MODUL TUTOR SKENARIO KEEMPAT
NAMA MAHASISWA KELOMPOK
Tim Kurikulum Pendidikan Preklinik Fakultas Kedokteran Universitas Islam Malang 2 0 13
SKENARIO KEEMPAT “Demam & Berat badan Turun”
URAIAN S K ENARIO
Tn Marijo, 48 tahun, Karyawan BUMN, pergi berobat ke Poliklinik karena demam, sesak napas dan tidak nafsu makan. Dua bulan terakhir pasien mengalami penurunan berat badan yang tidak direncanakan serta berkeringat di malam hari. Hasil pemeriksaan fisik dokter menunjukkan pasien
mengalami pembesaran limpa, hepar dan kelenjar limfe di inguinal serta purpura pada bagian ekstremitas inferior. Apa yang terjadi pada Tn. Marijo ?
Apa diagnosa banding demam pada kasus Tn. Marijo ? Bagaimana penegakan diagnosa demam pada kasus Tn. Marijo ?
Bagaimana penatalaksanaan pada kasus Tn. Marijo ?
I. IDENTIFIKASI KATA SULIT & ADDITIONAL DATA ANAMESA - Identitas a. Nama/Umur b. Suku/Bangsa c. Pekerjaan d. Pendidikan -
: Tn. Marijo, 48 tahun (TB = 170 cm / BB=70 kg saat ini) : Madura/Indonesia : Karyawan : Sarjana
History of present Illness : (1 minggu yang lalu) o Demam (38-39°C) o Sesak napas saat beraktifitas berat o Luka memar tanpa alasan yang jelas terutama di bagian kaki o Benjolan di selangkangan o Mudah lelah o Tidak nafsu makan History of past Illness (2 bulan yang lalu) o Common colds o Penurunan nafsu makan
Pulmo (dbn) suara pernafasan vesikuler.c malignancy
. Abdomen : Soefl. Vital Sign Kesadaran Tensi Nadi RR T.Cor (dbn). ka Ø=3 cm. multiple.o . ki Ø=2). 16-20 x/ min) : 38.Pembesaran kelenjar getah bening inguinal (bilateral.Fever e.o Dalam sebulan terakhir. pasien mengalami penurunan berat badan yang tidak direncanakan dan lebih dari 10 % (80 kg 70 kg) o Riwayat merokok (sehari 2 bungkus) dan minum kopi o Riwayat penggunaan jamu disangkal. o Riwayat MRS disangkal o Tidak ada riwayat penyalahgunaan obat terlarang History of Treatment & Medical o Obat penurun demam mengandung Parasetamol o Multivitamin untuk meningkatkan nafsu makan History of Family illness • Tidak diketahui
PEMERIKSAAN FISIK a. refleks patologik (-). meteorismus (-) Pembesaran Limpa (S-1) disertai nyeri tekan perut pada bagian kiri atas Pembesaran Hepar 2 cm di bawah arcus costae (teraba saat pemeriksaan) .5°C :
b. tidak dijumpai ronkhi . d.Ax : Tampak sakit sedang : Compos mentis : 110/90 mm hg : 85 x/min. murmur (-) c. konsistensi padat.Wajah pucat & konjuctiva anemis . Refleks fisologik normal. tidak dijumpai edema DIFERENTIAL DIAGNOSA DEMAM : . Ekstremitas Superior/Inferior • Kaki : Purpura.Fever e.Gusi bengkak dan mengalami perdarahan . immobile.c Infeksi m. (N : 60 – 80 x / min) : 24 x/min (N .
• Eritrosit : (-) • Lekosit : (-) • Protein : (-)
= kuning/jernih = 1..5mg/dl) • Mean corpuscular hemoglobin (MCH) 27 pg/cell (N: 28 -33pg/cell) • Mean corpuscular hemoglobin concentration (MCHC) 30g/dL (N: 32 -36pg/cell) • Mean corpuscular volume (MCV) 85 μm3 (N: 86-98 μm3) • Hematocrit 35 % (N: 37 – 48%) • Diff eo/ba/stab/seg/lym/mo = 6/1/4/50/35/4 (N:0-7/0-2/0-4/45-74/16-45/4-10) 3 • Reticulosit 60.5%)
b. Normositer.000/mm3 (N:6000 – 10800/mm3) 3 • Trombosit 100. > 8.000/mm3) • Hemoglobin 9.000 – 400. Urobilin. Hipokrom.4 %
a.Fever e. • Leukosit : Kesan Jumlah meningkat & tampak sel blast kurang lebih 30 % • Trombosit : Kesan Jumlah menurun
FAAL PEMBEKUAN • PTT 14 detik • APTT 40 detik • BT 6 menit • TT 20 detik • FDP (D-dimer) 0.000 /ml (N : 50.2 mg/dl (N in female 12 – 16. URINE LENGKAP • Warna/keadaan • BJ/pH • Albumin . > 16 %) • Feritin 16 ug/l (N .005 /6. > 15 ug/L) • Serum transferin receptor concentration (TfR) 10 mg/L (N .
(N < 11.c drug induced .Limfadenopathy PEMERIKSAAN TAMBAHAN LAB DARAH LENGKAP • Erytrocyte counts 4.000/mm (N: 130.W= 20-25) • Saturasi Transferin 17 % (N .9 x 106/mm3) • Leucocytes counts 20.8 detik ) (N : 2-5 menit) (N : 15-17 detik) (N< 0.Bilirubin • Sedimen : Silinder hialin.2 – 4.0 = (-)
(N < 30 mg/dl)
.5 mg/L) • Coomb’s Test direct (-) Evaluasi Hapusan darah: • Eritrosit : Kesan Jumlah menurun.0 x 106/mm3 (N: 4. granuler.000/ ml3) • TIBC 3500 µg / L (W = 2500-3500 µg / L ) • Saturasi Iron 20 % (N.3 detik) (N < 27.Reduksi.
2.0 mg/dl • SGOT = 50 U/L. Bagaimana penegakan diagnosa demam pada kasus Tn. SGPT = 45 U / L • LDH = PEMERIKSAAN SUMSUM TULANG • Sumsum tulang hiposeluler • Peningkatan jumlah leukoblast 30 % • Peningkatan megakariosit • Auer rods di sitoplasma sel blast (khas untuk AML)
SEROLOGI • Ig M • ANA test (-) (-)
WORKING DIAGNOSA Acute Myeloid Leukemia (AML)
1. Marijo ? 7. 4. Mengapa Tn. Marijo ? 6. Marijo mengalami penurunan berat badan dan berkeringat di malam hari ? 3.4 mg/dl • Creatinin = 0. Bagaimana interpretasi hasil laboratorium Tn.85 mg/dl • Uric acid = 5. Marijo ?
