Primary cerebellar extramedullary myeloid cell tumor mimicking oligodendroglioma

Extramedullary myeloid cell tumors (EMCTs) are tumors consisting of immature cells of the myeloid series that occur outside the bone marrow. Most of them are associated with acute myelogenous leukemia or other myeloproliferative disorders, and a small number occur as primary lesions, i.e., are not associated with hematological disorders. Occurrence inside the cranium is rare, and there has been only one case of primary EMCT involving the cerebellum reported in the literature. The case we report here is a blastic EMCT occurring in the cerebellum of a 3-year-old boy who had no signs of leukemia or any hematological disorder throughout the entire course. The cerebellar tumor was at first misdiagnosed as an “oligodendroglioma” because of the uniformity and “fried egg” artifact of the tumor cells. The tumor disappeared during chemotherapy consisting of 12 treatments. However, it recurred and metastasized to the cerebrospinal fluid (CSF) shortly after the therapy was completed. A diagnosis of EMCT was suspected because of the presence of immature myeloid cells in the CSF, and was confirmed by anti-myeloperoxidase and anti-lysozyme immunoreactivity of the cerebellar tumor. The patient succumbed 1 year and 3 months after the first presentation of the disease. Received: 6 December 1996 / Revised, accepted: 14 March 1997     

Inferior vena cava thrombosis and its relationship with the JAK2V617F mutation and chronic myeloproliferative disease

Background

Splanchnic vein thrombosis (SVT) is a typical manifestation of polycythaemia vera (PV) or essential thrombocythaemia (ET). The recently discovered JAK2V617F somatic mutation is closely associated with chronic myeloproliferative disease (CMD). We investigated whether thrombosis involving the inferior vena cava (IVC) is also related to the JAK2V617F mutation or CMD.

Methods

Blood samples were obtained from 40 IVC thrombosis patients. Fifty-three patients with isolated lower extremity deep vein thrombosis (LE-DVT) and 20 SVT patients served as controls. The presence of the JAK2V617F mutation was assessed by real-time polymerase chain reaction (RT-PCR).

Results

The JAK2V617F allele was not detected in any of the IVC thrombosis patients but was detected in one patient (2%) with isolated LE-DVT. However, the mutation-carrying patient did not exhibit symptoms of CMD. Even after an observation period of 30 months, the patient's complete blood cell count did not exhibit any pathology. In contrast, the JAK2V617F allele was detected in four patients with SVT (20%) and CMD.

Conclusion

According to our data, there is no evidence that IVC thrombosis is associated with the JAK2V617F mutation or the presence of chronic myeloproliferative disease.     

Pineal region myeloid sarcoma

The overwhelming majority of pineal region tumors are malignant germ cell tumors, pineal cell tumors, or glial tumors. To our knowledge we report the first patient with myeloid sarcoma in the pineal region. Myeloid sarcomas are composed of immature granulocytic precursor cells and are associated with acute myelogenous leukemia. Thus, myeloid sarcoma should be considered in the differential diagnosis of pineal region masses in patients with a known history of acute myelogenous leukemia.     

Outcome of patients with splanchnic venous thrombosis presenting without overt MPN: A role for the JAK2 V617F mutation re-evaluation

Introduction

Although investigation for JAK2 V617F mutation is recommended in patients presenting with splanchnic venous thrombosis (SVT), no specific clinical advice is given to SVT patients presenting without myeloproliferative neoplasms (MPN) and JAK2 V617F mutation. In MPN-free SVT patients, to investigate the clinical outcome, the clinical impact of re-evaluation for the JAK2 V617F mutation, and relationships with the occurrence and time to diagnosis of MPN.

Materials and Methods

A cohort of non-cirrhotic SVT patients, enrolled at a single centre and prospectively analyzed.

