Tumors of infancy n childhood

BY: DR. SHWETA MOD: DR. BHALE C. P.

Tumours of Infancy & Childhood

Tumors of Infancy and Childhood

Tumor-like lesions hamartoma = focal overgrowth of tissue in organ

where it normally occurs hem- and lymphangioma, heart rhabdomyomas

choristoma = normal cells in abnormal location pancreatic tissue in stomach wall

Benign tumors

Hemangioma - cavernous + capillary skin of face, scalp red blue mass („port

wine stains“) regress

Benign tumors

Lymphangioma – cystic skin + deep tissues (neck, axilla, mediastinum,

retroperitoneum) growth compression Turner syndrome

Sacrococcygeal teratoma 10% cases + congenital anomalies of cloacal region,

midline defects (spina bifida) 75 % benign (mature) 12% malignant (immature) lethal

Malignant tumors

Hematopoietic system leukemias (ALL) lymphomas – Hodgkins

CNS – medulloblastoma, ependymomaLiver - hepatoblastomaKidney - Wilms tumor Neural crest – neuroblastomaEye – retinoblastomaSoft tissues – rhabdomyosarcomaBones –Ewing Sarcoma

Common Malignant Neoplasms of Infancy and Childhood

0-4 yrs 5-9 yrs 10-14 yrs

Leukemia Leukemia

Retinoblastoma Retinoblastoma

Neuroblastoma Neuroblastoma

Wilms Tumor

Hepatoblastoma HCC HCC

Rhabdomyosarcoma Rhabdomyosarcoma Rhabdomyosarcoma

Teratoma

CNS Tumors CNS Tumors

Ewings Sarcoma

Lymphoma Osteogenic Sarcoma

Thyroid Carcinoma

Hodgkin Disease

Preponderance of Cancer

Leukemia is the most common childhood cancer

Brain tumors are second most commonLymphomas are the third most commonThen solid tumors outside the CNS

Neuroblastoma - neural crest derived Wilms - renal tumors and syndromes Bone tumors Rhabdomyosarcoma - soft tissue sarcomas

Brain Brain TumorsTumors

Childhood CancersChildhood Cancers

OtherOther

LymphomaLymphoma NeuroblastomaNeuroblastomaSoft tissue sarcomas

Kidney tumors

Bone tumors

Retino-blastoma

LeukemiaLeukemia

Small Round Blue Cell Tumors

Frequent in pediatric tumorsDifferential diagnosis

Lymphoma Neuroblastoma Wilms tumor Rhabdomyosarcoma Ewings tumor

Abdominal Masses

Renal 55% Wilms (& other)

25% Hydronephrosis 20% Cystic disease

5% Non Renal

Retroperitoneal 23% Neuroblastoma 21% Teratoma 1% Other(RMS) 1%

Gastrointestinal 12% Appendiceal Abscess Lymphoma

Hepatobiliary 6% Tumors

Hepatoblastoma HCC

Genital 4% Ovarian Cysts and

Teratoma

A MALIGNANCY OF THE BLOOD FORMING TISSUES/ BONE MARROW IN WHICH NORMAL BONE

MARROW IS REPLACED BY MALIGNANT IMMATURE WBC’S

Leukemias

Classification of acute leukemias

ALLmainly childrenM > Fcurable in 70% of

childrencurable in minority of

adults

AMLmainly adults, <1yrM > F

curable in minority of adults

Causes of acute leukemias

idiopathic (most) underlying hematologic disorders chemicals, drugs ionizing radiation viruses (HTLV I) hereditary/genetic conditions

ALL

ALL most common type of leukemia-- 80% of leukemias in children

The malignant cell involved is the lymphoblast, which is an immature lymphocyte from stem cell.

Highest incidence in children 2-6 yrs of age.Survival rates have improved substantially but are dependent on

several factors such as age, diagnosis made, initial WBC count, and presence of invasion into other organs.

90-95% go into initial remission, 70% survive at least 5 yrs

CLASSIFICATION OF ALL

• FAB: ALL-L1 TYPE ALL-L2 TYPE ALL-L3 TYPE

• WHO: PRECURSOR B CELL LEUKAEMIA/LYMPHOMA PRECURSOR T CELL LEUKAEMIA/LYMPHOMA LEUKEMIC PHASE OF BURKITT LYMPHOMA

Morphology of Cells

MORPHOLOGY L1 L2 L3

1) Size of blast Small Large, heterogeneous

Large, homogenous

2) Cytoplasm Scanty Moderate Mod, intensly basophilic

3) N/C ratio High Lower Lower

4) Cytoplasmic Vacuoles

+/- +/- Prominent

5) Nuclear Membrane

Reg Irregular with clefting

Regular

6) Nucleoli indistict

Prominent, 1-2 Prominent, 1-2

LAB DIAGNOSIS

PBS: - Anemia: severe, NCNC - TLC : N/ raised/ decreased - DLC : Granulocytes: decreased Lymphocytes : raised - Platelets : decreased

BME: - Hypercellular : leukemic blasts > - later may become hypocellular (AA)

