Introduction

Acute lymphoblastic leukemia (ALL) is a malignant transformation and

proliferation of lymphoid progenitor cells in the bone marrow, blood and
extramedullary sites. The signs and symptoms includes fever, weight loss, night
sweats, easy bleeding or bruising, fatigue, dyspnea and infection.
Lymphadenopathy, splenomegaly or hepatomegaly occurs in 20% of patients.
Central nervous system symptoms such as cranial nerve deficits or meningismus
also appears in 5% to 8% of patient.1 Incidence of ALL is one in 100.000 in
adults.2 However, in childhood it represents 34 per 1 milion persons.3 The
incidence’s peak occurs on childhood and a second peak occurring around the age
of 50. Increasing age portends a worsening prognosis. The patients over the age of
60 have a poor outcomes with only 10% to 15% long term survival.1
Neuromuscular complication are common in patients with cancer. They
can be a direct effect of the primary malignancy, infiltration, compression by
leukemic masses, a paraneoplastic effect, or a treatment complication. Malignant
neoplasms may infiltrate or compress nerve roots, plexi, and peripheral nerves,
causing various sensory and motor symptoms. Peripheral neuropathies arise from
disorders associated specifically outside the central nervous system (CNS) and
within the peripheral nervous system. Symptoms of peripheral neuropathy include
numbness, tingling, paresthesia (pins and needles sensations), sensitivity to touch,
or muscle weakness. In patients with extreme symptoms, they may present with
burning pain, muscle wasting, paralysis, or organ dysfunction. The fate of patients
with leukemia has greatly improved in the past decades. Survival has been
increased and the once stereotypic pattern of Cerebrospinal fluid (CSF) infiltration
and diffuse infiltration of nerves and muscles has entirely changed.4,5
Peripheral nervous structures as cranial nerves, nerve roots, plexus and
peripheral nerves can be affected in different types of leukemia, by different
mechanisms and at different time points. Treatment side effects become more
apparent, as the number of long term survivors increases. In some cases also
isolated relapses of leukemia in the nervous system occurs and effects of stem cell
transplantation on the nervous system became apparent.

1
 The purpose of this case report is to present a case of Acute
Lymphoblastic Leukemia with paraparese inferior LMN Type in 9 years old boy
focusing on pathogenesis.

2
Case Report

CM, 9 years old boy, was referred from Soewandi Hospital to hematology
oncology outpatient clinic Dr. Soetomo Hospital with the chief complaint fever
since 1 month, no cough, no colds, no seizures. There was no history of
tuberculosis contact in the family or patient environment. Patients also
complained of both legs were painful since 3 months ago and followed by
weakness in both legs. In March 2018 patients started limping, weakness,
especially on the left leg, no history of trauma or falls. Patients complain of
stomach ache and nausea with no vomiting, no diarrhea and normal defecation.
Abdomen also felt increasingly enlarged. Currently the patient can not stand and
the muscles on both legs look atrophy. Patients have received analgetic and
antipiretic treatment to reduce pain, but complaints still persist. Other complaints
that accompany in this patient were nausea, decreased appetite, and weight loss
since last 3 months. On June 13, 2018, the patient felt his stomach getting sick and
his body was getting weaker and the patient went to the emergency unit of DR
Soetomo Hospital
He was born delivered spontaneously at term, by healthy mother. His birth
weight was 3300 gram. He was breastfeed until 12 months old. His immunization
was up to dated. The growth and development was normal. He could stand when
he was 10 months old and able to walk by his self when he was 13 months old.
Physical examination showed an alert boy with body weight 21 kg and
body height 132 cm (Figure 1). Ideal body weight of this patient is 28 kg, so we
assessed nutritional status of the patient was moderate malnutrition (75 % of Ideal
Body Weight). The blood pressure was 100/70 mmHg, the pulse rate was 102
times per minute, the respiratory rate was 24 times per minute and the body
temperature was 36.8oC. He looked weak and pale. There was no jaundice, no
cyanotic, no dyspnea observed. There was lymph node enlargement on the right
and left neck with diameter 1 cm and no pain was complaint. The chest was
symmetric, and no retraction was observed. The heart sounds no murmur, no
gallop and lungs were normal. The abdomen was not distended and the bowel
sounds were normal. There was enlargement of the liver and spleen. The liver size
was 5 x 6 x 6 cm with sharp edges and spleen was Scuffner 2 Hacket 2.The

