3PEDIA6 - Childhood Cancer UERM2015B

Melgar | Mendoza | Montenegro | Moshtaghi |

Pascual | Patricio |Santos, P. UERM 2015B Page 1 of 15

6.3 CHILDHOOD CANCER Dr. Castro February 27, 2014

Powerpoint

Recording

Nelsons Textbook of Pediatrics

Important/Emphasized points

Topics not discussed but were included in the chapters in Nelsons

2014 trans

Actually, cancer in children is really rare. Hematologic malignancies are more common in children. Leukemia and lymphoma are the most common malignancies in children.

WORLDWIDE INCIDENCE OF

CHILDHOOD CANCER

Figure 1. Here, we can see the incidence of childhood cancer in the

Philippines, it is around 11.5/100,000 population of children.

LEADING CAUSES OF

MORBIDITY AND MORTALITY 1. Communicable diseases

2. Cardiovascular diseases

3. Cancer

STATISTICAL DATA ON CANCER

AGE-SPECIFIC CANCER INCIDENCE RATE

Figure 2. Note bimodal peak in the age specific cancer incidence rate

During the first 4 years of life and during adolescence,

cancer in children differs very much from the adults:

o 1.) Type

Adults: Epithelial Cancer (Colon Cancer, Breast

Cancer, Cervical Cancer)

Children: Embryonal (Neuroblastoma, Primitive

Neuroectodermal)

o 2.) Age incidence

Adults: Increasing incidence with increasing age

Children: Bimodal distribution

INCIDENCE OF CHILDHOOD CANCER BY AGE

Figure 3. Again, note bimodal peak in the age-specific cancer

incidence rate

Note nadir during childhood and rise again during the early

adolescence because of the lymphomas and sarcomas

First year of life: Neuroblastoma, Wilms Tumor, Retinoblastoma

and the Primitive Neuroectodermal Tumor predominate

1-4 y/o: peak incidence; secondary to ALL

Adolescence: Osteosarcoma, Ewing Sarcoma, Soft tissue

Sarcoma or the Rhabdomyosarcoma, Hodgkin disease and the

germ cell tumors (testicular and ovarian cancer)

5-YEAR RELATIVE SURVIVAL RATE OF

ALL CANCERS IN CHILDREN

6.3 | Childhood Cancer

Candice de Belen. Nika Gil. Alexandra de Rossi.

Lucien Torres-Gomez. F-PJ. Clariz Pempengco. Piocholo Pascual. UERM 2015B Page 2 of 15

RELATIVE FREQUENCIES OF

CHILDHOOD CANCER

Figure 5. From Laudico, et. al in 1998

Leukemias are the most common (almost 50%), followed by

CNS tumors, retinoblastomas and lymphoma

Others consist of rhabdomyosarcoma, germ cell tumors and bone

tumors

HEMATOLOGIC MALIGNANCIES Leukemias

o Acute lymphoblastic leukemia: 77%

o Acute myeloblastic leukemia: 11%

o Chronic myelogenous leukemia: 2-3%

o Juvenille myelomonocytic leukemia: 1-2%;

childhood-adult CML

Lymphomas

o Hodgkins lymphoma

o Non hodgkins lymphoma

Figure 6. Cells that are involved in leukemogenesis

Any problem in the maturational process causes maturational

arrest, thereby resulting to acute myelogenous leukemia

Ex: arrests of the development lead to proliferation of blasts =

genesis of acute lymphoblastic leukemia

THE FOLLOWING WERE NOT DISCUSSED BUT WERE IN THE

2014A TRANS. ONCOGENESIS: GENES INVOLVED

So how does cancer develop? This is explained by oncogenesis. Among all of

us, there is a potential for the development cancer. Fortunately, our immune

system is competent to arrest the development of these oncogenic materials.

Proto-oncogenes: normal genes, which secrete proteins for the survival

of the cells; mutation = ONCOGENE

Oncogenes

Tumor suppressor genes p53 For immunocompetent individuals,

the tumor suppressor genes (specifically p53) is very strong. It prevents

the expression of the oncogene and therefore the development of cancer.

But in patients who would have problems with the suppressor genes, as

well as the proto-oncogenes, cancer expression may be expected.

.

Figure 7. Oncogene transformation

For example, this is a proto-oncogene which encodes for normal cellular

proteins involved in growth signaling pathways. They can be mutated

by chemicals, radiation or viruses and therefore, once mutated they

become an oncogene with a potential for cancerinogenesis.

Table 1. Some of the oncogene activators of pediatric tumors

ONCOGENE ACTIVATOR OF PEDIATRIC TUMORS

MECHANISM CHROM GENES PROTEIN

FUNCTION

TUMOR

Chromosomal

translocation

t(9;22) BCR-

ABL

Chimeric

tyrosine

kinase

CML, ALL

t(1;19) E2A-

PBX1

Chimeric

transcription

factor

Pre-B ALL

t(14;18) CMYC Transcription

factor

Burkitts

lymphoma

t(15;17) APL-

RAR

Chimeric

transcription

factor

APL

Gene

amplification

Amplicon NMYC Transcription

factor

Neuroblastoma

EGFR growth factor

kinase,

tyrosine

kinase

Glioblastoma

Point mutation 1p NRAS GTPase AML

10q RET Tyrosine

kinase

MEN2

BCR-ABL (Break Cluster Region-Abelson) gene is generated by the

translocation 9.22 is also called the Philadelphia chromosome

o Hallmark of CML

o In some ALL, the translocation 9:22 is also seen; generates the

BCR-ABL gene

Most commonly seen are BCR-ABL and the NMYC and APL-RAR

GUARDIAN OF THE GENOME

Figure 8. Mechanism by which genomic integrity is maintained despite

chromosomal aberrations




The p53 protein repairs the damage from chemical carcinogens, UV

radiation or anything

Can also cause cell cycle arrest to prevent multiplication of abnormal

cells and therefore maintain the integrity of the cell

In some patients, p53 may be destroyed by radiation, and viruses;

destruction may cause carcinogenesis.

