INTERHOSPITAL CONFERENCE17 NOVEMBER 2009

10 years old boy Prolong fever,

arthritis

PATIENT DATAผู้��ป่�วยเด็กชายไทย อาย� 10 ป่�ท��อย�� อ�าเภอเมื�อง จั�งหว�ด็กาฬสิ!นธุ์�$Chief complaintไข้�สิ�ง ป่วด็ข้�อ 1 สิ�ป่ด็าห$ ก�อนมืาโรงพยาบาล

PRESENT ILLNESS

1 เด็�อนก�อน มืาด็�วยไข้� 7 ว�น ป่วด็ข้�อ ข้�อบวมื

SEM at LUPSB, liver 4cm below RCM

Lt wrist, Lt knee and ankle then Rt ankle arthritis (migratory polyarthritis)

INVESTIGATION 1 เดื�อนก่�อนCBC: Hct 28.6%, Hb 9 g/dl, corrected WBC 9,600, N 37%, L 43%, M 18%, NRC 153/100 WBC, plt 117,000

MCV 72.9, MCH 22.9, MCHC 31.4, RDW 20.8ESR 82 mm/hr, ANA-, ASO positive 1:1, RF -, CRP + 1:64,

Melioid titer 1:40, H/C no growth, PPD -CXR: mild cardiomegalyEKG: NSR, HR 120/min, QRS axis 750, PR 0.12 sec, QTc 0.38 sec, borderline LVH

Echocardiogram: EF 76.8%, mild LV enlargement, trivial MR

Dx: acute rheumatic fever: 1 major (poly arthritis), 2 minor ( fever, ESR, CRP), + evidence Strep infection (ASO+)

Rx: cefotaxime x 8 d, amoxy+clavulanic acid x 6d, ASA gr V (90mkd)

Severe joint pain, pain score= 10 : suspected malignancy/ JRA

Brufen, tramol, MST, morphine syrup prn Prednisolone 2 MKD x 2 wk LDH 2,476 U/L uric acid 6.3 mg/dl, ESR 135 mm/hr, CRP 1:16,

Coomb’s test –, ANA-, RF-, UA normaleye exam: no uveitis

BMA: inadequateBM biopsy: fragment of cartilage, no bone marrow tissue seen

Film bone survey: multiloculated cystic lesion at distal of Lt femur, no osteolytic lesion, suspected benign condition,

No malignancy conditionBone scan: ?Ultrasound abdomen: hepatomegaly

PRESENT ILLNESS1 สิ�ป่ด็าห$ก�อนมืาโรงพยาบาล มื�ไข้�สิ�ง สิ�วน

ใหญ่�เป่-นไข้�กลางคื�น ป่วด็เมื��อยต้�นข้า 2 ข้�าง ป่วด็ข้�อศอก ท�1ง 2 ข้�าง ข้�อมื�อ ข้�อน!1วมื�อ ข้�อเข้�าข้วา ไมื�ไอ ไมื�หอบ ป่วด็ศ�รษะเลกน�อย ป่4สิสิาวะอ�จัจัาระป่กต้! ไมื�มื�น�1าหน�กลด็ ร�บป่ระทานอาหารได็�

2 ว�น ก�อนมืา ไข้�ต้ลอด็ว�น ป่วด็ข้�อมืากข้51น ป่วด็สิะโพก 2 ข้�าง เด็!นล�าบาก

PAST HISTORYมื�เล�อด็ก�าเด็าไหลเป่-นๆหายๆ (ต้�1งแต้�อาย� 3-4 ป่� ป่�ละ 3-4 คืร�1ง)7 เด็�อนก�อน มืาด็�วยไข้� 2 เด็�อน เบ��ออาหาร อ�อนเพล�ย ท�องโต้ข้51น