Lab Investigations (cont)

CYTOCHEMISTRY: - Neg for MPO - +ve for PAS- Large, block like, around nucleus L1-2 +ve and L3 neg - T-ALL- Acid Phosphatase +ve - L3 – vacuoles – Oil o red +ve


Immunophenotyping: - B Cell : TdT, CD 10, CD 19, CD 20, CD 22, HLA DR - T Cell : Cyt CD 3, CD 5, CD 7

Cytogenetic : - Hyperploidy - t(9;22) BCR/ABL , others

D/D

Reactive Lymphocytosis : EBV, CMV

AML

Metastatic Tumors of BM: - Neuroblastoma, - Ewings Sarcoma etc

Leukemic Phase of NHL

AML

Accounts for 20% of childhood leukemias. overproliferation of myeloblasts- blast stage is immature. overproliferation limits production of RBC's & platelets usually seen in infants <1yr age. Remission more difficult than in those with ALL 25% 5 year survival rate-depends on type cell, extent involved,

age

Classification of AML

• FAB : - M0 - Acute Myeloblastic Leukaemia-min diff - M1 - Acute Myeloblastic Leukaemia-without

maturation - M2 - Acute Myeloblastic Leukaemia-with maturation - M3 - Promyelocytic Leukaemia - M4 - Acute Myelomonocytic Leukaemia 4Eo – with BM Eosinophilia - M5 - Acute Monocytic Leukaemia 5a - Undiff 5b - Diff - M6 - Acute Erythroleukaemia - M7 – Acute Megakaryocytic Leukaemia

Classification of AML• WHO : -- Acute Myeloid Leukaemia with recurrent genetic abnormalities - AML with t(8;21)(q22;q22) - AML with abnormal BM eosnophils inv16(p13q22)or t(16;16)(p13q22) - AML with t(15;17) (q22;q12) - AML with 11q23 Abnormalities -- Acute Myeloid Leukaemia with multilineage dysplasia - Following MDS - Without antecedent MDS -- Acute Myeloid Leukaemia & MDS therapy related - Alkylating agent related - Topoisomerase type 2 related - Others -- Acute Myeloid Leukaemia not otherwise specified - Acute Myeloid Leukaemia minimally diff - Acute Myeloid Leukaemia without maturation - Acute Myeloid Leukaemia with maturation - Acute Myelomonocytic Leukaemia - Acute Monoblastic and monocytic Leukaemia - Acute Erythroid Leukaemia - Acute Megakaryoblastic Leukaemia - Acute basophilic Leukaemia - Acute Panmyelosis with Myelofibrosis - Myeloid Sarcoma

Lab Investigations

PBS : - Anemia : NCNC - TLC : Raised with blasts - DLC : Absolute granulocyte count :low Auer Rods seen - Platelets : Decreased

BME: - Hypercellular - >20% blasts seen


Cytochemistry : - MPO : +ve - Non Specific Esterase : M4 & M5 +ve - PAS +ve : M6 (ringed sideroblasts seen)

Ag Mo M1 M2 M3 M4 M5 M6 M7

Primitive SCCD34 + + +/- - - - - +/-HLA DR + + +/- - + + +/- +/-MyeloidCD 13 + + + + + + + +/-CD 33 + + + + + + + +/-MonocyticCD 14 - - - - + + - -CD 64 - - - - + + - -ErythroidGlycophorinA

- - - - - - + -

MegakaryocyticCD 41, CD61 - - - - - - - +

Lab Investigations (cont)• Immunophenotyping:

Auer rods in AML

D/D

Leukamoid ReactionMDSALLBlast crisis of CML

Juvenile CMML

• Proliferation of granulocytic and monocytic lineages.

• Myelomonocytic proliferation seen PBS & BM.

• Age of diagnosis : 75% at age of <3 yrs

• Associated with NF1 gene mutations.

• Splenomegaly present in most cases.

Juvenile cmml

• PB: - Anemia : NCNC - TLC : < 1,00,000 - DLC : Granulocytes inc Monocytes inc Blasts <20% - Platelets decreased• BM : - Hypercellular - Granulocytic & Monocytic (5-30%) proliferation. - Blasts <20% - Erythroid hyperplasia

Juvenile cmml

Dyspoiesis: - pseudo Pelger- Huet abn - hypogranularity of granulocytes - megloblastoid erythroblasts

Ph chromosome –ve

+ve for RAS mutations (20%)

Neutrophil LAP score N

Parameter ALL AML1) Age > In children <1yr

2) Significant Lymphadenopathy > one location

Common Uncommon

3) Meningeal Disease More common Less Common

4) Mediastinal Lymphadenopathy

Seen in T-ALL Rare

5) Morphology of Blasts

Size Small to medium Large

Cytoplasm Scanty Mod to Abundant

Auer Rods Absent Pathognomic

Nuclear Chromatin Coarse Fine

Nucleoli Indistinct Prominent

6) Myelodysplasia Absent May be seen

7) Cytochemistry

MPO - +

PAS + Diffuse

CNS TUMORS

Brain tumors are second only to leukemias in children

Brain tumors are the most common solid organ tumor in children

70% of pediatric brain tumors are in the posterior fossa Pilocytic astrocytoma Medulloblastoma Ependymoma