3. Marijo demam. PENENTUAN PROBLEM LIST
1. Marijo ? 5.
Leukosit Leukoblast Auer rods LDH Purpura
2.c. Mengapa Tn. 3. 3. sesak napas dan tidak nafsu makan ? 2. 4. IDENTIFIKASI KATA SULIT/KUNCI
1. KIMIA DARAH • GDS = 110 mg/dl • Ureum = 40. 5. Marijo terdapat pembesaran limpa. 2. Apa diagnosa banding demam pada kasus Tn. hepar dan KGB ringan serta purpura di ekstremitas inferior ? 4. Bagaimana penatalaksanaan pada kasus Tn. Mengapa pemeriksaan fisik pada Tn. BRAIN STORMING
1. Baca Tentang : Biologi Molekular Neoplasma Baca Tentang : Keganasan pada hematologi Baca Tentang kausa AML Baca tentang patofisologi AML
Baca tentang alur penegakan diagnosa pada AML Baca tentang Penatalaksanaan AML Baca Maping Konsep Baca Maping Kasus
. 7.5. 8. 6.
MAPPING KONSEP HEMATOPOESIS JALUR MYELOID & LYMPHOID
Disorder Type Granulosit Target Neurophilia ↓ Proliferasi Progenitor Sel Inefektif granulopoesis ↑ Apoptosis Fungsi Fagosit Congenital abnormality Chemotaxis Defect Corticosteroid Leukemic cell Opsonisasi ↓
RA. histoplasmosis. • Are the nodes very large and/or very firm and thus suggestive of malignancy ? Perform a biopsy. mediastinal).g. intrathoracic (hilar vs. lymphogranuloma venereum) e. • Is the patient very concerned about malignancy and unable to be reassured that malignancy is unlikely? Perform a biopsy.
epitrochlear.. medications. supraclavicular. Gaucher's disease. gastrointestinal malignan
Storage diseases (e. femoral • Localized vs. Hodgkin's disease.Defect Killing & Digestion bacteri Defect Digestion
Hipogamaglobulinemia. sinus histiocytosis with massive lymphadenopath y. catscratch disease. mesenteric vs.g. hyperthyroidi sm.. Parasitic (e. General Exams
Imaging • Chest radiography Lymphangiography • Ultrasonography
* * Computed
Sampling • Needle aspiration • Cutting needle
AN APPROACH TO A PX WITH LYMPHADENOPATHY FACTORS TO CONSIDER IN THE DIAGNOSIS OF LYMPHADENOPATHY • Associated systemic symptoms • Patient's age • History of infection.. trauma.
Malignant disorders of Immune system (e.. drug reactions such as to phenytoin. amyloidosis. axillary. inguinal.melan oma.g. disseminated • Tenderness / inflammation
. head & neck cancer.
a. • Is there an obvious infection to explain the lymphadenopathy (e. adrenal
PENEGAKAN DIAGNOSA GANGGUAN SISTEM LIMFATIKA
METHODS OF LYMPH NODE EVALUATION
Miscellaneo us (e.. all pyogenic bacteria. breast ca. Fungal (e.g. HOW TO DIAGNOSE LYMPHADENOPATHY • Does the patient have a known illness that causes lymphadenopathy ? Treat and monitor for resolution. ALL. Mycobacterial (e.g. dermatopathi
Physical examination Vitals.g. Chlamydial (e. previous malignancy.g.. CLL.g.g. thyroiditis. iliac. angioimmunoblas tic-like T-cell lymphoma. coccidioidomycosis) d.
• Location: cervical.g. nonHodgkin's lymphoma. serum sickness. intra-abdominal (retroperitoneal vs. tularemia) b. ↓ Complement Myeloperoksidase Chediak-Higashi syndrome
KLASIFIKASI SISTEM LIMFATIKA
INFEKSI Bacterial (e. toxoplasmosis. sarcoidosis. tuberculosis. CML.g.g. syphilis.. leprosy) c.. Castleman's disease. AML.. other). etc. infectious mononucleosis) ? Treat and monitor for resolution. Waldenström's Benign disorder of the immune system (e. Langerhans Other maligna ncies (e..
Endocrinopa thies (e.
travel experience. SLE.
Proses Penegakan Diagnosa Pasien dg Febris menggigil
PROSES PENEGAKAN DIAGNOSA PASIEN DENGAN FEBRIS/DEMAM AKUT
immune evasion metastasis di organ lain
. 3 pada proto onkogen shg mjd Onkogen (tumor jinak) Over expressi . 2.DNA DAMAGE IN GEN MUTATION
CARSINOGENIK AGENT PROTO ONKOGEN Gen pengkode protein perkembangan dan Pertumbuhan Gen rusak. gen instabil Peningkatan jumlah sel yang berubah di tempat asal Mutasi ke 4 (karsinoma) TSG in aktif Mutasi ke 5 (metastase) Invasi ke PD. apoptosis gagal Mutasi ke 1. angiogenesis transisi epitel mesenkim vaskuler remodelling. mobilisasi bone marrow. DNA repair gagal. Transformasi sel. modifikasi protein hasil Pertumbuhan >>>. extravasasi.
SINDROMA MYELODISPLA SIA
INISIASI & METASTASIS TUMOR
FAB CLASIFICATION OF AML
RUNX1/RUNX1T1 • AML with inversions in chromosome 16 [inv(16)] (ICD-O 9871/3). This category includes patients who have had prior chemotherapy and/or radiation and subsequently develop AML or MDS.11).21)(q22. t(11.PML • AML with translocations in chromosomes 9 and 11 [t(9. therapyrelated
AML not otherwise categorized
ATP + Panas ↑
. t(9. t(16.22)
Sub Type AML
Acute myeloid leukemia with recurrent genetic abnormalities
• AML with translocations between chromosome 8 and
21 [t(8.16) del (11q). and often carry a worse prognosis.17) inv(16)(p13q22). without maturation promyelocytic.9) t(15. This category includes patients who have had a prior myelodysplastic syndrome (MDS) or myeloproliferative disease (MPD) that transforms into AML. MLLT3-MLL Patients with AML in this category generally have a high rate of remission and a better prognosis compared to other types of AML.q22). Includes subtypes of AML that do not fall into the above categories
AML with multilineage dysplasia
AML and MDS.17)] (ICD-O 9866/3).Type
M0 M1 M2 M3 M4 M4eo M5 M6 M7
Name minimally differentiated acute myeloblastic leukemia minimally differentiated acute myeloblastic leukemia acute myeloblastic leukemia.19)
25% 10% 20% 5% 10% 5%
t(1.21)] (ICD-O 9896/3). This category of AML occurs most often in elderly patients and often has a worse prognosis. t(6. or acute promyelocytic leukemia (APL) acute myelomonocytic leukemia myelomonocytic together with bone marrow eosinophilia acute monoblastic leukemia (M5a) or acute monocytic leukemia (M5b) erythroleukemia (M6a) and very rare pure erythroid leukemia (M6b) acute megakaryoblastic leukemia
Percentage of adult AML patients 5% 15%
t(8. del(16q) inv(16). RARA. CBFB/MYH11 • APL with translocations between chromosome 15 and 17 [t(15. These leukemias may be characterized by specific chromosomal abnormalities.11)].