ซี�ด็ลง น�1าหน�กลด็ลง 2 ก!โลกร�มื ใน 1 เด็�อน ต้รวจัร�างกาย พบซี�ด็ มื�ามืโต้ 10 cm below LCM, CBC: pancytopenia BMA: erythroid hyperplasia, no blastBM biopsy: bony tissue with paucity number of

hematopoietic cells without evidence of leukemia

Lymph node biopsy at inguinal: reactive lymphoid hyperplasia

PAST HISTORY

CT abdomen: diffuse splenomegalySplenectomy:

diffuse sinusoidal hemangiomatosis with extramedullary hemopoeisis

EBV Ig M +, IgG+, CMV IgM-, IgG+Antibiotic 17 daysHb typing: Homozygous Hb E

PAST HISTORY

จัากน�1นมืา follow up ท�ก 1 เด็�อน มื�ไข้�บางคืร�1ง เล�อด็ก�าเด็าไหลเลกน�อย admit 1 คืร�1ง เมื��อ 4 เด็�อนก�อน x 2 ว�น

Hct 29% WBC, platelet ป่กต้! ได็�ร�บ folic, MTV, zyrtecFamily history

มืารด็าเป่-นโรคืหอบห�ด็มื�ญ่าต้!ทางบ!ด็าเป่-นโรคืเล�อด็ (ไมื�ทราบว�า

เป่-นโรคือะไร)ป่ฏิ!เสิธุ์ป่ระว�ต้!มืะเรงในคืรอบคืร�ว

PHYSICAL EXAMINATIONVital signs: BT 39.70 C BP 110/70 mmHg PR 112/min RR 22/min

BW 23 kg (P3-10) Ht 130 cm (P25)GA: A boy, fully consciousness, well co-operate

HEENT: mild pale conjunctiva , anicteric sclera pharynx and tonsils: not injected Rt cervical lymph node 0.5 cm

PHYSICAL EXAMINATION

Heart : systolic ejection murmur gr II at LPSB

Lungs : normal and equal breath sound, no adventitious sound

Abdomen: soft, liver 3 cm below RCM

Extremities: no edemaTender and swelling of bilateral elbow, wrist, 4th, 5th MCP, Lt 2nd, 5th MCP, Rt knee joint

PROBLEM LISTS

Prolong feverPolyarthritisAnemiaHepatomegalySEM gr IIS/P splenectomyHomozygous HbE

DDX

Infection: TB, virus (EBV, CMV), Bacteria, fungus

Connective tissue disease: JRA, SLE

Malignancy: acute leukemia, lymphoma

IAHSLCH

INVESTIGATION

INVESTIGATION CBC: Hb 10.2 g/dL, Hct 31%, WBC corrected 4,900

N 45%, L 36%, M 18%, E 8%, NRC 91/100 WBC, Platelet 131,000 MCV 85.7 fl, MCH 28.2 pg, MCHC 32.9 g/dL BUN 5 mg/dL, Cr 0.4 mg/dL, Uric acid 3.4 mg/dL Na 139, K 3,8, Cl 97, CO2 29 mmol/L, Ca 8.9, Mg 2,

P 4 mg/dL Albumin 2.4 g/dL, AST 54 U/L, ALT 37 U/L. ALP 520

U/L Hemoculture; no growth UA : pH 5.5 ,sp.gr. 1.025, wbc 1-2 , rbc 0-1 ESR : 75 mm/hr

INVESTIGATION

LDH 542 U/LFerritin 3,840 ng/ ml

B-HCG 1.11 mIU/ml, AFP 3.08 IU/ml

ASO-, CRP-, Melioid 1:20

Bone marrow aspiration

Multiple radiolucency lesions

Ultrasound whole abdomen:diffuse hepatomegaly

BMA: inadequate, rare nucleated cell, no blast

Cytochemistry: numerous cell debris and very rare blood cell

have been observed, no hematologic malignancy cell

:Other cause of bone marrow destruction should be ruled out

Flow cytometry: blast gate 2.63% of total event

No evidence of hematologic malignancy

1st admission

HISTOPATHOLOGY REPORT

1st admission

Splenic hemagiomatosis(1st admission)

