2. Dipti’s Page 2 of 16
13.1. Acute Lymphoblastic Leukemia (ALL).
1) Definition: It is malignant neoplasm of haemopoietic stem cell characterized by
clonal proliferation of immature white blood cells.
2) Incidence:
25% of childhood cancers.
75% of all leukemias.
3) Etiology: Unknown.
I. Genetic factors:
II. Immunological factors: Wiskott Aldrich syndrome.
III. Environmental factors:
a) Ionizing radiation.
b) Drugs.
c) Viral infection: E.B. Virus.
IV. Advanced maternal age.
4) Classification:
I. FAB (French American British) Classification:
Three subtypes: According to lymphoblast cells of bone marrow L1, L2, L3.
II. Immunological classification:
a) ꞵ cell precursor
i. Stem cell.
ii. Precursor ꞵcell Ig negative.
iii. Precursor ꞵcell Ig Positive
b) T cell precursor
i. Stem cell.
ii. Early T cell.
iii. Intermediate T cell.
iv. Late T cell.
5) Clinical features:
1. Early features: Anorexia, fatigue, irritability, intermittent low-grade fever,
History of preceding URI 1to2 months back.
2. Late features:
a) Marrow failure: features:
i. Anemia: Manifesting as pallor, fatigue, irritability.
ii. Neutropenia: Fever, infections.
iii. Thrombocytopenia: Petechiae, purpura, Bleeding.
b) Features of organ infiltration by leukemic cells:
i. Pain in bones and joints.
ii. Hepatosplenomegaly.
iii. Generalized lymphadenopathy.
iv. Testicular swelling
3. CNS Manifestations:
a) Symptoms of raised intracranial pressure like headache,
vomiting.
3. Dipti’s Page 3 of 16
b) Neck stiffness.
c) Cranial nerve palsies.
d) Papilledema.
4. Another site infiltration (Less common):
Kidney, skin, eye, lung, heart, GIT, ovaries.
6) Diagnosis:
1. Clinical features:
a) Anemia.
b) Hepatosplenomegaly.
c) Generalized lymphadenopathy.
d) Bleeding diathesis.
2. Laboratory Diagnosis:
a) Hemogram (CBC).
b) HB decrease.
c) Leukocytosis or leukopenia.
d) Thrombocytopenia.
3. Peripheral blood smear (PBS)
a) Atypical lymphocytes.
b) Immature WBC.
4. Bone marrow examination:
>25% blast cells are diagnostic
5. X-Ray chest mediastinal mass.
6. CSF Examination:
a) Cells are increased.
b) Single blast in CSF is diagnostic CNS involvement.
7. Blood uric acid.
8. Sr. electrolytes.
9. Sr. phosphate levels.
7) Prognostic features:
1. Age: Bad prognosis if age is bellow 1year or above 10years.
2. Initial leukocyte count (Single most important factor. Count more than
50,000 has bad prognosis)
3. Speed of response to treatment: Slower response caries bad prognosis.
4. Chromosome number: Patients having chromosomes more than 48 have
good prognosis while less than 48 having bad prognosis.
5. Specific chromosome abnormalities: Like t 9:22, 4:11 have higher risk of
relapse.
6. Mediastinal mass: Bad prognosis.
7. CNS involvement: CNS involvement at the time of presentation carries bad
prognosis.
8) Differential Diagnosis:
1. AML:
• It has all the features of ALL.
4. Dipti’s Page 4 of 16
• Infiltration in gingiva more common.
• Subcutaneous nodes: Blueberry muffins.
• Discrete masses chloroma.
• Features of DIC highly suggestive of AML.
2. Infectious mononucleosis.
3. Acute infectious lymphocytosis.
4. Aplastic anemia.
5. ITP.
6. Pertussis.
7. Juvenile rheumatoid arthritis.
8. Myelofibrosis.
9) Treatment:
a) Specific chemotherapy.
b) Supportive therapy.
c) Monitoring of patient during therapy.
d) Bone marrow transplantation.
e) Observation and treatments of late effects.
1. Specific Chemotherapy: Four components.
A. Remission induction (4to6 weeks)
a) Prednisolone: 40mg/m2
/(max. 60mg) orally for 1to28days.
b) Vincristine: 1.4mg.m/I.V. max 2mg/weekly.
c) L Asparaginase: 10,000 units/m/Biweekly I.M.
