Myeloid sarcoma in JAK2-positive myelodysplastic neoplasms with fibrosis: a case report and literature review

Abstract

Myeloid sarcoma (MS) occurs in patients with acute myeloid leukemia (AML). In rare cases, MS can represent a form of blast transformation in patients with myeloproliferative neoplasms (MPN), myelodysplastic neoplasms (MDS), or MDS/MPN. The most frequent chromosomal alterations in MS are t(8;21) or inv(16), with other alterations being reported. Cases of MS in Janus kinase 2 (JAK2)-positive MDS with fibrosis are exceedingly rare. Here, we describe such a case. To the best of our knowledge, this is the first report of a JAK2 V617F mutation-positive MDS case occurring concurrently with MS involving the posterior aspect of the left seventh rib. No clear association has been previously demonstrated between the intramedullary AML cytogenetics and extramedullary disease occurrence. Interestingly, samples from the intramedullary MDS and extramedullary mass in this patient presented the same JAK2 V617F mutation. Following a treatment regimen of azacitidine and venetoclax, the patient achieved complete remission. The chest CT scan showed that the seventh posterior rib mass disappeared. This case provides valuable information for the potential future treatment of this disease.

Introduction

Myeloid sarcoma (MS), also known as granulocytic sarcoma, is defined by the World Health Organization (WHO) as a tumor mass consisting of myeloblasts with or without maturation involving any anatomical site other than the bone marrow. MS most often occurs in patients with acute myeloid leukemia (AML), ¹ while in rare cases it can represent a form of blast transformation in patients with myeloproliferative neoplasms (MPN), ² myelodysplastic neoplasms (MDS), ³ or MDS/MPN. ⁴ The most common chromosomal alterations in MS are t(8;21) and inv(16). ¹ Others that have frequently been associated with MS regardless of involved sites include t(9;11), tetrasomy 8, + 22, del(16q), +4, +8, t(8;17), and t(8;16). ¹

The incidence of MS in Janus kinase 2 (JAK2)-positive MDS with fibrosis (MDS-f) is exceedingly rare. Here, we report a case of MDS-f with a JAK2 V617F mutation occurring concurrently with MS involving the posterior aspect of the left seventh rib. To the best of our knowledge, this is the first report describing such a case. We also review the relevant literature on this topic.

Case report

A 56-year-old female patient was admitted to the hospital on 5 January 2024 after suffering from persistent back pain and fatigue for 1 month. After admission, a complete blood count (CBC) showed pancytopenia, with a white blood cell count of 3.35 × 10⁹ cells/L, platelet count of 83 × 10⁹ cells/L, and hemoglobin level of 87 g/L. Immunoglobulin IgG, IgA, and IgM levels were all normal. Analysis of the bone marrow aspiration showed hypercellular bone marrow with an increased myeloblast number (7.2%). Dysgranulopoiesis, such as a decreased level or absence of granules and abnormal chromatin aggregation in some granulocytes, and dysmegakaryocytopoiesis, including polynuclear megakaryocytes and small megakaryocytes, were also observed (Figure 1). Circulating blasts were not seen in the peripheral blood. Bone marrow biopsy indicated granulocyte, erythrocyte, and megakaryocyte proliferation with more visible blast cells, as well as abnormal megakaryocyte morphology, with grade 2 myelofibrosis (Figure 2). Flow cytometry analysis revealed 1.1% (accounting for the proportion of nuclear cells) CD13+, CD33+, and CD117+ immature myeloid cell population. Chromosomal analysis showed a complex karyotype: 45–50, XX, - X, del (1) (q23q44), +? 2, -5, -6, +7,? 7q -, +? 8,? 8q -, der (9) t (9;?) (p11;?),? 10, +11, +? 12, +13, -14, add (14) (q32), +? 16, -17, +? 18, +20, -21, inc [Cp7] (Figure 3). A JAK2 V617F gene mutation was detected in the bone marrow cells. A PET-CT scan revealed a localized area of increased fluorodeoxyglucose (FDG) metabolism in the posterior aspect of the left seventh rib, with a maximum standardized uptake value of approximately 4.6 (Figure 4). Hematoxylin and eosin staining of the fine needle-biopsied samples from the mass of the seventh posterior rib showed the proliferation of immature myeloid cells with atypical nuclei (Figure 5). Immunohistochemistry analysis suggested the presence of infiltrating myeloblasts that were positive for CD43, myeloperoxidase (MPO), CD117, and Ki-67 (70%), while negative for CD3, CD20, and other antibodies tested, including S100, Ckp, Desim, and MDM2. The biopsy tissue also tested positive for the JAK2 V617F gene mutation. According to the 5th edition of the WHO of Haematolymphoid Tumours, ⁵ the patient was diagnosed as MDS-f, Revised International Prognostic Scoring System (IPSS-R), very high-risk, and MS. The patient was subsequently treated with azacitidine (100 mg, quaque die (qd), days 1–7) and venetoclax (100 mg, qd, day 1; 200 mg, qd, day 2; 400 mg, qd, days 3–28). The bone pain was relieved after 2 weeks. Three weeks later, a repeated bone marrow smear showed a decrease in blast cells to 1.2%, the CBC indicated that the white blood cell, hemoglobin, and platelet levels all returned to normal, and the chest CT scan demonstrated that the seventh posterior rib mass had disappeared. Therefore, complete remission was achieved. She is currently undergoing further treatment. Because allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only potentially curative option for patients with high-risk MDS, this will be the next treatment strategy for the patient. All patient details have been removed to ensure her privacy. Written informed consent was obtained from the patient prior to treatment. In addition, the patient signed a data publishing consent form. The reporting of this study conforms to the CARE guidelines. ⁶

