Japanese Journal of Clinical Oncology

INTRODUCTION

Granulocytic sarcoma (GS), of which synonyms are chloroma, myeloblastoma and extramedullary leukemia, is a localized tumor composed of leukemic myeloblasts and myeloid precursors. GS is generally observed as a complication of acute myeloblastic leukemia (AML), myelodysplastic syndromes or myeloproliferative disorders (1-3). The incidence of GS was reported to be 3-5% in these hematological patients (4,5). GS involves almost all organs such as skin, lymph nodes, spine, orbit and bone (1). In the central nervous system (CNS), dissemination of leukemic cells into cerebrospinal fluid (CSF) (meningeal leukemia) sometimes occurs, but leukemic infiltration to brain parenchyma is rare (6,7).

Clinical situations of GS have been classified into four groups by Byrd et al., i.e. (1) primary GS, (2) GS at presentation of AML, (3) GS as isolated recurrence of AML (new isolated focus of GS that occurs during bone marrow remission and is not followed by medullary relapse in less than 30 days) and (4) GS with concurrent bone marrow relapse of AML (1). Among these, an isolated relapse of GS is uncommon during the course of AML and only a small number of cases, especially in the brain, have been reported to date (8). The prognosis of these patients seems to be very poor. We present here a rare case of an isolated recurrence of GS of the brain. The patient has been in complete remission for more than 21 months by intensive and combined treatment.

CASE REPORT

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Figure 1. CT and MRI of GS of the brain. (A) CT scan without enhancement: Irregular hyperdense tumor mass and the hypodense massive peritumoral white matter edema in the left temporal lobe. (B) The Gd-DTPA-enhanced T1-weighted MR image: dense, well defined homogeneous enhancement of GS. (C) Contrast-enhanced T1-weighted MR image after combined therapy: No residual tumor of GS.

A 38-year-old male was admitted to our hospital because of bleeding gums in April 1994. Peripheral blood examination showed hemoglobin 8.8 g/dl, platelets 13 × 10⁹/l and white blood cells (WBC) 64 × 10⁹/l with 82% myeloblasts. The bone marrow was markedly hypercellular with 49% myeloblasts, which were strongly positive for myeloperoxidase and chloroacetate esterase stainings. They did not contain typical Auer rods. Surface marker analysis of the bone marrow mononuclear cells revealed that they were positive for CD13 (65%), CD33 (81%) and HLA-DR (65%). Chromosomal analysis of the bone marrow cells showed 46, XY in all metaphases analyzed. He was diagnosed as having acute myeloblastic leukemia (AML) M2 in the French-American-British (FAB) classification. An induction therapy with enocitabine, daunorubicin, 6-mercaptopurine and prednisolone, according to the JALSG AML-87 protocol (9), was started and complete remission was achieved. Three courses of prophylactic intrathecal injection with 40 mg of cytarabine, 15 mg of methotrexate and 10 mg of prednisolone were performed at the end of each consolidation therapy. On lumbar punctures, cell counts were two, five and one per microliter of CSF, respectively. There was no unequivocal leukemic blast in the CSF. Eight courses of maintenance therapy were repeated up to December 1995 and he remained in complete remission.

In March 1996, he was readmitted to our hospital after a 1-week history of headache, vomiting and dysphasia. Computed tomography (CT) scans of the brain showed an irregular hyperdense tumor mass with hypodense peritumoral edema in the left temporal lobe and basal ganglia (Fig. 1). The hyperdense mass was homogeneously enhanced with iodinated contrast medium. Compression of the left lateral ventricle and shift of the cerebral midline structure by the progressive massive edema were also detected. Magnetic resonance (MR) images demonstrated the mass to be isointense with gray matter on T1-weighted sequences. There was uniform enhancement after intravenous administration of gadolinium-DTPA (Fig. 1). A T2-weighted MR image showed the peritumoral edema much better, and also the relatively hypointense central tumor mass. These CT and MR findings were compatible with those of GS, as reported previously (5,10-17). There was no evidence of leukemic relapse in the bone marrow and peripheral blood. An isolated recurrence of GS of the brain was suspected.

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Figure 2. Pathological findings of GS of the brain (A) Monotonous leukemic cells proliferating around the vessels and infiltrating diffusely into the brain parenchyma (hematoxylin and eosin, ×100) (B) Many of the leukemic cells with large nuclei, prominent nucleoli and scanty cytoplasm strongly stained with CAE (×400)

Consciousness disturbance of the patient progressed owing to the increased intracranial pressure. He then underwent an emergency left temporal tip lobectomy and partial tumor resection for internal decompression. Pathological examination revealed that the tumor was GS of the brain parenchyma (Fig. 2). Positive staining of the tumor cells for leukocyte common antigen (LCA) and chloroacetate esterase (CAE) confirmed their myeloid origin (Fig. 2) (18). The karyotype and immunophenotype of GS could not be determined. Subsequently, five courses of cytarabine (40 mg) and prednisolone (20 mg) were infused through an Ommaya reservoir set up in the left middle fossa at intervals of 4 days. MR images showed a minimal presence of hyperdense tumor lesion and peritumoral edema by intrathecal infusions. Whole brain irradiation (total dose 40 Gy) was also carried out. After these treatments, contrast-enhanced CT scans and MR images demonstrated no residual finding of the tumor in the brain (Fig. 1). Furthermore, the patient had no neurological deficit. Although there was no sign of relapse in the bone marrow, prophylactic systemic chemotherapy with cytarabine (600 mg ×2, days 1-5) and etoposide (ETP) (290 mg, days 1-5) was added. He was discharged in July 1996.

