|Year : 2020 | Volume
| Issue : 2 | Page : 201-204
Chronic neutrophilic leukemia presenting as secondary gout: Report of a rare myeloproliferative disorder
Sugandha1, Naveen Kakkar1, M Joseph John2
1 Department of Pathology, Hemato-oncology and Bone Marrow (Stem Cell) Transplantation, Christian Medical College and Hospital, Ludhiana, Punjab, India
2 Department of Clinical Hematology, Hemato-oncology and Bone Marrow (Stem Cell) Transplantation, Christian Medical College and Hospital, Ludhiana, Punjab, India
|Date of Submission||23-Aug-2018|
|Date of Decision||23-Aug-2018|
|Date of Acceptance||02-Nov-2019|
|Date of Web Publication||17-May-2020|
Department of Pathology, Hemato-oncology and Bone Marrow (Stem Cell) Transplantation, Christian Medical College and Hospital, Ludhiana, Punjab
Source of Support: None, Conflict of Interest: None
Chronic neutrophilic leukemia is a rare leukemia seen in middle aged and elderly people, characterized by neutrophilic leukocytosis with no significant increase in granulocytic precursors. The chief criteria for diagnosis include total leukocyte count ≥25 × 109/L, >80% of white blood cells being mature neutrophils (segmented and band forms), immature granulocytic precursors ≥10% in the peripheral blood, and hypercellular marrow. In addition to this, there must be no evidence of dysplasia, monocytosis or BCR-ABL1, PDGFR-A, PDGFR-B, or FGRF-1 rearrangements. Moreover, the cause of neutrophilia should not be attributed to any other myeloproliferative disorders or to physiologic neutrophilia.We present two patients with this rare disorder who presented with gout as the initial symptom.
Keywords: Chronic neutrophilic leukemia, gout, myeloproliferative disorder
|How to cite this article:|
Sugandha, Kakkar N, Joseph John M. Chronic neutrophilic leukemia presenting as secondary gout: Report of a rare myeloproliferative disorder. Indian J Cancer 2020;57:201-4
|How to cite this URL:|
Sugandha, Kakkar N, Joseph John M. Chronic neutrophilic leukemia presenting as secondary gout: Report of a rare myeloproliferative disorder. Indian J Cancer [serial online] 2020 [cited 2021 Jan 16];57:201-4. Available from: https://www.indianjcancer.com/text.asp?2020/57/2/201/284478
| » Introduction|| |
Chronic neutrophilic leukemia (CNL) is an uncommon myeloproliferative disorder. It is characterized by clonal proliferation of mature neutrophils, absence of BCR/ABL transcripts, and increased uric acid level. There is no evidence of other myeloproliferative disorders or a secondary cause of neutrophilia.,, Since the first description of this disorder by Tuohy in 1920, less than 200 cases have been reported in the literature., We present two patients with this rare disorder.
| » Case Summary|| |
A 45-year-old woman was evaluated for persistently high white cell counts and presented with a history of bilateral lower limb pain. She had symptoms of gout for 2–3 years with frequent episodes of pain in the great toe. She had hepatosplenomegaly with the liver palpable 6 cm below the right costal margin and spleen, 7 cm below the left costal margin. Peripheral blood smear showed neutrophilia with minimal left shift [Figure 1]. Bone marrow (aspirate and trephine biopsy) was solidly cellular with myeloid predominance [Figure 2] and [Figure 3]a. The clinical profile and detailed investigations are shown in [Table 1].
|Figure 1:Peripheral blood smears of both patients showing neutrophilic leucocytosis without toxic changes and minimal left shift (Leishman ×400)|
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|Figure 2:Hypercellular bone marrow aspirate smears of both patients showing myeloid predominance and no increase in blasts (May–Grunwald–Giemsa ×400)|
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|Figure 3:Hypercellular bone marrow trephine biopsy in patient 1 and patient 2 (a and b) (H and E ×100). Myeloid predominance is seen (c) (H and E ×400)|
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She was started on cytoreductive therapy with hydroxyurea 500 mg twice a day to which she responded well for 7 years. She presented again with recurrent leg ulcers probably secondary to hydroxyurea which was then discontinued and she was started on cytosine and later, busulphan. Seven months later, she presented with cough, fever, and breathlessness with signs of lobar pneumonia and pleural effusion. In view of poor overall condition, the patient and relatives opted for palliative and supportive care.