3
extremities were warm, dry, pale, and no edema observed. There were muscle
atrophy on both legs, weakness on the inferior extremity and flaccid. Muscle
strength on the right hand was 5/5/5/5, left hand 5/5/5/5, on the right leg was
3/3/3/3, and left leg was 3/3/3/3. The physiological reflexes with decreased in the
lower extrimities and normal in upper extrimities. There is no pathological
reflexes was found. Sensory examination within normal limit.

NAME : C
.

Figure 1. Growth chart (CDC, 2000) showed body weight 21 kg, body height 132 cm and
percentage of IBW 75%.

4
 Laboratory examinations revealed hemoglobin 10.0 g/dL, MCV 81.6 fL,
MCH 28.6 pg, MCHC 35.1 g/dL, hematocrit 28.6 %, leukocytes 38320/mm3,
leukocytes differential count eosinophil 0.1/basophil 6.4/neutrophil
8.1/lymphocyte 40.7/monocyte 44.7, thrombocyte 84000/ mm3, ALT 325 U/L,
AST196 U/L, BUN 7 mg/dL, creatinin 0.49 mg/dL, sodium 141 mmol/L,
potassium 4.3 mmol/L, calcium 8.7 mEq/L, and chloride 102 mmol/L, Albumin
3,69 g/dL, CRP 9,63 mg/L, PPT 9,5 seconds, APTT 33,8 seconds, IgM
Salmonella negative result. Peripheral blood smear revealed normochromic
microcytic anisopoikylocytosis anemia, leukocytosis with 41% monoblast,
thrombocytopenia. Bone marrow aspiration (BMA) was done and revealed
hypocellular, erythropoietic system activity is pressed, activity of the
granulopoietic system is pressed, no megacaryocytes present, and dominated by
mononucleus cells with a thin cytoplasm without a core 70-80%. The conclusion
of BMA was Acute Lymphoblastic Leukemia (ALL) L1.
On June 7, 2018, the patient was examined electromyography (EMG) on
both legs with the result of currently clinically neurophysiologically we get
demyelinating with axonal degeneration of motoric polyradiculoneuropathy.
Abdominal x-ray revealed liver and spleen enlargement (Figure 2).

Figure 2. . Abdominal X-Ray revealed liver and spleen enlargement

5
 Based on clinical manifestations, laboratory and radiology findings, he
was diagnosed as ALL L1 SR with paraparese inferior lower motor neuron
(LMN) type and moderate Malnutrition. The patient got chemotherapy, nutritional
therapy and palliative therapy and we gave chemotherapy using Acute
Lymphoblastic Leukemia Protocol (LLA) Indonesia 2013 Standard Risk.

6
DISCUSSION
A 9 years old boy suffered fever since 1 month ago, painful and weakness
in both legs since 3 months ago without history of trauma or falls. He also
complaint of stomach ache and abdominal enlarged, nausea, decreased appetite,
and weight loss since last 3 month. After physical examination and some
investigations, it is concluded that the patient is diagnosed acute lymphoblastic
leukemia (ALL) and paraparese LMN type.
The differential diagnosis in this case may be aplastic anemia which is
obtained from the patient's history of complaining weakness, the patient also
appears pale and from investigations showing anemia and thrombocytopenia.
However, there is no malignant cells on examination of bone marrow aspiration in
aplastic anemia so that this diagnosis can be excluded.
Another differential diagnosis in this case is Guillian-Barre syndrome
(GBS), which is an inflammation of acute demyelin polineuropathy that causes
nerve cell damage without a clear cause. However, on GBS there is ascending
weaknesses that are not found in this case and there is no malignant cells so this
diagnosis can be excluded.
Acute flaccid paralysis (AFP) is one of the differential diagnoses for this
case. However, in AFP, the development of paralysis is fast, 1-14 days since the
onset of early symptoms and weakness usually affects the leg muscles, thigh
muscles, arm muscles, shoulder muscles, back muscles. In this case the weakness
has occurred 3 months since the initial symptoms and only on the legs so that the
diagnosis of AFP can be excluded.
The weakness in this case is flaccid, muscle atrophy is present, and no
pathologic reflex is present so this patient is classified into lower motor neuron
(LMN) syndrome. The difference between upper motor neuron (UMN) and LMN
syndrome is presented in Table 1.

