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Small round cell tumors
- 1. SMALL ROUND CELL TUMOR DIAGNOSTIC APPROACH Dr Niharika Singh MD Pathology II yearResident Gandhi Medical College. Bhopal
- 2. Definition Group of highly aggressive malignant neoplasm which are composed predominantly of small, round and monotonous undifferentiated cells with high nuclear-cytoplasmic ratio.
- 3. Diagnostic Approach Clinical Findings Radiological Findings Pathological Findings Molecular Genetics Immunohistochemical Features Age Sex Site Clinical presentations Cytology Findings Gross Findings Light Microscopy Electron microscopy FISH Techniques. RT PCR. Flow Cytometry
- 4. Ewing’s Sarcoma/PNET Nephroblastoma Rhabdomyosarcoma Neuroblastoma Retinoblastoma Small Round cell tumors of Pediatric age group
- 5. Medulloblasto ma Desmoplastic round cell tumor Small cell osteosarcoma Hepatoblastoma Pineoblastoma Small Round cell tumors of Pediatric age group Lymphoblastic Lymphoma
- 6. Primitive Neuroectodermal Tumors (Neural crest tumor) Batsakis et al(1996) CNS PNETs Tumors derived from the central nervous system Tumors derived from the autonomic nervous system Neuroblastoma Tumors derived from tissues outside the central and autonomic nervous system Peripheral PNETs/ Ewing Family of tumors Based on the tissue of origin Ewing sarcoma Malignant peripheral PNETs Askin tumor *Other *Neuroectodermal tumor, ectomesenchymoma, peripheral medulloepithelioma. These tumors were thought to arise directly from nerves.
- 7. Ewings Sarcoma/PNETAge:5-20 yrs Sex:M>F Site: -Bone: Medulla of diaphysis or metaphysis of femur, pelvis, tibia,humerus, ribs and fibula. -Soft tissue: Deep soft tissue of extremities Presentations: Bone: Clinically the tumor may simulate osteomyelitis Soft tissue: Rapidly growing, deeply located mass measuring 5-10cm in greatest diameter. Can cause
- 17. Positive for Vimentin. Neuron specific enolase Neurofilament Leu 7 CD -99. Immun0histochemical Features
- 20. Molecular Genetics Over 95% show reciprocal translocation of chromosome 11 : 22 (q24 : q 12). This leads to fusion of EWS gene with FLI-1. Detected by the • RT-PCR • Fluorescent in situ hybridization (FISH) technique *in cytologic preparations, frozen sections, or paraffin sections.
- 22. Retinoblastoma Age:16 months- 2yrs. Sex:M=F. Site:Intraocular Presentations:Leukocoria (characterstic) Strabisumus(Less often esp.in macula). Rarely, extraocular extension with the format an orbital mass is the presenting manifestati Bilateral in 30% of all cases and in over 90% familial cases. Trilateral retinoblastoma
- 26. Gross Findings Of Retinoblastoma Gross:May be flat and diffuse or elevated, and may show multicentric foci of origin, especially in the hereditary type. Three patterns of growth are recognised : 1Endophytic:growth occurs inwards into the vitreous. Cell clusters may detach and float in the vitreous (vitreous seeding)
- 27. 2Exophytic Growth occurs outwards Grow between the retina and the pigment epithelium Associated with non-rhegmatogeneous retinal detachm 3 Diffuse infiltrating growth
- 34. Immun0histochemical Features Reactivity for • Neuron-specic enolase • Synaptophysin • S-100 protein • Glial fibrillary acidic protein • Myelin basic protein • Leu7 (CD57)
- 35. Immun0histochemical Features Specific markers of retinal differentiation • Retinal-binding protein • Retinal S-antigen • Interphotoreceptor retinal-binding protein • Cone opsin • Rod opsin • MLGAPC
- 36. Loss-of-function mutations in the RB gene Molecular Genetics
- 37. Neuroblastoma Age: Under 4 yrs (21 month) Sex:M=F Site: Retroperitoneum (70%), and the majority of these involve the adrenal gland. Other sites-along sympathetic chain, posterior mediastinum, neck, brain Presentations • An abdominal mass first noted by the parents. • Rarely watery diarrhea,Cushing syndrome,heterochromia iridis and horner syndrome (in cervical or mediastinal tumors) and opsoclonus/myoclonus
- 44. Immun0histochemical Features Reactivity for • Neuron-specic enolase • NB-84(anti neuroblastoma antibody) • S-100 • Insulin-like growth factor 2 • Neurofilament • Chromogranin • Synaptophysin • Secretogranin II • Vasoactive intestinal peptide • Microtubule-associated proteins • Growth factor receptors, and other neural-related antigens, including the cell surface ganglioside GD2.
