Isolated Intracranial Myeloid Sarcoma Mimicking Malignant Lymphoma: A Diagnostic Challenge and Literature Reviews.

Isolated intracranial myeloid sarcoma (MS) is an unusual variant tumor with few cases reported so far in the medical literature. A 29-year-old woman was admitted to our hospital presenting progressive visual loss in the right eye and weight loss (20 kg) without a previous history of hematological disease (HD). Radiologic evaluation showed the evidence of intracranial mass. Histologically, the resected tumor was composed of a uniform population of primitive cells and primarily misdiagnosed as a T-cell non-Hodgkin's lymphoma (NHL). Chemotherapy with cyclophosphamide, doxorubicin, vinblastine, and prednisone (CHOP) was ineffective. A biopsy and histopathological evaluation were repeated, and immunohistochemical staining revealed the positivity of immature cells to an extensive panel of myeloid markers. These findings were consistent with a diagnosis of MS and bone marrow infiltration. Literature reviews of previous cases were also undertaken.

Introduction

Myeloid sarcoma (MS), also known as granulocytic sarcoma, is a locally invasive tumor mass of extramedullary tissues consisting of myeloid blasts with or without maturation. It is a rare and peculiar disease that can occur in any part of the body, with intracranial MS being extremely rare.1,2 MS diagnosis is challenging, particularly without a known history of any hematological disease (HD). Thus, isolated MS is easily misdiagnosed.3 According to a population-based study, the misdiagnosis rate of MS can be as high as 40%.2 MS is one of the most likely to be misdiagnosed as malignant lymphoma.2,4,5 Misdiagnosis is often corrected after bone marrow and/or blood tests for suspected acute leukemia.5 We found an unusual and challenging case of isolated intracranial MS with myelofibrosis that was misdiagnosed as T-cell non-Hodgkin’s lymphoma (NHL) and reviewed literature to raise awareness on this disease.

Case Presentation

In May 2018, a 29-year-old woman who was healthy until she was admitted to our hospital for a one-month history of progressive visual loss in the right eye and unexplained weight loss of 20 kg within one year. The physical evaluation showed that the patient had signs of anemia but no fever and superficial lymphadenopathy. Complete blood count was normal except for a red blood cell count of 2.82 × 109/L and hemoglobin levels of 85 g/L. Computed tomography (CT) of the brain showed saddle area-occupying lesions (Figure 1A). The patient immediately underwent an endoscopic sellar region tumor resection.

Figure 1

Computed tomography (CT) scan findings. (A) Preoperative CT showed an irregular soft tissue density mass in the saddle area, and the boundary with surrounding tissues was not clear. (B and C) Chest CT showed abnormal density of the thoracic spine and discontinuity of the sternal bone.

The mass was a small pile of greyish-yellow, dark red broken tissue with a volume of approximately 2.0 ×1.5 × 0.5 cm. Microscopically, the tumor was composed of diffuse infiltration of primitive and small blue cells (Figure 2A). A subset of tumor cells was eosinophilic with large round or oval nuclei, fine chromatin, and small nucleoli (Figure 2B). In certain areas, heterogeneous cells were characterized by diffuse infiltration of tissues with large nuclei, high nucleo-cytoplasmic (N:C) ratio, irregular nuclear contours, and small nucleoli (Figure 2C). At high magnification, the chromatin was fine, and the nucleoli could be noted (Figure 2D). The tumor cells were positive for LCA, CD4 (Figure 3A) and CD43; scattered positive for CD3 (Figure 3B) and CD8; but negative for AE1/3, EMA, S-100, CD10, CD20, and CD79a. Approximately 60% of tumor cells were positive for Ki-67, indicating a high proliferation index (Figure 3C). Morphological examination of bone marrow cells documented a decrease in myeloproliferative disorder with 6% of the primitive cells, without evidence of neoplastic cells (Figure 4A). Subsequently, further cytogenetic examinations were recommended, but the bone marrow is dry pumped in vain. On the basis of these results, the initial diagnosis was considered as T-cell NHL. Considering that the patient had no contraindications for chemotherapy, CHOP regimen chemotherapy was initiated in 1 month following resection.