Results

In 121 SVT patients prospectively followed from 1994 to 2012, a MPN was present in 28 (23.1%). Additional 13 patients (10.7%) showed only the JAK2 V617F mutation. During the follow-up, the JAK2 V617F mutation and/or MPN were identified in 8 patients (median time of development: 21 months, range 6-120), whereas 72 remained (MPN and JAK2 V617F)-free until the end of the observation.The mortality rate was higher among patients presenting with MPN and/or the JAK2 V617F mutation than in patients who developed later or remained disease-free (p = 0.032). The thrombosis-free survival was lower in patients with (p = 0.04) or developing later MPN and the JAK2 V617F mutation (p = 0.005) than in patients (MPN and JAK2 V617F)-free. The incidence of bleeding was similar among groups.

Conclusions

MPN with or without circulating positive clones for JAK2 V617F mutation can occur long after a SVT, identifying at risk patients for new thrombotic events. If confirmed in other studies, re-evaluation for JAK2 V617F mutation may be of help in early MPN detection and clinical management of SVT patients.     

Sarcoma granulocítico del sistema nervioso central: reporte de 2 casos y revisión de la literatura

Granulocytic sarcomas are solid, extramedullary-located neoplasms composed of immature myeloid cells, associated with myeloproliferative syndromes. Central nervous system involvement is very rare and may develop either after complete remission, coexist with or precede the systemic disease, being the last one that guides the radiological diagnosis and marks the prognosis. In this work, we report 2 pathologically-verified cases of intracranial granulocytic sarcoma treated by surgical means. Their clinical, diagnostic, therapeutic and prognostic features are discussed in the light of the most relevant scientific literature published to date.     

Granulocytic sarcoma in a patient with essential thrombocythemia presented as acute spinal cord compression--case report and review of the literature

Granulocytic sarcoma (GS) is a rare solid tumor of myeloid origin, which usually precedes or occurs concurrently with myeloid leukemia, or with other types of myeloproliferative and myelodysplastic disorders. Spinal affections of GS have been described but are uncommon, particularly in association with essential thrombocythemia. We present a case of a 75-year-old woman with a long history of essential thrombocythemia who developed 2 tumors: 1 in the bodies of T3 - 6 vertebras extending epidurally, and the other in the right frontal lobe, adherent to dura, thus, mimicking meningioma. The patient died because of massive pulmonary thrombembolia. Microscopical and immunohistochemical features of spinal and intracranial tumor samples obtained at autopsy were consistent with the diagnosis of GS with focal megakaryocytic differentiation. Clinicians and pathologists should be aware of this rare tumor being so diverse in its clinical presentation, as well as in microscopical and immunohistochemical features. Careful evaluation of morphology, in conjunction with immunohistochemistry for evidence of myeloid differentiation are required to avoid frequent errors in diagnostics of GS. The suggested panel includes chloroacetate esterase, myeloperoxidase, lysozyme, CD117, CD43, CD79a and CD3. Only early correct diagnosis will enable proper treatment which may be successful despite the highly malignant potential of GS.     

Intraparenchymal Myeloid Sarcoma and Subsequent Spinal Myeloid Sarcoma for Acute Myeloblastic Leukemia

Myeloid sarcoma is a solid, extramedullary tumor composed of leukemic myeloblasts or immature myeloid cells. Intraparenchymal myeloid sarcoma without the involvement of the skull or meninges is extremely rare. Here, we present the case of a 49-year-old man who developed intraparenchymal myeloid sarcoma on the left cerebellum after allogeneic bone marrow transplantation (BMT). He received radiotherapy after complete removal of intraparenchymal myeloid sarcoma, but he was diagnosed spinal myeloid sarcoma three month later. Nine months after the operation, new intracranial and spinal myeloid sarcoma were diagnosed and the patient''s condition had been worsened rapidly. Although the spinal myeloid sarcoma was not histologically diagnosed, this report provides valuable insights into the clinical course of progression of intraparenchymal myeloid sarcoma.     

