Isolated meningeal myeloid sarcoma with recurrent MLL-AF6 translocation: a case report

Abstract

This study aimed to help improve the diagnosis and treatment of isolated myeloid sarcoma. We report the case of a female adolescent patient with isolated meningeal myeloid sarcoma. She was admitted to our department because of vomiting, headache and hearing loss. Positron emission tomography-computed tomography and brain magnetic resonance imaging showed multiple intracranial space-occupying lesions. A complete examination, including morphology, cytology, immunophenotyping, cytogenetics and molecular biology tests of cerebrospinal fluid and bone marrow, was conducted. The diagnosis of primary myeloid sarcoma of the central nervous system with mixed lineage leukemia gene rearrangement with AF6 was established. The patient underwent systemic chemotherapy and intrathecal treatment followed by whole-brain radiotherapy. She achieved complete remission for 84 months and has not developed bone marrow involvement during follow-up. The combination of morphology, cytology, flow cytometry, cytogenetics and molecular analysis can improve the definite diagnosis of isolated myeloid sarcoma.

Introduction

Myeloid sarcoma (MS), also known as green tumor or granulocytic sarcoma, refers to the infiltration of myeloid blast cells into extramedullary sites other than bone marrow (BM). ¹ The 2016 World Health Organization has classified MS as a special subtype of acute myeloid leukemia (AML). Both sexes are equally affected with MS, and the ages of these patients range from 0 to 81 years old, with a preference for children and young adults. ² When MS appears in extramedullary sites and precedes BM involvement, it is called non-leukemic, isolated or primary MS. ³ Isolated MS is rare, with an incidence of 2/1 million in adults and 0.7/1 million in children. ⁴ The early diagnosis of isolated MS is extremely difficult and is often misdiagnosed as non-Hodgkin’s lymphoma. ⁵ Currently, the diagnosis of isolated MS mainly depends on pathology and immunohistochemistry (IHC). Laboratory tests, such as flow cytometry (FC), cytogenetics, fluorescence in situ hybridization and molecular analysis, have been widely used for the diagnosis of MS in recent years.

Isolated MS is rarely involved in the central nervous system (CNS). To date, only six patients with isolated meningeal MS have been reported in the literature (Table 1). We describe a patient with isolated meningeal MS with recurrent mixed lineage leukemia gene rearrangement with AF6 (MLL-AF6). She was efficiently and definitely diagnosed by auxiliary examinations without surgical biopsy. To date, she has survived for 84 months after being treated by systemic chemotherapy, intrathecal injection and brain radiotherapy.

Table 1.

Summary of cases of isolated meningeal myeloid sarcoma from 1970 to 2020.

Case	Age (years)/sex	Initial diagnosis	CSF cytology	Immunophenotyping	Cytogenetics	Treatment	Follow-up (months)	Outcome
1 15	52/M	High-grade NHL	Cytoplasmic granulations, Auer bodies	Cytoplasmic chloroacetate esterase activity+	None	Surgical resection, systemic chemotherapy, local radiotherapy	21	Remission
2 16	35/M	High-grade NHL	none	Biopsy and IHC showed CD45 and neutrophilic elastase strongly+, chloroacetate esterase nearly 15%	None	Systemic chemotherapy, local radiotherapy auto-HSCT	20	Remission
3 17	5/F	Isolated meningeal MS	Atypical mononuclear blast cells	IHC of CSF showed MPO+, CD68+. Meningeal biopsy and IHC showed CD68+	t(9;11)translocation with split MLL gene	Systemic chemotherapy, intrathecal treatment	60	Remission
4 18	40/F	Reticulum cell sarcoma-microglioma	None	None	None	Surgical excision, systemic chemotherapy, radiotherapy	9	Remission
5 19	NA	Lymphoma	NA	NA	NA	NA	NA	NA
6 19	NA	Lymphoma	NA	NA	NA	NA	NA	NA
7 (present case)*	13/F	Isolated meningeal MS	Small purplish red granules, obvious nucleolus	IHC of the CSF showed CD68+, FC showed CD45+, CD13+, CD11c+, CD33+, CD64bri+, CD15+, CD117p+, CD11bp+	t(6;11)(q27;q23), +8[10] with split MLL gene	Systemic chemotherapy, intrathecal treatment, local radiotherapy	84	Remission

CSF, cerebrospinal fluid; M, male; NHL, non-Hodgkin’s lymphoma; IHC, immunohistochemistry; auto-HSCT, autologous hematopoietic stem cell transplantation; F, female; MS, myeloid sarcoma; MPO, myeloperoxidase; MLL, mixed lineage leukemia; NA, not available; FC, flow cytometry.

