Interhospital Conference 17 November 2009 10 years old boy Prolong fever, arthritis

Patient data Chief complaint ผู้ป่วยเด็กชายไทย อายุ 10 ปี ที่อยู่ อำเภอเมือง จังหวัดกาฬสินธุ์ Chief complaint ไข้สูง ปวดข้อ 1 สัปดาห์ ก่อนมาโรงพยาบาล

1 เดือนก่อน มาด้วยไข้ 7 วัน ปวดข้อ ข้อบวม Present illness 1 เดือนก่อน มาด้วยไข้ 7 วัน ปวดข้อ ข้อบวม SEM at LUPSB, liver 4cm below RCM Lt wrist, Lt knee and ankle then Rt ankle arthritis (migratory polyarthritis)

Investigation 1 เดือนก่อน CBC: 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 20.8 ESR 82 mm/hr, ANA-, ASO positive 1:1, RF -, CRP + 1:64, Melioid titer 1:40, H/C no growth, PPD - CXR: mild cardiomegaly EKG: 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

Brufen, tramol, MST, morphine syrup prn Prednisolone 2 MKD x 2 wk 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 normal eye exam: no uveitis

BMA: inadequate BM 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 condition Bone scan: ? Ultrasound abdomen: hepatomegaly

2 วัน ก่อนมา ไข้ตลอดวัน ปวดข้อมากขึ้น ปวดสะโพก 2 ข้าง เดิน ลำบาก Present illness 1 สัปดาห์ก่อนมาโรงพยาบาล มีไข้สูง ส่วนใหญ่เป็นไข้กลางคืน ปวดเมื่อยต้นขา 2 ข้าง ปวดข้อศอก ทั้ง 2 ข้าง ข้อมือ ข้อนิ้วมือ ข้อ เข่าขวา ไม่ไอ ไม่หอบ ปวดศีรษะเล็กน้อย ปัสสาวะอุจจาระปกติ ไม่มีน้ำหนักลด รับประทานอาหารได้ 2 วัน ก่อนมา ไข้ตลอดวัน ปวดข้อมากขึ้น ปวดสะโพก 2 ข้าง เดิน ลำบาก

มีเลือดกำเดาไหลเป็นๆหายๆ (ตั้งแต่อายุ 3-4 ปี ปีละ 3-4 ครั้ง) Past history มีเลือดกำเดาไหลเป็นๆหายๆ (ตั้งแต่อายุ 3-4 ปี ปีละ 3-4 ครั้ง) 7 เดือนก่อน มาด้วยไข้ 2 เดือน เบื่ออาหาร อ่อนเพลีย ท้องโตขึ้น ซีดลง น้ำหนักลดลง 2 กิโลกรัม ใน 1 เดือน ตรวจร่างกาย พบซีด ม้ามโต 10 cm below LCM, CBC: pancytopenia BMA: erythroid hyperplasia, no blast BM biopsy: bony tissue with paucity number of hematopoietic cells without evidence of leukemia Lymph node biopsy at inguinal: reactive lymphoid hyperplasia

diffuse sinusoidal hemangiomatosis with extramedullary hemopoeisis Past history CT abdomen: diffuse splenomegaly Splenectomy: diffuse sinusoidal hemangiomatosis with extramedullary hemopoeisis EBV Ig M +, IgG+, CMV IgM-, IgG+ Antibiotic 17 days Hb typing: Homozygous Hb E

ได้รับ folic, MTV, zyrtec Past history จากนั้นมา follow up ทุก 1 เดือน มีไข้บางครั้ง เลือดกำเดาไหล เล็กน้อย admit 1 ครั้ง เมื่อ 4 เดือนก่อน x 2 วัน Hct 29% WBC, platelet ปกติ ได้รับ folic, MTV, zyrtec Family history มารดาเป็นโรคหอบหืด มีญาติทางบิดาเป็นโรคเลือด (ไม่ทราบว่าเป็นโรคอะไร) ปฏิเสธประวัติมะเร็งในครอบครัว