Hepar Inspeksi & Palpasi Kelenjar Limfe • Radiologi : X-Ray. t (6:9) Ag : CD 13 & CD 33
Chemotherapy Radiotherapy Antibiotic (fight infection)
Tx Non Farmakologi
Transfusion : Platelet. Translocation Chr : t(8:21). Platelet. MRI. C-ONC)
Invasi ke Pembuluh Limfatika Imuno Tolerance Infiltrasi ke Gums Pembesaran KGB inguinal
• Anamnesa : Usia. USG.• Sitostatika • Radiasi : X-Ray • Chemical : Benzene • Infeksi • Bone marrow transplant
Antigen (Ag) Tn. Hb ↓ • Uji Biopsi : KGB inguinal (neoplasma) • Bone Marrow aspiration : Sel blast leukemic ↑ • Sitogenetik : Auer rod (+) AML. RPS • Pemeriksaan Fisik : Inspeksi & Palpasi Limpa. RBC Bone marrow transplantation Stem Cell transplantation
. Marijo Ag inducing NF KB & Mutasi DNA Myeloblast Innate/Adaptive Immun Cells Activated Sel Myeloma Gen Supresor Tumor ↓ (p53) Gen Apoptosis ↓ (bcl-2 >>) DNA Repair ↓ Aktivasi Oncogen (V-ONC. RPD. CT Scan • Hematologi : CBC. WBC. Pekerjaan.
Genetic disorder .LDH. ALT ↑ Bleeding Ptechiae
Produksi abnormal Hematopoesis inefektif Leukosit (blast ↑)
Eritrosit ↓ Rentan Infeksi Anemia Sesak Trombosit ↓
Sel Leukemic (blast)
Systemic Sign (B)
Fever Apetite Loss Weight Loss
Interaksi dg Limfosit Host Proliferasi Comp Limfonodi Emboli Limfatika Lymphedema Hiper metabolism
• Bleeding • DIC • Infeksi berat • Metastase • Relapse of ALL • Organ damage
Risk Factor :
Hepatomegali Swelling Gums
5. LEARNING OBJECTIVE
. AST.Down syndrome .
Mampu menjelaskan pencegahan keganasan hematologi 7. MM. CML) 3. Mampu menjelaskan hematopoesis pada jalur lymphoid dan myeloid 2. Mampu menjelaskan komplikasi keganasan hematologi
. Mampu menjelaskan alur diagnosa keganasan hematologi (AML) 5. Mampu menjelaskan penatalaksanaan keganasan hematologi (AML) 6.1. Mampu menjelaskan jenis-jenis keganasan sistem hematology (ALL. AML. Mampu menjelaskan Patogenesa keganasan hematologi (AML) 4. CLL.
and dyspnea. Most of the clinical findings in acute leukemia are due to replacement of normal bone marrow elements by the malignant cell. The most dramatic presentation is hyperleukocytosis. • Blasts in peripheral blood in 90% of patients. other alkylating agents. • Classify as acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). death within a few hours may occur if treatment with appropriate antibiotics is delayed. It is also seen in adults. The most common pathogens are gram-negative bacteria (Escherichia coli. In addition. On examination. meninges).Essentials of Diagnosis • Short duration of symptoms. and perirectal infections. a number of chemotherapeutic agents (especially cyclophosphamide. One subtype. fever. with neutrophil counts less than 100/mcL. Bleeding (usually due to thrombocytopenia) occurs in the skin and mucosal surfaces.17). with the risk of infection rising as the neutrophil count falls below 500/mcL. pneumonia. and bleeding. radiation and some toxins (benzene) are leukemogenic. The leukemias seen after toxin or chemotherapy exposure often develop from a myelodysplastic prodrome and are often associated with abnormalities in chromosomes 5 and 7. Common presentations include cellulitis. General Considerations Acute leukemia is a malignancy of the hematopoietic progenitor cell. confusion. acute promyelocytic leukemia (APL). causing approximately 20% of adult acute leukemias. Less common manifestations result from organ infiltration (skin. • Cytopenias or pancytopenia. Acute leukemia is potentially curable with combination chemotherapy. • More than 20% blasts in the bone marrow. widespread bleeding is seen in patients with disseminated intravascular coagulation (DIC) (in APL and monocytic leukemia). Infection is due to neutropenia. Clinical Findings Symptoms and Signs Most patients have been ill only for days or weeks. These cells proliferate in an uncontrolled fashion and replace normal bone marrow elements. gastrointestinal tract. and etoposide) may cause leukemia. presenting as headache. or menorrhagia. Stomatitis and gum hypertrophy may be seen in patients with monocytic
. infection within days is the rule. epistaxis. including fatigue. which produces the fusion gene PML-RAR which interacts with the retinoic acid receptor to produce a block in differentiation that can be overcome with pharmacologic doses of retinoic acid (see below). with gingival bleeding. However. and those related to etoposide may have abnormalities in chromosome 11q23. in which a markedly elevated circulating blast count (usually > 200. Acute lymphoblastic leukemia (ALL) comprises 80% of the acute leukemias of childhood. Acute myeloid leukemia (AML) is primarily an adult disease with a median age at presentation of 60 years and an increasing incidence with advanced age.000/mcL) leads to impaired circulation. Klebsiella. Most cases arise with no clear cause. is characterized by chromosomal translocation t(15. melphalan. The peak incidence is between 3 and 7 years of age. patients appear pale and have purpura and petechiae. Patients may also seek medical attention because of gum hypertrophy and bone and joint pain. Aspergillus). Less commonly. Such patients require emergent leukapheresis and chemotherapy. Pseudomonas) or fungi (Candida. Much has been learned about the molecular biology of the leukemias. signs of infection may not be present.