In standard risk ALL above three drugs are given. In severe cases
following drugs are to be added.
d) Daunorubicin: 30mg/m2
/I.V. Day 8, 15, 29.
Bone marrow examination is repeated at the end of induction to see
the remission.
Complete remission is defined as:
a. Blast cells in Bone marrow should be 5%.
b. Neutrophil and platelet count should be normal in PBS.
B. CNS Prophylaxis:
a) Intrathecal medicines are given:
i. Methotrexate:
o <1 year = 10mg once a week during.
o 2 to 8yrs = 12.5mg induction then every.
o >8yrs = 15mg 2months for 2years.
ii. Hydrocortisone:
o <1 year = 10mg once a week during.
o 2 to 8yrs = 12.5mg induction then every.
o >8yrs = 16mg.
iii. Cytosine Arabinoside:
o <1 year = 20mg.
o 2 to 8yrs = 25mg.
5. Dipti’s Page 5 of 16
o >8yrs = 30mg.
b) Cranial Irradiation:
Total dose: ≤ 200cGy daily for 9days.
Age: above 2.5yrs.
C. Consolidation (Intensification phase) – Given shortly after induction
phase. Given in poor risk patients:
a) Cyclophosphamide: 50mg/m2
/I.V. Day 1to15.
b) Vincristine: 1.4 mg/m2
/I.V. Day 1to15.
c) Cytosine Arabinoside: 70mg/m2
/SC/ (2hourly 6doses) Day 1to3.
d) 6 M.P. (Mercaptopurine): 5mg/m2
/orally day 1to7, 15to21.
D. Maintenance phase: (Six cycles are given)
a) Prednisolone: 40mg/m/orally, Days 1to7.
b) Vincristine: 1.4mg/m2
/I.V., Day 1.
c) Daunorubicin: 30mg/m2
/I.V. Day 1.
d) L. Asparaginase: 6,000mg/m2
/orally/ daily for three weeks to
1month.
e) S Mercaptopurine: 5mg/m2
/orally once a week for three weeks
to 1 month.
Begin on day 15, 4 cycles.
f) Methotrexate: 15mg/m/orally once a week for three weeks stop
for 1week begin on day 15,4 cycles.
2. Supportive therapy:
A. Treatment of infection: Broad spectrum antibiotics
B. Prophylactic cotrimoxazole for Pneumocystis carinii infection
C. Fluid and electrolyte balance. Potassium fluid.
D. Blood component therapy
• Packed cells for anemia.
• Platelet transfusion for thrombocytopenia.
E. Treatment bleeding tendencies by platelet transfusion.
F. Nutritional support
G. Allopurinol for hyperuricemia.
H. Psychosocial support.
3. Monitoring of patient during therapy:
A. Monitor WBC count during the chemotherapy.
B. Keep absolute neutrophil count above 1000/mm3
.
C. Monitor clinical signs of relapse.
4. Bone marrow transplantation:
Indicated in relapse cases.
5. Observation and treatment of late effects
A. Second malignancies.
B. Gonadal toxicity.
C. Cardiac toxicity – Anthracycline induced.
D. Endocrinal:
6. Dipti’s Page 6 of 16
o Obesity.
o Precautious puberty.
o Growth failure.
o Osteoporosis.
o Thyroid dysfunction
E. Neuropsychiatric complications.
13.2. Hodgkin’s Disease.
1) Definition: It is malignancy of lymphoid tissue arising from activated B or T
lymphocytes.
2) Etiopathogenesis:
• Hodgkin’s disease arises in lymphoid tissue.
• Initially it spreads to adjacent lymph nodes.
• Hematogenous spreads involves liver, spleen, bone marrow and brain.
• It causes immunosuppression.
• Reed Sternberg cell is considered hallmark of Hodgkin’s disease.
• Age:
a) Childhood from <14 years.
b) Young from 15to34 yrs.
c) Older adult from 55to74 yrs.
• Sex: Male predominate in childhood form.
• More commonly develops in person having immunodeficiency.
• Genetic predisposition may be the cause.
• There can be role Epstein – Barr virus.
3) Histological subtypes: Four types.