WARNING SIGNS IN CHILDREN

Table 2. Acronym for general s/sx in children with CA- CHILDREN

C Continued, unexplained

weight loss

Usually unexplained weight loss of 10-

15% in the last 6 mos despite good

appetite

H Headaches with vomiting

in the morning

Suggestive of CNS tumors

I Increased swelling or

persistent pain in bones or

joints

Leukemias and bone tumors

L Lump or mass in

abdomen, neck or

elsewhere

Lymphadenopathies and abdominal

masses

D Development of a whitish

spot in the pupil of the eye

Retinoblastoma

R Recurrent fevers not

caused by infections

Increasing WBC count with

lymphocytic predominance

E Excessive bruising or

bleeding

Leukemias and other tumors

infiltrating the bone marrow

N Noticeable paleness or

prolonged tiredness

Anemia, thrombocytopenia and

leukopenia

MULTIDISCIPLINARY CARE

Figure 9. Multi disciplinary care of children with cancer

Treatment of chidren would entail chemotherapy primarily and then

surgical and radiotherapy plus molecular biology. Those on the outside

ring are more of supportive care. Includes: analgesia, use of cytokines,

transfusion, antibiotics, antiemetics and of course nutritional support

PRIMARY MODALITIES OF THERAPY

Figure 10. Also illustrating multi disciplinary care of children with cancer

COMMONLY USED ANTI-CANCER DRUGS

Figure 11. Some of the commonly used drugs with their mechanism

We will not really be dealing on the specific drugs and there are still a

lot being investigated in cooperative groups

THE LEUKEMIAS CLASSIFICATION

Incidence rates:

o Acute Lymphoblastic Leukemia: 77%

o Acute myelogenous Leukemia: 11%

o Chronic Myelogenous Leukemia: 2-3%

o Juvenile Myelomonocytic Leukemia: 1-2% Acute: characterized by conal expansion of immature hematopoietic

precursors

Chronic: characterized by clonal expansion of mature marrow elements

Congenital: diagnosed within the first 4 weeks of life

ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) Peak incidence at 2-3 years old

Boys > girls: 1.1:1 in ratio

Chromosomal abnormalities

o Down syndrome Trisomy 21 confers good prognosis

o Bloom syndrome

o Ataxia telangiectasia

o Fanconi anemia Identical twins: 70% risk for 2nd twin

SIGNS and SYMPTOMS

Feverbecause of neutropenia; there are not enough functional

neutrophils to conquer the infection

Bleedingbecause of thrombocytopenia

Bone painif the bone marrow is involved Particularly in the lower extremities

Less often joint pain

Reticulo-endothelial organ system manifestations:

Lymphadenopathy

Hepatomegaly

Splenomegaly General Systemic Effect

Anorexia, fatigue, malaise, and irritability often are present, as is an intermittent, low-grade fever.

Patients often have a history of an upper respiratory tract infection in the preceding 1-2 mo.

Less commonly, symptoms may be of several months duration, may be localized predominantly to the bones or

joints, and can include joint swelling. Bone pain is severe

and can wake the patient at night. As the disease progresses, signs and symptoms of bone

marrow failure become more obvious with the occurrence of

pallor, fatigue, exercise intolerance, bruising, or epistaxis, as

well as fever, which may be caused by infection or the

disease.




Organ infiltration can cause lymphadenopathy, hepatosplenomegaly, testicular enlargement, or central

nervous system (CNS) involvement (cranial neuropathies

headache, seizures). Respiratory distress may be due to

severe anemia or mediastinal node comparison of the

airways.

LABORATORY STUDIES

CBC1st laboratory test to be done, including platelet

count.There may be varying anemias, thrombocytopenias,

increase WBCs or very low WBCs, and lymphocytic

predominance. Peripheral Blood Smear may show presence of

blasts.

Bone Marrow Aspiration

May also show blasts if the CBC is abnormal/does not show

any conferring findings. ALL is diagnosed by a bone marrow evaluation that

demonstrates >25% of the bone marrow cells as a

homogeneous population of lymphoblasts. Staging of ALL is based partly on a cerebrospinal fluid (CSF)

examination. If lymphoblasts are found and the CSF

leukocyte count is elevated, overt CNS or meningeal

leukemia is present. This finding reflects a worse stage and

indicates the need for additional CNS and systemic

therapies.

Chest X-ray

Blood Chemistriesin preparation for chemotherapy

Lumbar Tapto monitor CNS involvement

CLASSIFICATION of ALL

Morphologic Classification: French American British

(FAB) Very common, you look at the morphology of blast cells

o L1: blasts with very scanty cytoplasm

o L2: moderate amount of cytoplasm and nucleoli resembling

the blasts of the myeloid series

o L3: Burkitt leukemia; cytoplasmic vacuolization

The most important distinguishing morphologic

feature is the French American British L3 subtype

which is evidence of mature B-cell leukemia. The L3

type also known as Burkitt leukemia is one one of the

most rapidly growing cancers in humans and requires

a different therapeutic approach.

Aside from looking at the cells under the microscope, you can

also type the cells present using flow

cytometry/immunophenotype so you have the T and the B cell

ALL.

WHO Classification: errors in the diagnosis are encountered

in the morphologic classification, so the WHO incorporated

chromosomal abnormalities, as well as immunotypic

abnormalities, in classifying leukemias, giving rise to:

B lymphoblastic leukemia/lymphoma

o Not Otherwise Specified (NOS)

o With recurrent genetic abnormalities

T lymphoblastic leukemia/lymphoma

RECURRENT GENETIC ABNORMALITIES

Used in determining the prognosis of leukemias

These are the genetic abnormalities found in children that cause

leukemias:

t(9;22) [Philadelphia chromosome: presence indicates a poor

prognosis] (q34;q11.2); BCR-ABL-1

t(v;11q23); MLL rearranged

t(12;21) (p13;q22) TEL-AML1 (better prognosis; most common

in ALL) (ETV6-RUNX1)

With Hyperdiploidy

With Hypodiploidy

t(5;14) (q31;q34) IL3-IGH

t(1;19) (q23;p13.3) TCF3-PBX1

PROGNOSTIC FACTORS IN CHILDHOOD ALL (Table 3)

Factor Favorable

Prognosis

Intermediate

Prognosis

Unfavorable

Prognosis

Age (years) 1-9 10

50 or DNA index

> 1.16

Trisomies 4, 10,

17 t(12;21)/ETV6-

CBFA2

Diploid

t(1;19)/TCF3-

PRX1

t(9;22)/BCL-ABL-1

t(4;11)

CNS status CNS1 CNS2

Traumatic

spinal tap

with blasts

CNS3

Minimal

Residual

Disease (end of

induction)




Consolidation For maximal cell kill

Delayed intensification

MaintenanceDone monthly for three years. After, the

abnormal cells are totally eradicated giving cure to the

leukemia.

CNS prophylaxis/chemotherapy This is direct

intrathecal chemotherapy. Do a lumbar tap and inject

the drugs. Supportive care Through blood transfusion and antibiotic

therapy.

Bone marrow transplant For patients who fail at the first chemo

remission, do another cycle but if it fails again, they are

candidates for BMT already.

COMMONLY USED DRUGS IN ALL

Vincristine

Prednisone

Doxorubicin

L-asparaginase

6-mercaptopurine

Methotrexate

ACUTE MYELOGENOUS LEUKEMIA May also present like ALL so we must differentiate the two.

Most common recurrent abnormality is the TEL-AML.

Pancytopenia WITH organomegaly: ALL

Pancytopenia WITHOUT organomegaly: most likely

AML

Age incidence is constant except for a peak in the neonatal

period and a slight increase during adolescence.