Figure 2

Histopathological features of MS. (A) Diffuse infiltration of tumor cells and round-shaped malignant lymphoid cells with less cytoplasm (H&E; ×200). (B) A small amount of mature or naive eosinophils and abundant interstitial blood vessels can be found between neoplastic cells (H&E; ×200). (C) High N:C ratio, small nucleoli, and numerous mitotic figures (H&E; ×400). (E) The neoplasm consists of blasts with round–oval nuclei with finely dispersed chromatin (H&E; ×200). (D and F) The neoplasm consists of blasts with round–oval nuclei with finely dispersed chromatin and distinct nucleoli. Various numbers of lymphocyte infiltrations are present (H&E; ×400).

Figure 3

Immunohistochemical findings (original magnification ×200). (A)Infiltrative cells are CD4 positive. (B) CD3 diffuse positivity. (C) Ki-67 proliferation index is 60%. Neoplastic cells positive for (D) CD68, (E) CD117, (F) CD99, and (G) CD34 and negative for (H) MPO and (I) TdT.

Figure 4

Bone marrow cell morphology. (A) Cells were medium, round, or elliptical; the nucleus is round or oval, and the chromatin is granular. (B) Tumor cells were round; certain cells were slightly irregular; the chromatin was loose; the nucleolus was obvious, and the cytoplasm was less. (C and D) Occasionally visible primitive cells.

With regard to the clinical conditions of the patient, no improvement was noted on the blindness in the right eye, refractory anemia (minimum hemoglobin levels of 43 g/L), and sternal tenderness. 8 months after tumor resection, morphological evaluation of bone marrow cells documented that immature/primitive cells accounted for 81.5%, and the proliferation of granulocytic, erythrocytic and megakaryocytic cells were inhibited (Figure 4B). CT showed diffuse abnormal bone density in the limbs, ribs, sternum (Figures 1B and C), spine, and pelvis. Successful bone marrow puncture displayed a population of medium-sized myeloid primitive cells associated with fibrosis and scattered eosinophils (Figures 2E and F). However, karyotype analyses failed.

The previous diagnosis was reviewed, and additional immunohistochemistry staining showed positive for CD68 (Figure 3D), CD117 (Figure 3E), CD99 (Figure 3F), CD1a and CD34 (Figure 3G), but negative for MPO (Figure 3H) and TdT (Figure 3I). The final diagnosis of MS was confirmed after the patient’s pathological files were sent to another hospital for consultation. At present, the chemotherapy regimen was adjusted to high-dose cytosine arabinoside and the patient has postoperatively received consolidation chemotherapy for 4 cycles (1 g/m2 cytarabine per half a day for 3 days). Bone marrow biopsies and radiological examination were performed to evaluate patient’s post-treatment results. Bone marrow cytology showed reduced nucleated cell proliferation and occasional primitive cells (Figure 4C). Detection of minimal residual disease (MRD) (through flow cytometry) revealed no abnormal primitive (myeloid/NK precursor) cells (). Chest radiograph showed normal sternum and thoracic vertebra. The ribs, clavicle and scapula still have diffuse bone density unevenness. After 3 months, the latest bone marrow cytology occasionally showed primitive cells (Figure 4D), and no obvious myeloid primitive cells were found in MRD (below the lower detection limit: 104) (). The patient’s condition is stable, and follow up will be continued.

Discussion

Burns first described MS in 1811,6 commonly known as chloroma7 and granulocytic sarcoma.8 In 1893, Dock established its association with leukemia. MS may occur previously, simultaneously, or secondary to AML, chronic myeloid leukemia, myeloproliferative disorder, myelodysplastic syndrome, and essential thrombocythemia.2,9 The 2016 revised WHO classification continued to classify MS as a unique clinical manifestation of AML subtype and pointed out that MS can occur independently of the peripheral blood and bone marrow. MS extramedullary infiltration frequently affects the bone, eyelids, lymph nodes, and skin.1,2 The involvement of the central nervous system is only 0.4%,4 while the cases of intracranial MS are fewer. Literature search only shows eight similar reports (isolated intracranial MS) from January 2000 to June 2019 (Table 1).10–17

Table 1.