Clinical presentation

Clinical symptoms depend upon: Age, location, and type of tumor and grade

Symptoms may include: Increased intracranial pressure

secondary to obstruction of CSF at aqueduct hydrocephalus (infants), headache, papilledema, vomiting

seizures focal neurological deficits hormonal changes (pituitary adenoma) visual changes (diplopia, field defects)

Pituitary adenoma - pressure on optic chiasm

Pilocytic astrocytomas

Most common in children Cerebellum (posterior fossa), optic nerve

Thalamic, spinal cord, cerebral Discrete, well circumscribed mass, solid. Often with associated cystic area Contrast enhancing Histologic appearance:

Biphasic: piloid cells and microcystic areas Rosenthal fibers no mitoses

Pilocytic Astrocytoma

• Microscopy: Bipolar cell seen as

parallel bundles of elongsted fibrillar cytoplasmic process remebling mats of hair. GFAP +

Rosenthal Fibers : Eosinophilic hyaline structures, represent chronicity of process.

Eosinophilc granular bodies: Intra cellular or extracellular seen. PAS+

MedulloblastomasPNET of posterior fossa in children arising from

cerebellum or 4th ventricle roof.

Genetics: -Most common- Loss of material from 17p -MYC amplification.

Ki67 is expressed in high percentage.

Neuronal or glial differentiation may be present Homer Wright rosettes GFAP positive cells

Gross: Well circumscribed, grey & friable.

Can extend upto leptomeninges.

Microscopy: Extremely cellular with

anaplastic cells. Tumour cells are small,

scant cytoplasm, hyperchromatic nuclei.

Mitosis abundant.

Desmoplastic variant- areas of stromal response, collagen reticulin deposition.

EPENDYMOMA Near to IVth ventricle in first 2 decades. In adults, spinal cord.

Have distinct margins with parenchyma. Cells regular, round to oval nuclei with abundant granular

chromatin. Between nuclei dense fibrillary background. Perivascular Pseudorosettes seen with long delicate

processes directed toward lumen. GFAP +ve.

Ependymoma

Hodgkins Lymphoma

Definition:Neoplastic disorder with

development of specific infiltrate containing pathologic Reed-Sternberg cells. It usually arises in lymph nodes and spreads to contiguous groups.

Hodgkin LymphomaIncidence:

- 2-4 cases per 100000 population / year

- bimodal age distribution : 15-35 years and above 50

years- male predominance M:F = 1,7:1

Clinical PresentationNontender lymph nodes enlargement

( localised ) neck and supraclavicular area 60-80% mediastinal adenopathy 50% other ( abdominal, extranodal disease )

systemic symptoms (B symptoms) 30% fever night sweats unexplained weight loss (10% per 6 months)

other symptoms fatigue, weakness, pruritus cough , chest pain, shortness of breath, vena cava

syndrome abdominal pain, bowel disturbances, ascites bone pain

Classification—HL

Classical Hodgkin disease lymphocyte rich (LR) nodular sclerosis 1 and 2 (NS) mixed cellularity (MC) lymphocyte depletion (LD)

Hodgkin lymphoma with lymphocyte predominance (LP)

WHO

Pathologic classification

Reed-Sternberg Cell

Popcorn cell variant

Lymphocyte Rich

Lymphocyte Deplete

Mixed Cellularity

Nodular Sclerosis

HL vs NHL

NeuroblastomasMost common extra cranial tumor.

Neural crest origin adrenal gland – 40 % sympathetic ganglia – 60%

Germline mutation of Anaplastic Lymphoma Kinase Gene (ALK)

Median age at diagnosis is 22 months

Clinical Presentation

Pain, abd mass, other masses, malaise; skin

Can occur anywhere in sympathetic NS

>50% are retroperitoneal; head/neck, pelvis, posterior mediastinum; +/- spinal cord compression

Metastatic to lymph nodes, bone, BM, liver ( Bone pain, respiratory symptoms, GI symptoms)

catecholamine secretion: HTN, sweats, irritability; diarrhea;

• Gross:

- Minute nodules to large masses may be 1kg in wt. - May remain as insitu masses. - Majority regress leaving a small foci of calcification

or fibrosis in adults. -Some have a surrounding pseudocapsule & may

invade surrounding structures. C/s: Soft, gray tan, Areas of hemorrhage & necrosis seen Foci of calcification seen

Neuorblastoma Morphology

Small round blue cell tumor neuorpil formation rosette formation immunochemistry – neuron specific enolase EM – secretory granules (catecholamine)

Usual features of anaplasia high mitotic rate is unfavorable evidence of Schwann cell or ganglion differentiation

favorable

Microscopy:

Small cells in sheets, Nuclei : dark, Cytoplasm scant Cells have poorly defined cell boders Background shows Fibrillar matter called neurophil Homer Wright Rossettes: tumor cells are

concentrically arranged surrounding central space with neuropil.