Secondary AML: MDS and use of alkylating agents

Treatment-related AML. These are the patients who have

received chemotherapy for another tumor, and then after 6-

10 years, will develop AML.

o Cyclophosphamide

o Ifosfamide

o Etoposide

AML FAB CLASSIFICATION

The most common classification of the subtypes of AML is the French American British (FAB) system. Although this system is

based on morphologic criteria alone, current practice also requires

the use of flow cytometry to identify cell surface antigens and use

of chromosomal and molecular genetic techniques for additional

diagnostic precision and also to aid the choice of therapy.

Table 5. FAB System

M0 Acute UNDIFFERENTIATED leukemia

M1 AML WITHOUT maturation

M2 AML WITH maturation

M3 Acute PROMYELOCYTIC leukemia (APL)can be cured

by Vitamin A (retinoic acid). This is usually seen in adolescent,

associated with increased bleeding tendencies. Other

classifications will require chemotherapy and bone marrow

transplantation.

M4 Acute MYELOMONOCYTIC leukemia

M5 Acute MONOCYTIC leukemic

present with very huge liver and spleen, and CNS infiltration

M6 Erythroleukemia

diGuglielmo syndrome or

leukemia of the red cell precursor

M7 Megakaryocytic leukemia

leukemia of the platelet precursor

The World Health Organization (WHO) has proposed a new

classification system that incorporates morphology, chromosome

abnormalities, and specific gene mutations. This system provides

significant biologic and prognostic information.

AML WHO CLASSIFICATION

AML with recurrent genetic abnormalities

AML with myelodysplasia-related changes

Therapy-related myeloid neoplasms

AML, NOS

Pure erythroid leukemia

Erythroleukemia, erythroid/ myeloid

Myeloid sarcoma

Myeloid proliferation related to DS

Blastiplasmacytoiddendritic cell neoplasm

CLINICAL MANIFESTATIONS

Marrow failure

Anemia, thrombocytopenia and neutropenia; with bleeding,

infection and pallor

Subcutaneous nodules ("blueberry muffin" lesions)

Gingival hyperplasia (M4, M5)

DIC (M3) especially indicative of acute promyelocytic

leukemia

Chloromas or granulocytic sarcoma (M2) t(8;12)

translocation The characteristic feature of AML is >30% of bone marrow cells

on BMA or biopsy constitute a fairly homogenous population of

blast cells, with features similar to those that characterize early

differentiation states of the myeloid-monocyte-megakaryocyte

series of blood cells.

The production of symptoms and signs of AML, as in ALL, is due to replacement of bone marrow by malignant cells and due to

secondary bone marrow failure. Patients with AML can present

with any or all of the findings associated with marrow failure in

ALL. In addition, patients with AML present with signs and symptoms

that are uncommon in ALL, including subcutaneous nodules or

blueberry muffin lesions (especially in infants), infiltration of

the gingiva (especially in M4 and M5 subtypes), signs and

laboratory findings of disseminated intravascular coagulation

(especially indicative of acute promyelocytic leukemia), and

discrete masses, known as chloromas or granulocytic sarcomas.

These masses can occur in the absence of apparent bone marrow

involvement and typically are associated with the M2 subcategory

of AML with a t(8;21) translocation. Chloromas also may be seen in the orbit and epidural space

TREATMENT

Chemotherapy

Matched-sibling bone marrow or stem cell transplant

For those who go into complete remission

Matched-unrelated donor (MUD) stem cell transplant Has significant risk of graft vs host disease.

M3: all-trans retinoic acid Acute promyelocytic leukemia

has gene rearrangement involving retinoic acid receptor

Supportive care

Transfusion and antibiotics AML is harder to treat. ALL has better prognosis.

Aggressive multiagent chemotherapy is successful in inducing

remission in about 85-90% of patients.

Targeting therapy to genetic markers may be beneficial.

Matched-sibling bone marrow or stem cell transplantation after

remission has been shown to achieve long-term disease-free

survival in 60- 70% of patients.

Continued chemotherapy for patients who do not have a matched

sibling donor is generally less effective than marrow

transplantation but nevertheless is curative in about 45-50% of

patients.




DIFFERENCE BETWEEN ALL AND AML

MORPHOLOGY

Figure 12. The coalescing cytoplasmic granules in M3 are called Auer

rods; Consider AML.

For ALL vs AML differentiation. Usually the lymphoblast is

mononuclear with a very scanty cytoplasm. Myeloblasts, on the other

hand, have more cytoplasm with distinct nucleoli.

CYTOCHEMISTRY

Another method of differentiating ALL and AML done by

staining bone marrow samples.

ALL

o (+) periodic acid schiff (PAS)

AML

o (+) myeloperoxidase (MPO)

o (+) sudan black

o (+) specific and non-specific esterase The characteristic feature of AML is that >20% of bone marrow

cells on bone marrow aspiration or biopsy touch preparations

constitute a fairly homogeneous population of blast cells, with

features similar to those that characterize early differentiation

states of the myeloid-monocyte-megakaryocyte series of blood

cells.

IMMUNOPHENOTYPE (FLOW CYTOMETRY)

For ALL and AML differentiation. This identifies the clusters of

antigens present on cells.

ALL

o B cell: CD 19, CD 20, 21, 22, 23, 24

o Pre B: CD 10 (Common Acute Lymphocytic

Leukemia Antigen (CALLA))

o T cell: CD 3, CD 5, CD 7

o mixed lineage, biphenotypic

AML

o CD 13, CD 33

5-YEAR SURVIVAL RATE

Five years after the diagnosis, the patient is still alive and free of

the symptoms of the disease.

ALL

o 85% survival rate

AML

o 50-60% survival rate

CHRONIC MYELOGENOUS LEUKEMIA 3% of all childhood leukemias

Cytogenetic hallmark the Ph chromosome t(9:22)

Figure 13. Philadelphia chromosome: translocation between

chromosome 9 and 22

PHILADELPHIA CHROMOSOME

t(9;22)

Bcr-abl gene attachment

Secretes p210 protein

o A tyrosine kinase protein

o Makes the cell resistant to apoptosis, which results to

increased WBC count

Figure 14. Philadelphia chromosome

Philadelphia Chromosome

The disease is characterized clinically by an initial chronic phase

in which the malignant clone produces an elevated leukocyte

count with a predominance of mature forms but with increased

numbers of immature granulocytes.

The spleen is often greatly enlarged, resulting in pain in the left

upper quadrant of the abdomen. In addition to leukocytosis,

blood counts can reveal mild anemia and thrombocytosis.

