HematologyOncology Grand Rounds

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Hematology/Oncology GrandRounds

• February 6, 2004
• Shachar Peles

An Unusual Aplastic
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Patient DL June 26, 2003

• 72 year old white male
• June 2003 new onset fatigue, dizziness and
  shortness of breath with activity.
• Was seen by PCP, Diagnosis Marked Anemia
• Hospitalized for PRBC Transfusion

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• PMH 1.Allergic Rhinitis. 2.Frequent sinusitis.
  3.Hypogammaglobulinemia, receives monthly IVIG.
  4.Gout 5.Prinzmetals Angina. 6.Osteoarthritis,
  Spinal Stenosis 7.Colon polyps. 8.GERD 9.Carpal
  Tunnel Syndrome
• Social History Retired Editor of The St. Louis
  Post Dispatch, quit smoking 20 yrs ago,
  Occasional Drink, Married with 2 children
• Family History Mother Hodgkins disease, CAD
• Medications Allegra, Ranitidine, Diazide,
  Cardizem, Flomax, Astelin NS, Nasonex NS, ASA,
  Metamucil, MV, PRN Tylenol, Ibuprofen.
  Allergies Sulfa drugs.

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• Physical Examination
• VSS
• Well nourished and in No acute distress
• Conjunctival pallor, anicteric
• Regular heart sounds
• Chest clear
• Spleen tip palpable
• No peripheral edema
• Neurological exam normal
• No lymphadenopathy

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Data

• Hgb 5.6 Wbc 3.1 Plt 100 ANC 1400 MCV 102
• Reticulocyte count 0.4
• Vit B12 734 Folate 16.4
• RBC Folate 1119 Ferr 425
• Haptaglobin 74 Direct Indirect Coombs
  negative
• LDH 148
• Erythropoietin Level 2432
• PTT 27.4 PT 13.9 INR 1.11
• Chemistries and Liver function tests normal
• CXR PALAT no abnormalities

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FINDINGS Two views of the chest demonstrates no
infiltrate, pleural effusion or pneumothorax. The
heart size and pulmonary vascularity are normal.
The aorta is mildly tortuous.
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Bone Marrow

• HYPERCELLULAR MARROW WITH MARKED ERYTHROID
  HYPOPLASIA AND MILD DYSPLASIA  IN THE MYELOID
  CELLS AND MEGAKARYOCYTES
• Bone marrow core biopsy (HE and Leder stains) 
• Specimen quality Adequate
•   Cellularity 80 
• Myeloid/Erythroid ratio 101
•   Megakaryocyte Number
  Increased
•   Myeloid Maturation Normal 
• Erythroid Maturation Normal
•   Megakaryocytic Maturation Normal
•   Other Findings Scattered
  multiple small lymphoid  aggregates consisting of
  mature-appearing small lymphocytes. 

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Bone Marrow

• Bone marrow aspirate smear (Wright-Giemsa stain)
•   Specimen quality Adequate 
• Spicules Present 
• Cellularity Increased
•   Myeloid/Erythroid ratio 21 
• Megakaryocyte Number Normal
•   Myeloid Maturation Mild
  dysplasia with hypolobulations. 
• Erythroid Maturation Markedly
  decreased.
• Megakaryocytic Maturation
  Dysplasia in the megakaryocytes with
   osteoclastic- like cells. 
• Stainable iron Present 

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Data

• Blood Parvovirus PCR Negative
• BM Cytogenetics 45,X,-Y/46,XY
• Requiring weekly/2 weekly PRBC TF to maintain Hgb
  gt 8g/dl
• Wkly Retic Count 0.1

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CT Scan July 21, 2003
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CT Scan July 21, 2003

• A large anterior mediastinal mass is seen
  measuring 7.4 cm in its left right dimension and
  5.4 cm in its anteroposterior dimension at slice
  position -96. The lesion measures 5.2 cm in its
  craniocaudal dimension. A distinct fat plane is
  seen between this mass and the pulmonary artery
  as well as between the mass in the aorta. 

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Surgery July 29, 2003

• Resection of anterior mediastinal mass via a
  median sternotomy.
• OPERATIVE FINDINGS
• The patient had a large anterior mediastinal
  mass, consistent with a thymoma.
• This was resected, taking great care to dissect
  the phrenic nerve away from the specimen.
• There was no evidence of any invasion into the
  great vessels.
• I did take a rim of pericardium with the specimen.

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Pathology

• MEDIASTINUM, ANTERIOR, EXCISION  -
  THYMOMA, SPINDLE CELL TYPE
• 1. A neoplasm is PRESENT
• 2. The specimen was received INTACT 
• 3. The MAXIMUM DIMENSION OF THE TUMOR is 9
  cm.
• 4. The WEIGHT of the thymus is 165 g. 
• 5. The HISTOLOGICAL CLASSIFICATION OF THE TUMOR
  is Thymoma, Spindle-cell type 
• 6. The NON-NEOPLASTIC THYMUS is  Not
  evaluable 
• 7. Regional lymph nodes are NOT submitted with
  the resected tumor 

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Pathology

• 8. STAGING  (AJCC SCHEME) 
• "T Substage"  T1 (Tumor is
  macroscopically encapsulated and shows
  no microscopic invasion of capsule)
• "N Substage"  N0 (No lymph node
  metastases are present) 
• THE FINAL AJCC/UICC STAGE GROUPINGS 
  I (T1 or T2/ N0/ M0) 

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Diagnoses

• 1. Thymoma
• 2. Pure Red Cell aplasia - paraneoplastic
• 3. Hypogammaglobulinemia ( Goods Syndrome ) -
  paraneoplastic

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Post Operative Follow Up September 11, 2003

• September 11, 2003 6 weeks post-op
• Recovering well from surgery but complaining of
  light-headedness and dyspnea with exertion.
• Transfused with 2 Units PRBC 2 weeks prior to
  visit.
• Hgb 8.5 WBC 6200 Plt 138,000 Retic 0.1
• Plan Start treatment with immunosuppression for
  PRCA associated with Thymoma.

