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| CASE REPORT |
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| Year : 2023 | Volume
: 14
| Issue : 2 | Page : 163-166 |
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Primary myelofibrosis with extramedullary hematopoiesis – A case report with a review of literature
Gaurav Mehta, Vaishnavi M Rathod, Tejasvi M Patel
Department of Internal Medicine, SSG Hospital, Baroda Medical College, Vadodara, Gujarat, India
| Date of Submission | 29-Mar-2023 |
| Date of Decision | 20-May-2023 |
| Date of Acceptance | 05-Jun-2023 |
| Date of Web Publication | 27-Jul-2023 |
Correspondence Address:
Dr. Tejasvi M Patel
8/A Sujata Park, Sainath Marg, Diwalipura, Vadodara - 390 007, Gujarat
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/joah.joah_14_23
Primary myelofibrosis (PMF) is the least common of all myeloproliferative neoplasms (MPNs), characterized by a neoplastic transformation of early hematopoietic stem cells, predominantly megakaryocytes and granulocytes. The disease shows gradual evolution from an initial prefibrotic stage to an overt fibrotic stage. Janus kinase (JAK) 2, CALR, and MPL mutations are most common in nonchronic myeloid leukemia MPNs but are not always present. Ineffective marrow hematopoiesis leads to extramedullary hematopoiesis and associated symptoms such as splenomegaly, hepatomegaly, anemia, and pro-inflammatory cytokines-induced constitutional symptoms. The WHO criteria, 2016, consider the combination of clinical, morphological, and molecular genetics features for the diagnosis of the condition. Currently, Dynamic International Prognostic Scoring System is most widely used to predict the prognosis. Here, we report the case of a 63-year-old male diagnosed with the rare disease PMF with extramedullary hematopoiesis and bleeding gastric varices. PMF was diagnosed by bone marrow biopsy showing diffuse fibrosis, positive JAK2-V617F mutation in genetic analysis, negative Philadelphia chromosome, pancytopenia, splenomegaly, and raised leukocyte dehydrogenase.
Keywords: Extramedullary hematopoiesis, Janus kinase 2-V617F, myeloproliferative neoplasms, primary myelofibrosis
How to cite this article:
Mehta G, Rathod VM, Patel TM. Primary myelofibrosis with extramedullary hematopoiesis – A case report with a review of literature. J Appl Hematol 2023;14:163-6 |
How to cite this URL:
Mehta G, Rathod VM, Patel TM. Primary myelofibrosis with extramedullary hematopoiesis – A case report with a review of literature. J Appl Hematol [serial online] 2023 [cited 2023 Sep 27];14:163-6. Available from: https://www.jahjournal.org/text.asp?2023/14/2/163/382410 |
| Introduction | |  |
Primary myelofibrosis (PMF) is one of the myeloproliferative neoplasms (MPNs), primarily driven by unregulated Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling.[1] It is most prevalent in older adults (mean age is 60 years) with an equal gender predisposition. The annual incidence of an overt phase of PMF is only 0.5–1.5 cases per 100,000 population. About 1/3 of patients remain asymptomatic during the early stage of the disorder. Symptomatic patients present with splenomegaly, hepatomegaly, and constitutional symptoms such as low-grade fever, fatigue, night sweats, cachexia, and weight loss. Blood investigations show anemia, leukocytosis, or thrombocytosis in the early stage and pancytopenia in the late stage.[2] Here, we present a case of a 63-year-old male diagnosed with PMF with extramedullary hematopoiesis and gastric fundal varices, which has been reported in the literature in only 7% of the patients presenting with PMF.[3]
| Case Presentation | | |
Case history
A 63-year-old male patient presented to the medicine outpatient department with complaints of generalized weakness, low-grade fever, decreased appetite, early satiety, and dragging type of left upper quadrant abdominal pain for 2 years. He also reported black stool for 15 days. He is nonalcoholic and does not have any other addiction. The patient was vitally stable. On physical examination, pallor was present, and per abdomen examination showed a palpable spleen 15 cm below the left costal margin (Hackett's Class III) and palpable liver 4 cm below the right costal margin. The patient was admitted into medical ward for further evaluation of hepatosplenomegaly.