and megakaryoblastic leukemia (M7). and T cell. and femur. The Auer rod. In considering the various types of AML. The phenotype of leukemia cells is usually demonstrated by flow cytometry. as may rectal fissures. The majority of cases of AML are of intermediate risk and have either normal cytogenetics or abnormalities that do not confer strong prognostic significance. ALL is most usefully classified by immunologic phenotype as follows: common. Thus. The uncommon Burkitt type of ALL has a "lymphoma" phenotype. a relatively favorable group of patients has been defined based on a molecular signature that includes mutations of nucleophosmin 1 (NPM1) and lacks the internal tandem duplication of the FLT3 gene. Meningeal leukemia will have blasts present in the spinal fluid. an eosinophilic needle-like inclusion in the cytoplasm. If DIC is present. acute myelomonocytic leukemia (M4). Within this large subgroup. particularly in the sternum. cytogenetic studies are the most powerful prognostic factors. expressing CD19. The bone marrow is usually hypercellular and dominated by blasts. British) classification was based on morphology and histochemistry as follows: acute undifferentiated leukemia (M0). American. A poor prognosis is conferred by the
. erythroleukemia (M6). The "FAB. APL is characterized by the cytogenetic finding of t(15. The World Health Organization (WHO) has sponsored a classification of the leukemias and other hematologic malignancies that incorporates cytogenetic. the fibrinogen level will be reduced. Hyperuricemia may be seen. and most cases will express CD10. However. acute myeloblastic leukemia with differentiation (M2). These patients have a higher chance of achieving both short.17) and the fusion gene PML-RAR alpha. and immunophenotype information. Almost all ALL cells express terminal deoxynucleotidyl transferase (TdT). Patients with ALL (especially T cell) may have a mediastinal mass visible on chest radiograph. Among the other types of AML. or 8. is pathognomonic of AML (see micrograph) and. if seen. More than 20% blasts are required to make a diagnosis of acute leukemia. Favorable cytogenetics such as t(8. Bone tenderness may be present. Leukemia cells retain properties of the lineages from which they are derived. early B lineage. whereas ALL cells will not contain either of these enzymes. formerly known as the "common ALL antigen. A number of other laboratory abnormalities are noted. termed the "core-binding factor" leukemias because of common genetic lesions affecting DNA-binding elements." ALL cells of T lineage will usually not express mature T-cell markers. the prothrombin time prolonged.leukemia. Laboratory Findings The hallmark of acute leukemia is the combination of pancytopenia with circulating blasts (see micrograph). seen in approximately 5% of cases at diagnosis." (French. but will express some combination of CD 2. histochemistry will demonstrate peroxidase in myeloid cells and butyrate esterase in monocytic cells. molecular.and long-term disease control. common to all B cells. acute monoblastic leukemia (M5). ALL cells of B lineage will express CD19. tibia. spleen. and 7 and do not express surface immunoglobulin. acute promyelocytic leukemia (APL) (M3). AML cells usually express myeloid antigens such as CD 13 or CD 33. 4. acute myeloblastic leukemia (M1). and lymph nodes. CD20 and surface immunoglobulin but not TdT AML has been characterized in several ways. blasts may be absent from the peripheral smear in as many as 10% of cases ("aleukemic leukemia"). There is variable enlargement of the liver. it is more common in monocytic types of AML. 5. such as CD 3. and fibrin degradation products or fibrin D-dimers present.21) and inv(16)(p13. APL is now considered separately because of its unique biologic features and unique response to non-chemotherapy treatments.q22) are seen in 15% of cases and are. secures the diagnosis.
Once leukemia has recurred after initial chemotherapy. Once a patient has entered remission. either alone or in combination with other agents. the addition of arsenic trioxide may be beneficial. arsenic trioxide can produce second remissions in 90% of cases. Only the uncommon group of high-risk patients (based on initial white blood cell count > 10. the hyperdiploidy (with more than 50 chromosomes) is associated with a better prognosis. The optimal treatment strategy depends on the patient's age and clinical status. 90% of patients remain in long-term remission. but cure rates are only 20–30%. APL is treated differently from other forms of AML. lymphomas. Differential Diagnosis AML must be distinguished from other myeloproliferative disorders. also known as acute myelogenous leukemia or acute nonlymphocytic leukemia (ANLL). For patients with highrisk APL based on an initial white blood cell count > 10. but studies of the potentially synergistic combination of retinoic acid and arsenic trioxide may improve results here. and myelodysplastic syndromes. and hairy cell leukemia. and chemotherapy. characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. the prognosis is much more guarded. In ALL.22) and t(4. or complex cytogenetics with more than three separate abnormalities. and autologous transplant in second remission produces cure rates of 60–70%. and 50–60% for allogeneic transplantation. AML is the most common
. Significant advances have been made in the treatment of APL. For intermediate-risk patients with AML. Acute leukemia may also resemble a left-shifted bone marrow recovering from a previous toxic insult. with cure rates of 50–60% with chemotherapy and 70–80% with autologous transplantation. AML Acute myeloid leukemia (AML). With this approach 90–95% of patients will achieve complete remission. and the addition of this biologic agent may be helpful in other cases as well. For patients in second remission. transplantation (autologous or allogeneic) offers a 20–40% chance of cure. With the use of all-trans retinoic acid. Induction therapy should include an anthracycline plus all-trans-retinoic acid.000/mcL. Allogeneic transplantation is the treatment of choice.cytogenetics finding of monosomy 5 or 7. It may also be confused with the atypical lymphocytosis of mononucleosis and pertussis AML Most patients with AML are treated with a combination of an anthracycline (daunorubicin or idarubicin) plus cytarabine. This therapy will produce complete remissions in 80% of patients under age 60 years and in 50–60% of older patients (see Tables 39–3 and 39–4). For those patients with APL who relapse. and the risk factor profile of the leukemia. a bone marrow study should be repeated in several days to see if maturation has taken place.000/mcL) have not shared in this favorable outcome. If the question is in doubt. is a cancer of the myeloid line of blood cells. but is seldom seen in adults. which has fusion genes involving the MLL gene at 11q23.11). 40–50% for autologous transplantation. Patients who do not enter remission or who have high-risk cytogenetics (such as monosomy 7 and complex cytogenetics) do far more poorly and are rarely cured with chemotherapy. ALL must be separated from other lymphoproliferative disease such as chronic lymphocytic leukemia. postremission therapy should be given with curative intent whenever possible. Unfavorable cytogenetics in ALL are the Philadelphia chromosome t(9. Some types of AML whose cytogenetics involved core-binding factors have a more favorable prognosis. chronic myeloid leukemia. cure rates for postremission therapy are 35–40% for chemotherapy. Options include standard chemotherapy and autologous and allogeneic transplantation. arsenic trioxide.
. easy bruising and bleeding. treatment and prognosis varies among subtypes. chemotherapy and/or radiation and subsequently develop AML M9920/3 therapy-related or MDS. World Health Organization The World Health Organization (WHO) classification of acute myeloid leukemia attempts to be more clinically useful and to produce more meaningful prognostic information than the FAB criteria. Several risk factors and chromosomal abnormalities have been identified. however. its incidence is expected to increase as the population ages. AML not otherwise Includes subtypes of AML that do not fall into the above M9861/3 categorized categories. RUNX1/RUNX1T1 • AML with inversions in chromosome 16 [inv(16)] (ICD-O 9871/3). RARA. The symptoms of AML are caused by replacement of normal bone marrow with leukemic cells. and normal white blood cells. patients may go on to receive additional chemotherapy or a hematopoietic stem cell transplant. depending on subtype. and its incidence increases with age. shortness of breath. The WHO subtypes of AML are: Name Description ICD-O Includes: • AML with translocations between chromosome 8 and 21 [t(8.acute leukemia affecting adults. Although AML is a relatively rare disease. As an acute leukemia. CBFB/MYH11 Acute myeloid leukemia with • APL with translocations between chromosome 15 and Multiple recurrent genetic 17 [t(15. accounting for approximately 1.11)]. This category includes patients who have had prior AML and MDS. AML progresses rapidly and is typically fatal within weeks or months if left untreated.17)] (ICD-O 9866/3). AML is treated initially with chemotherapy aimed at inducing a remission.2% of cancer deaths in the United States. Five-year survival varies from 15–70%. which causes a drop in red blood cells. platelets. and relapse rate varies from 33–78%. These symptoms include fatigue. most of the clinically significant information in the WHO schema is communicated via categorization into one of the subtypes listed below. and often carry a worse prognosis. Each of the WHO categories contains numerous descriptive subcategories of interest to the hematopathologist and oncologist. as well as how long that patient is likely to survive. Recent research into the genetics of AML has resulted in the availability of tests that can predict which drug or drugs may work best for a particular patient.PML abnormalities • AML with translocations in chromosomes 9 and 11 [t(9. This category includes patients who have had a prior AML with myelodysplastic syndrome (MDS) or myeloproliferative multilineage disease (MPD) that transforms into AML. MLLT3-MLL Patients with AML in this category generally have a high rate of remission and a better prognosis compared to other types of AML.21)] (ICD-O 9896/3). AML has several subtypes. but the specific cause is not clear. These leukemias may be characterized by specific chromosomal abnormalities. and increased risk of infection. This category of M9895/3 dysplasia AML occurs most often in elderly patients and often has a worse prognosis.
