Primary intracranial granulocytic sarcoma: A case report and review of literature

Abstract

Granulocytic sarcoma (GS) is a rare extramedullary proliferation of myeloblasts or immature myeloid cells leading to the disruption of normal architecture of tissue in which it is found. It may precede, be concomitant with or appear after diagnosis of acute/chronic leukemia, in acute or relapse setting. Herein, we report a case of 12-year-old male who presented with left-sided hemiparesis. Neuroimaging revealed a space occupying lesion in basal ganglia and thalamus. Stereotactic biopsy with immunohistochemistry (IHC) studies was suggestive of lymphoid malignancy versus GS. However, immunophenotyping (IPT) done on cerebrospinal fluid leukemic blasts was positive for GS. The patient initially received therapeutic cranial radiotherapy with biweekly triple intrathecal chemotherapy followed systemic high-dose cytarabine chemotherapy. Since bone marrow examination failed to reveal any evidence of hematologic malignancy, a diagnosis of aleukemic, primary, or isolated GS of brain was made. Our case emphasizes the importance of early suspicion, diagnostic dilemma associated with GS, the role of histopathology, IHC, and IPT in diagnosis, and various treatment modalities of aleukemic intracranial GS.

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169© 2017 Journal of Dr. NTR University of Health Sciences | Published by Wolters Kluwer - Medknow
Address for correspondence:
Dr. Asha S. Anand, Department of Medical and Paediatric
Oncology, The Gujarat Cancer and Research Institute
(M. P. Shah Cancer Institute), New Civil Hospital
Campus, Asarwa, Ahmedabad - 380 016, Gujarat, India.
E-mail: ashaanand1757@yahoo.com
Primary intracranial granulocytic sarcoma: A case
report and review of literature
Dhruv Pankaj Mehta, Priti Trivedi1, Asha S. Anand, Sonia Parikh, Pushpak Chirmade
Departments of Medical and Paediatric Oncology and 1Pathology, The Gujarat Cancer and Research Institute,
Ahmedabad, Gujarat, India
ABSTRACT
Granulocytic sarcoma (GS) is a rare extramedullary proliferation of myeloblasts or immature myeloid cells leading to the disruption
of normal architecture of tissue in which it is found. It may precede, be concomitant with or appear after diagnosis of acute/chronic
leukemia, in acute or relapse setting. Herein, were port a case of  12‑year‑old male who presented with left‑sided hemiparesis.
Neuroimaging revealed a space occupying lesion in basal ganglia and thalamus. Stereotactic biopsy with immunohistochemistry (IHC)
studieswassuggestiveof lymphoidmalignancyversusGS.However,immunophenotyping(IPT)doneoncerebrospinaluidleukemic
blasts was positive for GS. The patient initially received therapeutic cranial radiotherapy with biweekly triple intrathecal chemotherapy
followedsystemichigh‑dosecytarabinechemotherapy.Sincebonemarrowexaminationfailedtorevealanyevidenceof hematologic
malignancy, adiagnosis of aleukemic,primar y,or isolatedGS of brain wasmade. Ourcase emphasizesthe importance of early
suspicion, diagnostic dilemma associated with GS, the role of histopathology, IHC, and IPT in diagnosis, and various treatment
modalities of aleukemic intracranial GS.
Key words: Brain, chloroma, extramedullary tumor, immunohistochemistry, leukemia, myeloid sarcoma
Case Report
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How to cite this article: Mehta DP, Trivedi P, Anand AS, Parikh S,
Chirmade P. Primary intracranial granulocytic sarcoma: A case report
and review of literature. J NTR Univ Health Sci 2017;6:169-73.