The presenting symptoms of CML are nonspecific and can

include fever, fatigue, weight loss, and anorexia. Splenomegaly

also may be present. The diagnosis is suggested by a high white

blood count with myeloid cells at all stages of differentiation in

the peripheral blood and bone marrow and is confirmed by

cytogenetic and molecular studies that demonstrate the presence

of the characteristic Philadelphia chromosome and the BCR-ABL

gene rearrangement.

SIGNS AND SYMPTOMS (CHRONIC PHASE)

Clinically stable for several years

5-10,000 WBC count is normal but patient present with 50,000

without any symptoms or infection

Upon diagnosis, the patient is usually in the chronic phase.

Patient is asymptomatic and will only be seen on routine CBC

or PE

Non-specific complaints: fever, night sweats, bone pain,

abdominal pain

Symptoms resulting from hyperviscosity, headaches,

strokes, retinal hemorrhages, papilledema, priapism

Hepatomegaly

Splenomegaly

Pallor

CML PHASES Table 6. Phases of CML and corresponding findings

Chronic Accelerated Blastic

Median

Duration

5-6 years 6-9 months 3-6

months

WBC >20,000 Thrombocytopenia

Blasts 0% >20% >30%

Basophils Increased >20%

Platelets Normal/increased Increased/decreased decreased

When patients develop into blastic phase, AML/ALL can

develop but usually AML so treatment is now directed towards

treating AML

CHRONIC

70% are diagnosed in this phase

Patients are usually asymptomatic

Stable for several years

Will present with non-specific complaints: fever, night sweats,

bone pain, abdominal pain (due to splenomagaly)




ACCELERATED

After 10 years of being in the stable phase, if the patient did not

receive a tyrosine kinase inhibitors (TKI) or did not respond to

TKI, patients may move to the accelerated phase

Increasing blood and bone marrow leukemic blasts (20%)

and cytopenias

Rising basophil count

Refractoriness to therapy

Fever, night sweats, weight loss

Patients may still go back to chronic phase and eventually

become cured

10%, however, proceed to blastic phase

BLASTIC/BLASTIC CRISIS

Blasts >20% in blood or bone marrow

May become:

o Myeloid blast crisis: 80%

o Lymphoid blast crisis: 20%

Treated as an acute leukemia depending on type of cell

Poor prognosis

LABORATORY TESTS

CBC: leukocytosis and basophilia

Leukocyte Alkaline Phosphatase score: Low (usually 0)

To differentiate from infection

Infection has high WBC and high LAP score

BMA: granulocytic hyperplasia (numerous white cell

precursors)

Karyotype: Philadelphia chromosome t(9:22)

FISH: identification of bcr-abl gene

o Request for this if Philadelphia chromosome is

negative

Identification of p210

TREATMENT

Tyrosine kinase inhibitors (TKI)

o 1st generation: most common is Imatinib (Glivec)

100 mg tablet is usually Php1,500

Required dosage is 400-600 mg/day everyday =

Php 6,000/day

2nd generation: Dasatinib, Nilotinib

3rd generation: Bosutinib

Cytoreductive chemotherapy

o Symptomatic to decrease WBC count and prevent

hyperviscosity (in the form of hydroxyurea)

o Php 30/capsule

Interferons (IV)

Bone Marrow Transplant

Hematopoietic Stem Cell Transplant Imatinib mesylate (Gleevec), an agent designed specifically to

inhibit the BCR-ABL tyrosine kinase, experience in children

suggests it can be used safely with results comparable to those

seen in adults. While waiting for a response with imatinib, disabling or

threatening signs and symptoms of CML can be controlled during

the chronic phase with hydroxyurea, which gradually returns the

leukocyte count to normal. Prolonged morphologic and cytogenetic responses are expected,

but the opportunity for cure is enhanced by HLA-matched family

donor allogeneic stem cell transplant, with up to 80% of children

achieving a cure.

JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) Previously known as Juvenile Chronic Myelocytic Leukemia

(JCML)

Also known as infantile monosomy syndrome

Usually presents in children < 2 years old

Rare JMML is a clonal proliferation of hematopoietic stem cells. JMML is rare, constituting 1,000/uL

Bone marrow blasts < 20% Analysis of the peripheral blood often shows an elevated

leukocyte count with increased monocytes, thrombocytopenia,

and anemia with the presence of erythroblasts. The bone marrow shows a myelodysplastic pattern, with blasts

accounting for 10,000

Clonal abnormalities (Monosomy 7)

GM-CSF hypersensitivity of myeloid progenitors in vitro

LYMPHOMAS

HODGKIN LYMPHOMA Progressive enlargement of the lymph nodes

Unicentric in origin

Predictable pattern of spread by extension to contiguous

nodes

Usual LNs involved are cervical, axillary, epitrochlear, inguinal,

and abdominal. Hodgkin lymphoma differs from Non-Hodgkin

wherein in Hodgkin lymphoma, the nodal spread is usually

towards contiguous/adjacent nodes, whereas in Non-

Hodgkin lymphoma, the nodal spread has no pattern.

ETIOLOGY AND EPIDEMIOLOGY

Cause is unknown

Bimodal age: 15-35 years old and >50 years old

Sex ratio in children: M:F = 3:1

Increased incidence among consanguineous family

members and among siblings with Hodgkin Lymphoma

Immunologic disorders: SLE, Rheumatoid arthritis, Ataxia

telangiectasia, Swiss-type agammaglobulinemia

High association with EBV




REED-STERNBERG CELL

Hallmark of classical Hodgkin lymphomahowever, not

all Hodgkin lymphomas will be positive for RS-cells

Owls eye appearance

Arise from germinal center B cells

Large cell in a reactive background of normal

lymphocytes, plasma cells, and eosinophils

Figure 14. Reed Sternberg cell

WHO/REAL CLASSIFICATION

Lymphocyte predominant, nodular (with or without

diffuse areas)

Classical Hodgkin Lymphoma

Lymphocyte-rich Classical HL

Nodular Sclerosis Classical HL

Mixed Cellularity Classical HL

Lymphocyte Depletion Classical HL

PRESENTING SIGNS AND SYMPTOMS IN CHILDREN (Table 7)

Presenting symptoms Percentage

Lymphadenopathy 90%

Mediastinal adenopathy

- Adolescents and young adults

- Children 39C, weight loss of

>10% of the total body weight over 3 months, and drenching

night sweats. Less common and not considered of prognostic significance are

symptoms of pruritus, lethargy, anorexia, or pain that worsens

after ingestion of alcohol. Patients also exhibit immune system abnormalities that often

persist during and after therapy.