1. Lymphocyte predominance.
2. Nodular sclerosing.
3. Mixed cellularity.
4. Lymphocyte depletion.
4) Clinical features:
1. HD is characterized by: Progressive painless enlargement of lymph
nodes.
a) 80% children present with cervical lymphadenopathy.
b) 20% have mediastinal disease.
2. Systemic symptoms:
• Unexplained fever.
• Night sweats.
• Weight loss >10% of body weight.
3. Rare features:
• Features of Airway obstruction.
• Pleural/epicardial effusion.
• Liver Dysfunction.
7. Dipti’s Page 7 of 16
• Features of bone marrow infiltration like anemia, neutropenia,
thrombocytopenia.
4. Evaluation and staging: Modified Ann Arbor staging.
Stage I:
• Single lymph node involvement.
OR
• Single extra lymphatic organ involvement.
Stage II:
• Two lymphoid region involvement on same side of diaphragm.
Or
• One lymph node involvement, One extranodal involvement on same side of diaphragm.
Stage III:
• Involvement of lymph node on both sides of diaphragm may accompanied by extra nodal
involvement like splenic enlargement.
Stage IV
• Disseminated involvement of extra lymphatic organ with or without lymph node disease.
A – No symptoms.
B – Fever, weight loss (>10%, Night sweats.
X – Bulky disease.
CS – Clinical stage.
PS – Pathological stage.
5) Diagnostic work up:
1. History.
2. Physical examination – any peripheral lymph node>1cm, does not
regress after 6 weeks should be biopsies.
3. Chest X-Ray/CT scan for mediastinal lymphadenopathy.
4. Complete blood count.
5. ESR.
6. Liver and kidney function test.
7. Adequate lymph node biopsy.
8. USG of thorax and abdomen.
9. Bone marrow biopsy.
10. Gallium scan.
6) Treatment:
A. Chemotherapy:
• 4to6 courses of ABVD: Adriamycin (Doxorubicin), Bleomycin,
Vinblastine, Dacarbazine.
8. Dipti’s Page 8 of 16
• COPP: Cyclophosphamide, Vincristine, Prednisolone, Procarbazine.
B. Low dose radiation:
Combined therapy: for stage II B, Stage III and IV.
1. Chemotherapy – Six courses of ABVD or COPP.
2. Full dose radiation for involved field.
13.3. Non – Hodgkin’s Lymphoma.
1) Definition: It is a malignant clonal proliferation of lymphocytes of T, B, in
terminate cell origin.
2) Classification: Three histological subtypes:
1. Small non cleared cell: Origin B – cells.
i. Burkitt’s.
ii. Non Burkitt’s
2. Lymphoblastic: Origin T – Cells.
3. Large cell lymphoma.
3) Clinical features:
1. Age: 5 – 15Yrs.
2. Sex: M:F = 3:1.
3. Predisposing factors:
a) Congenital or Acquired immunodeficiency.
b) Pesticide exposure.
c) EB virus infection – causes Burkitt’s lymphoma.
4. Clinical presentation: Typically present with extranodal diseases involving
mediastinum, abdomen, head neck region.
a) Mediastinum:
a. Large intestinal mediastinal mass may present as superior
vena cava syndrome – distended neck, veins, edema, face,
breathlessness, headache and alter mental status.
b. Can involve bone marrow meninges gonads.
c. Can cause pleural and epicardial effusion.
b) Abdomen:
a. Primary site is ileocecal region, appendix, colon,
retroperitoneal.
b. Present with abdominal pain, vomiting, abdominal
distension, palpable mass, intussusception, ascites,
obstructive jaundice, hepatosplenomegaly and spinal cord
compression.
c) Head & Neck: Can present as:
a. Cervical lymphadenopathy.
b. Parotid gland enlargement.
c. Jaw swelling.
d. Unilateral tonsillar hypertrophy.
e. Nasal obstruction.
9. Dipti’s Page 9 of 16
f. Cranial nerve palsies.
4) Staging:
• According to murphy’s classification – 4 stages.
• St Jude’s classification – 4 stages.
5) Staging: The stages are described by Roman numerals I through IV (1-4). Limited
stage (I or II) lymphomas that affect an organ outside the lymph system (an
extranodal organ) have an E added (for example, stage IIE).
a) Stage I: Either of the following means the disease is stage I:
• The lymphoma is in only 1 lymph node area or lymphoid organ such as the tonsils (I).