7
 Table 1. The difference between Upper Motor Neuron and Lower Motor Neuron
Syndrome

Leukemia is a heterogenous group of disorders, caused by neoplastic

transformation in blood cell precursors during their differentiation in bone
marrow. Acute lymphoblastic leukemia is the most prevalent leukemic cancer;
comprising 75% of all leukemia cases. It could be suspected through a wide range
of clinical and laboratory findings. Eventually it is diagnosed via complete cell
count and histopathology.7
Acute lymphoblastic leukemia (ALL) encompasses a group of lymphoid
neoplasms that morphologically and immunophenotypically resemble B-lineage
and T-lineage precursor cells. These neoplasms may present predominantly as a
leukemic process, with extensive involvement of the bone marrow and peripheral
blood or may be limited to tissue infiltration, with absent or only limited (less than
25%) bone marrow involvement.8
According to three retrospective case reviews of childhood leukemia (in
which 75% to 100% of the cases were acute lymphoblastic leukemia), common
presenting signs and symptoms in acute leukemia include fever (17% to 77%),
lethargy (12% to 39%), and bleeding (10% to 45%). Central nervous system
involvement is present in approximately 7% of children at diagnosis.9 While ALL

8
could present clinically with a wide range of symptoms, which the most frequent
is systemic symptoms such as fever, loss of appetite and pallor. Neurologic
symptoms such as nausea, headache and lethargy, facial nerve palsy, weight loss
and behavior change can be seen at the time of diagnosis. In this case, fever is felt
since 1 month ago, with nausea, loss of appetite, and weight loss since last 3
month. Patient also looked weak and pale, and also had moderate malnutrition
after assessment of nutritional status.
Bone pain is commonly one of the presenting features of acute leukemia
in childhood. Bone and joint pain have been reported to occur in 21–59% of
children with acute leukemia. Bone pain can occur in leukemia patients when
the bone marrow expands from the accumulation of abnormal white blood cells
and may manifest as a sharp pain or a dull pain, depending on the location.10 Bone
pain, particularly affecting the long bones, which caused by periosteum
involvement, is reported to be a dominant presenting symptom in 21 to 38 percent
of cases of acute leukemia in other studies as well.7 The symptoms of skeletal
involvement can involve bones, joints, and soft tissues. For example, bone pain,
limping, arthritis, osteomyelitis, transient synovitis, and fractures may all
present.10 This patient complaint of pain in both legs since 3 months ago and
followed by weakness in both legs. Patients begin to limp and feel the weakness,
especially on the left leg, without history of trauma or falls since March 2018. The
physical examination showed muscle atrophy on both legs and the weakness on
inferior extremity. Pain in both leg in this patient can be manifestated of bone pain
as a features of ALL.
Neuromuscular complication are common in patients with cancer. They
can be a direct effect of the primary malignancy, a paraneoplastic effect, or a
treatment complication. Various mechanisms of neoplastic nerve damage as
infiltration, compression by leukemic masses and hemorrhage into nerves and in
addition toxicity of drug treatment, and rarely autoimmune and paraneoplastic
cases.4,11
The mechanisms of nerve infiltration in neoplastic disease have been
elucidated in cancer, several types of lymphoma, neurolymphomatosis,
intravascular lymphoma and combinations thereof. Leukemic infiltration has been

