Diagnostic Techniques Neuroblastoma Not Obvious Obvious

Small Round Blue Cell Tumors of Childhood

• Neuroblastoma Differential Diagnosis of Small Round • Wilms tumor Blue Cell Tumors of Childhood • Rhabdomyosarcoma • Malignant lymphoma • Hepatoblastoma Jesse J. Jenkins, III, M.D. Director of Pathology • Germ cell tumors for the • Desmoplastic small round cell tumor International Outreach Program St. Jude Children’s Research Hospital 2

SMALL ROUND CELL TUMOR

Neuronal differentiation, rosettes, ganglion cells, neurofibrillary material Diagnostic Techniques Neuroblastoma Not obvious Obvious

Histology Catecholamines + • Light microscopy – routine stains Synaptophysin+ EM Chromogranin+ Neuroblastoma – Routine H&E

IHC LCA+ EM Lymphoma/leukemia – Special stains MP Actin+ Rebiopsy Desmin+ Inconclusive • Immunohistochemistry Myogenin+ t(11;22) Histology Synaptophysin+/- t(21;22) EM • Molecular cytogenetics HBA-71+

Rhabdomyosarcoma • Cytogenetics Ewing’s family of tumors Histology t(1;13) or t(2;13)

Alveolar Rhabdomyosarcoma 3 4

FAB Classification of Leukemia

L1 L2 L3 5 6

1 7 Bone Marrow Aspirate 8

Bone Marrow Aspirate - Synaptophysin 9 Bone Marrow Biopsy 10

Bone Marrow Biopsy - Synaptophysin 11 Bone Marrow Biopsy - Synaptophysin 12

2 13 14

15 16

Rhabdomyosarcoma

• Definition – Malignant solid tumor – Derived from primitive mesenchyme – Striated muscle differentiation

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3 Rhabdomyosarcoma Lesions Misdiagnosed as International Classification Rhabdomyosarcoma • Superior prognosis • Ewing sarcoma • Synovial sarcoma – Botryoid rhabdomyosarcoma • Malignant lymphoma • Pleuropulmonary • Wilms tumor blastoma – Spindle cell rhabdomyosarcoma • Langerhans cell • Rhabdoid tumor • Intermediate prognosis histiocytosis • Desmoplastic small cell – Embryonal rhabdomyosarcoma • Inflammatory tumor pseudotumor • Mesothelioma • Poor prognosis • Malignant peripheral • Epithelioid angiosarcoma – Alveolar rhabdomyosarcoma nerve sheath tumor • Epithelioid – Undifferentiated sarcoma hemangioendothelioma

19 20

Rhabdomyosarcoma, botryroid type 21 Rhabdomyosarcoma, embryonal type 22

Rhabdomyosarcoma, embryonal type 23 Rhabdomyosarcoma, alveolar type 24

4 Rhabdomyosarcoma - Muscle Specific Actin25 Rhabdomyosarcoma - Desmin 26

Rhabdomyosarcoma - Synaptophysin 27 Rhabdomyosarcoma - Myogenin/MyoD1 28

Ewing Sarcoma Family of Tumors Ewing Sarcoma • T(11;22)q24;q12 or variant of Bone –Ewing sarcoma • Bone • Soft tissue – Askin tumor – Desmoplastic small cell tumor – Ectomesenchymoma – Esthesioneuroblastoma

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5 Ewing Sarcoma Family of Tumors 31 Ewing Sarcoma Family of Tumors 32 Touch Prep -Wright Stain

Ewing Sarcoma Family of Tumors 33 Ewing Sarcoma Family of Tumors 34 Touch Prep - H&E Stain Spinal Fluid Cytospin - Wright Stain

Ewing Sarcoma Family of Tumors 35 Ewing Sarcoma Family of Tumors 36 CD99 (HBA-71, O13 clone) CD99 (HBA-71, O13 clone)

6 Ewing Sarcoma Family of Tumors 37 Ewing Sarcoma Family of Tumors 38 Synaptophysin Desmoplastic Small Cell Tumor

Ewing Sarcoma Family of Tumors 39 Ewing Sarcoma Family of Tumors 40 Desmoplastic Small Cell Tumor Desmoplastic Small Cell Tumor - HBA-71