Figure 1.

Bone marrow smear of the patient. (a) Abnormal chromatin agglutination of granulocytes (Giemsa staining, 100×). (b) Blast cell. (c) Double round nucleus megakaryocyte and (d) Micromegakaryocyte.

Figure 2.

Bone marrow biopsy results. (a) Hematoxylin and eosin (H&E) staining, 100×. (b) and (c) Megakaryocytes with small cell bodies and few lobes (400×) and (d) reticular fiber (reticular fiber staining, 400×).

Figure 3.

Complex karyotype of the patient: 45-50, XX, - X, del (1) (q23q44), +? 2, -5, -6, +7,? 7q -, +? 8,? 8q -, der (9) t (9;?) (p11;?),? 10, +11, +? 12, +13, -14, add (14) (q32), +? 16, -17, +? 18, +20, -21, inc [Cp7].

Figure 4.

The PET/CT scan demonstrating a hypermetabolic focus in the seventh posterior rib with a maximum standardized uptake value (SUV) of approximately 4.6 (red arrow).

Figure 5.

The biopsy of the seventh posterior rib mass, showing myeloid sarcoma. Hematoxylin and eosin (H&E) staining of the biopsy tissue showing diffuse infiltration of large atypical immature cells. These cells vary in size and morphology, with abundant cytoplasm and visible nuclear division. The immature cells were positive for CD43 (75%), myeloperoxidase (MPO) (55%), CD117 (24%), and Ki-67 (70%), consistent with myeloblasts and the diagnosis of myeloid sarcoma. (a) H&E staining, 400×. (b) CD43+ staining, 400×. (c) MPO+ staining, 400× and (d) Ki-67 (70%), 200×.

Discussion

Patients with high-risk MDS characterized by an increased blast count and/or poor prognosis cytogenetics may develop MS, which is considered to represent leukemic transformation. The patient in this case presented with pancytopenia, two lineage pathological hematopoiesis and increased blasts (7.2%), and myeloid fibrosis, which meet the MDS-f diagnostic criteria according to the WHO 5th edition. The IPSS-R scoring criteria suggested that the case was very high-risk. Although the case was positive for the JAK2 V617F gene mutation, the spleen was not large, MDS was present, and primary myeloid fibrosis was ruled out. Therefore, we considered this as secondary to MDS. The PET-CT scan revealed a localized area of increased FDG metabolism in the posterior aspect of the left seventh rib, with pathological biopsy confirming MS. The patient was ultimately diagnosed with MDS-f concurrently with MS.

