time, and due to outdoor farming, there is a long-term exposure to the sun\u0026rsquo;s ultraviolet rays. Therefore, the history of smoking and drinking, and more importantly, whether the above environmental risk factors can lead to the appearance and mutation of oncogenes including CSF3R are issues worthy of in-depth research in the academic community.\u003c/p\u003e \u003cp\u003eMoreover, it is worth mentioning that although CSF3R mutations are of great significance in CNL, mutant variants of CSF3R include point mutations of T618A and T618I, membrane-proximal mutations, and nonsense or frameshift mutations observed in the cytoplasmic tail of CSF3R [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. And there are two different types of CSF3R mutations have been discovered: one is truncating mutations caused by Src family-TNK2 kinase dysregulation, while the other is a membrane-proximal mutation that results in JAK family kinase dysregulation [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], the two different types of CSF3R mutations described above have distinct clinical responses to tyrosine kinase inhibitors [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The former is sensitive to dasatinib, while the latter appears to respond well to ruxolitinib [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Fleischman used a bone marrow transplant mouse model to determine the ability of CSF3R T618I (the most common CSF3R mutation) to drive leukemia in CNL, and found that the CSF3R T618I mutation acts through the JAK-STAT signaling pathway [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Therefore, splenomegaly and agranulocytosis respond to treatment with the JAK inhibitor ruxolitinib [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In addition, some studies suggest that CNL may be associated with genes such as SETBP1, ASXL1, TET2, and CALR [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], however, the specific regulatory network and mechanism of action have not yet been unveiled, and further research is still required [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn 2016, the WHO issued the diagnostic criteria for CNL, but it is frustrating that there is no international standard treatment plan and standard of care for the treatment of CNL. Many researchers have used hydroxyurea, interferon-α or splenectomy as first-line treatments for the CNL patients, while the clinical effectiveness and remission rate are worrying [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Although CNL is a hematological malignancies, whether CNL patients can benefit from hematopoietic stem cell transplantation lacks sufficient data and consensus among hematologists [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In conclusion, CNL is indeed a unique myeloproliferative tumor, and as the driving oncogenic mutation gene of the disease, CSF3R deepens our understanding of the molecular pathogenesis of CNL and provides diagnostic biomarkers, and gives scientific and prospective significance to novel targeted therapies for CNL.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors express their gratitude to the patient which sharing the clinical data in the study. Besides, thanks for the approval from the patient for the publication of the case.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave fnal approval of the version to be published; and agree to be accountable for all aspects of the work. All authors read and approved the fnal manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was supported by the\u0026nbsp;National Natural Science Foundation of China (No.82073582), Special Innovation Project of Guangdong Provincial Department of Education (No.2020KTSCX048), Discipline Construction Project of Guangdong Medical University (No.4SG22003G, No.4SG21209G), Science and Technology Innovation Special Project of Guangdong Medical University (No.4SG22046G), and the Science and Technology Foundation of Jiangxi Provincial Health Commission (SKJP520201086-202130697).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study obtained with the ethical standards of the Ethics committee of the First Affiliated Hospital of Gannan Medical University. The data were obtained with the informed consent of the participant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this report and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conficts of interest to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u0026nbsp;\u003c/sup\u003eDepartment of Hematology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China. \u003csup\u003e2\u0026nbsp;\u003c/sup\u003eDepartment of Hematology, Institute of Environmental and Occupational Health, Dongguan Key Laboratory of Environmental Medicine, Graduate School of Guangdong Medical University, Dongguan, Guangdong, China\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eLi YP, Chen N, Ye XM, et al. 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Cancer Res. 2018 Dec 15;78(24):6762\u0026ndash;6770. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1158/0008-5472.CAN-18-1638\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eDwivedi P, Greis KD. Granulocyte colony-stimulating factor receptor signaling in severe congenital neutropenia, chronic neutrophilic leukemia, and related malignancies. Exp Hematol. 2017 Feb;46:9\u0026ndash;20. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.exphem.2016.10.008\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMaxson JE, Gotlib J, Pollyea DA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. 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Clin Med Insights Case Rep. 2015 Apr 19;8:33\u0026ndash;6. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4137/CCRep.S22820\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eShi J, Ni Y, Li J, et al. Concurrent chronic neutrophilic leukemia blast crisis and multiple myeloma: A case report and literature review. Oncol Lett. 2015 May;9(5):2208\u0026ndash;2210. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3892/ol.2015.3043\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eItonaga H, Ota S, Ikeda T, et al. Allogeneic hematopoietic stem cell transplantation for the treatment of BCR-ABL1-negative atypical chronic myeloid leukemia and chronic neutrophil leukemia: A retrospective nationwide study in Japan. Leuk Res. 2018 Dec;75:50\u0026ndash;57. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.leukres.2018.11.003\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Chronic neutrophilic leukemia, CSF3R, ruxolitinib, diagnostic biomarker, targeted therapy, prognosis","lastPublishedDoi":"10.21203/rs.3.rs-1776640/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1776640/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackgroud:\u003c/strong\u003e Although the pathogenesis of hematological tumors has not been fully elucidated, the academic community believes that genetic mutation abnormalities caused by a wide range of environmental factors play a crucial role in the occurrence and development of hematological malignancies. Chronic neutrophilic leukemia (CNL) is a rare hematological tumor in the world. It is characterized by a Philadelphia chromosome BCR-ABL1-negative myeloproliferative tumor. In addition, it can be accompanied by mutations in various genes. Among them, Colony-stimulating factor 3 receptor (CSF3R) is a classic mutation in CNL and is included in the diagnostic criteria for CNL.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCase presentation: \u003c/strong\u003eThis article describes a 46-year-old male patient who came to the hospital with non-specific clinical manifestations such as unrelieved abdominal distension and edema of both lower extremities as the first symptoms. The middle-aged male patient was given a peripheral blood routine test and biochemical tests revealed abnormalities, and was then given a bone marrow biopsy to complete various tests such as bone marrow morphology, immunology, molecular biology, cytogenetics, and imaging. Finally, he was diagnosed as a rare chronic neutrophilic leukemia. After the diagnosis, the patient took ruxolitinib orally targeted therapy as prescribed by the doctor and regularly reviewed the peripheral blood examination and bone marrow status. The current condition is well controlled.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eCNL is extremely rare, and the disease usually has non-specific clinical features and manifestations as the first symptoms, which can easily lead to missed or misdiagnosed by clinicians. It is necessary to increase the awareness and vigilance of CNL.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"The extremely rare chronic neutrophilic leukemia characterized by unrelieved abdominal distention and swollen painful limbs","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-07-01 20:22:00","doi":"10.21203/rs.3.rs-1776640/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4df4372e-9742-4210-8d35-6765f8b21187","owner":[],"postedDate":"July 1st, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-07-01T20:22:02+00:00","versionOfRecord":[],"versionCreatedAt":"2022-07-01 20:22:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1776640","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1776640","identity":"rs-1776640","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}