tumors of infancy n childhood
TRANSCRIPT
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
Lab Investigations (cont)
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
ALL
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
Lab Investigations (cont)
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:
AML
AML
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
Clinical Presentation
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.
Clinical Presentation
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
Emphysema Pathophysiology
Two types: Centrilobular (central part of lobule)
Most common
Panlobular (destruction of whole lobule)Usually associated with AAT deficiency
Emphysema Pathophysiology
Structural changes are: Hyperinflation of alveoli Destruction of alveolar capillary walls Narrowed, tortuous small airways Loss of lung elasticity
Emphysema Pathophysiology
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
Emphysema Pathophysiology
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
Emphysema Pathophysiology
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
Emphysema Clinical Manifestations
Patient becomes chest breather, relying on accessory muscles Ribs become fixed in inspiratory position
Emphysema Clinical Manifestations
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 BronchitisPathophysiology
Chronic inflammation Primary pathologic mechanism causing changes
Narrow airway lumen and reduced airflow d/t hyperplasia of mucus glandsInflammatory swellingExcess, thick mucus
Chronic BronchitisPathophysiology
Greater resistance to airflow increases work of breathing
Hypoxemia and hypercapnia develop more frequently in chronic bronchitis than emphysema
Chronic BronchitisPathophysiology
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
Chronic BronchitisClinical Manifestations
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
Chronic BronchitisClinical Manifestations
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