Isolated Myeloid Sarcoma in Cranial Lesion Between 2000 and 2019

Case	Age, Years	Sex	Site(s) Involved	Symptoms	Initial Histological Diagnosis	Immunophenotype on Immunohistochemistry	Latency Time to AML Development	Treatment	Outcome	Follow-Up
110	35	M	Meninx	Left eye vision decline, diplopia	NHL	N.A.	No determined AMLor HD	S+R+Allo MBT	CR	20 months
211	3	M	Bilateral sphenoidal bone, orbit	Sporadic pain in both eyes	No	Naphthol-ASD-cl+, S-100-	AML, 1 month	S+C+R	CR	39 months
312	35	F	Right parietal lobe, T3–5, S1–4	Bilateral frontal headaches, S1 radiculopathy	No	CD34+, CD43+, CD117+, MPO+	No determined AMLor HD	Bx+C+R+Allo MBT	CR	7 years
413	29	M	Right thalamus, caudate nucleus basal ganglia	Disturbance of consciousness, headache, fever	No	MPO+	N.A.	N.A.	Death	N.A.
514	41	F	Left-sided middle cranial fossa	Refusing to talk,decreased movement	No	CD13+, CD33+, CD117+, CD34+, MPO+	No determined AMLor HD	Bx+S+C	Improved	Reported to be alive at 7 months
615	22	M	Parasagittal line	Headache	No	MPO+, TdT+, CD117+, CD1a–, S-100+	No determined AMLor HD	Bx+C	Improved	18 months
716	27	M	Bilateral temporal lobes, L2–3, S2–3	Headache, bilateral visual field defects, right thigh pain and numbness, sphincter dysfunction	No	MPO+, CD34+, CD45+, CD68+, CD99+, lysozyme+	No determined AML or HD	S+C	CR	13 months
817	0.5	F	Left frontotemporal region	Fever, vomiting, convulsions	No	CD68+, CD43+, CD117+, MPO+, CD138+, Vim+, LCA+, Ki-67 90%+	No determined AMLor HD	S	Death	N.A.
Current case	29	F	Saddle area	Right eye vision decline, weight loss	T-cell NHL	CD117+, CD34+, CD99+, CD3+, CD1a+, CD68+, CD4+, CD43+, MPO-, Ki-67 60%+	AML, 9 months	S+C	Improved	Alive

Abbreviations: M, male; F, female; Bx, biopsy; S, surgical resection; C, chemotherapy; R, radiotherapy; Allo MBT, allogeneic bone marrow transplantation; CR, complete remission; AML, acute myeloid leukemia; HD, hematological disease; NHL, non-Hodgkin’s lymphoma; N.A., not applicable.

MS is generally diagnosed by a comprehensive analysis of clinical and imaging features, tissue biopsy, immunohistochemistry and molecular analyses. MS nodules or masses, which are characterized using radiologic evaluation, are denser than the brain parenchyma or are equivalent to muscles on CT scans. Enhanced scans show moderate-to-severe intensification.9,18 Given the lack of understanding and attention to this disease, clinical and pathological diagnosis is challenging. The freshly cut surface of the tumors generally appears green due to peroxidase oxidation, whereas approximately 30% of the surface do not exhibit this color.7,8 When the tumor displays a greyish red or greyish yellow color, pathologists tend to ignore the possibility of MS. Morphologically, MS lesions infiltrate into granulocytes, monocytes, or mononuclear cells. The tumor cells are diffusely distributed, uniform in shape and small-to-medium size, and therefore be confused with T-cell lymphoma, diffuse large B-cell lymphoma, or poorly differentiated carcinoma in adults, particularly under the hematoxylin-eosin (H&E) stain. MS is often misdiagnosed as NHL (Table 2).4,5,10,19 Another feature that supports MS diagnosis is the presence of eosinophils in tumor cells. However, eosinophils are not specific and often unnoticed. Unfortunately, we ignored this feature during the initial diagnosis.

Table 2.

Misdiagnosed Myeloid Sarcoma Cases

Case	Age, years	Sex	Site(s) Involved	Symptoms	Initial Histological Diagnosis	Initial Immunohistochemistry	Initial HD Diagnosis	Correct Diagnosis Method and Result
14	47	M	Skin of the nasolabial fold, testis	N.A.	ML	N.A.	NO	N.A.
24	50	M	Supraclavicular	N.A.	ML	N.A.	NO	N.A.
319	48	M	Left testicle	Left testicular swelling	ML	N.A.	N.A.	N.A.
410	35	M	Meninx	Left eye vision decline	NHL	N.A.	N.A.	Chloroacetate esterase stain+, myelomonocytic markers+, leukocyte common antigen+, B-/T-cell-specific antigens-
55	64	M	Left testis	Swelling of his left testis	NHL	MPO+, lysozyme+	NO	AML was suspected by bone marrow and blood examinations
619	71	M	Left testicle	Left testiculai swelling	Plasmacytoma	N.A.	N.A.	N.A.
74	49	F	Cervical	N.A.	Lymphoblast proliferation	N.A.	N.A.	N.A.
Current case	29	F	Saddle area	Right eye vision decline, weight loss	T-cell NHL	LCA+, CD3+, CD4+, CD43+, CD20-, CD79a-, Ki-67 60%+	NO	Re-biopsy, further IHC: myelomonocytic markers+