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Immune Suppression

• September 25, 2003
• IVIG 0.4g/kg/day for 5 days

• no appreciable response.
• Hb 8.3, Retics 0.2

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Immune Suppression

• October 9, 2003
• Cytoxan 50mg daily
• November 13, 2003
• Cytoxan 75mg daily

• no appreciable response.
• Hb 8.0, Retics 0.1
• no appreciable response.
• Hb 8.2, Retics 0.1
• Wbc 2.9, Plt 55

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Cyclosporine

• December 11, 2003 Cyclosporine started at
  initial dose of 50mg PO BID.
• Dose gradually escalated to 150mg PO BID over
  next 6 weeks.
• Target trough levels of about 200.
• December 30, 2003 CSA 100mg BID
• Hb 8.4, Retics 0.1, CSA Level 53

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Cyclosporine

• January 14, 2004 Hb 7.9, Retics 2.1,
  CSA Level 73
• January 21, 2004 Hb 9.6, Retics 7.2, CSA
  Level 104
• January 28, 2004 Hb 10.8, Retics 5.3,
  CSA Level 136
• February 4, 2004 Hb 11.7, Retics 4.1

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Thymoma and Pure Red Cell Aplasia

• Thymomas are rare epithelial neoplasms.
• Associated with autoimmune disorders
• Pure Red Cell Aplasia (PRCA)
• Myasthenia Gravis
• PRCA is a rare disorder characterized by
• Anemia
• Reticulocytopenia
• Severe erythroid hypoplasia of bone marrow
• 5-13 of PRCA patients have thymoma (spindle
  cell).
• 5 Thymoma patients have PRCA.
• Thymectomy led to normalization of the Hb in
  approximatley 30 in one case series.

ASH Education Program 2000
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Classification of Pure Red Cell Aplasia

• Congenital Diamond-Blackfan syndrome
• Acquired
• Transient
• Primary Transient erythroblastopenia of
  childhood
• Secondary Parvovirus B19, hemolytic anemia,
  drugs
• Sustained
• Primary
• Secondary Immunocomprimised patients, B19
• Lymphocytic malignancies
• Autoimmune Disorders Thymomas
• Drugs
• Blood Reviews (1996) 10, 20-28

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Pure Red Cell Aplasia

• 3 etiologies
• Immunologic
• T Cell mediated
• Antibody Mediated
• Viral Parvovirus B19
• MDS

ASH Education Program 2000
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Lab features in PRCA

• Reticulocytopenia, bone marrow erythroid
  hypo/aplasia.
• Normal cytogenetics.
• Increased iron stores, normal B12 Folate.
• Appropriately increased Erythropoietin Level.
• When associated with Thymoma
• Low CD4/CD8 ratio due to increased CD8 cells
  (activation of cytotoxic T cells).
• Liley T cell mediated immune mechanism for PRCA.
• No evidence of TCR gene rearrangements.

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Management Recommendations PRCA

• Drug History
• Chest XR/CT to ro thymoma
• TCR gene rearrangement studies
• Marrow cytogenetics
• Parvovirus B19 PCR
• As indicated Drug withdrawal, Thymectomy, IVIG

ASH Education Program 2000 Blood 874831, 1996
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Transmission Electron Micrographs Showing Native
Parvovirus B19 in Serum and Cells and Recombinant
Capsids
Young, N. S. et. al. N Engl J Med 2004350586-597
Chen, S. et. al. N Engl J Med 2004350598
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Clinical Manifestations of Parvovirus B19
Infection
Young, N. S. et. al. N Engl J Med 2004350586-597
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Pathophysiology of Parvovirus B19 Infection
Young, N. S. et. al. N Engl J Med 2004350586-597
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Management Recommendations Immunologic PRCA

• Corticosteroids Prednisone 1mg/kg, RR 40
• Cyclophosphamide 50-100mg/day, RR 50
• Cyclosporine trough 200-300ng/ml, RR 60-80
• Antithymocyte Globulin 150mg/kg, RR 50
• Low Dose Methotrexate (LGL)
• Azathioprine
• Rituximab(Rituxan)(anti-CD20)
• Alemtuzumab(Campath-1H) (anti-CD52)
• Plasmapheresis

ASH Education Program 2000
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Management Recommendations PRCA

• Immunosuppressive therapy
• 8-10 week trial of each drug
• Responding patients treated for 3-6 months
• Most do not relapse with discontinuation of
  therapy
• 83 at 5 year follow up in U Washington series
• If refractory to first and second line agents
  consider in vitro erythroid culture
• If BFU-E mature poorly -gt ?myelodysplasia/B19
• If BFU-E grow well -gt consecutive
  immunosuppressive therapies
• Durable Remissions can be obtained in most (80)
  patients

ASH Education Program 2000 Blood 874831, 1996
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