A 70-year-old woman presented with pain in the right great toe and ankle for 6 months along with intermittent fever. Her uric acid levels were high. As the complete blood count showed leucocytosis, she was referred to our center. She also had hepatosplenomegaly with the liver palpable 6 cm below the right costal margin and spleen 8 cm below the left costal margin. Peripheral blood smear showed neutrophilic leucocytosis with minimal left shift [Figure 1]. Aspirate smears and trephine biopsy were solidly cellular with myeloid predominance [Figure 2], [Figure 3]b and [Figure 3]c. Marked megakaryocytic proliferation or megakaryocytic atypia was not seen and there was no significant alteration in megakaryocytic topography. She did not have associated thrombocytosis (platelet count 129 × 10/L). The clinical profile and detailed investigations are shown in [Table 1].
She was started on cytoreductive therapy with hydroxyurea 500 mg twice a day initially which was reduced to once a day. She was lost to follow-up after two outpatient visits and then presented one and a half years later with persistent high total leukocyte count (TLC) (48,800/mm) and neutrophilia (92%). Her dose of hydroxyurea has been increased in view of high TLC.
| » Discussion|| |
CNL is a rare BCR-ABL-negative myeloproliferative neoplasm (MPN) seen primarily in older adults with slight male predominance (M:F = 1.6:1). It is characterized by persistently high total leukocyte count (TLC) comprising mainly of mature neutrophils in the peripheral blood, hypercellular bone marrow with myeloid predominance, and hepatosplenomegaly. The diagnosis of CNL requires exclusion of secondary causes of neutrophilia such as infection, malignancy, and other MPNs.
The most frequently reported clinical findings are fatigue, weight loss, night sweats, easy bruising, and splenomegaly. Bleeding, hepatomegaly, and symptoms of gout may also be seen. Leukocyte alkaline phosphatase score is usually normal or elevated. Serum vitamin B12, lactate dehydrogenase, and uric acid levels are frequently raised. In both our patients, gout was the initial presenting symptom.
The currently established diagnostic criteria for CNL include peripheral blood leukocytosis, TLC ≥25 × 10/L, >80% of white blood cells being mature neutrophils (segmented and band forms), immature granulocytic precursors ≤10% in the peripheral blood, and hypercellular marrow with less than 5% blasts.,, Fibrosis is uncommon.
Karyotypic studies were normal in both our patients. In 10% of the patients, clonal karyotypic abnormalities may be seen which include gain of chromosomes 8, 9, and 21; del(7q), del(20q), del(11q), del(12p), and nullisomy 17. Identification of molecular markers like JAK2 (V617F) mutation helps in demonstrating the clonality of cells and thus supports the diagnosis. In patient 2, the presence of JAK2 mutation established the clonal nature of the disease. However, the test was unavailable at the time of diagnosis of the first patient.
Earlier, there were no known disease-defining markers for CNL. But now, CSF3R, the gene for receptor for colony-stimulating factor 3 (CSF3) which is the chief growth factor responsible for neutrophil production, is established to be associated with most cases of CNL.,, It is now regarded as the disease-defining mutation in CNL. Besides, other potentially prognostically relevant mutations (SETBP1 or ASLX1) have also been identified. A few studies have also reported an association of multiple myeloma with CNL., Morphological findings in both cases were suggestive of CNL. BCR-ABL study was done in both patients. JAK-2 mutation was done in case 2. JAK-2 study for case 1 was not done due to its non-availability at the time of diagnosis (2008). Other mutations were not done in case 2 due to financial constraints.
The differential diagnoses for CNL are secondary causes of neutrophilia, atypical chronic myeloid leukemia (CML) and chronic myelomonocytic leukemia (CMML)., In contrast to CNL, CML shows the presence of immature granulocytes ≥10% of white cells and granulocytic proliferation with or without dysplasia in the erythroid and megakaryocytic lineages. The presence of peripheral blood monocytosis of ≥1 × 10/L helps in distinguishing CNL from CMML.
Since both patients had persistent leukocytosis with minimal left shift and no BCR/ABL1 mutation, CML was ruled out. Bone marrow biopsy in both patients was markedly hypercellular which goes against the diagnosis of essential thrombocythemia. Prefibrotic phase of myelofibrosis was ruled out as there was no megakaryocytic atypia or marked megakaryocytic proliferation and significant left shift or thrombocytosis. Polycythemia was ruled out as both patients lacked panmyelosis.
The treatment rests primarily on cytoreductive therapy with hydroxyurea being the most commonly administered drug. Thalidomide, cladribine, and interferon therapy have also been used. The prognosis is variable and survival varies from months to years although the median survival in most patients is less than 2 years., The neutrophilia is usually progressive with thrombocytopenia and anemia emerging later on. Transformation to AML has also been reported in few patients.
CNL is a rare myeloproliferative disorder and must be considered in patients with persistent neutrophilc leukocytosis with minimal left shift and no secondary cause for the same. Patients may have unusual initial clinical presentations like gout.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]