1 Background

Blood cancer can be divided into two subgroups in general definition: myeloid origin and lymphocytic origin. [1]. AML is a blood cancer that affects the myeloid line of blood cells, causing abnormal myeloblasts to multiply uncontrollably, [2]. Accumulating immature cells can harm the quantity and quality of blood cells.

AML also can cause extramedullary symptoms such as splenomegaly. However, this usually happens gradually and without complaining symptoms. Lymph node enlargement is uncommon in most AML subtypes, except for acute myelomonocytic leukemia (AMML) [3]. Although it is commonly believed that AML cells rarely invade the CNS and form tumors, this is frequently the case in pediatric patients; although CNS involvement as the first presenting symptom has been rarely reported. Adult CNS involvement often goes undetected, which may not fully represent reality [2, 3]. This is due to the absence of routine diagnostic lumbar puncture (LP), which is only carried out when CNS signs or symptoms are present, leading to undetected CNS leukemia in adult AML patients [4, 5]. Therefore, LP assessment is recommended in cases of hyperleukocytosis at diagnosis, even without additional symptoms [6, 7].

2 Case presentation

A 19-year-old female previously healthy patient was admitted to our department with a frontal headache that had progressively worsened for a month. She also reported experiencing right eye strabismus, diplopia, and exophthalmia since 25 days ago. Other symptoms included recent vomiting, nocturnal sweating, loss of appetite for a month, and sudden weight loss of approximately 2 kg in two weeks. In addition, she also mentioned that she had lost her sense of smell and taste. She had dry, red, itchy, and bumpy patches on her skin, which appeared on her neck, back, and abdomen.

Rather than this admission, she had no remarkable family history was also negative. The patient did not use any cigarette, alcohol or illicit drugs. She was the only child and living with her parents.

2.1 Physical examination

During the physical examination, the patient appeared unwell but not toxic. She was able to answer questions appropriately and was aware of her surroundings. Her temperature was 36.6 °C, pulse was 88 beats per minute, blood pressure was 110/80 mm Hg, respiratory rate was 14 breaths per minute, and oxygen saturation was 99% on ambient air. On the neurological examination, her pupils did not react to light. Diplopia was observed during the eye test when looking to the right. She had difficulty turning her right eye outwards and was found to have right sixth nerve paralysis.

Furthermore, the ophthalmologist detected leukemic infiltration during the retina examination. On cardiac auscultation, tachycardia was noted with a steady rhythm. The radial pulses were normal. The lungs were clear. The abdomen was soft and not distended, but tenderness was noted in the epigastric region. The skin on her neck, back, and abdomen was dry and had generalized itchy erythematous macules.

2.2 Para-clinics and imaging

In the next step, a full lab profile at the time of admission, including complete blood count (CBC) result, is shown in Table 1. In addition to CBC, blood culture, lactate dehydrogenase (LDH), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were initially requested. After conducting a thorough physical examination and reviewing the patient's history, our initial diagnosis indicated a possible case of chronic meningitis, characterized by long-lasting inflammation in the CSF, typically lasting at least one month. The symptoms include persistent headaches, nausea, vomiting, increased intracranial pressure, and specific neurological deficits [8]. In some developing countries like Iran and Afghanistan, chronic meningitis is commonly caused by extrapulmonary Mycobacterium tuberculosis (TB).TB meningitis accounts for 10% of extrapulmonary TB cases, typically lasting between 14 and 16 days. [9]. Due to the high mortality rate associated with chronic meningitis, the patient was treated empirically with an anti-TB drug. However, further testing revealed a negative purified protein derivative (PPD) test and incompatible CSF results, ruling out TB meningitis as the cause of the patient's symptoms.

Table 1 Complete blood count (CBC)
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Several epidemiology-based infectious tests were conducted in addition to PPD. These tests included Wright, 2-Mercaptoethanol (2ME) Wright titer, enzyme-linked immunosorbent assay (ELISA) for Human Immunodeficiency Virus (HIV), and Human T-cell Lymphotropic Virus (HTLV) antibody, which all were negative. The polymerase chain reaction (PCR) tests for COVID-19 and Influenza virus were also negative. Additionally, the urinalysis results and blood culture were normal.

In imaging, spiral computer tomography (CT) scan showed in level IIb regions and the posterior triangle of the neck, several lymph nodes with a size of 10 mm were seen. Cranial MRI showed dural thickening and increased enhancement adjacent to the left temporal lobe (Fig. 1).