Intracranial granulocytic sarcoma in a patient with acute myeloid leukemia]

Granulocytic sarcoma (GS) is extramedullary tumor composed of immature leukemic cells. GS is presenting usually as a complication during the course of hematologic neoplasm, such as acute myeloblastic leukemia as well as myeloproliferative and myelodysplastic syndrome. The tumor was also called chroloma based on the green color of the tumorous mass. Central nervous system manifestations of GS are extremely rare. We report a 41-year-old man with acute leukemia type M7, who developed GS in the right occipital lobe after complete remission was achieved. Operative findings revealed the color of the hard tumor was greenish, which suggested the tumor was chroloma. Histological findings showed the tumor was GS. The majority of reported cases of GS in acute myeloid leukemia were M2 FAB classification and have chromosome translocation. Our patient was M7 FAB classification, not have specific chromosome translocation. GS occurrence in AML: M7 patient was extremely rare. This is the first case report of AML: M7 with GS in the central nervous system.     

骨髓增殖性疾病患者并发血栓性疾病的分析

目的 回顾性分析骨髓增殖性疾病患者血栓性疾病发生的危险因素。方法 收集北京航天总医院和北京天坛医院2007年8月至2012年2月收治的107例骨髓增殖性疾病（包括原发性血小板增多症和真性红细胞增多症）患者的临床资料和实验室检查结果,其中并发血栓性疾病的患者65例。对其临床特点、实验室检查结果（包括病史、年龄、白细胞数、JAK2V617F基因突变及骨髓分析）进行回顾并利用多元Logistic回归分析进行统计分析。结果 107例患者中男性64例,女性43例,年龄28岁至84岁。同时并发血栓性疾病的患者65例,其中缺血性卒中34例。65例血栓性疾病的患者中存在高白细胞（白细胞大于11.0×109／L）的41例（占63.1%）、JAK2V617F阳性39例（占60.0%）。两项比率均较非血栓组同类患者比率升高。血栓性疾病患者中60岁以上的老年人比例占72.3%,高于非血栓性疾病组,差异有显著性（χ2=0.014,P =0.009）。多因素Logistic回归分析显示存在高白细胞［比值比（odds ratio,OR）3.393,P＜0.05］、JAK2V617F基因阳性（OR 3.104,P＜0.05）及年龄大于60岁（OR 2.523,P＜0.05）是导致血栓发生的危险因素。结论 本研究显示骨髓增殖性疾病患者出现高白细胞血症、JAK2V617F基因阳性和（或）年龄大于60岁,可能是发生血栓性疾病的独立危险因素,尤其以发生缺血性卒中多见。     

Dendritic cells derived from patients with multiple sclerosis show high CD1a and low CD86 expression.

Dendritic cells (DC) are important antigen presenting cells (APC) and play a major role in initiating and orchestrating immune responses by priming T cells. Little is known about involvement of DC in multiple sclerosis (MS), where auto-aggressive T cells against myelin autoantigens are considered to contribute to inflammation and demyelination in the central nervous system. In this study, we compared phenotype and cytokine secretion of DC from patients with MS, other neurological diseases (OND) and healthy subjects. DC were generated from blood adherent mononuclear cells (MNC) by culture for 7 days with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). The yield and morphology of DC were similar in MS patients and controls. In both, the DC phenotype was that of immature myeloid lineage, comprising CD1a+ and CD11c+. The proportion of CD1a+ DC, being important for presentation of lipid antigens to T cells, was higher in MS patients compared to controls. The proportion of CD86+ DC, a co-stimulatory molecule that is assumed to promote Th2 differentiation, was low in MS. Low proportions of CD86+ DC were only observed in untreated MS patients but not in patients treated with IFN-beta. Production of IL-10 and IL-12 p40 by DC did not differ in MS patients and controls. These findings indicate that alterations of functionally important surface molecules on DC are associated with MS.     