- 45. Molecular Genetics Amplification of the N-myc oncogene detected by FISH techniqu Catecholamines demonstration in sections or touch preparations formaldehyde-induced fluorescence technique. Expression of genes involved in catecholamine biosynthesis can with the polymerase chain reaction (PCR) technique. Trk receptor protein by Northern analysis and immunohistochem
- 46. Nephroblastoma Age:Infants (primarily), less than 3 years ( 50%) & less than 6 years (90%) Sex:M=F Site: Kidney; Presentations:Large abdominal mass Hematuria Pain in abdomen Hypertension Conditions associated with wilms’ tumor are • WAGR syndrome • Beckwith wiedemann Syndrome • Denys Drash Syndrome
- 53. Electron microscopic appearance Ultrastructurally, the cells of Wilms tumor closely resemble those of the developing metanep
- 54. Immun0histochemical Features Reactivity for • Vimentin • Keratin • Epithelial membrane antigen • Myogenin • Desmin • Neuron specific enolase • S-100 • Glial fibrillary acid protein • WT-1(90%) • CD56(96%) • Type I insulin-like growth factor Blastematous elements Epithelial elements Mesenchymal /Stromal elements Neural elements
- 55. Molecular GeneticsGenetic loci predisposing to wilms’ tumor are • WT1 ( located on chromosome 11p 13 ) • WT2 ( located on chromosome 11p15.5) • Mutations of B catenin gene-14-20%
- 56. Rhabdomyosarcoma Age: • Embryonal:3-12 yrs; • Alveolar:10-25 yr Sex:M>F Site: Embryonal: Unsegmented and undifferentiated mesoderm Common in the - Head and neck region (particularly the orbit, nasopharynx, middle ear, and oral cavity), - Retroperitoneum -Urogenital tract -Extremities -Skin. Alveolar: • Mostly extremities (forearm, arm) -Perirectal & perineal region Presentations: • Based on location. • Usually manifests as an expanding mass. • Hypercalcemia or with elevated parathormone levels in some cases.
- 57. Radiological Findings Embryonal Rhabdomyosarcoma Computed tomography (CT) scanning Magnetic resonance imaging (MRI) Bone scanning Ultrasonography
- 68. Histochemical studies PTAH Masson’s trichome Silver impregnation technique
- 73. Immun0histochemical Features Reactivity for • Vimentin • Enzymes( creatine kinase) • ILGF-2 • Neurofilament • S-100 protein • CARP- cardiac ankyrin related protein
- 74. Molecular Genetics Translocation t(2;13) or t(1;13), which results in the gene fusions PAX3–FOXO1A and PAX7– FOXO1A, respectively. Translocations can be detected in paraffin embedded tissue with the FISH technique. MYCN amplification in close alveolar rhabdomyosarcomas.
- 75. Medulloblastoma Age: 5-10 yr Sex:M>F Site: Commonly arise from Cerebellar vermis. Presentations: • Truncal ataxia • Disturbed gait • Lethargy • Headache • Morning emesis
- 76. Mostly sporadic. Heritable cases are associated with: • Type 2 Turcot syndrome • Nevoid basal cell carcinoma – or ‘Gorlin’ – syndrome • Li–Fraumeni syndrome • Rubinstein–Taybi syndrome • Coffin–Siris syndrome
- 85. Microscopic variants of Medulloblastomas: Classical. Desmoplastic/Nodular. Medulloblastoma with extensive nodularity. Large cell variant/ Anaplastic. Melanotic medulloblastoma. Medullomyoblastoma.