DIAGNOSTIC INVESTIGATIONS & STAGING

Surgical

Excisional lymph node biopsy

Bilateral bone marrow biopsies/aspiration

Imaging studies (immediate)

CT Scan of neck, chest, abdomen, and pelvis (scan of

all the lymph node chains)

FDG-PET

Technetium 99 bone scintography

Laboratory studies

CBC

Blood chemistries for renal and hepatic functions (in

preparation for chemotherapy)

ESR (for prognostication)

Ferritin (for prognostication)

DIFFERENTIAL DIAGNOSES

TB (most common DDx due to mediastinal adenopathy)

Toxoplasmosis (also due to mediastinal adenopathy)

Non-Hodgkin Lymphoma

Metastatic cancer (due to generalized lymphadenopathy)

ANN ARBOR STAGING SYSTEM FOR

HODGKINS LYMPHOMA (Table 8)

I One LN involvement

II 2/more LNs but on the same side of the diaphragm

III 2/more LNs on both sides of the diaphragm

IV Involvement outside the LNs: bone marrow, liver,

extranodal sites

A Absence of B symptoms

B Presence of B symptoms

X Bulky disease

S Splenic involvement

E Extranodal

Stage I localized

Stage II and III (+) lymph node involvement

Stage IV metastatic disease

POOR PROGNOSTIC FACTORS

Advanced stages of disease (IIB, IIIB, IV)

Presence of B symptoms

Presence of bulky disease (large lymph nodes measuring >10

cm or presence of mediastinal mass occupying >1/3 of the chest

cavity)

Extranodal extension (spleen, ovaries, etc.)

Male sex

Elevated ESR

WBC 11.5 or higher

Hgb < 11 g/dL

TREATMENT

Combined chemotherapy

Low-dose involved field radiation (LD-IFRT) (in children

>6 years of age)

PROGNOSIS

Treated with curative intent

Overall survival rate:

> 90% with early stage

> 70% with advanced stage

10-20% with advanced stage may relapse




NON-HODGKIN LYMPHOMA Malignant clonal proliferation of lymphocytes of T-, B-, or

indeterminate cell origin

Lymph nodes, Peyers patches, spleen

Bone marrow involvement in children

Rare: Bone and primary CNS

The bone marrow is more commonly involved compared to

Hodgkin lymphoma. If Hodgkin lymphoma presents with bone

marrow involvement, treatment already involves protocol for

leukemia.

INCIDENCE & EPIDEMIOLOGY

60% of all lymphomas in children and adolescents < 20

years old

Isolated cases of familial non-hodgkin lymphoma occur

M : F = 2.5 : 1 (slight male preponderance)

Peaks at 15-29 years of age

RISK FACTORS

Genetic: Immunologic defects (Agammaglobulinemia,

Ataxia telangiectasia, WAS, Severe combined

immunodeficiency)

Post-transplant immunosuppression

Drugs: Diphenylhydantoin

Radiation

Viral: EBV, HIV

CLASSIFICATION OF CHILDHOOD

NON-HODGKIN LYMPHOMA

Diffuse Large B cell Lymphoma (DLBCL)

Burkitt Lymphoma (B cell)

Lymphoblastic (usually T cell)

Anaplastic Large Cell Lymphoma (ALCL)

The clinical manifestations of childhood and adolescent NHL

depend primarily on pathologic subtype and primary and

secondary sites of involvement.

Approximately 70% of patients with NHL present with advanced

disease, at stage II or IV, including extranodal disease with

gastrointestinal, bone marrow, and central nervous system (CNS)

involvement.

BL commonly manifests as abdominal (sporadic type) or head

and neck (endemic type) disease with involvement of the bone

marrow or CNS.

LL commonly manifests as an intrathoracic or mediastinal

supradiaphragmatic mass and also has a predilection for

spreading to the bone marrow and CNS.

DLBCL commonly manifests as either an abdominal or

mediastinal (PMB subtype) primary and, rarely, dissemination to

the bone marrow or CNS.

ALCL manifests either as a primary cutaneous manifestation

(10%) or as systemic disease (fever, weight loss) with

dissemination to liver, spleen, lung, mediastinum, or skin; spread

to the bone marrow or CNS is rare.

MORPHOLOGIC & IMMUNOLOGIC FEATURES (Table 9)

MORPH DLBCL BURKITT LYMPHO-

BLASTIC

ALCL

CELL SIZE Large Intermediate Small

Intermediate Small Large

NUCLEAR

CHROMAT

IN

Clumped,

vesicular Coarse Fine, blastic

Clumped,

vesicular

NUCLEOLI Variable Variable Absent Variable

CYTOPLAS

M

Moderate

Abundant

Moderate

Scanty with

prominent

vacuoles

Scanty Moderate

Abundant

NODAL

PATTERN Diffuse

Diffuse,

starry-sky

pattern

Diffuse, starry-

sky pattern

Sinusoidal or

Diffuse

IMMUNOP

HENOTYPE

CD20+,

CD22+

CD20+,

CD22+

CD2 (80%),

CD19 (20%)

T cell, null

cell, CD30+,

ALK+

GENETIC FEATURES

Nice to know according to Dra.

Table 10. Genetic features of NHL

DLBCL Burkitt Lymphoblastic ALCL

t(8;14)(q24;q3

2), 12 gain, 21

gain, 15 loss,

3q27

rearrangeme

nts, 6q

deletion, 7q

gain, 11q

gain

t(8;14)(q24;q32),

t(8;22)(q24;q11),

t(2;8)(q11;q24),

1q duplication,

13q

abnormality, 6q

deletion, 7p

abnormality,

11q

abnormality

T cell receptor

arrangements TCL-1

t(7;14)(q35;q32),

t(14;14)(11;32), TCL-

2 t(11;13)(p13;p11),

TCL-3

t(10;14)(q24,q11),

TAL-1

t(1;14)(q32;q11)

t(2;5)(p23;

q25), ALK

translocati

on with

chromoso

me 1, 2, 3,

17

Figure 15. Starry sky pattern.

Some lymphoma cells die out and leave spaces, resulting to the appearance of

stars within a sky.

DIAGNOSIS

CBC (to rule out metastatic disease to the bone marrow)

Serum electrolytes, uric acid, LDH, creatinine, calcium,

phosphorus

Liver function tests

CXR and chest CT if abnormal

Abdominal and pelvic ultrasound and/or CT

Gallium scan and/or bone scan

Bilateral BMA and biopsy (for staging)

CSF cytology (for staging)

FAB STAGING SYSTEM FOR

CHILDHOOD DBCL, BL, BLL

Group A

Completely Resected Stage I (Murphy)

Completely Resected Abdominal Stage II (Murphy)

Group B

All patients not eligible for Group A or Group C

Group C

Any CNS involvement and/or bone marrow involvement

(>25% blasts)

TREATMENT & PROGNOSIS

Proliferation of lymphoblasts are rapid with doubling

time as short as 24 hours

Some mediastinal masses may grow very large and cause

superior vena cava syndrome

Multi-agent systemic chemotherapy

Intrathecal chemotherapy (for those with CNS involvement)

Prognosis depends on appropriateness of protocol

PROGNOSTIC FACTORS

FAVORABLE:

Localized (Stages I and II)

Low LDH (




UNFAVORABLE:

High LDH (>500 or twice the upper normal level)

Combined bone marrow or central nervous system B-

NHL

Poor response to cyclophosphamide, vincristine,

prednisone (COP) reduction therapy in B-NHL

Primary mediastinal B cell lymphoma as primary B-

NHL

Visceral ALCL (Mediastinal, hepatic/splenic, or skin

involvement)

Minimal disease in bone marrow at diagnosis

SOLID TUMORS I. Neuroblastoma

II. Wilms Tumor

III. Retinoblastoma

IV. Tumors of the brain and spinal cord

V. Hepatoblastoma

VI. Rhabdomyosarcoma

VII. Ewing's sarcoma

VIII. Osteosarcoma

IX. Germ cell tumor

X. Histiocytosis

NEUROBLASTOMA Originates from the PRIMORDIAL NEURAL CREST

CELLS that give rise to the adrenal medulla (in the

abdomen) and sympathetic ganglia (beside the spinal cord).

You have risk of tumor from the pineal gland down to the

adrenal medulla.

MOST COMMON OF THE EXTRACRANIAL SOLID

TUMORS IN CHILDREN (8-10% OF ALL

CHILDHOOD CANCER)

MOST COMMON CANCER DIAGNOSED IN

INFANCY

2 years old: median age at diagnosis

90% of cases are diagnosed before the age of 5

Boys > girls

GENETIC: SOMATIC DELETION of CHROMOSOME

BAND 1P36, which is a frequent site in neuroblastoma

cells.

CLINICAL PRESENTATION

Adrenal mass - USUAL PRESENTATION or any MASS

ALONG THE SYMPATHETIC NEURAL CHAIN

65% - Abdomen

Unilateral palpable neck mass (lymphadenopathy)

Raccoon eyes: orbital hemorrhage

Bone pain, limping, back pain

Opsomyoclonus ataxia syndromerepetitive uncontrolled

movement of the eye (dancing eyes and dancing feet: primary tumor is in the chest or abdomen w/o any in the brain)

ABDOMINAL MASS CROSSES THE MIDLINE

Internet: In children, most cases are associated with

neuroblastoma and most of the others are suspected to be

associated with a low-grade neuroblastoma that spontaneously

regressed before detection. In adults, most cases are associated

with breast carcinoma or small-cell lung carcinoma. It is one of

the few paraneoplastic (meaning 'indirectly caused by cancer')

syndromes that occur in both children and adults, although the

mechanism of immune dysfunction underlying the adult

syndrome is probably quite different.

May resemble other small round cell tumors, such as

rhabdomyosarcoma, Ewing sarcoma, and non-Hodgkin

lymphoma.

On plain radiograph or CT, the mass contains hemorrhage and

calcification (in Wilms, no calcification).

RECOMMENDED CRITERIA FOR DIAGNOSIS

ESTABLISHED IF:

o Unequivocal pathologic diagnosis (biopsy) is made

from tumor tissue by light microscopy (with or

without, immunohistology, EM) and/or increased

urine or serum cathecholamines or metabolites

OR

o Bone marrow aspirate or Trephine biopsy contains

unequivocal tumor cells (syncythia or

immunologically positive clumps of cells) and

increased urine or serum catecholamines

Cathecholamine metabolites:

o Homovanillic acid (HVA)

o Vanillylmandelic acid (VMA)

Figure 16. Homer Wright Rosettes - neuroblastoma cells

INTERNATIONAL NEUROBLASTOMA

STAGING SYSTEM (Table 11)

STAGE 1 Tumor confined to the organ of origin

STAGE 2

A

B

Tumor extend beyond the organ of origin but

does not cross midline

Without ipsilateral LN involvement

With ipsilateral LN involvement

STAGE 3 Tumors extend beyond the midline with or

without LN bilateral involvement

STAGE 4 Disseminated to distant sites

STAGE 4S




What is important here? The Shimada Histology and the N-Myc.

N-Myc is an oncogene for neuroblastoma. Poorer prognosis if you

have more N-Myc.

THERAPY

LOW RISK:

o Surgery to remove the entire mass for Stage 1 and

Stage 2

o Observation for Stage 4s

INTERMEDIATE:

o Surgery

o Chemotherapy

o Radiation For incomplete response to chemotherapy

Children with stage III and infants younger than 1 y/o with stage

IV and favorable characteristics= excellent prognosis

Diagnostics should be done for classification of Shimada and

MYCN amplification so that those with unfavorable

characteristics can have more aggressive treatment and those

with favorable characteristics can have less toxic therapy.

HIGH RISK:

o Chemotherapy Induction then high dose

o Bone Marrow Transplant Autologous bone marrow transplantation or stem cell

WILMS TUMOR A complex mixed embryonal neoplasm composed of three

elements: blastema, epithelia, stroma

MOST COMMON PRIMARY MALIGNANT RENAL

TUMOR OF CHILDHOOD, a.ka. nephroblastoma

Most are SOLITARY lesions

Multifocal:

o 7% involve in both kidneys

o 12% within a single kidney

>85% can cured by current therapies

Table 13. CONGENITAL ANOMALIES

ASSOCIATED WITH WILMS TUMOR (WT)

Cryptorchidism 43.6

Sporadic hemihypertophy 25.1

Hypospadias 20.0

Bechwith Weidermann: hemihypertrophy,

macroglossia, visceromegaly

10.7

Wilms tumor, aniridia, GU malformation, MR

(a.k.a. WAGR syndrome)

7.5/1000

Denys-Drash Syndrome: male

pseudohermaphrodism, early onset renal failure

4.0

RISK FACTORS

Environmental vs. genetic

WT appears to result from the loss of function of certain

suppressor genes as opposed to the activation of

oncogenes

GENETIC: autosomal dominant

o WT 1 (band 11p13): WILMS TUMOR SUPPRESSOR

GENE -obliterated or absent

o WT 2 (band 11p15): WILMS TUMOR GENE - present

that promotes the development of WT

o FWT 3 (17q) and FWT2 (19q): FAMILIAL LOCUS Usually sporadic

Familial cases: decreased age at diagnosis and increased

frequency of bilateral disease, absent congenital anomalies

SIGNS AND SYMPTOMS

Table 14. INITIAL SIGNS AND SYMPTOMS OF WILMS TUMOR

SIGNS AND SYMTOMS FREQ. %

Palpable mass in the abdomen 60

Hypertension 25

Hematuria 15

Obstipation 4

Weight loss 4

UTI 3

Diarrhea (watery) 3

Previous Trauma 3 Others: nausea and vomiting, abdominal pain, inguinal

hernia, cardiac insufficiencies, acute surgical abdomen,

pleural effusion, polycythemia, hydrocephalus

8

MASS THAT DOES NOT CROSS THE MIDLINE

STAGING FOR RENAL TUMORS (Table 15)

STAGE I Completely resected tumor limited to kidney with

intact capsule

STAGE II Completely resected tumor

Penetration of renal capsule

STAGE III Residual tumor present after surgery

STAGE IV Presence of Hematogenous Metastasis (lung, liver,

bone, brain)

STAGE V BOTH KIDNEYS

TREATMENT

Figure 17. TREATMENT -depends on the stage and histology.