• The cancer is found only in 1 area of a single organ outside of the lymph system (IE).
b) Stage II: Either of the following means the disease is stage II:
• The lymphoma is in 2 or more groups of lymph nodes on the same side of (above or below)
the diaphragm (the thin band of muscle that separates the chest and abdomen). For
example, this might include nodes in the underarm and neck area (II) but not the
combination of underarm and groin nodes (III).
• The lymphoma is in a group of lymph node(s) and in one area of a nearby organ (IIE). It
may also affect other groups of lymph nodes on the same side of the diaphragm.
c) Stage III: Either of the following means the disease is stage III:
• The lymphoma is in lymph node areas on both sides of (above and below) the diaphragm.
• The lymphoma is in lymph nodes above the diaphragm, as well as in the spleen.
d) Stage IV
The lymphoma has spread widely into at least one organ outside the lymph system, such as the
bone marrow, liver, or lung2
.
6) Evaluation:
1. History and physical examination.
2. Complete blood count.
3. Biochemistry.
a. Kidney function test – BUN, Creatinine and uric acid.
b. LFT.
c. Sr. Electrolyte.
d. LDH.
4. Biopsy.
5. Bone marrow aspiration and Biopsy.
6. Chest X – Ray.
7. C.T. Scan.
8. USG/CT abdomen.
9. Gallium scan.
7) Treatment:
10. Dipti’s Page 10 of 16
1. Surgical excision of tumor.
2. Multiagent chemotherapy.
i. Six cycles of COMP (Cyclophosphamide, Vincristine, Methotrexate,
Prednisolone).
ii. Three cycles of COPA (Cyclophosphamide, Vincristine,
Prednisolone, Adriamycin)
3. T – Cells lymphoblastic type: Treat as acute lymphoblastic leukemia.
Difference between Hodgkin’s and Non-Hodgkin’s Lymphoma.
Hodgkin’s Non-Hodgkin’s Lymphoma
1. Clinical course Gradual progression Rapid progress
2. Histological subtypes Not very important Crucial
3. Bone marrow Biopsy. Required only for severe cases Essential for all cases.
4 Bone involvement Rare 5 to 15%
5. Liver involvement Rare. 40 to 60%
6. CNS Disease Rare 75%
7. Peak age 5 – 15 years. 10 14 years.
8. Treatment Chemotherapy + Radiation Chemotherapy is mainstay
9 Histological classification Ann Arbor classification Murphy’s classification
10. Clinical presentation Present as lymphadenopathy
Cervical Lymphadenopathy 80%
Mediastinal Lymphadenopathy 20%.
Typically present as extranodal
diseases involving:
1. Mediastinum 29% superior
vena cava syndrome.
2. Abdominal 35%.
3. Head & Neck 29%
11. Origin. Lymphoid tissue. Lymphocytes T or B origin.
13.4. Brain Tumors.
1) Introduction: Second most commen malignancy during childhood and adolescent.
They include (most commonly):
• Medulloblastoma.
• Juvenile pilocytic astrocytoma.
• Low grade Astrocytoma.
• Ependymoma.
• Cranial pharyngioma.
Majority do not extend locally and do not metastasize.
2) Etiology:
Not known
Possibilities are:
1. Familial.
2. Genetic association.
3. Occupational exposure.
4. Post-natal irradiation.
11. Dipti’s Page 11 of 16
5. Viruses.
Age distribution:
<1 year = Supratentorial.
Adolescent = Supratentorial.
1 to 10yrs = Infratentorial are more commen.
Clinically:
a) 55% tumors are in posterior fossa so cause:
i. Hydrocephalus.
ii. Cerebellar sign.
iii. Cranial nerve deficit.
iv. Long tract signs.
b) Increase ICP present as:
i. Morning headache.
ii. Vomiting.
iii. Visual disturbance.
iv. Behavior changes.
c) Supratentorial tumor: Present as Headache, Seizures, motor weakness,
sensory changes, speech disorder.
d) Optic pathway tumors: Present as:
i. Decreased visual acuity.
ii. Marcus Gunn pupil.
iii. Nystagmus.
iv. Visual field defects.
e) Suprasellar region tumors.
i. Diabetes insipidus.
ii. Hypothyroidism.
f) Diencephalic syndrome – Suprasellar and III ventricle tumors.