M8. with t(8. while the leukemic cells themselves are derived from white blood cell precursors. bone and joint pain. Some generalized symptoms include fever. Percentage of Type Name Cytogenetics adult AML patients minimally differentiated acute myeloblastic M0 5% leukemia acute myeloblastic leukemia. easy bruising or bleeding. This is done by examining the appearance of the malignant cells with light microscopy and/or by using cytogenetics to characterize any underlying chromosomal abnormalities.q22). anemia. A lack of normal white blood cell production makes the patient susceptible to infections. weight loss or loss of appetite.19) acute erythroid leukemias. t(9.
. pin-head sized spots under the skin caused by bleeding). M0 through to M7. based on the type of cell from which the leukemia developed and its degree of maturity. including M6 erythroleukemia (M6a) and very rare pure 5% erythroid leukemia (M6b) M7 acute megakaryoblastic leukemia t(1. such as acute basophilic leukemia. in 1999.21)(q22. A drop in red blood cell count (anemia) can cause fatigue. they have no infection-fighting capacity.17) 10% leukemia (APL) inv(16)(p13q22). paleness. or where both types of cells are present. which was proposed as a ninth subtype. shortness of breath. fatigue. t(16. and persistent or frequent infections.11). or acute promyelocytic M3 t(15. M5 10% monocytic leukemia (M5b) t(11. Eight FAB subtypes were proposed in 1976. and may be similar to those of influenza or other common illnesses. Although the WHO classification (see above) may be more useful. M4 acute myelomonocytic leukemia 20% del(16q) myelomonocytic together with bone marrow M4eo inv(16).16) 5% eosinophilia acute monoblastic leukemia (M5a) or acute del (11q).
Signs and symptoms
Most signs and symptoms of AML are caused by the replacement of normal blood cells with leukemic cells. The subtypes have varying prognoses and responses to therapy. without M1 15% maturation acute myeloblastic leukemia.22) 5% The morphologic subtypes of AML also include rare types not included in the FAB system. the FAB system is still widely used. petechiae (flat. M2 25% granulocytic maturation t(6.Acute leukemias of ambiguous lineage (also known as mixed phenotype or biphenotypic acute leukemia) occur when the leukemic cells can not be classified as either myeloid or lymphoid cells.9) promyelocytic. and shortness of breath. A lack of platelets can lead to easy bruising or bleeding with minor trauma. The early signs of AML are often vague and nonspecific. French-American-British The French-American-British (FAB) classification system divides AML into eight subtypes.
 While a presumptive diagnosis of AML can be made via examination of the peripheral blood smear
. and the leukemia may be discovered incidentally during a routine blood test. and genetics. Preleukemia "Preleukemic" blood disorders. Survivors of the atomic bombings of Hiroshima and Nagasaki had an increased rate of AML. if any. or even with a low white blood cell count (leukopenia). can evolve into AML.
The first clue to a diagnosis of AML is typically an abnormal result on a complete blood count. a paraneoplastic inflammation of the skin. Benzene and many of its derivatives are known to be carcinogenic in vitro.
A number of risk factors for developing AML have been identified. specifically epipodophyllotoxins and anthracyclines. but it is typically mild and asymptomatic. and leukemic blasts are sometimes seen.to 18-fold increase in the risk of AML. the most common is probably Down syndrome. The risk of developing AML is increased threefold in first-degree relatives of patients with AML. in particular alkylating agents. Some patients with AML may experience swelling of the gums because of infiltration of leukemic cells into the gum tissue. The risk is highest about three to five years after chemotherapy. others have suggested the attributable risk. Genetics A hereditary risk for AML appears to exist. Other chemotherapy agents. Occasionally. including: other blood disorders. the first sign of leukemia may be the development of a solid leukemic mass or tumor outside of the bone marrow.Enlargement of the spleen may occur in AML. have also been associated with treatment-related leukemia. can occur with AML. Chemical exposure Exposure to anticancer chemotherapy. in contrast to acute lymphoblastic leukemia. ionizing radiation. While an excess of abnormal white blood cells (leukocytosis) is a common finding. can increase the risk of subsequently developing AML. Rarely. is slight. as did radiologists exposed to high levels of X-rays prior to the adoption of modern radiation safety practices. Lymph node swelling is rare in AML. Radiation Ionizing radiation exposure can increase the risk of AML. These treatmentrelated leukemias are often associated with specific chromosomal abnormalities in the leukemic cells. the exact risk depends on the type of MDS/MPS. Several congenital conditions may increase the risk of leukemia. chemical exposures. The skin is involved about 10% of the time in the form of leukemia cutis. While some studies have suggested a link between occupational exposure to benzene and increased risk of AML. a person may show no symptoms. Occupational chemical exposure to benzene and other aromatic organic solvents is controversial as a cause of AML. Sweet's syndrome. red blood cells. which is associated with a 10. such as myelodysplastic syndrome or myeloproliferative disease. Multiple cases of AML developing in a family at a rate higher than predicted by chance alone have been reported. called a chloroma. Rarely. AML can also present with isolated decreases in platelets.
 According to the widely used WHO criteria. and should be performed by a qualified hematopathologist or hematologist.when there are circulating leukemic blasts. The nonspecific esterase stain is used to identify a monocytic component in AMLs and to distinguish a poorly differentiated monoblastic leukemia from ALL.ALL). The chromosomal translocations encode abnormal fusion proteins. as it readily identifies the chromosomal translocation (t[15. Genetic studies may also be performed to look for specific mutations in genes such as FLT3. which are treated differently. leading to the clinical entity of AML. it is important to quickly establish or exclude the diagnosis of this subtype of leukemia. Much of the diversity and heterogeneity of AML stems is because leukemic transformation can occur at a number of different steps along the differentiation pathway. nucleophosmin. in the absence of such features. Such a mutation alone does not cause leukemia.17]) that characterizes APL. to differentiate AML from other types of leukemia (e. In normal hematopoiesis. as well as flow cytometry. The myeloperoxidase or Sudan black reactions are most useful in establishing the identity of AML and distinguishing it from ALL. Fluorescent in situ hybridization performed on blood or bone marrow is often used for this purpose. a definitive diagnosis usually requires an adequate bone marrow aspiration and biopsy. The combination of a myeloperoxidase or Sudan black stain and a nonspecific esterase stain will provide the desired information in most cases. the diagnosis of AML is established by demonstrating involvement of more than 20% of the blood and/or bone marrow by leukemic myeloblasts. a single myeloblast accumulates genetic changes which "freeze" the cell in its immature state and prevent differentiation. The French–American–British (FAB) classification is a bit more stringent. In straightforward cases. A sample of marrow or blood is typically also tested for chromosomal abnormalities by routine cytogenetics or fluorescent in situ hybridization. the presence of certain morphologic features (such as Auer rods) or specific flow cytometry results can distinguish AML from other leukemias.