MS is a tumor type that is composed of immature myeloid precursor cells, sometimes developing as a de novo isolated sarcoma without bone marrow involvement. MS is not a common disease. One of the oldest studies, which collected patients diagnosed from 1949 to 1969 in Japan, documented an MS incidence of 8% on autopsy from patients who died from AML. ⁷ Additional reports showed a higher proportion of patients with the (8;21) (q22;q22.1)/RUNX1::RUNX1T1 translocation, ⁸ but subsequent larger studies demonstrated that RUNX1::RUNX1T1 is a rare event (2% to 3% of cases) in MS. ⁹ Moreover, the inv(16)(p13.1q22)/CBFB::MYH11 translocation was associated with MS, particularly at abdominal sites.^10,11 Others reported cytogenetic alterations in MS to include t(9;11), del(16q), t(8;17), t(8;16), and t(1;11), as well as chromosome 4, 7, 8, or 11 abnormalities. ¹² However, no clear association has been demonstrated between the intramedullary AML cytogenetics and extramedullary disease occurrence. ¹ Interestingly, samples from the intramedullary MDS and extramedullary mass in this case presented the same JAK2 V617F mutation.

A somatic JAK2 V617F mutation is commonly found in most patients with MPN, such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis patients. JAK2 V617F occurs less frequently in AML and MDS, with the incidence of this mutation being 6.7% in MDS, ¹ 40% in MDS/MPN-unclassifiable, and 53% in refractory anemia with ringed sideroblasts associated with marked thrombocytosis. ¹³ Fu et al. ¹⁴ retrospectively analyzed the clinicopathological features of a large cohort of patients with myelodysplastic syndromes with bone marrow fibrosis. They found that JAK2 V617F mutations were detected in 6/28 (21%) MDS patients with bone marrow fibrosis compared with 1/41 (2%) patients without fibrosis. Hepatosplenomegaly, consumptive symptoms, and transfusion dependency were more commonly observed in MDS with bone marrow fibrosis. This JAK2 gene mutation has not been reported in cases of MDS or AML combined with MS. To the best of our knowledge, this is the first report demonstrating a JAK2 V617F mutation-positive MDS-f case occurring concurrently with MS.

Notably, this patient also has a complex karyotype, which indicated a poor prognosis and higher probability of the disease transforming into AML. Ren et al. ¹⁵ retrospectively analyzed 101 primary MDS patients with complex karyotypes, who had a median overall survival time of 13 (95% confidence interval: 9.98–16.02) months. Among these patients, TP53 mutations occurred at a high frequency and were associated with worse survival.

Because of the rarity of MS and lack of randomized clinical trials, treatment strategies are currently limited. ¹ Different therapeutic approaches are dictated by the size and location of MS, as well as specific patient factors, such as age, performance status, and comorbidities. If feasible, systemic therapies, local radiotherapy, allo-HSCT, targeted therapies, and immunotherapies should be considered.

No MS-specific treatment regimens have been adopted. Intensive therapy-eligible patients have classically been treated with anthracycline and cytarabine-based regimens. ¹⁶ For unfit patients, hypomethylating agents, such as azacitidine (5-azacytidine) and decitabine (5-aza-2′-deoxycytidine), could reportedly induce clinical remission.^17,18 Targeted therapies for AML or high-risk MDS have broadened the options and potentially improved patient outcomes. Several targeted drugs have received regulatory approval to be administered alone and/or in combination with chemotherapy. These include kinase inhibitors, such as sorafenib, midostaurin, and gilteritinib, the isocitrate dehydrogenase type 1 (IDH1) inhibitor ivosidenib, the IDH2 inhibitor enasidenib, and the B-cell lymphoma-2 inhibitor venetoclax. ¹⁹ The patient in this case achieved complete remission, with the seventh posterior rib mass disappearing, after 4 weeks of treatment with azacitidine in combination with venetoclax. Although this report only describes one case, we believe that this therapeutic approach is a good treatment practice for future cases.

In summary, we report here for the first time a rare case of JAK2 V617F mutation-positive MDS-f concurrently with MS in the seventh posterior rib. Furthermore, samples from the intramedullary MDS and extramedullary mass in this patient presented the same JAK2 V617F mutation.