Past history
Patients had a significant history of similar complaints 2 years back and had gone to a peripheral hospital with a low-grade fever, weakness, exertional breathlessness, chest pain, and fatigue. At that time, his hemoglobin (Hb) was 7.3 g%, white blood cell (WBC) counts were 15,290/mm3, and platelet count (PC) was 453,000/mm3. His ultrasonography (USG) abdomen was suggestive of splenomegaly which was attributed to hypersplenism. He was treated with broad-spectrum antibiotics for his fever and with one unit of packed cell volume transfusion for his symptomatic anemia. He was not investigated further for the cause and was discharged on oral iron and folic acid, which he took for 1 month but lost to follow-up.
Diagnostic assessments
On admission, Hb was 6.4 g%, WBC counts were 3700/mm3, and PC was 53,000/mm3. Peripheral blood smear revealed microcytic hypochromic red blood cells (RBCs) with anisocytosis, teardrop RBCs, and nucleated RBCs. The reticulocyte count was raised (5.64%) with corrected reticulocyte count of 2.4%. Other biochemical investigations revealed low ferritin (12.97 ng/ml), high leukocyte dehydrogenase (LDH) (1118 u/L), and high serum alkaline phosphatase (126 u/L). USG confirmed the massive splenomegaly (220 mm) and hepatomegaly (152 mm). Occult blood was detected in stool examination and gastric fundal varices were confirmed with endoscopy. Bone marrow biopsy was done under strict aseptic conditions. H and E (H and E) stained biopsy showed hypercellular marrow (60%) with areas of diffuse fibrosis in the form of sheets of fibers and fibroblasts (Grade 2–3 fibrosis). Megakaryocytes are reduced in number and showed enlargement in size with decreased nuclear contours suggestive of dysmegakaryopoiesis [Figure 1]. Reticulin special stained [Figure 2] and Masson's trichrome special stained [Figure 3] biopsy shows very few fat spaces with abundant crisscross bundles of fibers. Homozygous (V617F) mutation in the JAK2 gene was detected on polymerase chain reaction-based analysis. Cytogenetic analysis showed the presence of 46 (X, Y) chromosome complements in all metaphases. Fluorescence in situ hybridization revealed the absence of the Philadelphia chromosomes. | Figure 1: (H and E stain) - Biopsy shows hypercellular marrow (60%) with areas of diffuse fibrosis in the form of sheets of fibers and fibroblasts (Grade 2–3 fibrosis)
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 | Figure 2: (Masson's trichrome stain) biopsy shows very few fat spaces with abundant crisscross bundles of fibers
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 | Figure 3: (Reticulin special stain) biopsy shows very few fat spaces with abundant crisscross bundles of fibers
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On the bases of all investigations and clinical features, the patient was diagnosed with PMF, hemato-oncologist was consulted and treatment commenced as per their advice and the availability of drugs in our hospital setup. His MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) was 64. As cytogenetics and molecular analysis were not available, we used Dynamic International Prognostic Scoring System (DIPSS) to prognosticate the patient. The DIPSS of the patient was three (intermediate-2 risk) suggesting median overall survival of 4 years.[4]
Therapeutic intervention
The patient was started on tablet prednisolone (10 mg) with iron, folic acid, Calcium, and Vitamin D3 supplements. The gastric fundal varices were treated with glue therapy.
Follow-up and outcomes
After 2 months of regular monthly follow-ups, constitutional symptoms improved but anemia deteriorated. Hence, he was started on an injection of erythropoietin (EPO) 10,000 units once a week in view of low EPO level and tablet thalidomide 100 mg once a day.