All must undergo BIOPSY and SURGERY, and MULTI-AGENT

CHEMOTHERAPY. No RT for STAGE 1.

Bilateral WT: unilateral nephrectomy and contralateral partial

nephrectomy or bilateral partial nephrectomy

IN COMPARISON (Table 16)

NEUROBLASTOMA VS WILMS TUMOR

Neuroblastoma Wilms tumor

Arise in the celiac axis: (adrenal

gland paravertebral sympathetic

ganglia)

EXTENDS ACROSS the midline

contains often CALFICATIONS

and hemorrhage

Intrarenal

DOES NOT CROSS midline

NO CALCIFICATION

Other renal tumors in Nelsons: congenital mesoblastic

nephroma, nephroblastomatosis, multicystic nephroblastoma,

renal cell carcinoma.

RETINOBLASTOMA MOST COMMON EXTRACRANIAL SOLID TUMOR

IN CHILDREN

Most commonly diagnosed in INFANTS

2/3 cases before 2 years and 95% before 5 years

Clinical forms:

o BILATERAL (40%): characterized by germline

mutations in RB1 gene

o INHERITED from Affected survivor (25%)

o NEW GERMLINE MUTATION (75%)

o UNILATERAL (60%)

Classification:

o Laterality: Unilateral, or Bilateral

o Focality: Unifocal or Multifocal

o Genetics: Hereditary or non-hereditary

o Family History: Familial or Sporadic




Genetics:

o AUTOSOMAL DOMINANT (85-90%)

o Majority of Children acquire new mutation (15-25%)

Risks of RB

o Risk of RB in offspring of RB survivors:

Bilateral disease - 45%

Unilateral disease- 2%

o Risk of RB in siblings

Bilateral - 45%

Unilateral - 30%


AGE at presentation correlated with LATERALITY

Bilateral:




Headache + nausea/vomiting + papilledema:midline/infratentorial

Torticollis: cerebellar tonsil herniation

UMN (clonus, hyperreflexia): brainstem

Focal disorders such as motor weaknesses, sensory changes,

speech disorders, reflex abnormalities: supratentorial

Infants with hand preference: supratentorial

Parinaud syndrome (upward gaze paresis, pupillary dilatation

reactive to accommodation but not to light, nystagmus to

convergence, eyelid retraction): pineal region

DIAGNOSTIC EVALUATION

CT scan (Cranial)

MRI: for posterior fossa tumors; gold standard

MRA

Magnetic Resonance Spectroscopy

PET

CSF Analysis

Bone Marrow Aspiration

Bone scan

TREATMENT

Surgery

Radiotherapy

Chemotherapy

There are discussions on certain tumors in Nelsons, such as on astrocytoma, oligodendroglioma, mixed gliomas, ependymal,

choroid plexus, embryonal, pineal parenchymal, neuronal,

craniopharyngioma, meningeal, brainstem and germ cell. Read on

them further if you prefer but Doctora told us that she will be

asking questions mainly from her lecture.

HEPATOBLASTOMA Occurs primarily in young children, 80% diagnosed before

3 years of age

Increased risk: VLBW infants, familial adenomatous polyposis, Beckwith-Wiedemann syndrome

Presents as an upper abdominal mass or as generalized

abdominal enlargement

90% with elevated alpha feto protein

TREATMENT

Only those in whom complete resection of mass can be

achieved have a reasonable chance for cure

Possible in 40-50% of children

Chemotherapy plays an ancillary role in eradicating

subclinical metastasis in completely resected disease

CHEMO + RT in unresectable diseases

Liver transplant

5-YEAR SURVIVAL RATE

Stage I/II: 90%

Stage III: 60%

Stage IV: 20%

RHABDOMYOSARCOMA 3RD most common extra-cranial tumor (neuroblastoma (#1)

and Wilms tumor(#2) ) Most common pediatric soft tissue sarcoma

Two age peaks: 2-6 years and 15-19 years

Arise from the same embryonic mesenchyme as striated

skeletal muscles

Anatomic sites:

o Head and Neck 40%

o GUT 29%

o Extremities 14%

o Trunk 12%

o Others 5% Associated with neurofibromatosis and maternal breast cancer in

the Li Fraumeni syndrome

HISTOLOGIC SUBTYPES (Table 19)

Pathologic Subtypes Usual Site of Origin Usual Age (years)

Distribution

Embryonal (ERMS):

60% of cases,

intermediate

prognosis

Head & Neck, Orbit,

GUT

3-12

Solid Botryoid

(grape-like

projection)

Bladder, Vagina,

Nasopharynx, Bile

Ducts

0-8

Spindle Cell Paratesticular 2-12

Alveolar (ARMS):

poorest prognosis

Extremities, Trunk,

Perineum

6-21

RMS, NOS Extremities, Trunk 6-21

On light microscopy, it belongs to small round blue cell tumors

including Non-Hodgkin lymphoma, neuroblastoma and Ewing

sarcoma

CLINICAL MANIFESTATIONS

Mass that may or may not be painful

Metastatic sites (20% at diagnosis): lung, bone marrow,

lymph nodes, bones


History and PE: measurement and lymph node

involvement

Blood Chemistry

Primary Tumor Imaging

Metastatic Work-up High index of suspicion because its presentation is similar with

other conditions that involves masses/tumors

IMAGING WORK-UP

CT Scan or MRI of Primary: to evaluate the extent of loco-

regional disease

Chest CT: to evaluate presence of metastasis

Bone Scan: to evaluate for distant metastasis

STAGING

Pre-treatment clinical stage

Post-treatment clinical stage

PROGNOSIS

Curable in majority of children receiving optimal therapy

(>70% survival after diagnosis)

Extent of disease is the most important prognostic factor

Alveolar histology has the worst prognosis

TREATMENT

Local Control: radiotherapy

Systemic Control: chemotherapy

Complete resection = best prognosis; however, not all are

completely resectable

Based on the primary tumor location and disease stage (clinical

group)

o Group I: complete local excision then chemotherapy

o Group II (microscopic residual tumor): surgery local

radiation and systemic multiagent chemotherapy

o Group III (gross residual tumor): systemic multiagent

chemotherapy irradiation surgery (if possible)

o Group IV (metastatic): systemic chemotherapy and

irradiation

Other nonrhabdomyosarcoma soft tissue sarcomas are relatively

rare in children. Most common, in order of descending

prevalence, are synovial sarcoma, fibrosarcoma, malignant

fibrous histiocytoma and neurogenic tumors.