The malignant cell in AML is the myeloblast. the result is the uncontrolled growth of an immature clone of cells. and KIT. however. though. Modern classification schemes for AML recognize the characteristics and behavior of the leukemic cell (and the leukemia) may depend on the stage at which differentiation was halted. and to classify the subtype of disease (see below). requiring a blast percentage of at least 30% in bone marrow (BM) or peripheral blood (PB) for the diagnosis of AML. diagnosis may be more difficult. The diagnosis and classification of AML can be challenging. the myeloblast is an immature precursor of myeloid white blood cells. Cytochemical stains on blood and bone marrow smears are helpful in the distinction of AML from ALL. usually transcription factors whose altered
. a normal myeloblast will gradually mature into a mature white blood cell. which may influence the outcome of the disease.g. when such a "differentiation arrest" is combined with other mutations which disrupt genes controlling proliferation. to diagnose the presence of leukemia. and in subclassification of AML. acute lymphoblastic leukemia . In AML. however. Marrow or blood is examined via light microscopy. Because acute promyelocytic leukemia (APL) has the highest curability and requires a unique form of treatment. the types of chromosomal abnormalities often have prognostic significance. Specific cytogenetic abnormalities can be found in many patients with AML. AML must be carefully differentiated from "preleukemic" conditions such as myelodysplastic or myeloproliferative syndromes.
although this may vary based on the prognostic factors described above. in acute promyelocytic leukemia.
First-line treatment of AML consists primarily of chemotherapy. Therefore. more therapy is necessary to eliminate nondetectable disease and prevent relapse — that is. This leads to neutropenia. which can cause various symptoms depending on its location. leukemic cells likely remain in numbers too small to be detected with current diagnostic techniques. almost all patients will eventually relapse. anemia. In general. it signifies no disease can be detected with available diagnostic methods. The symptoms of AML are. Complete remission is obtained in about 50%–75% of newly diagnosed adults. the t(15. is almost universally treated with the drug all-trans-retinoic acid (ATRA ) in addition to induction chemotherapy. patients can develop a chloroma. induction chemotherapy may not be offered to the very elderly. in turn. or solid tumor of leukemic cells outside the bone marrow.
. rather. The clinical signs and symptoms of AML result from the growth of leukemic clone cells. APL is eminently curable. Other alternative induction regimens. and thrombocytopenia. The M3 subtype of AML. The goal of the induction phase is to reach a complete remission. Care must be taken to prevent disseminated intravascular coagulation (DIC). including myelosuppression and an increased risk of infection. the goal of consolidation therapy is to eliminate any residual undetectable disease and achieve a cure. and the options may include less intense chemotherapy or palliative care. The length of remission depends on the prognostic features of the original leukemia. In rare cases. Induction All FAB subtypes except M3 are usually given induction chemotherapy with cytarabine (araC) and an anthracycline (such as daunorubicin or idarubicin). also known as acute promyelocytic leukemia (APL). usually an anthracycline. to achieve a cure. Hematopoietic stem cell transplantation is usually considered if induction chemotherapy fails or after a patient relapses. For example. Complete remission does not mean the disease has been cured. The goal of induction therapy is to achieve a complete remission by reducing the number of leukemic cells to an undetectable level.properties may cause the "differentiation arrest". Because of the toxic effects of therapy. which tends to displace or interfere with the development of normal blood cells in the bone marrow. and is divided into two phases: induction and postremission (or consolidation) therapy. often due to the low numbers of these normal blood elements. including high-dose cytarabine alone or investigational agents. although transplantation is also sometimes used as front-line therapy for patients with high-risk disease. This induction chemotherapy regimen is known as "7+3" (or "3+7"). Up to 70% of patients will achieve a remission with this protocol. complicating the treatment of APL when the promyelocytes release the contents of their granules into the peripheral circulation. all remissions will fail without additional consolidation therapy. Consolidation Even after complete remission is achieved. If no further postremission or consolidation therapy is given. may also be used.17) translocation produces a PML-RARα fusion protein which binds to the retinoic acid receptor element in the promoters of several myeloid-specific genes and inhibits myeloid differentiation. because the cytarabine is given as a continuous IV infusion for seven consecutive days while the anthracycline is given for three consecutive days as an IV push. with well-documented treatment protocols.
CML is characterized by a specific chromosomal abnormality and specific molecular abnormality. • Markedly left-shifted myeloid series but with a low percentage of promyelocytes and blasts. allogeneic stem cell transplantation is usually recommended if the patient is able to tolerate a transplant and has a suitable donor. Clinical trials Patients with relapsed AML who are not candidates for stem cell transplantion. The portion of 9q that is translocated contains abl. For patients who are not eligible for a stem cell transplant.e. such as farnesyl transferase inhibitors. a protooncogene that is the cellular homolog of the Ableson murine leukemia virus. immunotherapy with a combination of histamine dihydrochloride (Ceplene) and interleukin 2 (Proleukin) after the completion of consolidation has been shown to reduce the absolute relapse risk by 14%. inv(16). Relapsed AML For patients with relapsed AML.The specific type of postremission therapy is individualized based on a patient's prognostic factors (see above) and general health.
. • Presence of Philadelphia chromosome or bcr/abl gene. as well as targeted therapies. For patients at high risk of relapse (e. the break point cluster (bcr). the monoclonal antibody-linked cytotoxic agent gemtuzumab ozogamicin (Mylotarg) was approved in the United States for patients aged more than 60 years with relapsed AML who are not candidates for high-dose chemotherapy. the only proven potentially curative therapy is a hematopoietic stem cell transplant. may be offered treatment in a clinical trial. Agents under investigation include cytotoxic drugs such as clofarabine. The abl gene is received at a specific site on 22q. if one has not already been performed. as conventional treatment options are limited. and a smaller piece of 9q is moved to 22q.21). including the age and overall health of the patient. For good-prognosis leukemias (i. These myeloid cells retain the capacity for differentiation. Since treatment options for relapsed AML are so limited.g. In 2000. or who have relapsed after a stem cell transplant.17)). Chronic Myeloid Leukemia Essentials of Diagnosis • Elevated white blood count. decitabine. The fusion gene bcr/abl produces a novel protein that differs from the normal transcript of the abl gene in that it possesses tyrosine kinase activity (a characteristic activity of transforming genes). and whether a suitable stem cell donor is available. and normal bone marrow function is retained during the early phases. General Considerations Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by overproduction of myeloid cells. translating to a 50% increase in the likelihood of maintained remission. t(8. those with high-risk cytogenetics. patients will typically undergo an additional three to five courses of intensive chemotherapy. A large portion of 22q is translocated to 9q. Evidence that the bcr/abl fusion gene is pathogenic is provided by transgenic mouse models in which introduction of the gene almost invariably leads to leukemia. The Philadelphia chromosome is a reciprocal translocation between the long arms of chromosomes 9 and 22. The best postremission therapy for intermediate-risk AML (normal cytogenetics or cytogenetic changes not falling into good-risk or high-risk groups) is less clear and depends on the specific situation. palliative care may be offered. the patient's personal values. or therapy-related AML). known as consolidation chemotherapy. underlying MDS. and inhibitors of MDR1 (multidrug-resistance protein). and t(15.