Fig. 1
figure 1

There is thickening of the dura and increased enhancement next to the left temporal lobe on the coronal view of the brain MRI with contrast in Fluid-attenuated inversion recovery (FLAIR), as depicted by the black arrow

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CSF analysis was as remarkable for 1000 RBC and 4300 WBC per mm3. The composition consists of 90 percent monocyte-like dominancy; CSF cytology was positive for blasts; Furthermore, CSF flowcytometry was performed and confirmed them as myeloblasts. Other factors include sugar and protein, which were 50 mg/dl (50–80) and 29.5 mg/dl (15–60) respectively. LDH was 179 IU/l (< 50), and Adenosine deaminase (ADA) was 0.3 IU/l (0–24).

Additional infectious tests were done on CSF, and the panel was negative for Neisseria meningitides, Haemophilus Influenza, Streptococcus pneumonia, Streptococcus Agalactiae, Listeria Monocytogenes, Cryptococcus neoformans, Treponema Pallidum, Mycobacterium Tuberculosis complex, Coxiella burnetti, and Borrelia Burgdoferi.

In suspicious of carcinomatous meningitis, bone marrow biopsy, and flow cytometry was performed. Bone marrow aspiration was collected from the patient in EDTA test tube. Then smears was prepared on slides and stained by Giemsa methods. On pathologist request panel antibody composed CD13, CD33, CD34 and CD117, HLADR, CD5, CD10, CD19, CD23, CD20 and CD64 was done on this sample with BD FACSCanto II multicolor flow cytometry instrument (8 color) and analyzed with Flowjo7.6 software to detection of blasts.

Bone marrow biopsy also revealed a significant number of myeloid immature cells that were positive for CD (Cluster of differentiation)13, CD33, CD34, and CD117 by immune histochemistry (IHC) of bone marrow biopsy (Fig. 2).

Fig. 2
figure 2

IHC staining revealed positive for MPO (A) and CD34 (B) and negative reaction for Terminal deoxynucleotidyl transferase (TdT), CD20, CD19,CD3, CD10 (B). Keil(Ki-67) is estimated up to 70% of immature cells

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The transcript of the promyelocytic leukemia/retinoic acid receptor alpha (PML-RARA) was not detected in bone marrow aspiration.

The cytogenetic result of bone marrow biopsy was reported, and these mutations were found:

46,XX,t(3:8)(q26.2;p14.) 46,XX,t(3;16)(q28;p14.2).

All molecular mutational screening for FLT3-ITD, NPM1, CEBPA were negative.

Also, a lymph node biopsy from the largest cervical lymph node was done, and the histopathology results showed effacement of lymph node architecture with infiltration of monotonous immature cells (Fig. 3). IHC staining revealed positive for MPO (Myeloperoxidase) and CD34.

Fig. 3
figure 3

Histopathology sections of excised lymph node showed effacement of lymph node’s architecture with infiltration of monotonous immature cells with high n/c (nucleus/ cytoplasm ratio) ratio, irregular nuclei and scant cytoplasm which involving the surrounding fatty tissue as well.

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A summarized timeline of the most important features of this case is presented in Fig. 4.

Fig. 4
figure 4

A summarized timeline of this case with is presented in this figure

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2.3 Treatment

Finally, the patient was diagnosed with acute myeloid leukemia with CNS involvement. The patient underwent systemic chemotherapy with 7 + 3 regimen based on Cytarabin and Anthracycline. In Addition to systemic therapy, intrathecal chemotherapy twice a week with 15mg/dose Methotrexate was administered. She also underwent local right eye radiotherapy due to leukemic infiltration of the retina and optic nerve of the right eye. Visual symptoms improved and after intrathecal chemotherapy, CSF was cleared of blasts.

3 Discussion and conclusion

3.1 Epidemiology

Meningeal leukemia can be presented with intraparenchymal intravascular leukostasis, and nodular granulocytic sarcoma (chloroma) [10]. In children, acute lymphoblastic leukemia is the most common cause of meningeal leukemia, while secondary meningeal leukemia in adults is linked to myeloid leukemia in its monocytic or blastic stages and chronic lymphocytic leukemia [11] It is believed that AML cells seldom reach the CNS and establish tumors in adult patients, unlike pediatric patients where it is a frequent occurrence [12]. Risk factors for CNS leukemia include chromosome 11 abnormalities, such as trisomy with gene amplification, including myeloid, lymphoid leukemia (MLL), and chromosomal 16 inversions, resulting in core binding factor beta-myosin 11 heavy chain fusion protein [12]. Additionally, hyperleukocytosis > 100,000/microl, prominent monocyte components, and high serum LDH are risk factors that our patient has. APL with PML-RARA is also a risk factor for CNS involvement in AML [13].

3.2 Symptoms and pathophysiology

Contamination of CSF through the choroid plexus, invasion of leukemic cells from the brain parenchyma through capillaries, direct infiltration of the leptomenings through bone lesions, or spread through nerve roots are some of the hypotheses proposed in the pathophysiology of CNS involvement in acute myeloid leukemia [14]. The last hypothesis in our patient can be one of the causes of leptomeningeal involvement through optic nerve infiltration.

