Case Presentation

1. Case Presentation K. Myra Lalas, MD PGY 3

2. Chief Complaint • difficulty walking and difficulty breathing

3. What do you want to know about the HPI?

4. HPI • Clumsiness when walking that evolved over a month • (+) cough x 2wks • Tactile fever at home x 1wk • Difficulty breathing x 2 days • Decreased PO x 2 wks • Weight loss x 1 mo

5. Physical Exam VS Temp 38.2F HR 110 RR 44 O2sat 93% Gen awake, alert, mod resp distress HEENT PERRLA, EOMI, OP clearm no LAD Lungs no Rx, dec AE on R mid-lower lung field, no w/r/r Heart N S1/S2, no murmurs Abd soft, NT/ND Ext FEP, CRT < 2s Neuro CN intact, no sensory deficits, normotonic, no dysmetria, (+) ataxia, ++ reflexes

6. Course of Illness • 13 mo male with difficulty walking and clumsiness when walking. (+) history of cough, difficulty breathing, and decreased PO. Symptoms worsened over a month. • Went to PMD- referred to ER. In the ER was noted to have respiratory distress. • 7/6/08- CT of the abdomen and thorax revealed a large calcified posterior mediastinal mass.

7. What are your differentials for a posterior mediastinal mass?

8. Differentials for Posterior Mediastinal Mass • neurogenic tumors • esophageal tumors • esophageal duplication cysts • hiatal hernia, • neurenteric cysts • Aortic aneurysm

9. CT of the abdomen and thorax- large calcified posterior mediastinal mass with expansion of the neural foramina as well as mediastinal LAD. Most likely neuroblastoma; (+) multifocal pneumonia with right pleural effusion • MRI of the thoracic spine- large posterior mediastinal mass invading the epidural space of the central spinal canal. (+) cord compression with anterior and left lateral displacement of the cord at the T7-T9 level

10. Bone Marrow Aspiration/ biopsy (2 sites) were negative. • He was transferred to the ICU for chest tube placement and drainage of right pleural effusion.

11. Neuroblastoma • Most common extracranial malignancy of infancy • Embryonal malignancy of the the SNS arising from neuroblasts • In the developing embryo, these cells invaginate, migrate along the neuraxis, and populate the sympathetic ganglia, adrenal medulla, and other sites.

12. Pathophysiology: 1. MYCN gene (oncogene) amplification- overexpressed in approximately one quarter of cases of neuroblastoma via the amplification of the distal arm of chromosome 2. amplified in about 25% of de novo cases and is more common in patients with advanced-stage disease. 2. H-ras oncogene amplification- seen in lower disease stages 3. Disruption of normal apoptotic pathways

13. Anatomic Location • Location of tumors varies with age.: infants- thoracic and cervical tumors; older children- abdominal tumors. • Tumors can develop in the abdominal cavity (40% adrenal, 25% paraspinal ganglia) or other sites (15% thoracic, 5% pelvic, 3% cervical tumors, 12% miscellaneous).

14. Epidemiology • Whites > blacks • M: F ration of 1.2:1 40% of patients are < 1 year when diagnosed, 35% are aged 1-2 years 25% are older than 2 years when diagnosed. Incidence decreases every consecutive year up to age 10 years, after which the disease is rare.

15. Signs and Symptoms • Abdominal pain, emesis, weight loss, anorexia, fatigue, and bone pain • Hypertension (renal artery compression) • Unexplained fever • Periorbital ecchymosis (mets to orbits)

16. Signs and Symptoms • weakness, limping, paralysis, and even bladder and bowel dysfunction (tumors from parasympathetic ganglia can impinge on the SC) • Horner Syndrome • Intractable diarrhea(due to VIP secretion/ paraneoplastic)

17. Other Differential Diagnoses?

18. Differental Diagnosis • Rhabdomyosarcoma • Wilms Tumor • Osteomyelitis • Rheumatoid arthritis • Disseminated bone disease • Primary neurologic disease • Inflammatory bowel disease

19. Workup • CBC with differential count (to test for BM involvement) • CMP • Urine collection for VMA/HVA and UA • Uric acid • LDH • Ferritin • TFT’s

20. Imaging • CXR, AXR • CT Scan • MRI • MIBG accumulates in catecholaminergic cells and provides a specific way of identifying primary and metastatic disease if present. Tc 99 bone scan

21. Arrows point to pseudorosetttes (circles of tumor cells surrounding nerve fibers); small round blue cells with scant cytoplasm

22. International Neuroblastoma Staging System (INSS)

27. Chest CT Scan- Neuroblastoma on the left and over the spine

28. Other Tests Obtain the following as baseline studies before therapy with anthracyclines: • ECG • Echocardiogram Baseline hearing tests are recommended before cisplatin therapy.

29. Treatment • Prognosis dependent upon patient’s age and disease staging. • Early disease treatment may only involve tumor resection. • Surgery, radiation therapy, chemotherapy for advanced disease.

30. Chemotherapy • Cyclophosphamide (activates production of alkylating agents) • Doxorubicin (DNA strand breakage though topisomerase II) • Etoposide (DNA strand break) • Cisplatin, (binds and x-links DNA strands) • Vincristine (mitotic inhibitor by binding tubulin)

31. MIBG- selectively absorbed by neuroblastoma cells; used to deliver targeted radiation to neuroblastoma cells by binding it to I-131 ( iodine radioisotope) • Isotretinoin- Vitamin A derivative. Interacts with retinoic acid responsive elements on DNA, which results in gene activation and differentiation of target cells. • I-3F8- experimental; attached to GD 2 marker on NB cells, which activates the immune system (renders NB cells foreign and immune system attacks them)

32. 7/7/08- laminectomy and partial resection of the mass; started on ANBL0531 protocol x 4 cycles • 10/16/08- tumor resection; pathology consistent with bone mets • 5/26/09 – retrieval tx per N8 protocol for relapse

33. 6/11/09- extensive resection of the disease • 8/27/09- underwent neurosurgical resection for residual disease in the epidural space • 9/10/09- started a cycle of high dose cyclophosphamide, topotecan, and Vincristine • 10/09- no evidence of neuroblastoma • 11/16/09- 3 F8 tx • 11/17/09- started on isotretinoin

34. References • www.emedicine.com • www.mskcc.org • Nelson’s Textbook of Pediatrics