Neuorblastoma

*Neuropil **Homer-Wright Rosettes

*

**

Ganglioneuroblastoma

Larger cells with abundant cytoplasm & vesicular nuclei similar to ganglion cells.

Better prognosis.

Prognostic factors

Neuroblastoma Staging

1 Localized tumor; complete excision with or without residual disease Ipsilateral non adherent LNs neg for tumor.

2A Localized tumor, incomplete gross resection; Ipsilateral non adherent LNs negative for tumor.

2B Localized tumor; with or without complete excision Ipsilateral non adherent LNs +ve for tumor. Contralateral LNs neg for tumor

3 tumour across midline with or without LN involvment or Unilateral localized tumor with contralateral nodes +ve4 Dissemination: bone marrow, liver, skin, bones

4S <1y: local stage 1-2 with metastasis to BM, liver, skin

Wilms’ Tumor

Epidemiology Second most common pediatric solid abdominal

tumor, most common renal malignancy Affects 1 in 10000 children. Presents

50% before age 3 90% before age 6


No tumor-specific symptoms 1/3rd patients may have anorexia, fever, vomiting, malaise

Most common presentation is painless abdominal mass

Physical Exam Smooth, palpable large abdominal mass May reveal HTN in 25% of patients Hematuria & pain in abdomen- rare. Associated congenital abnormalities – 25% Check labs – associated with vonWillebrand’s Disease in up

to 10% of cases

Associated Congenital Abnormalities

WAGR Syndrome – deletion of 11p13, WT1 gene Wilms’ tumor (30%) Aniridia Genitourinary malformations Mental Retardation

Denys-Drash Syndrome – Chromosome 11p13, WT1 gene Progressive renal disease – diffuse mesangial sclerosis ->

proteinuria -> nephrotic syndrome ->ESRD Male Pseudohermaphrotidism due to gonadal dysgenesis Wilms’ tumor (90%)

Beckwith-Wiedemann Syndrome – Chromosome 11p15, WT2 gene

(Genomic imprinting) Macroglossia, hemihypertrophy, organomegaly,

omphalocele, adrenal cytomegaly. Wilms’ tumor (5%)

Beta- catenine also plays role in Wilm’s tumour.

Gain-of-function mutations in Beta-catenine has been demonstrated in 10% cases of Wilm’s tumour.

Genetics

Wilms’ tumor was one of the original examples in Knudson’s two-hit model of cancer development

Tumor supressor genes WT1 – 11p13 – WAGR, DDS WT2 – 11p15 – BWS

However, >90% of Wilms’ are sporadic mutations.

GENES

• WT1 gene : Encodes transcription factor within kidney & gonads of fetus.

It can be activator or repressor depending upon cellular context.

Encodes : p21- cell cycle inhibitor. BCl2, epithelial growth factor,

connective tissue growth factor. • WT2 gene: Normally one allele is silenced, but if both

are working then increase in IGF2 seen, hence effects.

Tumorigenesis

Wilms tumor is thought to rise from a foci of persistent metanephric cells called nephrogenic rests These normally occur in 1% of

newborn kidneys and regress in early childhood

Multiple foci of nephrogenic rests is called nephroblastomatosis Present in 35% of kidneys with

unilateral Wilms and almost 100% of bilateral Wilms

Need for continued surveillance after nephrectomy

Nephrogenic Rest Histology

A – Intralobar Earlier presentation Seen with WAGR, DDS

B – Perilobar Later presentation Seen with BWS

WILMS TUMOR

• GROSS:

large, well Circumscribed.

C/S: Pale gray, soft to homogenous,

Focal areas of hemorrhage and necrosis,

Calcification is uncommon,

Septae if present nodular pattern seen.

Histology Wilms’ tumor consists of three

cell types (a) Epithelial : abortive

tubules (b) Blastemal : small closely packed

cells with increased N:C ratio nuclei are round with

mod coarse chromatin nucleoli inconspicuous (c) Stromal : catilage, bone,

muscle, etc. All three are present in Wilms’

tumor and considered Favorable Histology

Anaplasia Nuclei with diameters

at least 3x those of adjacent tumor cells

Hyperchromasia Presence of

multipolar, polyploid mitotic figures

Considered Unfavorable Histology

Presenc of anaplasia correlates with the p53 mutations.

IHC markers:

Blastematous element- vimentin positive

epithelial element- keratin, EMA, lectin positive

Mesenchymal element- myogenin, desmin positive

Neural element- NSE, S-100

Also WT1, CD 56, IGF I may be positive.

Strong immunoreactivity for p53

Retinoblastoma

Cell of origin : Neuronal.

May be bilateral.

Trilateral Rb: Bilat Rb + Pinealoblastoma.

Important facts : RB

Most common primary, malignant, intraocular tumour of childhood (1:20,000).

No sexual predilection

Presents before age of 3 years (average 3 months)

Heritable (40%) or non-heritable (60%)

Predisposing gene on 13q14

Genetics

Mutations of RB gene on 13q14 seen, both alleles must be inactivated (Knudsons 2 hit hypothesis)

1st hit: Inherited 2nd hit: Somatic mutation (del)

Normlly Rb exsists in active hypophosphorylated form (quiescent cells) & inactive hyperphosphorylated form in G1/S cell cycle transition

If mutation is present remains hyperphosphyralated & cannot control E2F.