Five courses of the same systemic chemotherapy have been repeated every 3 months. He is free from symptoms and has remained in complete remission in both bone marrow and brain for more than 21 months.

DISCUSSION

GS as the first manifestation of relapse appears to be an uncommon event in AML. Byrd and Weiss (8) reviewed the 24 patients found in the literature since 1973 who presented with isolated recurrences of GS after prior AML. The presence of isolated GS recurrence generally heralds bone marrow relapse. The mean interval until bone marrow recurrence was 7 months (range, 1-19 months) in these patients. Their prognoses were very poor. Only three of 24 patients had GS of the brain (12-14). Furthermore, we found four additional patients with isolated GS of the brain (10,11,15,19). Clinical features of these patients are shown in Table 1. No preferential area in the brain could be demonstrated. A mean interval from initial diagnosis of AML to GS is 26 months. Except for those who refused treatment, all patients received intrathecal injection and/or operation in addition to irradiation. Systemic chemotherapy was applied in three patients during bone marrow remission (12,14). Unexpectedly, the prognosis of these patients was not so poor. Six patients were described as alive although the follow-up periods were variable. The present case received prophylactic systemic chemotherapy and achieved the longest disease-free survival among them. Therefore, isolated recurrences of GS of the brain could be improved by intensive and combined therapy if the bone marrow remains in complete remission. On the other hand, patients who did not receive systemic chemotherapy expired after bone marrow relapse (15), although it was sometimes possible to obtain a repeated bone marrow remission (13). The prognosis of patients with GS followed by bone marrow relapse is naturally poor (17). Judging from these findings, we propose that systemic chemotherapy should be started as soon as possible after completion of local therapy to the brain.

Table 1. Reported cases with isolated recurrence of granulocytic sarcoma (GS) of the brain

Age/gender	FAB	Site of GS	Diagnosis to GS (mo)	GS to BM relapse (mo)	GS to death (mo)	Local treatment	Systemic treatment	Reference
60/F	NM	Temporal (L)	4	NM (no relapse?)	2 dead	IT (MTX) refused	None	19
63/M	M1 or M2	Basal ganglia (R)	51	No relapse	>13 alive	RT (21 Gy) IT (Ara-C)	None	10
29/F	NM	CPA (L)	24	NM (no relapse?)	Alive	Craniotomy RT (24 Gy) IT (MTX)	NM	11
15/F	M4	Occipital (L)	18	6	>6 alive	Craniotomy RT (24 Gy) IT (Ara-C)	Maintenance therapy	12
34/M	M4	Occipital (L) temporal (R) cerebellum(L)	42	2	>13 alive	Craniotomy RT (30 Gy)	High-dose Ara-C at relapse	13
7/M	NM	CPA (R)	22	No relapse	Alive	Craniotomy RT	Denver protocol BMT	14
69/M	NM	Temporal (R)	26	7	7 dead	Craniotomy RT (39 Gy) IT (MTX, Ara-C, PSL)	None	15
40/M	M2	Temporal (L)	24	No relapse	21	Craniotomy RT (40 Gy) IT (Ara-C, PSL)	Ara-C ETP	Present case

Abbreviations: BM, bone marrow; NM, not mentioned; L, left; R, right; CPA, cerebellopontine angle; RT, radiation therapy; IT, intrathecal injection; BMT, bone marrow transplantation.

The pathophysiological mechanism for CNS leukemia was demonstrated by Price and Johnson (7) using 126 autopsy cases of childhood acute lymphoblastic leukemia (ALL). Leukemic cells do not directly penetrate capillaries of brain parenchyma. They originate in the walls of superficial arachnoid veins and extend into the CSF, resulting in meningeal leukemia. Then, the expanding leukemic masses infiltrate through pia-glial membrane into brain parenchyma and eventually constitute an intracerebral tumor. Disturbance of brain parenchyma also results from interference with local perfusion due to constriction of blood vessels by perivascular arachnoid leukemia. Leukemic infiltration in the perivascular region shown in Fig. 2 is compatible with this theory. Therefore, CNS leukemia is considered primarily as an arachnoid disease.

It is suggested that CNS leukemia arising after cessation of chemotherapy is the result of inadequacy of intrathecal and systemic chemotherapy or drug resistance (6). The present case received three courses of prophylactic intrathecal injections although no unequivocal leukemic cells were found in the CSF at diagnosis. The number of leukemic cells in the CNS at presentation must be small even if they exist, but they could not be eradicated by intrathecal injections. For prevention of a relapse in the brain parenchyma, high-dose cytarabine (HDAC) also seems to be effective therapy for CNS leukemia (6). One of the advantages of HDAC over the intrathecal route is the achievement of therapeutic concentrations in the brain tissues and in deep perivascular spaces (20). Therefore, we suggest that HDAC should be included in consolidation therapy combined with intrathecal injection.