In vitro differentiation of lineage‐negative bone marrow cells into microglia‐like cells

Microglia are believed to be the only resident immune cells in the CNS, originating from hematopoietic‐derived myeloid cells and invading the CNS during development. However, the detailed mechanisms of differentiation and transformation of microglial cells are not fully understood. Here, we demonstrate that murine microglial cells show two morphological forms in vitro, namely, small round cells expressing CD11b, Iba1, triggering receptor expressing on myeloid cells‐2 (TREM2), and weakly expressing major histocompatibility complex class II and large flat cells expressing only CD11b and Iba1. Moreover, lineage‐negative bone marrow (LN) cells cultured with primary mixed glial culture cells could differentiate into only the small round microglia‐like cells, despite the absence of CCR2 and Gr‐1 expression. Addition of macrophage colony stimulating factor (M‐CSF) to LN cell culture allowed the proliferation and expression of TREM2 in LN cells, and the addition of neutralizing anti‐M‐CSF antibodies suppressed the proliferation of LN cells despite the expression of TREM2. When LN cells were cultured with M‐CSF, the number of small round cells in the culture was considerably low, indicating that the small round morphology of the immature cells is not maintained in the presence of only M‐CSF. On the other hand, when LN cells were grown in the presence of astrocytes, the small round cells were maintained at a concentration of approximately 30% of the total population. Therefore, cell–cell contact with glial cells, especially astrocytes, may be necessary to maintain the small round shape of the immature cells expressing TREM2.     

Isolated meningeal chloroma (granulocytic sarcoma) in a child with acute lymphoblastic leukemia mimicking a falx meningioma

BACKGROUND: Isolated chloromas (granulocytic sarcomas) are rare tumors. Chloromas are masses composed of immature granulocytic cells. Granulocytic sarcoma occurs primarily in patients with acute myelogenous leukemia, but can also arise in patients with other myeloproliferative disorders, though rarely in patients with acute lymphoblastic leukemia (ALL). When dural-based, granulocytic sarcoma may be indistinguishable from meningioma radiologically. CASE HISTORY: We now describe one patient affected by ALL with isolated granulocytic sarcoma mimicking meningioma as initial CNS relapses. A 12-year-old girl who had been diagnosed with ALL and undergone chemotherapy presented with generalized tonic-clonic seizure while in complete remission. Computed tomographic scan and magnetic resonance imaging showed a small mass mimicking a meningioma at the anterior falx. The patient was developed speech disturbance 6 days later. Follow-up magnetic resonance imaging demonstrated a rapidly growing mass with intralesional hemorrhage. Bone marrow biopsy and cerebrospinal fluid study were negative for leukemia. The patient underwent open surgery. The pathological diagnosis was acute lymphoblastic leukemia. CONCLUSIONS: These unusual clinical manifestations and radiological findings in acute lymphoblastic leukemia should be regarded as a recurrence of leukemia. Early detection and antileukemic treatment of granulocytic sarcoma are necessary and important for a favorable prognosis.     

Combination treatment of Glatiramer Acetate and Minocycline affects phenotype expression of blood monocyte-derived dendritic cells in Multiple Sclerosis patients

The effects of Glatiramer Acetate (GA) in combination with Minocycline (MIN), a second-generation tetracycline, have been investigated on the course of EAE in mice, resulting in a significant reduction in disease severity and burden with attenuation of the inflammation, axonal loss and demyelination. Here we investigate the effects of combination therapy with GA and MIN on the induction, maturation and phenotyping of blood monocyte-derived dendritic cells (DCs) in Multiple Sclerosis (MS) patients. Hence the expressions of HLA-DR, CD11c, CD83 and CD1a were studied by flow cytometric analysis on immature (iDCs) and mature DCs (mDCs) from untreated and GA treated MS patients. Thirteen relapsing-remitting MS patients and 13 healthy controls (HCs) were included in the study. Ten of the MS patient group were re-tested after a 2 month period of GA treatment. The marker expressions on DC from untreated MS and HCs were studied in vitro in the absence or presence of GA and GA+MIN; and on DCs from GA treated MS patients without and with the in vitro addition of MIN. We found that in vitro GA alone or in combination with MIN downregulated DCs antigen presentation capability (HLA-DR), whereas the combination treatment only affected also myeloid DCs activation (CD83) in both MS and HCs. Prolonged GA treatment (in vivo for 2 months) affected antigen presentation capability by DCs, whereas when treated in vitro with MIN these cells also tended to reduce activation marker expression and myeloid phenotype acquisition (CD11c). The present data demonstrate possible combination effects of GA and MIN on peripheral blood monocyte-derived DCs in MS patients.     