9
described and also the term neuroleukemiosis has been introduced. Also muscles
can be diffusely infiltrated. Neuropathies are usually classified symmetric or
asymmetric types. Focal peripheral nerve lesions involve the nerve plexus and
individual nerves (mononeuropathies). Symmetric generalized neuropathies are
rarely caused by leukemic infiltration of peripheral nerves. Symmetric weakness
should rather rise the suspicion for myelopathy, polyradicular meningeal
involvement, or if occurring during treatment for chemotherapy induced
neuropathy. Rarely dysimmune neuropathies such as Guillain-Barré-Syndrome
(GBS) or Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) occur.
Their relation to leukemia is not well defined. However rarely symmetric
infiltration of nerves has been observed and their course can mimic GBS.
Conversely asymmetric multifocal or multiplex neuropathies are suggestive of
neoplastic nerve infiltration. Several reports have identified mono M4/5 leukemias
which seem to have a particular affinity to peripheral nerve infiltration. Several
nerve lesion due to leukemia have been described and this type of lesion has been
termed neuroleukemiosis. Diagnosis has been facilitated by imaging techniques as
MRI and ultrasound. Leukemic infiltration of peripheral nerves is a rare entity.
Slowly progressive, unremitting neuropathic symptoms of pain, numbness and
weakness might be the first presenting sign of leukemia, and should be considered
in the differential of unexplained neuropathy.4,12
Paraneoplastic neurologic syndromes (PNS) result from immune cross-
reactivity between tumor cells and components of the nervous system. In response
to a developing cancer, a patient produces tumor-directed antibodies known as
onconeural antibodies. Because of antigenic similarity, these onconeural
antibodies and associated onconeural antigen specific T lymphocytes
inadvertently attack components of the nervous system as well. In contrast to
paraneoplastic endocrine syndromes, PNS are detected before cancer is diagnosed
in 80% of cases. Depending on the affected nervous system compartment, PNS
symptoms may include cognitive and personality changes, ataxia, cranial nerve
deficits, weakness, or numbness. Paraneoplastic neurologic syndromes can affect
the central nervous system (eg, limbic encephalitis and paraneoplastic cerebellar
degeneration), the neuromuscular junction (eg, Lambert-Eaton myasthenia

10
 syndrome [LEMS] and myasthenia gravis), or the peripheral nervous system (eg,
autonomic neuropathy and subacute sensory neuropathy).13,14
A practical way to classify the paraneoplastic neuropathies is according to
the clinical features (Table 2). The neuronal cell body may be the primary target
of an immune attack induced by a tumor. The attack may selectively target a
specific type of neuron and cause pure motor, sensory, or autonomic
neuronopathies or damage more than one cell type. The latter setting is more
frequent in patients with small-cell lung carcinoma (SCLC) and Hu antibodies.
The most common combinations are sensory and autonomic neuronopathies,
whereas the combined damage of motor and sensory neurons is less frequent.13,15

Table 2. Paraneoplastic Neuropathies

Cited from Francesc G, Josep D. Paraneoplastic neuropathies. Curr Opin Neurol, 2013;26:489–95.

Onconeural antibodies are classified according to 3 main categories: (1)

those that are molecularly well characterized with a strong cancer association
(anti-amphiphysin, anti-CV2 [CRMP5], anti-Hu [ANNA-1], anti-Ma2,
antirecoverin, anti-Ri [ANNA-2], anti-Yo [PCA-1]); (2) those that are partially