Abbreviations: M, male; F, female; AML, acute myeloid leukemia; HD, hematological disease; NHL, non-Hodgkin’s lymphoma; ML, malignant lymphoma; N.A., not applicable.

To some extent, immunohistochemical staining allows making an appropriate diagnosis.20 Immunohistochemical markers are complex, and incorrect analysis can lead to misdiagnosis. In our case, initial immunohistochemical staining has demonstrated positive for T cell antibodies (CD3, CD4, CD8, and CD43) but negative for B-cell antibodies (CD20 and CD79a). We neglected that CD43 is not only a T-cell marker but is also expressed in almost all myeloid cell sarcomas.21 Moreover, a small number of MS can express T-cell antigens. Two studies have reported that MS can express CD4 (1.1%)2 and CD3 (20.7%).22 The common positive cell surface antigens of MS include MPO, lysozyme, CD68, CD117, CD99, CD34, and TdT. In our supplemental immunohistochemistry, CD117, CD34, CD99, CD1a, and CD68 are positive, further confirming the establishment of MS diagnosis. CD117 and MPO positivity often indicate that tumor cells have myeloid differentiation. MPO is a specific marker of myeloid cells, has high sensitivity and specificity and has been considered as a marker of MS in recent years.23 Keisuke Kawamoto analyzed 131 cases of MS and reported a 63.2% positive expression rate of MPO,22 demonstrating that not all MS express MPO. When MPO is negative, the expression of paraffin sections CD41 and CD61 contributes to the diagnosis. Thus, tissue biopsy and immunohistochemistry are particularly important for accurate diagnosis of MS when clinical features are inadequate.

A complete diagnosis of MS should include risk stratification of the disease and assessment of targeted therapy. Therefore, molecular analyses associated with MS is essential, which may remarkably improve the outcome and prognosis of patients.9,24 The chromosomal translocations t (8; 21) (q22; q22) are the commonest cytogenetic mutations, producing an AML1-ETO fusion gene at the molecular level.25

Given the lack of a large randomized controlled trial of MS, the treatment strategy of MS remains to be a controversy.25 Currently, systemic chemotherapy is the main treatment for MS. When the isolated MS is diagnosed, systemic chemotherapy should be initiated, a treatment regimen of systemic chemotherapy regimen for AML-like is recommended.9,20 Some studies have found that chemotherapy regimens containing cytarabine are an essential part of MS systemic chemotherapy.20 Other treatments include local radiotherapy, allogeneic bone marrow transplantation, molecular targeting and immunotherapy. The latest single-institution experience points out that after the first induction of remission, allogeneic hematopoietic stem cell transplantation (HSCT) is the effective modality to achieve long-term remission.26 Highly targeted therapies produce good results that offer opportunities for MS patients; for example, humanized anti-CD33 monoclonal antibodies are used for targeted therapy in patients with CD33-positive AML-related MS.27 And targeted therapy with tyrosine kinase inhibitors in MS patients associated with BCR-ABL1, FLT3-ITD and FIP1L1-PDGFRA mutations.28 Kanate et al29 reported that orally administered 400 mg of single-agent venetoclax induces a remarkable result for refractory MS. A new molecule CPI-613 (6,8-bis [benzylthio] octanoic acid) with cytarabine and mitoxantrone hydrochloride treatment has been entered into the pilot phase II trial. This study expects to be completed in February 2022 and is a promising approach for refractory/relapsed AML or MS.30

Conclusion

The diagnosis of intracranial MS pathologies in patients without HD is challenging. According to our case and literature reviews, local surgical decompression combined with high dose cytarabine is effective in controlling tumor masses, including progressive neurological deterioration. Both improvements in long-term survival and remission of isolated MS or MS with AML are still dependent on systemic chemotherapy and HSCT. In addition, sub-targeted therapy has potential application in emerging individualized medicine.