• Leukocoria - 60% • Strabismus - 20% • Secondary glaucoma

• Anterior segment invasion • Orbital inflammation • Orbital invasion

Presentations of retinoblastoma

Retinoblastoma Pathology

Gross: They are usually creamy white with chalky areas of

calcification & yellowish necrotic areas.

Types: - Endophytic : grow toward vitreous - Exophytic : grow towrds choroid - Mixed

Multiple seedings may be seen

Microscopy:

- Small undiffrentiated cells with scant cytoplasm & hyperchromatic Nuclei.

- In well differentiated, Flexner Wintersteiner Rossests: Tumor cells surround a central glycosaminoglycan containing lumen.

- Nuclei of cells are away from the lumen.

- Invasion of Optic Nerve seen, thus cells may reach CSF.

Histology of retinoblastoma

Well-differentiated with many Flexner-Wintersteiner rosettes

Poorly differentiated

IHC Markers:

Neuroectodermal origin NSE Synaptophysin S-100 Glial fibrillary acidic protein Myelin basic protein CD 57 positive

EWINGS SARCOMA/ PNET

2nd most common bone tumor in children. Small round cell tumor of bone & soft tissue. Tumour differentiation- PNET Undifferentiated- Ewing’s sarcoma B>G whites>blacks Common in the second decade of life.

GENETICS

Most have t(11;22) involving EWS gene.

After the translocation there is increase in chimeric transcription factors which alter the expression of target genes.

Recent evidences says precursor cell is multipotent mesenchymal stem cells.


Arise in diaphysis of long bones & flat bones.

Painful enlarging mass

Fever, anemia, leucocytosis.

On X-ray, Onion-skin appearance.

PathologyGross: Soft, Tan, Gray, Fleshy tissue, Areas of hemorrhage

& necrosis.

Pathology• Microscopy: Sheets of small cells, Nuclei uniform, Clear cytoplasm with

glycogen, Mitotic figures less as

compared to the cells, Necrosis extensive, Pseudorossets

seen ,ie, tumor cells around vessels.

Homer Wright rossets may be seen suggesting neural diffrentiation.

• No osteoid or chondroid

production

EM & IHC:

EM- PAS positive ( Glycogen) Not specific.

IHC- Vimentin positive Low molecular wt keratin positive Others- NSE, secretogranin II

CD99 positive (not specific)

Translocation can be detected on RT-PCR & FISH.

PAS positive with large amounts of cytoplasmic glycogen

CD99 positive in Ewing’s sarcoma

Hepatoblastoma

• Most common primary liver tumor in children (50% of liver malignancies in children)

• 90% occur by age 5 years, 70% by age 2 years• 2/3 male• Associated with hemihypertrophy (Beckwith-Wiedemann

syndrome), Wilm’s tumor, glycogen storage disease, familial colonic polyposis); not associated with cirrhosis

• Symptoms: variable virilization due to hCG production by multinucleated giant cells

• Laboratory: elevated serum AFP in 75%• Metastases to regional lymph nodes, lung, brain, adrenal

glands, bone marrow• Treatment: preoperative chemotherapy and surgery;

resect lung metastases; liver transplant if unresectable• Long term survival now 60-70%• Prognostic factors: stage, age, sex; increase mitotic

activity may confer poorer prognosis; presence of osteoid may confer favorable prognosis

Hepatoblastoma

Gross: tan-green, bulky,friable, 70% solitary, well circumscribed, variable hemorrhage and cysts; mean 10 cm (range 3-20 cm), often partially encapsulated; may be calcified in prominent mesenchymal component

Hepatoblastoma

This neoplasm is composed of a mixture of two cell types. Some neoplastic hepatocytes are arranged in irregular laminae (fetal) while others grow in a more embryonal pattern.

Hepatoblastoma

Epithelial type (56%) Fetal pattern (31%): tumor cells in trabeculae 2-3 cells thick (resembling fetal

liver), separated by sinusoids lined by CD34+ endothelial cells; tumor cells are same size or smaller than in non-neoplastic liver; distinct cell membranes, uniform, polyhedral, slightly higher nuclear/cytoplasmic ratio, inconspicuous nucleoli, may contain bile; minimal pleomorphism, no/rare mitotic figures;; no portal tracts, bile ducts or ductules; reduced reticulin

Embryonal pattern (19%): sheets, ribbons, rosettes, papillary patterns or trabeculae of variable thickness with immature appearance, discohesive small cells with poorly defined cell borders, basophilic cytoplasm, high N/C ratio, prominent nucleoli, coarse chromatin, increased mitotic figures; extramedullary hematopoiesis, necrosis and vascular lakes are common; no fat, glycogen or bile

Macrotrabecular pattern (3%): frequent trabeculae > 10 cells thick throughout the tumor, variable cytologic features