“+”, positive; “^bri”, bright; “^p”, partial.

Case report

A female adolescent patient with no prior medical history was admitted to our department in September 2015 because of vomiting, headaches lasting for 1 month and hearing loss lasting for 2 weeks. Positron emission tomography-computed tomography and magnetic resonance imaging (MRI) in a local hospital showed multiple intracranial space-occupying lesions. A physical examination showed a stiff neck and bilateral hearing loss. There was no lymphadenopathy or hepatosplenomegaly. Her blood counts were normal. Cranial MRI showed multiple masses on the left side of the pontine cistern and on both sides of the cerebellopontine angle and medulla oblongata (Figure 1a). The masses were isointense on T1-weighted imaging (T1WI) and T2WI with homogeneous contrast enhancement, and diffusion-weighted imaging showed limited diffusion. Multiple patchy masses were observed in the inferior tentorial margin of the cerebellum and were isointense on T1WI and isointense/mildly hypointense on T2WI with homogeneous contrast enhancement. On the right side, diffusion-weighted imaging showed slightly limited diffusion. The nucleated cell count in cerebrospinal fluid (CSF) was 1440 × 10⁶/L.

Figure 1.

Magnetic resonance imaging shows multiple lesions of the central nervous system: (a) coronal, (b) axial and (c) sagittal postcontrast images. Magnetic resonance imaging shows that lesions have disappeared subsequent to the combined therapy: (d) coronal, (e) axial and (f) sagittal postcontrast images.

Examinations comprising morphology, immunophenotyping, cytogenetics and molecular biology (MICM) tests of CSF and BM were performed. A large number of myeloid immature cells were observed in CSF cytology (Figure 2a,b) in which CD68 was positive as detected by IHC. FC showed that the abnormal cells in CSF were promonocytes (Figure 2c). The CSF karyotype was 47,XX, t(6; 11)(q27; q23), trisomy 8[10] (Figure 2d). Fluorescence in situ hybridization showed chromosomal translocation involving the MLL (11q23) locus (Figure 2e). MLL-AF6 translocation was considered. Polymerase chain reaction analysis showed that the MLL-AF6 fusion gene was positive. A missense mutation in exon 3 of the NRAS gene was detected by next-generation sequencing in CSF. BM examinations did not suggest any abnormality. These results suggested the diagnosis of isolated MS of the CNS with recurrent MLL-AF6 translocation.

Figure 2.

(a, b) Cerebrospinal fluid cytology shows a large number of myeloid immature cells (hematoxylin–eosin stain; a, ×100 and b, ×400). (c) Flow cytometry shows that blast cells are promonocytes. (d) Chromosome karyotype analysis shows 47,XX, t(6;11)(q27;q23), +8[10]. (e) Fluorescence in situ hybridization shows that approximately 90% of the cells express 1 fusion 1 red and 1 green MLL (11q23) signals, suggesting that there is a chromosomal translocation involving the MLL (11q23) site (a normal signal is a 2-fusion signal).

We obtained treatment consent from the guardian of the patient. She received one cycle of systemic chemotherapy of high-dose cytarabine (6 g/m² on days 1–3) in September 2015 and intermittent intrathecal injection (cytarabine 50 mg, methotrexate 10 mg, dexamethasone 5 mg) four times at 0, 4, 6 and 19 days after starting chemotherapy. The last time interval was longer owing to the subsequent myelosuppression. Some clinical manifestations were relieved except for the hearing loss. CSF was re-examined 3 weeks post-induction chemotherapy, and cytology and molecular results were negative. Four weeks post-first induction chemotherapy, the patient received one cycle of combined chemotherapy (decitabine 20 mg/m² on days 1–5, cytarabine 6 g/m² on days 6–8, mitoxantrone 20 mg/m² on days 8–10) and intermittent intrathecal injection in the local hospital, followed by whole-brain radiotherapy (24 Gy/20 F) in December 2015. To evaluate the treatment effect, a thorough clinical examination was performed 6 months after the first therapy. Cranial MRI showed that the preceding lesions had disappeared completely (Figure 1d–f). Cytology, FC and molecular tests were negative in CSF and BM. To date, she has maintained complete remission for 84 months.