Splenic hemagiomatosis(1st admission)

Bone marrow biopsy:

Bone marrow necrosis No malignancy cell

Bone biopsy at Lt humerous:

Bone marrow necrosis No malignancy cell

BONE MARROW NECROSIS (BMN)

Necrosis of myeloid tissue and medullary stroma in the large areas of hematopoietic bone marrow

On BM biopsy: disruption of the normal bone marrow architecture with a considerable loss of fat space

Aplastic anemia: only loss of myeloid tissue and no destruction of reticular structure

Aseptic necrosis: no destruction of the spicular architecture

Hypoxemia after failure of microcirculation: Inflammatory damage or mechanical obstruction

: DIC, sickle cell disease or tumor cell plug Immune processToxicity and the release of toxins, cytokines,

or vasoactive substances from damaged cells

: TNF

Major complication: pancytopenia, embolic processes Repopulation of the bone marrow cavity

can occur after BMN resolved

IDENTIFIED UNDERLYING MALIGNANCY 90%

Extensive search for neoplastic disease is justified whenever BMN is

diagnosed

1st described by Wade and Stevenson, 1942

: Sickle cell disease, died of cerebral infarction

Nies et al. 1965: define BMN in acute leukemia

34/ 316 (10.75%) postmortem

Kiraly and Wheby.1976: 13/664 (2%) in BM specimens during 12 –year period

Norgard, 1979. retrospectively reviewed 120/368 (32.5%), only 4 were diagnosed at initial

GRADING Small necrotic lesions: <25% of the dimention of

the biopsy (39%) Intermediate BMN < 50% (24%) Large BMN >75% (12%) Extensive: throughout the dimension of the

specimen

Pennaforte et al. 1986: extensive 4/1149 (0.3%) Maisel etal. 1988: severe BMN > 50% of

dimension (3%)

BMN IN CHILDREN

Macfarlane and Tauro: 4/379 (1%) in ALL Pui et al: 7/1419 (0.5%) in cancer patients

BONE MARROW NECROSIS (BMN)ANN M. JANSSENS ET AL. CANCER 2000

Clinicopathologic entity, rare condition Review 240 cases, 1980-1999 Inclusion

1. BMN diagnosed during life

2. necrosis > 50% of the diameter of

biopsy specimen

UNDERLYING DISEASE ASSOCIATION

Malignancy 91% Hematologic malignancies 60% Acute leukemia 41%, lymphoma 15% ALL 18%, AML 13% Children 18/25 cases were ALL BMN developed before diagnosis: ALL 26/37

(AML 16/24) After induction chemotherapy 1/37 At recurrence 10/37

UNDERLYING DISEASE ASSOCIATION

Solid tumors 30% Not found primary origin, even after extensive

search 12/43 Non malignancy only 9%: sickle cell crisis,

infection, drug, HUS, antiphospholipid syndrome, DIC, hyperparathyroidism, anorexia nervosa, idiopathic etc.

16/22 documented infection: underlying malignancy were found later (early - 1 yr)

Infection E.coli Streptococcus Staphylococcus Citrobacter freundii Salmonella Mucormycosis Q fever TB Parvovirus HIV

Drug Sulphasalazine Sulphathiazol Sulphanamide Interferon-alpha G-CSF ATRA Hydroxyurea Fludarabine

PRESENTATION

Bone pain 75% Fever 68.5% Anemia 91% Thrombocytopenia 78% Leukoerythroblastic picture 51% Elevated LDH, alkaline phosphatase 50%

primitive red cells (nucleated rbc or erythroblasts) primitive white blood cells (myelocytes)

Leukoerythroblastic picture

Cytology Bone marrow aspiration can be unsuccessful Multiple aspirates from different sites