Headaches, nausea, and vomiting are the most typical meningeal leukemia presenting symptoms, and they are occasionally accompanied by lethargy and irritability, sleepiness, coma, convulsions, and neck rigidity [15]. In addition to these signs and symptoms, increased intracranial pressure leads to pressure on the cranial nerves. The most common nerves include the 3rd, 5th, 6th, and 7th cranial. Right sixth nerve palsy was found in our patient during examination. The circulation of CSF is hampered by diffuse meningeal infiltration, which may lead to communicating or obstructive hydrocephalus. The most typical symptom is papilledema; in young children, the sutures in the skull might separate. The spinal nerve roots or cranial nerves may get compressed or infiltrated by leukemic deposits, which then disseminate between the nerve fibers [15].The lower cranial nerves are infrequently afflicted, but the second, third, sixth, seventh, and eighth cranial nerves are the most frequently impacted. Chronic lymphocytic leukemia meningeal infiltration has been linked to oculomotor palsy with pupillary sparing. The invasion of leukemic cells in the CNS is primarily driven by the production of certain adhesion molecules by a subset of leukemic cells known as “sticky cells.” These cells can interact with and attach to endothelial cells, such as very late antigen(VLA-4), intra cellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM), L-selectin, platelet endothelial cell adhesion molecule-1 (PECAM1), CD18, Lymphocyte function-associated antigen (LFA-1), CD58, CD44, and chemokine ligand (CXCL12) [15].

Additionally, the blood–brain barrier is broken, and the microenvironment becomes hypoxic, causing the release of VEGF-A by acute lymphocytic leukemia (ALL) or AML cells, which raises the permeability of the bone marrow's vasculature. Leukemic stem cells (LSCs) can withstand the new microenvironment due to their remarkable flexibility. The LCSs penetrate the arachnoid, move, and vigorously multiply in the CSF; after that, they permeate the brain parenchyma and perivascular spaces. Moreover, due to its favorable immune protection, the CNS can shield leukemic cells from chemotherapy. The most crucial surface molecule that leukemic stem cells frequently overexpress and allow them to invade the CNS is neural cell adhesion molecule(NCAM) of CD56 [12].

3.3 Diagnosis and prognosis

Confirmation of meningeal leukemia diagnosis is often done by identifying leukemic cells in the CSF. In about 90% of cases, elevated leukocyte counts are present in the CSF, and blast cells and mitotic figures can be identified through cytocentrifuge preparations. However, even with clear clinical signs of meningeal involvement, the CSF of 10% of patients may appear entirely normal despite an often-raised CSF pressure. Reduced CSF glucose and high protein contents are unreliable indicators of meningeal illness [15]. Our patient’s CSF examination revealed pyelocytosis, normal protein and sugar levels, but high LDH. Detecting central nervous system (CNS) leukemia primarily relies on CSF cytology, but false-negative and false-positive findings can occur [6, 10]. Combining CSF flow cytometry and polymerase chain reaction methods can improve diagnostic sensitivity and specificity. The overexpression of CD56/NCAM, a crucial surface molecule, allows leukemic stem cells to invade the CNS. However, our patient's IHC findings were positive for CD13, CD33, CD34, and CD117 [4, 16]. There are varied opinions on the effect of CNS involvement on the success of long-term therapy. Still, according to Shihadeh et al., adult AML patients with CNS involvement have a poor prognosis [13].

3.4 Treatment

In Patients with cranial nerve abnormality or other neurologic impairment associated with leptomeningeal involvement intrathecal chemotherapy with radiotherapy or/and systemic chemotherapy have been recommended. Due to our patient signs and symptoms compatible with nerve palsy and signs or symptoms of ICP rising, she underwent concurrent intrathecal chemotherapy and systemic chemotherapy despite possible adverse effects. After chemotherapy, the patients had mild headache with nausea and vomiting, No serious adverse effects such fever, paresthesia or back pain reported. The patient was overall well tolerated; however the annoying adverse effects of chemotherapy should not be ignored.

3.5 Limitations

It is important to note that there are some limitations to consider in our study. Other findings, such as skin rash and blasts in CBC, suggest that empirical treatment for chronic TB meningitis may not be necessary. However, dual diagnosis is not rare based on the endemic prevalence in Iran. Additionally, the patient’s age falls within the borderline group, between teenage hood and young adulthood, making the findings' novelty less helpful.

4 Conclusion

Physicians should consider underlying malignancy in patients with meningeal symptoms, cranial nerve involvement, and/or resistance to conventional therapies. Thus, although rare in adults and more common in children, AML can be presented with CNS involvement in young adults like our patient.