Small cell undifferentiated pattern (3%): discohesive sheets of small uniform cells with minimal cytoplasm, indistinct cell borders, oval hyperchromatic nuclei, variable prominent nucleoli and increased mitotic figures; resembles small cell carcinoma at other sites; may have mucoid stroma, hyalinized septae; tumor cells are keratin+, bile-

Mixed epithelial and mesenchymal type (44%) mixture of fetal/epithelial and mesenchymal cell types; teratoid (34%) or not (10%);

mesenchymal component has spindle-oval cells with minimal cytoplasm, frequent osteoid, fibrous septa, myxoid zones, hemorrhage and necrosis; teratoid features are keratinized squamous epithelium, intestinal epithelial, skeletal muscle, mature bone and cartilage, melanin and neuroectodermal structures

Rhabdomyosarcoma

Rhabdomyosarcoma is the most common of the childhood soft tissue sarcomas.

• Mainly occurs in head & neck and genitourinary system.

• two peak age ages 2 to 6 Adolescence children <1 year and >10 years having inferior

survival

Pattern of spread

locally invasive tumor often with a pseudocapsule, has the potential for local spread along fascial or muscle planes, lymphatic extension, and hematogenous dissemination

regional lymphatic spread-15%

Hematogenous metastases-15%

geneticsEmbryonal: Parental isodisomy of 11p15.5 causing

overexpression of IGF2

Alveolar : - t(2;13)(q35;q14) PAX3 to FOXO 1a –worse

prognosis - t(1;13)(p36;q14) PAX7 to FOXO 1a

Pathology• Rhabdomyoblast: - It is the diagnostic

Cell. - It has eccentric

eosinophilic granular cytoplasm rich in thick & thin filaments.

- May be round/ elongated called STRAP CELL or TADPOLE CELL with cross striations.

Pathologic Classification

Embryonal: - Most common type (60%) - Occurs in children <10 yrs of age and in cavities. - Presents as soft gray infiltrative mass. - Rhabdomyoblasts seen.

Botryoid subtype of embryonal - Has a CAMBIUM LAYER : Tumour cells present

submucosally

Other variants are pleomorphic subtype, spindle cell type, infantile rhabdomyofibrosarcoma, sclerosing rhabdomyosarcoma.

• Alveolar - Occupies 20% of the variety - Arises in deep musculature of extremities - Seen in adolesence (10-25 yrs) - There are septae that divide the tumor clusters similar

to pulmonary alveoli. - Tumor cells are moderate in size with little cytoplasm,

25% cells have cross striations.

• Pleomorphic - Large multinucleated, bizzare tumor cells. - It is rare & occurs in adults.

Electron microscopy: Z bands, thick & thin filaments in hexagonal array, A band

containing thick filaments etc can be seen.

IHC: 1. Myogenin- High specificity, expressed mainly in alveolar

type. 2.Desmin 3. Sarcomeric actin: One of the best marker. 4. Myosin 5. Myoglobin 6. Tropomyosin alpha-actinin, titin- High specificity 7. Vimentin- Lacks specificity 8. Enzymes 9. CARP- Cardiac Related Ankyrin Protein

10. Type IV collagen, Laminin 11. IGF II 12.Others: PAX, S-100

Electron Microscopy: Cytoplasm shows abortive cross striations

Nuclear immunoreactivity for Myogenin

Teratoma

They are the tumors representing atleast two, or all three embryonic layers.

Types: - Mature - Immature

Immature Teratoma

1/3rd primitive germ cell tumors.

10-20% cases 1st decade of life.

Ocassionally Inc in AFP & HCG seen.

Peritoneal seeding are common called peritoneal glimatosis.

Immature teratoma

• Gross: - Large - Encapsulated with

glistening surface - C/S : - Solid - Cysts with

mucinous/serous fluid/hair may be seen

- Areas of bone & cartilage may be seen

- Areas of hemorrhage & necrosis may be seen

• Microscopy: - Small-large areas of

neuroectdodermal elements seen

- Tubules/rossests / cellular foci of mitotically active glia seen

- Immature bone or cartilage may be seen, which may overgrow.

Immature teratoma

GRADING: - Grade 1 : Rare foci of embryonal neural elements

occupying <1lpf in any slide. - Grade 2 : Mod foci of embryonal neural elements occupying

>1lpf but <4lpfs in any slide. - Grade 3 : Large foci of embryonal neural elements

occupying >4lpfs in any slide.

Mature teratoma

2/3rd of ovarian tumor of young < 15yrs They are benign Malignant change : 1-2% I immature element seen chances of recurrence high

Mature teratoma

• Gross : - Mostly Dermoid Cyst : - White to gray ext

surface. - Yellow sebaceous

material with hair fill the cyst.

- Several polypoidal masses can be seen.

- Teeth, bone, cartilage, thyroid, neural tissue, muscle may be seen.

- If solid areas of necrosis & hemorrhage seen.

• Microscopy: - Adult + Fetal tissue

seen - Ectodermal :

Epidermis, neural, Pilosebaceous, sweat glands

- Mesodermal : S.M, bone, cartilage, fat

- Endodermal : RS, GI, Thyroid

- Mitotic figures rare - Nearby fibrosing

inflammation due to spill of fluid.