We have de-identified all of the patient’s details. The reporting of this case conforms to the CARE guidelines. ⁶

Discussion

The early diagnosis of primary MS of the CNS is difficult owing to the absence of a history of hematological malignancies. These patients can present with headache, nausea and vomiting, and eyesight deterioration, mimicking primary CNS neoplasms. Computed tomography (CT) and MRI are the most common imaging modalities for the discovery of isolated MS of the CNS. ⁷ MS lesions present with a hyperdense mass on a noncontrast CT scan. ⁸ Brain MRI shows typical isointensity to mild hypointensity on T1WI and T2WI, and generally shows homogeneous contrast enhancement. ⁹ MRI is the main method for the initial differentiation between vascular complications and CNS involvement of AML. ⁵ However, the sensitivity of MRI in diagnosing central infiltration in AML is limited. ¹⁰ In addition, patients with meningoencephalitis, meningioma, lymphoma and extra-axial tumors may show hyperintensity, and MRI alone cannot provide adequate information to differentiate them from MS.^10,11

CSF cytology is the standard method for diagnosing CNS leukemia. ⁵ However, the heterogeneity of blast cells is a great challenge for pathologists. IHC and specific staining help confirm the diagnosis of MS. CD68/KP1, myeloperoxidase, lysozyme, CD117 and CD43 are the most common positive markers of MS.^12,13 The positive markers CD68, CD14, CD11c and lysozyme often indicate the differentiation of monocytes. ¹² Only 29% of intracranial MS expresses myeloperoxidase, and MS can be positive for lymphoid lineage antigens, such as CD19, cCD79a and CD7. Therefore, this may lead to a misdiagnosis. ⁵ The addition of CSF FC and polymerase chain reaction methods is essential for a definite diagnosis of MS.^5,14 In our patient, an MRI scan of the brain suggested abnormality. CSF cytology, IHC and FC results showed that the blast cells were promonocytes (we determined the lineage and stage). Cytogenetics and molecular biology tests showed MLL-AF6 translocation (risk stratification). An accurate diagnosis was made on the basis of the clinical history, imaging results and MICM results. When we reviewed the relevant literature from 1970 to 2021, we found only six patients who had primary CNS MS (Table 1).^15–19 Our patient is the first to be efficiently and accurately diagnosed by comprehensive MICM examinations of CSF without surgery.

MS is often accompanied by cytogenetic abnormalities. ²⁰ Chromosome t(8; 21) translocation and inv (16) are the most common cytogenetic changes in MS, and are regarded as favorable indicators of the prognosis. ²¹ Other chromosomal abnormalities, such as monosomy 7 and trisomy 8, have also been reported. ¹² The median survival time of patients with MS and trisomy 8 is short. A study showed that, in children with primary MS, 73% had morphological features of myelomonocytic differentiation, which sorted to FAB AML-M4/M5, and there was a higher occurrence of MLL-rearrangement t(9;11) translation. ²² MLL-AF6 is also common in AML M4/M5 subtypes and is prone to occur in children or young patients. The presence of MLL-AF6 is a poor prognostic factor for AML. ³ Fortunately, our patient achieved long-term disease-free survival, although her hearing loss remained.

The optimal treatment for primary MS has not been determined. Systemic chemotherapy is recommended for MS. ²² AML-specific chemotherapeutic agents are effective for primary MS with CNS involvement.^16,17 Surgical treatment or local radiotherapy alone and delayed or insufficient treatment often lead to recurrence or progression.^22,23 Intrathecal treatment should be provided to patients with AML and central involvement. ⁷ Radiotherapy and allogeneic hematopoietic stem cell transplantation are often used as combinatorial therapy for primary MS. However, there is no evidence that this combination of therapies is better than timely chemotherapy alone for patients with primary CNS involvement. The third patient in Table 1 achieved 60 months of remission with systemic chemotherapy and intrathecal treatment without irradiation. ¹⁷ Because our patient had potential adverse factors, a chemotherapy regimen that included high-dose cytarabine was selected. Brain radiotherapy was used as consolidation treatment.

In conclusion, we describe a rare case of isolated meningeal MS that was accurately diagnosed by integrated MICM examinations of CSF. The patient achieved long-term disease-free survival, despite the potential adverse factors after proper therapy. We also reviewed the literature in terms of the clinical diagnosis and the treatment of isolated meningeal MS, with the aim of improving the diagnosis and management of isolated MS.

Research Data

Research Data for Isolated meningeal myeloid sarcoma with recurrent MLL-AF6 translocation: a case report

Research Data for Isolated meningeal myeloid sarcoma with recurrent MLL-AF6 translocation: a case report by Chunyan Wang, Li Zhu, Songya Liu, Cheng He, Shujuan Yi, Ying Wang, Fankai Meng, Min Xiao, Yicheng Zhang and Xia Mao in Journal of International Medical Research