Normal bone marrow function is retained. the spleen is enlarged (often markedly so).
. In recent years.000/mcL. The platelet count may be normal or elevated (sometimes to strikingly high levels .Early CML ("chronic phase") does not behave like a malignant disease.The bone marrow is hypercellular. In such cases. Blast phase CML is diagnosed when blasts comprise more than 30% of bone marrow cells. and the relentless progression to more advanced stages of disease is at least greatly delayed. Clinical Findings Symptoms and Signs CML is a disorder of middle age (median age at presentation is 55 years).000/mcL. With progression to the accelerated and blast phases. progressive anemia and thrombocytopenia occur. if not eliminated. Myeloblasts comprise less than 5% of marrow cells The hallmark of the disease is that the bcr/abl gene is detected in the peripheral blood. which has now supplanted cytogenetics. the patient complains of abdominal fullness related to splenomegaly. bone pain. the median white blood count at diagnosis is 150. and sternal tenderness may be present as a sign of marrow overexpansion. splenomegaly is absent. Laboratory Findings The hallmark of CML is an elevated white blood count. The white blood count in these cases is usually greater than 500. The myeloid series is left-shifted. an elevated white blood count is discovered incidentally. white blood cells differentiate and. Acceleration of the disease is often associated with fever in the absence of infection. the patient will present with a clinical syndrome related to leukostasis with blurred vision. Red blood cell morphology is normal. which is morphologically indistinguishable from acute leukemia. Basophilia and eosinophilia of granulocytes may be present. the patient is usually not anemic. and without treatment the disease progresses to an accelerated and then acute blast phase. Patients usually present with fatigue. although it is useful for prognosis and for detecting additional chromosomal abnormalities in addition to the Philadelphia chromosome. In cases discovered during routine laboratory monitoring. the white blood count is usually less than 50. and splenomegaly. with left-shifted myelopoiesis (see micrograph). despite some qualitative abnormalities. Differential Diagnosis Early CML must be differentiated from the reactive leukocytosis associated with infection. Rarely. At presentation. The peripheral blood is characteristic (see micrograph). CML is inherently unstable. However. or priapism. and low-grade fever related to the hypermetabolic state caused by overproduction of white blood cells. especially with the increased used of laboratory tests. Blasts are usually less than 5%. although in some cases the white blood cell count is only modestly increased (Table 13–14). these findings are often absent. remarkable advances in therapy have changed the natural history of the disease. In some cases. and nucleated red blood cells are rarely seen. At other times. night sweats.000/mcL. respiratory distress. On examination. with mature forms dominating and with cells usually present in proportion to their degree of maturation. the neutrophils combat infection normally. A bone marrow examination is not necessary for diagnosis. and the percentage of blasts in the blood and bone marrow increases (see micrograph). and the bcr/abl gene is not present. This is best done by the polymerase chain reaction (PCR) test.
Those with a proliferative syndrome including peripheral blood monocytosis greater than 1000/mcL are termed "chronic myelomonocytic leukemia" (CMML). a usually hypercellular marrow. A variety of
. Those with excess blasts are diagnosed as "refractory anemia with excess blasts" (RAEB 5– 19% blasts). Ultimately. weight loss. Myelodysplasia encompasses several heterogeneous syndromes.CML must be distinguished from other myeloproliferative disease (Table 13–14). General Considerations The myelodysplastic syndromes are a group of acquired clonal disorders of the hematopoietic stem cell. and neutropenia is common. the red blood cell morphology is normal. nuclear budding. Laboratory Findings Anemia may be marked and may require transfusion support. and a number of morphologic and cytogenetic abnormalities. cytogenetics. there are frequently abnormalities involving the long arm of chromosome 5 (which contains a number of genes encoding both growth factors and receptors involved in myelopoiesis) as well as deletions of chromosomes 5 and 7. The myeloid series is often left-shifted. The hematocrit should not be elevated. including deficient numbers of granules or deficient segmentation of the nucleus. Although no single specific chromosomal abnormality is seen in myelodysplasia. Erythroid hyperplasia is common. A characteristic abnormality is the presence of dwarf megakaryocytes with a unilobed nucleus. Those without excess bone marrow blasts are termed "refractory anemia. but may be hypocellular. bleeding. Many are diagnosed while asymptomatic because of the finding of abnormal blood counts. Deficient or abnormal granules may be seen. and nucleated red blood cells are rare or absent. The course may be indolent. and macro-ovalocytes may be seen on the peripheral blood smear. They are characterized by the constellation of cytopenias. and general debility. and the severity of cytopenias. On examination. and the disease may present as a wasting illness with fever. splenomegaly may be present in combination with pallor. the disorder may evolve into acute myeloid leukemia. Clinical Findings Symptoms and Signs Patients are usually over age 60 years. The myeloid series may be left-shifted. The neutrophils may exhibit morphologic abnormalities. The disorders are usually idiopathic but may be seen after cytotoxic chemotherapy. with variable increases in blasts. infection. characterized by the cytogenetic finding of loss of part of the long arm of chromosome 5. • Morphologic abnormalities in two or more hematopoietic cell lines.syndrome. and the term "preleukemia" has been used in the past to describe these disorders. and small numbers of promyelocytes or blasts may be seen. and hypogranular platelets may be present. and various signs of infection. The MCV is normal or increased. An International Prognostic Scoring System (IPSS) has been developed that classifies patients by risk status based on the percentage of bone marrow blasts. One important subgroup of the refractory anemia patients are those with the 5q. The Prussian blue stain may demonstrate ringed sideroblasts. The white blood cell count is usually normal or reduced. especially a bilobed nucleus (Pelger–Huet) (see micrograph). Patients usually present with fatigue. The platelet count is normal or reduced. or bleeding related to bone marrow failure. or multinucleated erythroid precursors (see micrograph). Myelodysplastic Syndromes Essentials of Diagnosis • Cytopenias with a hypercellular bone marrow. The bone marrow is characteristically hypercellular." with or without ringed sideroblasts. and signs of abnormal erythropoiesis include megaloblastic features. Definitive diagnosis is made by finding the bcr/abl gene.