INTRODUCTION
Granulocytic sarcoma (GS) is a rare but well‑known
extramedullary manifestation of acute/chronic
leukemia or myelodysplastic syndrome (MDS), with
estimated incidence of 0.7 in 1 million children
and 2 in 1 million adults,[1] can occur at any age
and can involve any organ throughout the body,
such as soft tissues, skin, bones, lymph nodes,
gastrointestinal and genitourinary tracts, heart, orbit,
head and neck region, mediastinum and sanctuary
sites, testis, and central nervous system (CNS).[2]
It was first described by Burns in 1811, named
chloroma by King in 1853 due to its green color
caused by myeloperoxidase (MPO) and renamed GS
by Rappaport in 1966 as approximately 25%–30%
of tumors were not green.[3,4] GS is reported in
2.5%–9.1% of patients with acute myeloid
leukemia (AML), 3.9% of patients with chronic
myelogenous leukemia (CML), and 4.2% of patients
at onset of blast crisis in CML.[3,5] CNS involvement
by GS is present in only 0.4% of patients with AML,
while aleukemic involvement of brain parenchyma
is rarer, mentioned only in case reports/series.[6]
Here, we present a case of isolated GS of basal
ganglia‑thalamus, treated initially with DeAngelis
protocol for primary CNS lymphoma on the basis of
histopathology and immunohistochemistry (IHC) and
then shifted on radiotherapy (RT) and AML systemic
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Mehta, et al.: Aleukemic intracranial granulocytic sarcoma
170 Journal of Dr. NTR University of Health Sciences | Volume 6 | Issue 3 | July-September 2017
chemotherapy after final immunophenotypic (IPT)
diagnosis from cerebrospinal fluid (CSF) leukemic
blasts, of myeloid sarcoma. We highlight
the diagnostic and therapeutic challenges faced
by pathologists and medical oncologists in the
management of this rare condition.
CASE REPORT
A 12‑year‑old male with no previous comorbidities
presented with complaints of deviation of
angle of mouth to the right side and weakness
of the left half of the body for 2 days. He had
no complaints of headache, seizures, vomiting,
blurring of vision, syncopal episodes, or bleeding
from any site of the body. He was first evaluated
by a local physician who did magnetic resonance
imaging (MRI) of brain [Figure 1a]. MRI showed
65 mm × 43 mm × 49 mm heterogeneously
hyperintense lesion with heterogeneous enhancement
involving right thalamo‑internal capsular region,
right cerebral peduncle, right side of midbrain,
and pons invading adjacent hypothalamus with
midline shift of 6 mm to the left side. The lesion
was hypointense on T1w and hyperintense on T2w
MRI. A radiological diagnosis of glioma was made.
He was referred to neurosurgical department of our
institute by a local physician who first evaluated
him for further management of primary brain tumor.
He was treated with decompressive medications and
dexamethasone for 15 days (but no response). The
neurosurgeon did stereotactic biopsy of the lesion
which revealed normal brain tissue with perivascular
collection of small‑ to medium‑sized round cells along
with abundant eosinophils [Figure 2a‑c]. Possible
morphological diagnosis of histiocytosis or lymphoid
malignancy was made. The patient was referred to our
department for further management. On examination,
he was oriented to time, place, and person. His vitals
were within normal range. No lymph nodes were
palpable. On neurological examination, pupils were
equally reacting to light. Fundus examination was
normal with no evidence of papilledema. He had
left‑sided supranuclear facial palsy with power of
3/5 in muscles of the left half of body. Babinski’s
sign was present on the left side. There was no neck
stiffness or nystagmus. The sensory examination
was normal. There was no evidence of spinal
tenderness or cord compression. Rest of the systemic
examination was normal. The complete blood
count (CBC) revealed the following: hemoglobin
of 12.5 g/dl, total leukocyte counts of 13,200/mm3,
and platelet counts of 36,700/mm3. There were no
evidence of blasts on peripheral smear (P/S). Rest
of serum biochemistries, including liver and renal
function tests, were within normal range. IHC from
biopsy sample was positive for vimentin, leukocyte
common antigen, cluster of differentiation (CD43),
CD117, S‑100 and negative for CD3, CD1a, CD20,
and CD79a with possible diagnosis of GS versus
lymphoid malignancy [Figure 3]. MPO was not
done due to nonavailability of the stain at the
time. Bone marrow aspiration and trephine biopsy
revealed normocellular marrow with no evidence of
any malignancy. CSF for routine, microscopy, and
cytology was performed as part of workup. CSF was
Figure 1: (a) Pretreatment magnetic resonance imaging showed
65 mm × 43 mm × 49 mm heterogeneously hyperintense lesion
with heterogeneous enhancement involving right thalamo-internal
capsular region, right cerebral peduncle, right side of midbrain, and
pons invading adjacent hypothalamus with midline shift of 6 mm to
the left side. (b) Postwhole brain radiotherapy and triple intrathecal,
magnetic resonance imaging show signicant regression in size of
the lesion
b
a
Figure 2: Granulocytic sarcoma of brain: (a) brain tissue shows
monotonous round cell inltration (H and E, ×4). (b and c) Large
monotonous cells showing eosinophilic cytoplasm with irregular
hyperchromatic nucleus with scattered eosinophils (H and E, ×40).