11
characterized (ANNA-3, anti-mGluR1, anti-Tr, anti-Zic4, PCA-2); or (3) those
occurring in both cancer- and non–cancer-associated syndromes (anti-
acetylcholine receptor [AchR], anti–nicotinic AchR, anti-VGCC, anti-VGKC).
For many PNS, the precise mechanism of antineuronal antibodies remains
unclear. Evidence supports a putative role in PNS pathogenesis for antibodies
with extracellular targets (such as anti-AchR, anti-VGCC, anti-VGKC, anti-
mGluR1, and anti-NMDA). For instance, anti-AchR and antiVGCC antibodies
interfere with acetylcholine binding and postsynaptic signal transduction,
respectively, resulting in dysfunction of the neuromuscular junction. However, a
number of antineuronal antibodies are directed against intracellular antigens, in
which case in vivo antigen binding is unlikely to occur. In such cases, T-cell–
mediated cellular immunity may contribute to pathogenesis. In general, conditions
associated with unclear antineuronal antibody mechanisms respond less well to
therapy and have a worse prognosis than other PNS.
Chemotherapy-induced neuropathy is a common, dose-dependent adverse
effect of several antineoplastics. It can lead to detrimental dose reductions and
discontinuation of treatment, and severely affects the quality of life of cancer
survivors. Clinically, chemotherapy-induced peripheral neuropathy presents as
deficits in sensory, motor, and autonomic function which develop in a glove and
stocking distribution due to preferential effects on longer axons. The
pathophysiological processes are multi-factorial and involve oxidative stress,
apoptotic mechanisms, altered calcium homeostasis, axon degeneration and
membrane remodeling as well as immune processes and neuroinflammation.13,14
Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse effect
of many chemotherapeutic agents and a major cause of ongoing pain in cancer
survivors. There are six main substance groups that cause damage to peripheral
sensory and motor neurons, resulting in development of CIPN: the platinum-based
antineoplastics (particularly oxaliplatin and cisplatin), the vinca alkaloids
(particularly vincristine and vinblastine), the epothilones (ixabepilone), the
taxanes (paclitaxel, docetaxel), the proteasome inhibitors (bortezomid) and
immunomodulatory drugs (thalidomide). The high success rate of these drugs in
cancer treatment has led to a steady increase in the survival rates of patients.

12
Consequently, the number of cancer survivors suffering from neuropathic pain
conditions is rising as well. Overall, approximately 68% of patients receiving
chemotherapy develop CIPN within the first month of treatment, the development
of which is related to both single as well as cumulative drug doses. Although the
mechanisms of action and molecular target(s) of these chemotherapeutic agents
are diverse and include both DNA and microtubular targets to arrest cell division
and induce cell death, the pathobiology of chemotherapy-induced neuropathy,
irrespective of the causative agent, shares some important similarities. Notably,
CIPN is characterized by predominantly sensory axonal peripheral neuropathy
that typically develops in a “stocking and glove” type distribution, with longer
axons affected first. The histopathological changes associated with CIPN
commonly involve large myelinated fibers, although bortezomibinduced
neuropathy also involves small fibers. These changes to the morphological and
molecular physiology of peripheral nerves result in the development of sensory
and motoric symptoms such as hypersensitivity to mechanical stimuli or distal
weakness due to mechanisms which are not entirely understood.16,17
In the Acute Lymphoblastic Leukemia Protocol (LLA) Indonesia 2013
Standard Risk, vincristine is one of the drugs administered. Despite widespread
use of vincristine for the treatment of pediatric cancers including acute
lymphoblastic leukemia, sarcoma, medulloblastoma and neuroblastoma as well as
a range of tumors in adults, the epidemiology of vincristine-induced peripheral
neuropathy (VIPN) is relatively poorly defined. While the reported incidence rates
vary considerably—depending on the severity of symptoms, diagnostic criteria
and concomitantuse of other neurotoxic agents—most patients receiving
vincristine develop some degree of sensory peripheral neuropathy at a cumulative
dose of >4 mg/m2. Symptoms of neuropathy can be present soon after initiation of
vincristine therapy but usually develop within several weeks, and generally
worsen with increasing cumulative doses of the drug. In addition, genetic factors
can enhance the susceptibility to develop vincristine-induced neuropathy.An
increased severity of VIPN was also observed in older compared with younger
children, suggesting that age can be a risk factor for development of VIPN.
Vincristine-induced sensory neuropathy is characterized by numbness, tingling

13
and neuropathic pain. in the upper and lower extremities. In addition, patients
receiving vincristine experience loss of sensory discrimination, specifically an
inability to detect light touch, pinprick sensations or vibration, and an inability to
differentiate between ho tand cold temperatures. Vincristine-induced motor
neuropathy is characterized by weakness in the upper and lower extremities and
the development of wrist- or foot-drop due to impaired dorsiflexion that arises
from damage to peripheral nerves. This is accompanied by gait abnormalities,
cramps, and loss of or reduction in deep tendon reflexes which can be severe.
Typical symptoms of autonomic neuropathy are constipation, urinary retention,
and orthostatic hypotension. As would be expected, these symptoms can
significantly reduce the quality of life of these patients. The mechanisms
contributing to development of VIPN include disruption of calcium homeostasis,
activation of the immune system and subsequent neuroinflammation, membrane
remodeling of peripheral neurons and loss of large myelinated fibers (Figure
3).16,18
In this case, the paraparese is found before administration of
chemotherapy, so the polyneuropathy occurring in this case is not caused by
chemotherapy. Giving chemotherapy in this case aims to reduce cancer cells and
improve nerve function that may be caused by cancer cells. However, to ascertain
the cause of a definite weakness in this case further investigation is required.