Referrences:

Pathologic basis of diseases, 8th Ed, Robbins and Cotran

Surgical Pathology, 10th Ed, Rosai and Ackermann

THANK YOU

COPDChronic Obstructive Lung Disease

COPD Definition

COPD, or chronic obstructive pulmonary disease, is a progressive disease that makes it hard to breathe. "Progressive" means the disease gets worse over time.

COPD Overview

COPD Overview

In COPD, less air flows in and out of the airways because of one or more of the following:

The airways and air sacs lose their elastic quality.

The walls between many of the air sacs are destroyed.

The walls of the airways become thick and inflamed.

The airways make more mucus than usual, which tends to clog them.

What is COPD?

A set of lung diseases that limit air flow and is not fully reversible. COPD patients report they are “hungry” for air Usually progressive and is associated with

inflammation of the lungs as they respond to noxious particles or gases

Potentially preventable with proper precautions and avoidance of precipitating factors

Symptomatic treatment is available

Two Major Causes of COPD

Chronic Bronchitis is characterized by Chronic inflammation and excess mucus production Presence of chronic productive cough

Emphysema is characterized by Damage to the small, sac-like units of the lung that

deliver oxygen into the lung and remove the carbon dioxide

Chronic cough*Source: Braman, S. Update on the ATS Guidelines for COPD. Medscape Pulmonary Medicine.

2005;9(1):1.

COPD Causes

SmokingAir pollutiongenetic (hereditary) risk

Are You At Risk?

Smoking Most common cause, however, as many of 1 out of 6

people with COPD never smokedEnvironmental exposure

Chemicals, dusts, fumes Secondhand smoke, pollutants

Genetic Factor Alpha-1 antitrypsin (AAT) deficiency

Primary Symptoms

Chronic Bronchitis Chronic cough Shortness of breath Increased mucus Frequent clearing of throat

Emphysema Chronic cough Shortness of breath Limited activity level

Normal versus Diseased Bronchi

Emphysema

Difference between COPD and Asthma

In COPD there is permanent damage to the airways. The narrowed airways are fixed, and so symptoms are chronic (persistent). Treatment to open up the airways, is therefore limited.

In asthma there is inflammation in the airways which makes the muscles in the airways constrict. This causes the airways to narrow. The symptoms tend to come and go, and vary in severity from time to time. Treatment to reduce inflammation and to open up the airways usually works well.

COPD is more likely than asthma to cause a chronic (ongoing) cough with sputum.

Difference between COPD and asthma (cont…)

Night time waking with breathlessness or wheeze is common in asthma and uncommon in COPD.

COPD is rare before the age of 35 whilst asthma is common in under-35.

COPDDescription

Characterized by presence of airflow obstruction

Caused by emphysema or chronic bronchitisGenerally progressive May be accompanied by airway

hyperreactivityMay be partially reversible

Emphysema Description

Abnormal permanent enlargement of the air space distal to the terminal bronchioles

Accompanied by destruction of bronchioles

Chronic Bronchitis Description

Presence of chronic productive cough for 3 or more months in each of 2 successive years in a patient whom other causes of chronic cough have been excluded

COPDCauses

Cigarette smoking Primary cause of COPD*** Clinically significant airway obstruction develops in

15% of smokers 80% to 90% of COPD deaths are related to tobacco

smoking > 1 in 5 deaths is result of cigarette smoking

COPDCauses

Cigarette smoking Nicotine stimulates sympathetic nervous system

resulting in: HR Peripheral vasoconstriction BP and cardiac workload

COPDCauses

Cigarette smoking Compounds problems in a person with CAD Ciliary activity Possible loss of ciliated cells Abnormal dilation of the distal air space Alveolar wall destruction Carbon monoxide

O2 carrying capacity Impairs psychomotor performance and judgment

Cellular hyperplasia Production of mucus Reduction in airway diameter Increased difficulty in clearing secretions

COPDCauses

Secondhand smoke exposure associated with: Pulmonary function Risk of lung cancer Mortality rates from ischemic heart disease

COPDCauses

Infection Major contributing factor to the aggravation and

progression of COPDHeredity

-Antitrypsin (AAT) deficiency (produced by liver and found in lungs); accounts for < 1% of COPD cases Emphysema results from lysis of lung tissues by

proteolytic enzymes from neutrophils and macrophages

Pathophysiology of Chronic Bronchitis and Emphysema

Fig. 28-7

Emphysema Pathophysiology

Hyperinflation of alveoli Destruction of alveolar walls Destruction of alveolar capillary walls Narrowed airways Loss of lung elasticity


Two types: Centrilobular (central part of lobule)

Most common

Panlobular (destruction of whole lobule)Usually associated with AAT deficiency


Structural changes are: Hyperinflation of alveoli Destruction of alveolar capillary walls Narrowed, tortuous small airways Loss of lung elasticity


Small bronchioles become obstructed as a result of Mucus Smooth muscle spasm Inflammatory process Collapse of bronchiolar walls