• Failure to thrive.
• Emaciation.
• Increase appetite.
• Euphoric state.
g) Pineal region tumors: Perinaud syndrome characterized by.
i. Paresis of upward Gaze.
ii. Pupillary dilatation, reaction to accommodation but not to light.
iii. Nystagmus.
iv. Eye lid retraction.
3) Management: General principle.
1. Ventricle peritoneal shunt to prevent the bad effects of hydrocephalus.
2. Modern neurosurgery.
3. Modern Brain radiotherapy.
4. Adjuvant by linear acceleration chemotherapy.
12. Dipti’s Page 12 of 16
13.5. Neuroblastoma.
1) Introduction:
• It is an embryonal cancer of peripheral sympathetic nervous system.
• It can go spontaneous regression and maturation.
• Age: 1 to 6 years, median age 2years.
2) Clinical features: Signs and symptoms depend:
i. Upon site of primary tumor.
ii. Site of metastasis.
Common site:
1. Abdominal mass
2. Thoracic mass
3. Pelvic mass
4. May be present as enlargement liver.
5. Features due to metastasis: Nonspecific features:
6. Rarely
7. Features of metabolic effect
8. Bone marrow disease as limping and pain.
3) Common sites:
a) Abdominal mass
1. Firm irregular mass.
2. Often crosses midline.
3. May causes hypertension.
4. Can compress spinal cord presenting as flaccid paralysis of legs,
bowel and bladder dysfunction.
b) Thoracic mass
1. Accidently found on chest radiograph.
2. Rarely can cause respiratory syndromes.
c) Pelvic mass is present as bowel and bladder dysfunction.
d) May be present as enlargement liver.
e) Features due to metastasis: Nonspecific features:
• Intermittent fever.
• Weight loss.
• Refusal to play.
• Generalized pain
f) Rarely rapid random eye movements due to acute cerebellar ataxia
Opsomyoclonus.
g) Features of metabolic effect due to high catecholamines like bouts of
sweating, pallor, diarrhea, hypertension.
h) Bone marrow disease as limping and pain
4) Diagnostic criteria:
1. Biopsy.
2. Urine catecholamine increase
13. Dipti’s Page 13 of 16
• Increase VHA.
• Increase VMA.
3. Bone marrow neuroblast.
4. CT, MRI, Mass calcification can be seen. Not seen in Wilms’s tumor.
5) Treatment: Three modalities.
1. Surgery.
2. Radiation.
3. Chemotherapy.
13.6. Wilms’s tumor (Nephroblastoma).
1) Introduction:
• It is mixed embryonal neoplasm of kidney.
• It is second most common abdominal tumor.
• Cause – Due to abnormalities in development of metanephric blastoma.
• Age 2 to 5 yrs.
2) Etiology:
Familial – Autosomal dominant.
Genetic – WT suppressor gene on chromosome 11p13 and 11p15.
It is associated with various abnormalities
3) Clinical presentation:
1. Detection of asymptomatic abdominal mass bulging in flanks.
2. Vague abdominal pain.
3. Hematuria hypertension may be present in >5% cases.
4. Nonspecific symptoms like fever, malaise, constipation, anorexia.
5. Physical examination: Smooth non tender firm metastasis mass in
abdomen.
6. Metastasis: Hematogenous to lung (85%) Liver (7%).
4) Differential Diagnosis:
Neuroblastoma.
Hydronephrosis.
Cystic kidney disease.
Lymphoma.
5) Laboratory investigations:
o CBC.
o Urine.
o USG.
o CT Scan.
o MRI.
o Biopsy.
6) Stages: Five stages.
14. Dipti’s Page 14 of 16
7) Stages: A staging system is a standard way for the cancer care team to sum up the
extent of the tumor. In the United States, the Children’s Oncology Group staging system is
used most often to describe the extent of spread of Wilms tumors. This system divides
Wilms tumors into 5 stages using Roman numerals I through V.
a) Stage I: The tumor is contained within one kidney and was removed completely
by surgery. The tissue layer surrounding the kidney (the renal capsule) was not broken
during surgery. The cancer had not grown into blood vessels in or next to the kidney. The
tumor was not biopsied before surgery to remove it.
b) Stage II: The tumor has grown beyond the kidney, either into nearby fatty tissue or into
blood vessels in or near the kidney, but it was removed completely by surgery without any
apparent cancer left behind. Nearby lymph nodes (bean-sized collections of immune cells)
do not contain cancer. The tumor was not biopsied before surgery.
c) Stage III: This stage refers to Wilms tumors that most likely have not have been removed
completely. The cancer remaining after surgery is limited to the abdomen (belly). One or
more of the following features may be present:
• The cancer has spread to lymph nodes in the abdomen or pelvis but not to more distant
lymph nodes, such as those inside the chest.