Central nervous system granulocytic sarcoma after bone marrow transplant: case report

Granulocytic sarcoma is a solid tumor, composed by granulocytic precursor cells at various levels of differentiation, located at an extra-medullary site. It is associated with acute myeloid leukemia, and its presence reveals a bad prognostic factor. The treatment usually consists of radiotherapy and chemotherapy. A case of an intracranial granulocytic sarcoma occurring six months after a bone marrow transplant in a patient with acute myeloid leukemia is reported. The patient presented with headache and left hemiplegia caused by a large fronto-parietal lesion with significant mass effect. After a complete surgical resection there was a full recovery of the deficit. The patient completed radiotherapy and chemotherapy with no evidence of disease after three months of follow-up. Surgery is indicated in the presence of progressive neurological deficit. Surgical decompression may provide rapid improvement and therefore, affect quality of survival.     

Cerebrospinal fluid cytology in granulocytic sarcoma with meningeal extension but without bone marrow involvement

Granulocytic sarcoma (GS) is a localized tumour of immature granulocytes that is usually associated with myelogenous leukaemia. We report an unusual case of mastoid GS with meningeal extension but no bone marrow involvement on presentation. Histological examination of the surgical specimen and the characteristic cerebrospinal fluid (CSF) cytology showing cytoplasmic granulations and Auer bodies led to the diagnosis of GS. Positive cytochemical staining of the immature CSF cells for naphtol-ASD chloroacetate esterase and myeloperoxidase confirmed their myeloid origin. Immunophenotyping did not reveal common acute lymphoblastic leukaemia antigen, cytokeratin, T or B-cell antigens. The patient underwent surgical resection of the localized tumour, followed by radiation therapy, intrathecal and systemic chemotherapy, as if he had acute myelogenous leukaemia (AML). He did not develop AML in the 21 months after the tumour resection. This case emphasizes the value of CSF cytological examination of tumour cells and the use of an immumocytochemical marker for differentiating GS from malignant lymphoma.     

CD83-positive dendritic cells are present in occasional perivascular cuffs in multiple sclerosis lesions

Multiple sclerosis (MS) has a wide spectrum of clinical courses, characterized by multifocal central nervous system (CNS) damage, postulated to be mediated by CNS antigen-specific T cells. Dendritic cells (DC), the most potent antigen-presenting cell, play a pivotal role in the decision between T-cell activation or anergy. Monoclonal antibodies to CD1a (immature DC) and CD83 (mature DC) were used to screen lesions with evidence of recent demyelinating activity and chronic plaque and normal appearing white matter (NAWM) tissue sections from 12 MS cases by immunocytochemistry. No CD1a-positive cells were detected in the MS or control CNS tissue blocks investigated. CD83-positive cells were not detected in tissues from any of the control cases or in the majority of perivascular cuffs in the MS tissue sections. However; in eight of the MS tissue blocks with evidence of recent demyelination, and in one block each from chronic plaque and NAWM, small numbers of distinct CD83-positive cells were present within occasional perivascular cuffs. In one area only of MS NAWM were CD83-positive cells detected in the tissue parenchyma, in an area of intense immunological activity. DC in MS tissue may originate in the peripheral circulation as monocytes or immature DC and migrate to areas of plaque in response to signals received from CNS-produced chemokines.     

T cell lymphoblastic lymphoma/leukemia within an adrenocorticotropic hormone and thyroid stimulating hormone positive pituitary adenoma: A cytohistological correlation emphasizing importance of intra‐operative squash smear