(d) Cerebrospinal uid cytology shows malignant cells
d
c
b
a
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Mehta, et al.: Aleukemic intracranial granulocytic sarcoma
171Journal of Dr. NTR University of Health Sciences | Volume 6 | Issue 3 | July-September 2017
clear and colorless with glucose concentration of
64.42 mg/dl, protein content of 25 mg/dl, chloride
concentration of 122.1 mmol/L, and leukocyte count
of 40 cell/mm3. CSF cytology examination was
positive for malignant cells [Figure 2d]. As there
was diagnostic confusion on IHC, CSF was sent for
IPT for conrmation of diagnosis. However, in view
of deteriorating neurological status, a provisional
diagnosis of primary CNS lymphoma was made,
and DeAngelis protocol (high‑dose methotrexate
based) was initiated while waiting for CSF‑IPT
report. The patient was administered week 1
chemotherapy. CSF‑IPT was done with six color
ow cytometer (uorescence – activated cell sorting
Canto II) on 26% of blasts gated which was positive
for CD13, CD33, MPO, CD117, CD34, and human
leukocyte antigen ‑ antigen D related and negative
for CD3, CD5, CD7, CD2, CD4, CD8, CD1b, CD19,
CD10, CD20, and TdT. A nal diagnosis of aleukemic
GS was made. In view of patient’s increasing
left‑sided neurological deficits and new symptom
of headache with MRI suggestive of midline shift,
the patient was started on whole brain RT of 24 Gy
in 12 fractions with boost of 10 Gy in 5 fractions
to thalamus with biweekly triple intrathecal (IT)
chemotherapy (methotrexate 12 mg, cytarabine
30 mg, and prednisolone 10 mg). Triple IT was
continued till three CSF cytospin preparations were
negative for malignant cells. Follow‑up MRI showed
significant regression in size of lesion [Figure 1b].
He has now been planned for 3 cycles of high‑dose
cytarabine (HiDAC) (2 g/m2 3 h infusion, 12 hourly
for 6 days). He has successfully completed 2 cycles
with complete recovery of neurological functions.
Serial CBC and P/S still do not show evidence of
leukemia as of today.
DISCUSSION
GS has been classied into four groups depending on
the clinical situation as (1) primary GS in 0.6% of
cases, (2) GS during active phase of AML, (3) GS
as isolated recurrence of AML (new isolated focus
of GS that occurs during bone marrow remission and
not followed by medullary relapse in <30 days), and
(4) GS with concurrent bone marrow relapse with GS
developing after allogeneic hematopoietic stem cell
transplantation (HSCT) in 0.2%–1.3% of patients.[1]
Certain sites such as CNS and reproductive organs are
commonly involved by GS during relapse due to their
being sanctuary sites for leukemic cells, which survive
treatment with chemoradiotherapy due to inherent
barriers.[7,8] The pathogenesis of intracranial GS
involves inltration of leukemic cells into supercial
arachnoid veins with local proliferation leading
to the formation of solid mass. This expanding
leukemic mass infiltrates the underlying brain
parenchyma through pial‑glial membrane or through
Virchow–Robin space leading to interference with
local perfusion.[4]
The common sites of intracranial GS in decreasing
order of frequency are temporal lobe, frontal
lobe, cerebellum, parietal lobe, occipital lobe,
cerebellopontine angle cistern, corpus callosum,
basal ganglia, and subdural space.[6] Our patient
had GS involving thalamo‑internal capsular region
invading adjacent structures such as cerebral
peduncle, midbrain, pons, and hypothalamus.