14
 Figure 3. Mechanism Vincristine induced polyneuropathy
Cited from Krzysztof B. Chemotherapy-induced polyneuropathy. Part I. Pathophysiology.
Wspolczesna Onkol. 2012;16:72–8.

About 75% of children with acute leukemia had an enlarged liver or

spleen, and nearly 60% had lymphadenopathy.9 Patients with precursor T-cell
ALL/LBL often present with a mediastinal mass with or without associated
pleural effusions, which may lead to respiratory distress and other signs of
superior vena cava syndrome. Common extramedullary sites of involvement
include lymph nodes, liver, spleen, and meninges, whereas less commonly, ALL
may infiltrate orbital tissues, testes, tonsils, and adenoids. Rare patients presenting
with B-LBL may show skin lesions of lymphadenopathy in the head and neck
area or discrete bone lesions.8 In this case, the extramedullary involvement were
observed in the enlargement of liver and spleen and also the enlargement of
lymph node on the neck without pain.
Patients with leukemia present with decreased hemoglobin and elevated
WBC count in around 60–70% of cases. In addition, coexisting anemia along with
thrombocytopenia may be present. Moreover, peripheral blood smear examination

15
reveals around 40–95% blast cells in usually most of the ALL patients.
Microscopic evaluation of peripheral blood samples, along with bone marrow
aspiration examination is an usual procedure for the diagnosis of ALL.
Furthermore, as per WHO, presence of more than 20% blasts in bone marrow is
essential for the confirmation of ALL. Moreover, it is also necessary to recognize
blast subtype present in the blood samples for prognosis assessment and for
suitable treatment planning.19 The result of laboratory examination in this case
showed that the patient had anemia, leukocytosis, trombocytopenia, and elevated
of liver enzyme. The peripheral blood smear examination showed normochromic
microcytic anisopoikylocytosis anemia, leukocytosis with 41% monoblast.
Laboratory diagnosis of ALL in modern hematology practice relies on
blood and bone marrow morphology, immunophenotyping, cytogenetics and
molecular analysis. However, regardless of such advanced techniques microscopic
examination of blood slides still remains as a standard procedure for ALL
diagnosis. Hence, since a long time human visual analysis of stained peripheral
blood and bone marrow samples has been the most economical way for initial
screening of ALL patients across the globe. Successful identification and
subtyping of lymphoblast in stained peripheral blood and bone marrow samples is
essential for accurate diagnosis of ALL. Clinically, ALL is characterized by
excess lymphoblast in the peripheral blood or bone marrow samples than healthy
conditions. Essentially, for obtaining the blast count on the smear mature
lymphocytes are required to be distinguished from lymphoblast based on nucleus
and cytoplasm morphology of the cells. Moreover, leukemic blast cells are
immature lymphocytes having a completely different morphology with respect to
healthy mature lymphocytes and are the basis of such microscopic diagnosis.
Popular French American British (FAB) classification of ALL blasts is based on
morphology and cytochemical staining, and can be L1, L2 or L3 subtypes.
Whereas, according to WHO, ALL subtypes is based on whether the precursor
cell is a T or B lymphocyte (Table 3).19

16
Table 3. FAB type L-1 and L-2
Criteria Score
High nuclear : cytoplasmic ratio > 75% cells +
Low nuclear : cytoplasmic ratio > 25% cells -
Nucleous : 0-1 (small) > 75% cells +
Nucleoli : 1 or more (prominent) > 25% cells -
Irregular/nuclear membrane irregular > 25% cells -
Large cell > 50% cells (size = 2x normal lymphocyte -
Cited from Mohapatra, S. Hematological Image Analysis for Acute Lymphoblastic Leukemia
Detection and Classification. Department of Electrical Engineering National Institute of
Technology Rourkela. 2013.