EWING SARCOMA 80% are younger than 20 years at diagnosis

Round blue cell tumor Undifferentiated sarcoma of the bone

Table 20. Round Blue Cell Tumors

MARKER EWING

SARCOMA

NEURO

BLASTOMA

RHABDOMYO

SARCOMA

LYMPH

OMA

Neuron Specific

Enolase

+/- +* +/- -

S-100 +/- +* +/- -

NFTP +/- + +/- -

Desmin +/- - +* -

Actin +/- - +* -

Vimentin +/- - +* +

Cytokeratin +/- - +/- -

LCA - - - +*

HNK-1 +/- + + -

32-

Microglobulin

+ - +/- +

CD99 +* - + +/-

CLINICAL FEATURES

Local Pain-96%

Local Swelling- 61%

Fever- 21%

Pathologic Fractures- 16%


History and PE

X-Ray of affected bone (with ONION SKINNING)

Blood Chemistry

Metastatic Evaluation:

Lung

Bone

Bone Marrow

Figure 18. Onion Skinning seen in Ewing Sarcoma

TREATMENT

Surgery

Radiation

Chemotherapy

PROGNOSIS

5 year disease-free survival: 60-70%

Metastatic Disease: 20-30%

OSTEOSARCOMA Bone growth: development is correlated with linear bone

growth

Genetic factors: Rb gene and p53

Environmental Factors: previously irradiated bones

Pathologic Hallmark: production of osteoid Children younger than 15 years old, taller than their peers

(adolescent growth spurt: association with rapid bone growth and

malignant transformation)

Associated with hereditary retinoblastoma, Li-Fraumeni

syndrome, Rothmund-Thomson syndrome, Paget disease, Ewing

sarcoma, enchondromatosis, multiply hereditary exostoses,

fibrous dysplasia

CLASSIFICATION

Classic (usually seen)

Osteoblastic

Chondroblastic

Fibroblastic

Telanglectatic

Small Cell

Periosteal

Parosteal

SYMPTOMS

Local pain- 90%

Local swelling- 50%

Decreased range of motion- 45%

Pathologic fracture-8%

Joint effusion

SKELETAL DISTRIBUTION

Lower long bones -74.5%

Upper long bones-11.2%

Pelvic region-3.6%

Face or skull-3.2%

Mandible-1.9%

Chest region-1.8%

Vertebral column-1.2%

Lower short bones-1.1%

Upper short bones -0.3%


Involve blood chemistries, imaging techniques, and work-up for

metastasis

Radiographic Findings:

Soft Tissue extension-75%

Radiating calcification/sunburst- 60%

Osteosclerotic lesions- 45%

Lytic lesions-30%

Mixed lesions -25%

Figure 19. Radiographs with typical osteosarcoma sunburst

PROGNOSIS

DFS, non-metastatic, treated with adjuvant chemotherapy:

60-80%

Metastatic Disease: 2 year survival 10-30%

30-40% of patients will have metastasis at diagnosis

TREATMENT

Surgery

Surgical biopsy

Amputation (if extensive)

Limb-salvaging surgery

Chemotherapy

Neoadjuvant (pre-op)

Adjuvant (post-op)




GERM CELL TUMOR From primordial germ cells of the human embryo

Occurs at gonadal and extragonadal sites

Bimodal age distribution:

o Peak < 3 years old: Extragonadal and testicular

tumors

o Peak adolescence: Gonadal tumors

Table 21. Germ Cell Tumors

SITES FREQUENCY

Sacrococcygeal 42%

Ovary 24%

Testis 9%

Mediastinum 7%

Pineal region 6%

Retroperitoneum 4%

Other sites 8%

For infants, the most common site is sacrococcygeal. For

adolescents, ovary and the testis. They may occur at gonadal and

extragonadal sites.

HISTOLOGIC VARIANTS

o Germinoma

Dysgerminoma (Ovary)

Seminoma (Testis)

o Immature teratoma

o Embryonal carcinoma

o Yolk sac tumor (endodermal sinus tumor)

o Choriocarcinoma


Depends on Primary Site:

Ovarian: abdominal pain (may mimic acute abdomen);

abdominal mass

Testicular: irregular, non-tender masses

Extragonadal: depends on tumor location

Constipation and urinary retention for sacrococcygeal

tumors

Respiratory distress for mediastinal tumors

Pineal Gland: neurologic signs and symptoms

LABORATORY WORK-UP (Table 22)

TUMOR MARKER Germ Cell Tumor HALF-LIFE

AFP Yolk sac tumor

Embryonal carcinoma

5-7 days

B-HCG Choriocarcinoma

Embryonal Carcinoma

Germinomas

24-36 hours

LDH Dysgerminomas

PLAP

AFP and B-HCG are usually elevated in germ cell tumors. AFP

is also elevated in hepatoblastoma. LDH and placental alkaline

phosphatase can also be elevated. But the primary tumor

markers of germ cell tumors are AFP and B-HCG.

TREATMENT

Surgery

Radiotherapy

Chemotherapy

LANGERHANS CELL HISTIOCYTOSIS Most cases occur between 1-15 years of age

Presumptive Diagnosis: Langerhans Cells

Definitive Diagnosis: CD1A( Birbeck Granules), Langerin Also known as histiocytosis X and involves the Class I histiocytes

Figure 20. Birbeck granules (tennis racket-like) on electro-microscope.

ORGANS INVOLVED

Bone: pelvis, femur, ribs, skull (punched out lesions of skull

is most common), orbit

Skin (lesions)

Lymph Nodes

Bone Marrow

Lungs

Hypothalamic-Pituitary Axis

Spleen

Liver

CLINICAL FEATURES

Eosinophilic granuloma (isolated skin lesion)

Hand-Schuller-Christian disease (skull)

ABT-Letterer Siwe disease (skull)

CANCER TREATMENT

Surgery

Chemotherapy

Radiotherapy

Immunotherapy (vaccines and monoclonal antibodies)

PREVENTION OF CHILDHOOD CANCER

IMMUNIZATION

o Hepatitis B vaccine: hepatocellular carcinoma

o HPV vaccine: cervical cancer

Adopt a HEALTY LIFESTYLE to reduce risk of cancer in

adults

o Tobacco

o Alcohol

o High-Fat Diet

o Obesity

o Exercise

Looking back, it's easy to see when a mistake has been made. To

regret a choice that seemed like a decent idea at the time.

But if we use our best judgment and listen to our hearts, we're more

likely to see that we chose wisely, and avoid the deepest most painful

regret of them all

the regret that comes from something amazing pass you by.

Greys Anatomy s10 e13

Documents

3PEDIA6 - Childhood Cancer UERM2015B