Radiologically intracranial GS is mostly extra‑axial
masses and is typically isodense to hyperdense on
computed tomography, hypointense or isointense
on T1w MRI, and heterogeneously isointense
to hyperintense on T2w MRI,[1] as was in our
case. GS is subclassified depending on degree
of maturation into three variants: (1) blastic
Figure 3: Immunohistochemistry: (a) CD43 positive (×10),
(b) CD79a negative (×10), (c) c-kit positive (×40), and (d) leukocyte
common antigen positive (×10)
d
c
b
a
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Mehta, et al.: Aleukemic intracranial granulocytic sarcoma
172 Journal of Dr. NTR University of Health Sciences | Volume 6 | Issue 3 | July-September 2017
with predominance of myeloblasts, (2) immature
with mix of myeloblasts and promyelocytes, and
(3) differentiated with promyelocytes, mature
granulocytes, and abundant eosinophils.[8] GS is
commonly misdiagnosed typically as non‑Hodgkin
lymphoma (NHL) in approximately 46% of
patients.[7] Other differentials include other forms of
NHL, Ewing’s sarcoma, undifferentiated carcinoma
or melanoma, extramedullary hematopoiesis,
malignant histiocytosis, and malignant mastocytosis
with atypical mast cells. The denitive diagnosis of
GS is usually based on IHC and/or IPT. The markers
expressed in decreasing order of frequency are: CD
68/KP‑1, MPO, CD43, lysozyme, CD117, CD45,
CD99, CD68/PG‑M1, CD34, TdT, CD56, CD61,
CD30, glycophorin, CD4, CD79a, CD20, CD3, and
CD10. CD13, CD33, CD117, and MPO are most
common markers in ow cytometric analysis of GS
with myeloid differentiation and CD14, CD163, and
CD11c in GS with monoblastic differentiation.[8]
In our case, IPT on CSF was sent for diagnostic
conrmation as IHC was inconclusive.
The recent guidelines from Bakst et al. recommend
the use of AML‑like induction therapy for isolated
GS, followed by consolidation with RT. RT is
considered in patients of isolated GS, poor response
to chemotherapy, recurrence after HSCT, and for
rapid symptom relief of vital structure compression
(as was in our case). RT dose of 24 Gy in
12 fractions is usually recommended,[7] but a higher
RT dose is needed when tumor is large (more than
6 cm or 30 cm2),[2] as was in our case. Since our
patient had positive CSF cytospin preparation, we
administered him with triple IT chemotherapy. The
proof that GS is extremely radiosensitive tumor
was provided by repeat MRI post‑RT which showed
marked reduction in the size of lesion with symptom
relief. However, RT alone may prolong failure‑free
survival but not overall survival (OS) in patients of
isolated GS. It has been established that OS is longer
in patients who are given AML‑based induction
regimens.[8] We preferred to give HiDAC to our
patient post‑RT to avoid radiation recall associated
with anthracyclines and to achieve higher therapeutic
concentrations in brain tissue and perivascular
space. Isolated GS may be associated with superior
event‑free survival and OS as compared to AML
when patients are treated with AML‑based regimens;
however, median survival is <24 months.[9] It has been
reported that 87% of patients who were diagnosed
as aleukemic GS but did not receive chemotherapy
developed acute leukemia at mean of 10.5 months
after diagnosis of GS. However, 25% of patients
who did receive chemotherapy did not develop
leukemia during follow‑up period of 3.5–16 years
after diagnosis of GS.[6] Patients of GS accompanying
AML have better outcomes than GS with CML
or MDS.[8] Allo‑HSCT can be potentially efficient
treatment modality in patients of isolated GS with
5‑year OS, leukemia‑free survival, and nonrelapse
mortality rate of 48%, 36%, and 17%, respectively.[9]
Hence, allo‑HSCT should be considered as rst‑line
therapy even in patients of isolated GS who achieve
complete remission following AML type therapy.
CONCLUSION
Isolated primary intracranial GS is extremely
rare, but relevant clinical information, including
symptomatology, past or present history of any
hematologic malignancy, proper neuroimaging,
prompt pathological evaluation with use of IHC and
IPT (from CSF when feasible) studies, and early start
of systemic AML‑like chemotherapy with cranial RT
and HSCT, would promise a longer survival to these
patients who are mostly young. Our case emphasizes
the importance of the above and also highlights the
diagnostic dilemmas associated with GS. Furthermore,
continuous monitoring of such patients is needed for
early detection of systemic leukemia.
Financial support and sponsorship
Nil.
Conicts of interest
There are no conicts of interest.
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