It’s not included if : a. Intermediete criteria, b. Nuclear membrane regular

> 75% and, c. < 50% large cell, heterogene size give score + and –. From above
definition, if the total score was 0 to +2, so it includes L1, while score -1 to -2 is
L2. Based on the result of bone marrow aspiration, this patient was diagnosed
with ALL-L1.
ALL is the most common childhood malignancy, accounting for close to
25% of all cancers in children and 72% of all cases of pediatric leukemia. ALL
occurs at an annual rate of 3 to 4 cases per 100.000 children less than 15 years of
age. Approximately 3,000 children in the United States and 5,000 children in
Europe are diagnosed with ALL each year. A sharp peak in incidence is observed
among children aged 2 to 5 years. Males are affected more often than females
except in infants, the difference being greater among pubertal children. There is a
geographic variation in the frequency of ALL. The incidence is lowest in North
Africa and the Middle East, and highest in the industrialized Western countries,
suggesting that this may reflect more exposure to environmental leukemogens.
Numerous investigators have reported the occurrence of leukemic clusters in
different geographic areas, thus pointing towards infectious and/or environmental
causes of at least some cases of ALL. Several studies have suggested a link
between maternal reproductive history and the risk of ALL. Fetal loss is
associated with a higher risk for ALL in subsequent children. There is evidence
that increased in utero growth rates and Insulin Growth Factor (IGF) pathways
play a role in the development of ALL.20
Acute lymphoblastic leukemia is the most common cancer seen in
children. The causes of most cases of acute lymphocytic leukemia (ALL) are
remains largely unknown, but some cases can be linked to certain risk factors.21

17
Even though the exact genetic malfunctions in the hematopoietic stem cells that
result in malignant transformation are not exactly understood, several risk factors
for the development of acute leukemia have been identified. However, the
majority of patients with acute leukemia do not meet any of these conditions.
Some of those are exposure of ionizing radiation, exposure to benzene, parental
alcohol consumption, and genetic condition.22 However, the only environmental
factor that is universally accepted as being associated with ALL is exposure to X-
rays in utero. Children that are born with a high susceptibility to ALL, such as
children with Down syndrome, should be the first among those that should be
protected from exposure to environmental factors that potentially provoke ALL,
such as tobacco smoke, exposure to magnetic fields of extremely low frequency,
etc.15 The patient in this case was a 9 years boy. But the data about radiation
exposure, benzene, and genetic involvement are unknown.
Childhood ALL cases are divided into standard-, intermediate- and high-
risk group (Table 4). Factors most often included into risk stratification are: age at
diagnosis, initial WBC count, sex, race, the presence of extramedulary disease,
blast immunophenotype and cytogenetics, early response to induction therapy,
and minimal residual disease (MRD). Age at diagnosis and initial WBC count are
the two features universally accepted as prognostic factors. Children under 1 year
and greater than 10 years of age have a inferior prognosis compared with children
in the intermediate age group. Infants with ALL who are younger than 1 year at
diagnosis have the worst prognosis. There is a linear relation between initial WBC
count and outcome in children with ALL; those with WBC greater than
50.000/mm3 are recognized as having poorer prognosis. In most studies, girls
have better prognosis than boys. This is partly due to the risk of testicular relapse,
the higher incidence of T-immunophenotype and unfavourable DNA index in
boys, but other genetic and endocrine effects may be present. The effect of race on
prognosis has been controversial, but some recent studies still report that
American black children have slightly poorer outcomes when compared with
white children. Asian children with ALL fare slightly better than white children.
Although early pre-B-cell ALL has better prognosis and mature T-cell ALL has a
worse survival, immunophenotype is not an independent prognostic factor in the

18
analyses of current trials. Clinical features indicating the extent of extramedullary
disease, i.e. the degree of hepatosplenomegaly and lymphadenopathy, presence of
a mediastinal mass, and CNS disease at diagnosis, once emerged as useful
prognostic indicators, disappeared as the treatment improved. The rapidity of
response to initial therapy is one of the most important prognostic indicators.20