After 3 months, the MPN-SAF TSS score became 42, and repeat stool occult blood was negative. After 1 year, the MPN-SAD score was 24.
| Discussion | | |
PMF is caused by a gene mutation within hematopoietic cells, which activates a signaling pathway called the JAK–STAT pathway. The mutation in the gene encoding JAK2 activates the JAK–STAT pathway to go into overdrive, which results in rapid cell division and quickly filling up the bone marrow. A large majority of these cells turn into megakaryocytes and produce pro-inflammatory cytokines, such as fibroblast growth factor (FGF). FGF induces the production of abundant connective tissues in bone marrow, eventually scarring and bone marrow failure. Ineffective intramedullary hematopoiesis results in extramedullary hematopoiesis, manifested by splenomegaly, hepatomegaly, and portal hypertension. Extramedullary hematopoiesis is often not able to fully compensate for the loss of bone marrow hematopoiesis and results in pancytopenia in the late stage. Pro-inflammatory cytokines cause constitutional symptoms such as low-grade fever, cachexia, and weight loss. Anemia causes fatigue. Leukocytopenia causes recurrent infections and thrombocytosis causes thromboembolic events. The peripheral blood smear shows teardrop shapes RBCs, immature nucleated RBCs, immature WBCs, and platelets, as can be seen in our patient.[2]
This patient had bone marrow fibrosis, JAK2 mutation, leukocytosis, splenomegaly, and elevated LDH without any evidence of other hematological diseases, which meets the WHO diagnostic criteria for PMF.[5] In addition, our patient also had gastric fundal varices, which are rarely seen in patients of PMF, documented in the certain literature in up to 7% of patients.[3]
PMF has the least favorable prognosis among the MPNs and patients are at risk of premature death due to disease progression, leukemic transformation, thrombohemorrhagic complications, and infections. Hence, the decision about the treatment of PMF should be individualized and based on the symptoms, risks, and life expectations of each patient. MPN-SAF TSS score is the best assessment tool available to measure the burden of symptoms in different stages of the disease and it allows us to know the effectiveness of the treatment over the period.[6] DIPSS is the most widely used clinically to predict the prognosis of the patient at different stages of PMF.[7]
Treatment of PMF is mainly palliative. An antineoplastic alkylating agent like hydroxyurea is used for cytoreduction in the hyperproliferative stage of the disease. It shows a significant response in the reduction of constitutional symptoms, but it deteriorates anemia as the most common adverse drug effect. Androgen like danazol is usually the initial treatment; however, due to unavailability of the drug, alternate treatment options such as thalidomide and prednisolone were started in our patient. Drugs such as thalidomide and lenalidomide are effective due to their antiangiogenic and immunomodulating effect. A high dose (100–400 mg) of thalidomide shows a good response in anemia, thrombocytopenia, and splenomegaly. Anemia in PMF might be multifactorial, due to bone marrow failure, hypersplenism, bleeding, iron deficiency, folate deficiency, and Vitamin B12 deficiency, secondary to the use of cytoreductive drugs or JAK2 inhibitors in therapy. For the treatment of anemia, recombinant human EPO is only used in patients not requiring transfusion support and/or those with inappropriately low EPO levels. Chronic RBC transfusions improve the quality of life in a patient with severe and refractory anemia. Iron chelation therapy should be considered in these patients to avoid iron overload. Splenomegaly is the main cause of discomfort and poor quality of life in PMF patients, so splenectomy or splenic irradiation is the treatment of choice in the case of failure of conventional therapy for refractory splenomegaly. JAK2 inhibitor, ruxolitinib, is the newer drug available.[8]
Above discussed treatment options improve quality of life but have no impact on survival. Allogenic stem-cells transplantation (ASCT) is the only curative option available for PMF. Because of the 30% mortality, ASCT is used only in young patients with high-risk diseases or resistant to conventional therapy.[9]
| Conclusion | | |
PMF is a rare myeloproliferative disorder. Ruling out differentials and earliest diagnosis is crucial. In young patients, appropriate treatment may result in more survival benefits. However, for elderly patients, who cannot tolerate allo-hematopoietic stem cell transplantation, combination therapies for palliation of symptoms may improve quality of life.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Acknowledgment
We thank Dr. Pushpit Gupta (MD Pathology) for providing the biopsy reports and images.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
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