• The cancer has grown into nearby vital structures so the surgeon could not remove it
completely.
• Deposits of tumor (tumor implants) are found along the inner lining of the abdominal
space.
• Cancer cells are found at the edge of the sample removed by surgery, a sign that some of
the cancer still remains after surgery.
• Cancer cells “spilled” into the abdominal space before or during surgery.
• The tumor was removed in more than one piece – for example, the tumor was in the kidney
and in the nearby adrenal gland, which was removed separately.
• A biopsy of the tumor was done before it was removed with surgery.
d) Stage IV: The cancer has spread through the blood to organs away from the kidneys such
as the lungs, liver, brain, or bones, or to lymph nodes far away from the kidneys.
e) Stage V: Tumors are found in both kidneys at the time of diagnosis3
.
8) Management: Combination of:
1. Surgery: Surgical resection.
2. Radiotherapy – Lower dose (less used)
3. Chemotherapy.
a) Actinomycin D.
b) Vincristine.
c) Adrinomycin.
15. Dipti’s Page 15 of 16
13.7. Retinoblastoma.
1) Introduction:
It is malignant tumor of embryonic neural retina.
2) Etiology:
Genetic predisposition.
RBI gene is situated on chromosome 13 band 14.
3) Clinical features:
1. Age: Early childhood Before 4yrs. Median age 2yrs.
2. Commonly presenting features.
a) Leukocoria or cats eye reflux.
b) Squint.
3. Other rare features
a) Orbital inflammation.
b) Hyphemia.
c) Fixed pupil.
d) Heterochronic iridis.
e) Poor vision.
4) Diagnostic Evaluation:
1. Evaluation under anesthesia.
2. USG with color doppler.
3. CT/MRI.
4. Bone marrow exam.
5. Lumbar puncture.
6. Bone scan.
5) Stages: Four stages.
6) Stages: TNM : The TNM staging system is used to stage many solid tumor cancers
that form lumps. For retinoblastoma, the TNM system is mainly used in countries
where cases are often advanced and the cancer has spread outside the eye
(extraocular retinoblastoma). In North America, retinoblastoma is usually found
before it spreads outside the eye, so the TNM system isn’t used very often.
For staging retinoblastoma using the TNM system, there are 4 stages. Often the
stages 1 to 4 are written as the Roman numerals I, II, III and IV. Generally, the
higher the stage number, the more the cancer has spread.
a) Stage 1: The tumor is only in the eyeball.
b) Stage 2: The tumor has grown into the optic nerve or the tissues surrounding
the eye within the eye socket (orbit).
c) Stage 3: The cancer has grown outside the eye or to nearby lymph nodes.
d) Stage 4: The cancer has spread to other parts of the body (called distant
metastasis), such as the brain or the lungs. This is called metastatic
retinoblastoma4
.
7) Treatment:
1. Chemo-reduction with I.V. Chemotherapy.
2. Focal treatment with:
a) Transpupillary thermal therapy.
16. Dipti’s Page 16 of 16
b) Laser’s therapy.
c) Cryotherapy
3. Plaque Radiotherapy.
4. Cataract surgery for post radiotherapy cataract.
5. Enucleation when conservative therapy fails.
References:
1. Parthasarathy, K Nedunchalian, Gowri Shankar HC, Textbook of Balram chowdhary’s Pediatrics
Lecture notes, PEE PEE Publication, 2nd edition, Pg. no. 314 – 323.
2. https://www.cancer.org/cancer/non-hodgkin-lymphoma/detection-diagnosis-staging/staging.html
3. https://www.cancer.org/cancer/wilms-tumor/detection-diagnosis-staging/staging.html
4. https://www.cancer.ca/en/cancer-information/cancer-type/retinoblastoma/staging/?region=qc