Table 4. Risk group classification according to CMCP-ALL200820

Risk group Criteria
Low All of the following:
Age ≥1 and < 10 years old
Initial WBC count < 50.000/mm3
Trisomies of 4, 10, 17 or ETV6/RUNX1 (+)
Standard As above, except lack of trisomies of 4, 10, 17 or ETV6/RUNX1 (+)
High Any of the following:
Age≥10 and < 15 years old
Initial WBC count > 50.000/mm3 and < 100.000/mm3
Initial CNS or testicular involvement
Precursor B cell ALL with poor prephase steroid response
E2A/PBX1 (+)
MLL rearrangement
MRD (+) at end of remission induction
T-cell ALL with good prephase steroid response
Very high Any of the following:
Age > 15 years old
Initial WBC count > 100.000/mm3
BCR/ABL1 (+) ALL
Infant ALL
Hypodiploidy with < 45 chromosomes
T-cell ALL with poor prephase steroid response
Complete remission not achieved after first remission induction
Cited from Roganovic, J. Acute Lymphoblastic Leukemia in Children. 2013. Available at
http://cdn.intechopen.com/pdfs/44135/InTech-Acute_lymphoblastic_leukemia_in_children.pdf.
Diakses pada 7 Juli 2018.

Early response to treatment may be measured by the clearance of

peripheral blasts after one week of prophase steroid, which may be utilized in risk
group assignment. Those with a good response to steroid, that is a peripheral blast
count < 1000/mm3 have better survival compared with those with a poor response
to steroid (a peripheral blast count > 1000/mm3). Minimal residual disease MRD
remains the most important prognostic factor in pediatric ALL. Current methods
of measuring MRD include polymerase chain reaction (PCR) for immunoglobulin
(Ig)/T-cell receptor (TCR) rearrangements, flow cytometry to detect aberrant
immunophenotypes, and PCR for recurrent genetic fusions such as realtime
quantitative (RQ)-PCR for BCR-ABL1. Both measurement of PCR for Ig/TCR

19
and flow cytometry have been accurate in determining post-treatment MRD, with
a cutoff level of >0.01% at end of induction according to flow cytometry based
MRD predicting patients with significantly lower EFS. Studies utilizing Ig/ TCR
PCR have also shown that MRD checked at both end of induction as well as end
of consolidation is able to determine patients with significant residual disease and,
hence, worse outcome.23
Based on the prognostic factors above, the patient of this case had criterias
of : age < 10 years old and the initial WBC count < 50.000/mm3. But we could
not determine the genetic feature of the patient. So he is likely to have low or
standard risk group.

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SUMMARY
A case report of 9 years old boy with acute lymphoblastic leukemia has
been reported. The patient came to hematology oncology outpatient clinic Dr.
Soetomo Hospital with chief complaint fever since 1 month. Patients also
complained of both legs were painful since 3 months ago and followed by
weakness in both legs. He also start to feel limping, weakness, especially on the
left leg without history of trauma or falls. He also feel pain on the stomach,
nausea, decreased appetite, and weight loss since last 3 months. Physical
examination showed that the patient had moderate malnutrition. Patient looked
weak and pale. There was no jaundice, cyanotic, or dypsnea observed. There was
lymph node enlargement on his neck, enlargement of liver and spleen, and muscle
atrophy on both legs with the weakness on the inferior extremity. We performed
investigations such as laboratory examination, peripheral blood smear, bone
marrow aspiration, and abdominal x-ray. Based on clinical manifestations,
laboratory and radiology findings, he was diagnosed as ALL L1 SR with
paraparese inferior LMN type and moderate malnutrition.
There are various mechanisms of ALL caused Polineuropathy such as
infiltration of cancer cells, compression by leukemic masses and hemorrhage into
nerves and in addition toxicity of drug treatment, and rarely autoimmune and
paraneoplastic cases. To determine the exact cause of a disease, a detailed history
from anamnesis, complete physical examination, and further examination are
required.

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