GA: A boy, fully consciousness, well co-operate Physical Examination Vital 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

Heart : systolic ejection murmur gr II at LPSB 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 edema Tender and swelling of bilateral elbow, wrist, 4th, 5th MCP, Lt 2nd, 5th MCP, Rt knee joint

Prolong fever Polyarthritis Anemia Hepatomegaly SEM gr II Problem lists Prolong fever Polyarthritis Anemia Hepatomegaly SEM gr II S/P splenectomy Homozygous HbE

DDx Infection: TB, virus (EBV, CMV), Bacteria, fungus Connective tissue disease: JRA, SLE Malignancy: acute leukemia, lymphoma IAHS LCH

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

LDH 542 U/L Ferritin 3,840 ng/ ml B-HCG 1.11 mIU/ml, AFP 3.08 IU/ml Investigation LDH 542 U/L Ferritin 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 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 process Toxicity 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%

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

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 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

Disorder Survival data available Alive Death Median survival Range of survival ALL (adult + childhood) 35/43 17 18 4 mos 2 days to 6.5 yrs Childhood ALL 18/25 13 5 2.5 yrs 4 mos to 6 yrs AML 25/31 20 2 mos 8 days to 3 yrs AL 22/24 22 Not available 2 mos to 2 yrs MPD 7/13 1 6 3 mos 5 days to 25 mos Lymphoma 24/35 7 1 mo Early to 8 mos Solid tumors 18/72 3 15 5 wks Early to 4 mos Sickle cell disease 6/6   Infections 5/6 2 3 wks Early to 29 days Drugs 1/2 Others 5/8 4 2.5 wks 1-4 wks

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 NRC N L M E other Plt D1 5.1 15.9 8.8 130 50 35 10 5   172 D3 6.7 21 3.3 200 32 41 13 4 band2, meta2,myelo1, atyp L5 144 D10 6.1 19.5 11.7 80 36 44 16 27 D15 6.9 21.3 4.1 60 30 2 band2 atypl1 7 D16 5.7 17.4 3.9 19 55 atyp3 74 D17 8.2 24.3 4.9 42 52 3 band 2, atyp1 D24 7.4 21.6 10.8 31 38 9 band6, atyp 5 40 D25 26.8 7.8 48 band2, meta3, myelo1, atyp 4, blast2 D30 22 3.2 49 blast10 D31 6.8 20.2 9.2 47 atyp2 34 D35 5.6 17 15.1 blast8,atyp2

PT INR PTT D-dimer 31.2 2.67 34.4 0.6 mg/L ABG pH PCO2 PO2 HCO3 ABE Developed massive GI bleeding treatment: LPB, Platelet, FFP, antibiotic Cardiac arrest: CPR x 30 min ABG pH PCO2 PO2 HCO3 ABE O2 sat 7.07 19.2 444 5.7 -22 100 PT INR PTT D-dimer 31.2 2.67 34.4 0.6 mg/L

Bone marrow aspiration at sternum

: precursor T lymphoblastic leukemia/ lymphoblastic lymphoma BM biopsy from 1. right ASIS: Abnormal blast cells infiltrate with focal necrosis and crush artifact 2. A small amount of marrow tissue from Lt ASIS: abnormal blast cells 3. Sternum: numerous blast cell infiltrate : precursor T lymphoblastic leukemia/ lymphoblastic lymphoma CD3+, CD20-, CD79a-, CD34-, MPO-, TdT+

: precursor T lymphoblastic leukemia/ lymphoblastic lymphoma Liver biopsy : precursor T lymphoblastic leukemia/ lymphoblastic lymphoma CD3+, CD20-, CD79a-, CD34-, MPO-, TdT+

Thank You Extensive search for neoplastic disease Multiple aspirates from different sites : biopsy site in which viable hematopoietic bone marrow