(sternal, posterior iliac crest, etc.) Serosanguineous, watery dark red or clear fluid

Histology Combination of gelatinous transformation and

necrosis of the myeloid tissue Background of gelatinous transformation

surrounds cellular debris with indistinct cellular margins, pyknotic nuclei, and abnormal eosinophilic staining cytoplasm

The hallmark of bone necrosis: loss of osteocytes, osteoblasts, and osteoclasts

background of amorphous extracellular eosinophilic material that surrounds cells that disintegrate.

shows cells that lose their normal staining characteristics. irregular or indistinct margins; the cytoplasm can shrink or vacuolate, and the nucleus shows pyknosis, karyorrhexis, and karyolysis

Bone Marrow Scanning Technetium 99m sulfur colloid and indium

chloride localize selectively to the reticuloendothelial elements of the marrow

Dx BMN, residual BM activity, guided biopsy, recovery

MRI: changes in bone marrow signal intensities

Life-threatening complication:

embolization of fat and necrotic bone marrow

to pulmonary arteries

PROGNOSIS

Median survival of the hematologic malignancies :1 - 4 months, 69% died

Childhood ALL: 13/18 alive Survival: 4 months- 6 years Solid tumor and BMN: widespread

metastasis, short survival

PROGRESSION OF THE PATIENT

High grade fever Petechiae hemorrhage at face, periorbital Increased hepatomegaly Blood component therapy, antibiotic, pain

management

Consult for liver biopsy Repeat BMA and biopsy Plan MRI liver and bone Steroid

Hepatomegaly

CBC

Hb

Hct

cWBC

NRCNL MEother

Plt

D15

1.

1

5.9

8 .8

1

3

0

5

0

3

5

1

05 

1

7

2

D36

7

2

1

3.3

2

0

0

3

2

4

1

1

34

band2, meta2,myelo1, atyp L5

1

4

4

D106

1

1

9.5

1

1.7

8

0

3

6

4

4

1

64 2

7

D156

9

2

1.3

4.1

2

1

6

0

3

052band2 atypl1 7

D165

7

1

7.4

3.9

1

9

4

1

5

52  atyp37

4

D178

2

2

4.3

4.9

4

4

4

2

5

23  band 2, atyp12

1

D247

4

2

1.6

1

0.8

3

1

4

2

3

89  band6, atyp 54

0

D25 9

2

6.8

7.8

4

8

3

8

4

0

1

0 

band2, meta3, myelo1, atyp 4, blast2

3

0

D307

4

2

2

3.2

5

0

4

9

3

29  blast104

9

D316

8

2

0.2

9.2

5

2

4

1

4

7

1

0  atyp23

4

D355

6

1

7

1

5.1

4

2

3

8

1

0    blast8,atyp21

3

ABG pHPCO

2PO2

HCO3

ABE

O2 sat

7.0

7 19.2

4

4

4

5 .7 -22

1

0

0

Developed massive GI bleedingtreatment: LPB, Platelet, FFP, antibioticCardiac arrest: CPR x 30 min

PT INRPTT D-dimer

3

1.2

2.6

7

3

4 .4

0.6 mg/L

Bone marrow aspiration at sternum

BM biopsy from 1. right ASIS: Abnormal blast cells infiltrate with focal

necrosis and crush artifact2. A small amount of marrow tissue from

Lt ASIS: abnormal blast cells3. Sternum: numerous blast cell infiltrate

: precursor T lymphoblastic leukemia/ lymphoblastic lymphoma

CD3+, CD20-, CD79a-, CD34-, MPO-, TdT+

Liver biopsy

: precursor T lymphoblastic leukemia/ lymphoblastic lymphoma

CD3+, CD20-, CD79a-, CD34-, MPO-, TdT+

Extensive search for neoplastic disease

Multiple aspirates from different sites

: biopsy site in which viable hematopoietic bone marrow

THANK YOU