Recurrent infections production/stimulation of neutrophils and macrophages release proteolytic enzymes alveolar destruction inflammation, exudate, and edema


Elastin and collagen are destroyed Air goes into the lungs but is unable to come out on

its own and remains in the lung Causes bronchioles to collapse


Trapped air hyperinflation and overdistention As more alveoli coalesce, blebs and bullae may

develop Destruction of alveolar walls and capillaries

reduced surface area for O2 diffusion Compensation is done by increasing respiratory rate

to increase alveolar ventilation Hypoxemia usually develops late in disease

EmphysemaClinical Manifestations

Dyspnea Progresses in severity Patient will first complain of dyspnea on exertion and progress to interfering with ADLs and rest

Emphysema Clinical Manifestations

Minimal coughing with no to small amounts of sputum

Overdistention of alveoli causes diaphragm to flatten and AP diameter to increase


Patient becomes chest breather, relying on accessory muscles Ribs become fixed in inspiratory position


Patient is underweight (despite adequate calorie intake)

Chronic BronchitisPathophysiology

Pathologic lung changes are: Hyperplasia of mucus-secreting glands

in trachea and bronchi Increase in goblet cells Disappearance of cilia Chronic inflammatory changes and narrrowing of

small airways Altered fxn of alveolar macrophages

infections


Chronic inflammation Primary pathologic mechanism causing changes

Narrow airway lumen and reduced airflow d/t hyperplasia of mucus glandsInflammatory swellingExcess, thick mucus


Greater resistance to airflow increases work of breathing

Hypoxemia and hypercapnia develop more frequently in chronic bronchitis than emphysema


Bronchioles are clogged with mucus and pose a physical barrier to ventilation

Hypoxemia and hypercapnia d/t lack of ventilation and O2 diffusion

Tendency to hypoventilate and retain CO2 Frequently patients require O2 both at rest and

during exercise

Chronic Bronchitis Pathophysiology

Cough is often ineffective to remove secretions because the person cannot breathe deeply enough to cause air flow distal to the secretions

Bronchospasm frequently develops More common with history of smoking or asthma

Chronic BronchitisClinical Manifestations

Earliest symptoms: Frequent, productive cough during winter

Frequent respiratory infections


Bronchospasm at end of paroxysms of coughing Cough Dyspnea on exertion History of smoking Normal weight or heavyset Ruddy (bluish-red) appearance d/t

polycythemia (increased Hgb d/t chronic hypoxemia)) cyanosis


Hypoxemia and hypercapnia Results from hypoventilation and airway resistance + problems with alveolar gas exchange

COPDComplications

Pulmonary hypertension (pulmonary vessel constriction d/t alveolar hypoxia & acidosis)

Cor pulmonale (Rt heart hypertrophy + RV failure) Pneumonia Acute Respiratory Failure

COPD Diagnostic tests

SymptomsPhysical examinationSample of sputum Chest x-rayHigh-resolution CT (HRCT scan)Pulmonary function test (spirometery) Arterial blood gases testPulse oximeter

How common is COPD?About 13.9% of the U.S. adult population

(25+ years) have been diagnosed with COPD*

An estimated 15-19% of COPD cases are work-related**

24 million other adults have evidence of troubled breathing, indicating COPD is under diagnosed by up to 60%***

*Braman, S. Update on the ATS Guidelines for COPD. Medscape Pulmonary Medicine. 2005;9(1):1. **CDC programs in Brief– Workplace Health and Safety-Work-related Lung Diseases.

www.cdc.gov/programs/workpl18.htm ***COPD Fact Sheet. Oct 2003. www/lungusa.org

COPD in the Mining Industry

Studies show:An increased number of cases of chronic bronchitis in

coal & gold miners

Long-term exposures to low levels of silica may lead to the development of chronic bronchitis & emphysema

Chronic exposure to coal dust, particularly high levels, may lead to severe respiratory impairment (emphysema)

*Hnizdo & Vallyathan Chronic obstructive pulmonary disease due to occupational exposure to silica dust: a review of epidemiological and pathological evidence. Occup Environ Med 2003;60:237-243.

Ways to prevent or slow the progression of COPD

Stop smoking, if you smoke, to prevent further damage to your body Smoking cessation is critical for all severities

of COPD

Avoid or protect yourself from exposures to Second-hand smoke and Other substances such as chemical vapors,

fumes, mists, dusts, and diesel exhaust fumes that irritate your lungs

How is COPD Treated?

COPD can be managed, but not cured

Treatment is different for each individual and is based on severity of the symptoms

Early diagnosis and treatment can Slow progress of the disease Relieve symptoms Improve an individual’s ability to stay active Prevent and treat complications Improve quality of life

What medications are used to treat symptoms?

Bronchodilators – Relaxes muscles around airways

Steroids Reduces inflammation

Oxygen therapy Helps with shortness of breath

What medications are used to prevent complications?

Annual flu vaccine Reduces risk of flu and its complications

Pneumonia vaccine Reduces risk of common cause of pneumonia

Tumors of infancy n childhood

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