Ewing Sarcoma Family of Tumors 41 Ewing Sarcoma Family of Tumors 42 Desmoplastic Small Cell Tumor - Vimentin Desmoplastic Small Cell Tumor - Muscle Specific Actin

7 Ewing Sarcoma Family of Tumors 43 Ewing Sarcoma Family of Tumors 44 Desmoplastic Small Cell Tumor - Desmin Desmoplastic Small Cell Tumor - Cytokeratin AE1-AE3

Ewing Sarcoma Family of Tumors 45 Ewing Sarcoma Family of Tumors 46 Desmoplastic Small Cell Tumor - Cytokeratin CAM 5.2 Desmoplastic Small Cell Tumor - Epithelial Membrane Antigen

9-year-old Boy

• Abdominal mass • Bilateral & multiple renal tumors • Right radical nephrectomy

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8 49 50

51 52

53 54

9 Final Diagnosis

• Wilms tumor • Diffuse anaplasia • Local stage III • Overall stage V

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Wilms Tumor Wilms Tumor Points to Remember • National Wilms Tumor Study (NWTS) • Clear cell sarcoma and rhabdoid tumor are – Established in 1969 NOT Wilms tumor variants – Three studies complete • “Unfavorable histology” – Preliminary data from the fourth – Anaplasia is the only criterion – Survival risen from 20% to 90% – Fifth activated June 1995 closed June 2002 • Therapeutic trial and biologic study

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Wilms Tumor Wilms Tumor “Unfavorable histology” “Unfavorable histology” • Diffuse anaplasia • Gigantic polyploid nuclei – Any extrarenal site – Size three times those of adjacent cells AND – Any random biopsy specimen – Multipolar/polyploid mitotic figures – Anaplasia in one region but with “extreme • New definition of focal anaplasia nuclear unrest” elsewhere – “Sharply restricted foci within the primary – Anaplasia in more than one tumor slide, unless tumor” • Every slide from same region • Minute foci surrounded by non-anaplastic tumor • Anaplasia same significance in treated

59 tumors 60

10 One-month-old Boy

•Liver mass, left lateral •Markedly elevated α-fetoprotein •Percutaneous needle biopsy

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11 Final Diagnosis

Hepatoblastoma, type indeterminate (needle biopsy)

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Hepatoblastoma Hepatoblastoma Stages Cytohistologic Types Surgical and Histologic Criteria • Fetal (favorable histology if pure) • Stage I • Embryonal – Gross total resection with clear margins • Fetal/embryonal • Stage II • Mixed (epithelial + mesenchymal) – Gross total resection with positive margins • Stage III • Macrotrabecular – Gross total resection with + lymph nodes or • Fibrolamellar – Incomplete resection • Stage IV • Small cell undifferentiated (“anaplastic”) – Metastatic disease

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Hepatoblastoma Hepatoblastoma Definition of Prognostic Groups Prognostic Cytohistology Stage I only

• Favorable Histology • Favorable – Pure fetal type, completely resected (stage I) – Pure fetal histology with minimal mitoses • “Unfavorable” Histology • zero mitoses (Haas et al.) – All other types and stages • <2 mitoses per 10 HPF (Ortega et al.) • Unfavorable – All other histologic types

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12 Hepatoblastoma Definition of Prognostic Groups References • Haas JE, Muczynski KA, Krailo M, Ablin A, Land V, Vietti TJ, Hammond GD. Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma. Cancer Jesse J. Jenkins, III, M.D. 64:1082-1095, 1989. Department of Pathology St. Jude Children’s Research Hospital • Ortega JA, Douglass EC, Feusner JH, Reynolds M, Quinn 332 North Lauderdale Street JJ, Finegold MJ, Haas JE, King DR, Liu-Mares W, Sensel Memphis, Tennessee 38105-2794 MG, Krailo MD. Randomized comparison of USA cisplatin/vincristine/fluorouracil and cisplatin/continuous [email protected] infusion doxorubicin for treatment of pediatric Phone: (901)495-3516 hepatoblastoma: A report from the Children’s Cancer Fax: (901)495-3100 Group and the Pediatric Oncology Group. J Clin Oncol Web site: www.Cure4Kid.org 18:2665-2675, 2000. 73