We present a rare case of primary pituitary T cell lymphoma/leukemia (T‐LBL) in association with adrenocorticotropic hormone (ACTH) and thyroid stimulating hormone (TSH) expressing pituitary adenoma in a 55‐year‐old woman highlighting the importance of intra‐operative squash smears examination. The patient presented with complaints of headache, diminution of vision and recent onset altered sensorium. MRI revealed a mass lesion in the sellar‐suprasellar region with non‐visualization of pituitary gland separately, extending to involve adjacent structures diagnosed as invasive pituitary macroadenoma. Intra‐operative tissue was sent for squash smear examination. The cytology showed a tumor comprising of sheets of immature lymphoid cells intermixed with clusters of pituitary acinar cells with many mitoses and tingible body macrophages. A diagnosis of presence of immature lymphoid cells within the pituitary was offered and differentials of infiltration by lymphoma cells from systemic disease versus primary central nervous lymphoma‐like lymphoma arising in the pituitary adenoma were considered. Later paraffin section examination and immunohistochemistry corroborated with the squash findings and a final diagnosis of primary pituitary T cell lymphoma/leukemia in association with ACTH and TSH expressing pituitary adenoma was made. To date, only six cases of primary pituitary T cell lymphomas, including three T‐LBL cases, have been reported. This is the seventh case and first one additionally describing cytohistological correlation and importance of intra‐operative cytology.     

Multiple intracranial de-novo chloromas presenting with Garcin's syndrome

Intracranial occurrence of a chloroma (myeloid sarcoma, MS) in the absence of a preceding hematological malignancy is unusual. We report the case of a 20-year-old man who presented with Garcin's syndrome of short duration. MRI revealed multiple extra-axial contrast enhancing lesions: two mirror lesions on the skull base, and one in the right parietal convexity. The parietal lesion was excised and histologically and immunohistochemically proved to be a differentiated variant of MS. Peripheral blood smear and bone marrow biopsy ruled out an underlying leukemia or myeloproliferative disorder. With a diagnosis of intracranial de-novo MS, he was referred for chemotherapy and radiation therapy. 15 months later, his clinical status remained the same while his imaging showed marginal decrease in size of the lesions. A repeat bone marrow biopsy remained normal. This is a first-of-its- kind report of multiple intracranial lesions of a de-novo MS presenting as Garcin's syndrome. Radiological differentials, immunohistochemical variants and management options related to MS are discussed in the light of the reported case.     

Low back pain and lumbar radiculopathy as harbingers of acute myeloid leukemia recurrence in a patient with myeloid sarcoma

Myeloid sarcoma (MS) is an extra-osseous, solid collection of myeloblasts. It is associated with myeloid leukemias, and rarely affects the spine. The most common clinical presentation of MS in spine patients is some form of pain related to compression of neural elements. Given that MS is rare, and its imaging characteristics are similar to other more common diagnoses, it is frequently missed on initial presentation. We present a 28-year-old female, in her fifth year of remission from AML, with low back pain and right lumbar radiculopathy. Initially, the leading diagnosis was schwannoma in preference to neurofibroma; however, intra-operative pathology and subsequent bone marrow biopsy revealed the tumor to be MS. This report highlights the difficulties of diagnosis of MS in patients in remission from acute myeloid leukemia. Thus, in patients with a history of leukemia, MS should be considered in the differential diagnosis of any epidural or nerve root tumor. Timely diagnosis and treatment are key to optimal outcomes.     

Monocyte-derived dendritic cells in multiple sclerosis: the effect of bacterial infection

We investigated whether monocyte-derived dendritic cells (MDDCs) generated in vitro from bacteria-infected MS patients modified autoreactive T cells activation patterns. T cell clones (TCCs) stimulated with MDDCs from infected MS patients responded with maximal proliferation, inducing IL-12, IL-17 and IFN-gamma secretion, at concentrations significantly lower than after incubation with MDDCs isolated from uninfected individuals and bacterial meningitis (BM) patients. Moreover, infected MDDCs promoted TCCs survival, and secreted more IL-12, IL-18, and IL-23. Finally, MDDCs from infected MS subjects showed higher expression of myeloid differentiation factor 88 (MyD88), as well as of HLA-DR, CD1a, CD80, CD86, CD273, CD40, CD83 and CCR7 when compared to MDDCs from uninfected MS individuals, and BM patients. Thus, activation of the innate immune system by microbial products in MS patients affects the generation MDDCs and their ability to modify autoreactive T cell activation patterns, which may be linked to MS relapse induction during bacterial infections.