- 99. Immun0histochemical Features Reactivity for • Class III beta tubulin • microtubule-associated protein 2 • Hu and NeuN • TrkA and TrkC neurotrophin receptors. • Photoreceptor-associated proteins -(rod-opsin and retinal S-antigen) • Neurofilament • Vimentin • Desmin • Myogenin • NSE
- 100. Molecular Genetics Chromosome 17q Wnt Cascade Patched gene mutation SUFU gene mutation INI1 gene. MYC gene Amplification
- 102. PineoblastomaAge:Children and adolescents Sex:M>F Site:Parenchyma of pineal gland Presentations: • Obstructive hydrocephalus • Parinaud syndrome • CSF seeding in 15% of patients at the time of diagnosis. • Trilateral retinoblastoma • Association with familial adenomatous colonic polyposis as a possible variant of type 2 Turcot syndrome.
- 104. Cytology Findings
- 110. Immun0histochemical Features Reactivity for • Synaptophysin • Rhodopsin • Retinal S antigen • Arrestin • Ki-67 • NSE
- 111. Molecular Genetics Most frequent rearrangement is that of chromosome 1 RB1 gene on Chromosome 13 germline deletion DICER1 gene mutation
- 112. Hepatoblastoma Age:. Primarily in infants, but isolated instances in older childr Sex:M>F. Site: Liver cells( Rt lobe) Presentations: • A large mass in the abdomen and swollen abdomen • Decreased appetite and weight loss • Vomiting • Jaundice (yellowing of eyes and skin) and Itchy skin • Anemia • Back pain • Virilization
- 113. Hepatoblastoma Associated with a variety of congenital abnormalties • Particularly hemihypertrophy • Wilms tumor of kidney • Glycogen storage disease • Familial colonic polyposis.
- 116. Cytology Findings
- 122. Immun0histochemical Features Reactivity for • β-catenin • Glypican-3 • Polyclonal CEA • Keratin • EMA • HepPar-1 • a1-antitrypsin • Vimentin • AFP • HCG
- 123. Immun0histochemical Features Reactivity for • Transferrin receptor • Delta-like protein • Neuron specific enolase • Chromogranin • Somatostatin • Serotonin • HMB-45 • Laminin, type IV collagen, and fibronectin.
- 124. Molecular Genetics Trisomies 2, 8, and 20, and rearrangements of 1q. CTNNB1 (β-catenin) gene. CGH analysis :High frequency of X-chromosome gains. Evaluation of DNA content by flow cytometry.
- 125. Desmoplastic small round cell tumor Age:Adolescents and young adults Sex:M>F Site:Intra Abdominal: Pelvic region and sometimes the entire tumor is limited to the paratesticular region • Other sites:bone, kidney, lung, ovary, pancreas, pleura, spermatic cord, uterus, central nervous system, sinonasal region and salivary glands. Presentation:Intra Abdominal:Characteristically presents as a single mass or multiple nodules within the abdominal cavity. • Accompanying ascites is the rule; Association with Peutz–Jeghers syndrome
- 126. Radiological Finding Desmoplastic small round cell tumor
- 127. Cytology Findings
- 128. Pathological Findings Desmoplastic small round cell tumor
- 135. Desmin
- 136. Immun0histochemical Features Reactivity for • Neural (neuron-specific enolase) markers • Leu-7 • WT-1 • Vimentin
- 138. Molecular Genetics
- 140. Lymphoblastic Lymphoma Age:Primarily in children and adolescents, but it also occurs in adults Sex:M>F Site: Mediastinum( Thymus). Presentations: • Typically presents with acute respiratory distress in teenager. • Extremely aggressive, with rapid multisystem dissemination. • Leukemic blood picture (acute lymphoblastic leukemia). • Death after a few months.
- 142. Cytological Findings
- 148. Histochemical studies Acid phosphatase β- glucuronidase α- naphthyl acetate esterase TdT
- 149. Immun0histochemical Features Reactivity for • TdT • CD1 • CD2 • CD3 • CD43 • CD99 • bcl2 • CD71 • LCA+
- 151. Molecular Genetics Translocation alpha & delta T-cell receptor loci beta T-cell receptor loci gamma T-cell receptor loci 14q11.2 7q35 7p14–15 Dysregulation of transcription Partner genes (MYC, TAL1, RBTN1, RBTN2, and HOX11)