Most cases arise with no clear cause. widespread bleeding is seen in patients with disseminated intravascular coagulation (DIC) (in APL and monocytic leukemia). with neutrophil counts less than 100/mcL. These cells proliferate in an uncontrolled fashion and replace normal bone marrow elements. fever. myelodysplasia is arbitrarily separated from acute myeloid leukemia by the presence of less than 20% blasts Acute Leukemia Essentials of Diagnosis • Short duration of symptoms. Acute lymphoblastic leukemia (ALL) comprises 80% of the acute leukemias of childhood. with the risk of infection rising as the neutrophil count falls below 500/mcL. which produces the fusion gene PML-RAR which interacts with the retinoic acid receptor to produce a block in differentiation that can be overcome with pharmacologic doses of retinoic acid (see below). Klebsiella. Most of the clinical findings in acute leukemia are due to replacement of normal bone marrow elements by the malignant cell. Clinical Findings Symptoms and Signs Most patients have been ill only for days or weeks. Acute myeloid leukemia (AML) is primarily an adult disease with a median age at presentation of 60 years and an increasing incidence with advanced age. Less common manifestations result from organ infiltration (skin. gastrointestinal tract.cytogenetic abnormalities in the bone marrow are characteristic of myelodysplasia. The leukemias seen after toxin or chemotherapy exposure often develop from a myelodysplastic prodrome and are often associated with abnormalities in chromosomes 5 and 7. with gingival bleeding. Infection is due to neutropenia. The most common pathogens are gram-negative bacteria (Escherichia coli. or menorrhagia. • More than 20% blasts in the bone marrow. and bleeding. The presence of other abnormalities such as monosomy 7 or complex abnormalities is associated with more aggressive disease Differential Diagnosis In subtle cases. As the number of blasts increases in the bone marrow. Acute leukemia is potentially curable with combination chemotherapy. Pseudomonas)
. General Considerations Acute leukemia is a malignancy of the hematopoietic progenitor cell. acute promyelocytic leukemia (APL). melphalan. However. causing approximately 20% of adult acute leukemias. In addition. radiation and some toxins (benzene) are leukemogenic.17). is characterized by chromosomal translocation t(15. and those related to etoposide may have abnormalities in chromosome 11q23. Some patients with an indolent form of the disease have an isolated partial deletion of chromosome 5 (5q– syndrome). • Blasts in peripheral blood in 90% of patients. epistaxis. • Cytopenias or pancytopenia. Less commonly. a number of chemotherapeutic agents (especially cyclophosphamide. infection within days is the rule. other alkylating agents. meninges). and etoposide) may cause leukemia. cytogenetic evaluation of the bone marrow may help distinguish this clonal disorder from other causes of cytopenias. It is also seen in adults. Much has been learned about the molecular biology of the leukemias. • Classify as acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). including fatigue. The peak incidence is between 3 and 7 years of age. One subtype. Bleeding (usually due to thrombocytopenia) occurs in the skin and mucosal surfaces.
American. early B lineage. expressing CD19. Leukemia cells retain properties of the lineages from which they are derived. presenting as headache. On examination. ALL cells of B lineage will express CD19. blasts may be absent from the peripheral smear in as many as 10% of cases ("aleukemic leukemia"). The bone marrow is usually hypercellular and dominated by blasts. Meningeal leukemia will have blasts present in the spinal fluid. and femur. signs of infection may not be present. Bone tenderness may be present. If DIC is present." (French.or fungi (Candida. erythroleukemia (M6). The uncommon Burkitt type of ALL has a "lymphoma" phenotype. The World Health Organization (WHO) has sponsored a classification of the leukemias and other hematologic malignancies that incorporates cytogenetic. is pathognomonic of AML (see micrograph) and. Common presentations include cellulitis. acute promyelocytic leukemia (APL) (M3). if seen. A number of other laboratory abnormalities are noted. British) classification was based on morphology and histochemistry as follows: acute undifferentiated leukemia (M0). pneumonia. as may rectal fissures. whereas ALL cells will not contain either of these enzymes. common to all B cells. Patients may also seek medical attention because of gum hypertrophy and bone and joint pain. and megakaryoblastic leukemia (M7). Laboratory Findings The hallmark of acute leukemia is the combination of pancytopenia with circulating blasts (see micrograph). and lymph nodes. and perirectal infections. particularly in the sternum. and most cases will express CD10. APL is characterized by the cytogenetic finding of t(15. histochemistry will demonstrate peroxidase in myeloid cells and butyrate esterase in monocytic cells. but will express some combination of CD 2. The most dramatic presentation is hyperleukocytosis. Such patients require emergent leukapheresis and chemotherapy. formerly known as the "common ALL antigen." ALL cells of T lineage will usually not express mature T-cell markers. In considering the various types of AML. the prothrombin time prolonged.
. molecular. and immunophenotype information. and dyspnea. APL is now considered separately because of its unique biologic features and unique response to non-chemotherapy treatments. and 7 and do not express surface immunoglobulin. and fibrin degradation products or fibrin D-dimers present. confusion. There is variable enlargement of the liver. Hyperuricemia may be seen. The phenotype of leukemia cells is usually demonstrated by flow cytometry. acute monoblastic leukemia (M5). an eosinophilic needle-like inclusion in the cytoplasm. More than 20% blasts are required to make a diagnosis of acute leukemia.17) and the fusion gene PML-RAR alpha. acute myeloblastic leukemia (M1). ALL is most usefully classified by immunologic phenotype as follows: common. death within a few hours may occur if treatment with appropriate antibiotics is delayed. Aspergillus). such as CD 3. Almost all ALL cells express terminal deoxynucleotidyl transferase (TdT). 4. CD20 and surface immunoglobulin but not TdT AML has been characterized in several ways. or 8. spleen. The Auer rod. acute myeloblastic leukemia with differentiation (M2). Patients with ALL (especially T cell) may have a mediastinal mass visible on chest radiograph. in which a markedly elevated circulating blast count (usually > 200. acute myelomonocytic leukemia (M4). it is more common in monocytic types of AML. Stomatitis and gum hypertrophy may be seen in patients with monocytic leukemia. seen in approximately 5% of cases at diagnosis. patients appear pale and have purpura and petechiae. tibia. secures the diagnosis. However. and T cell. Thus. 5. The "FAB.000/mcL) leads to impaired circulation. the fibrinogen level will be reduced. AML cells usually express myeloid antigens such as CD 13 or CD 33.
In ALL. Unfavorable cytogenetics in ALL are the Philadelphia chromosome t(9. Acute leukemia may also resemble a left-shifted bone marrow recovering from a previous toxic insult.000/mcL) have not shared in this favorable outcome. 90% of patients remain in long-term remission. chronic myeloid leukemia. A poor prognosis is conferred by the cytogenetics finding of monosomy 5 or 7. Options include standard chemotherapy and autologous and allogeneic transplantation. a relatively favorable group of patients has been defined based on a molecular signature that includes mutations of nucleophosmin 1 (NPM1) and lacks the internal tandem duplication of the FLT3 gene. These patients have a higher chance of achieving both short. the hyperdiploidy (with more than 50 chromosomes) is associated with a better prognosis. Differential Diagnosis AML must be distinguished from other myeloproliferative disorders. but studies of the potentially synergistic combination of retinoic acid and arsenic trioxide may improve results here.
.21) and inv(16)(p13.22) and t(4. the addition of arsenic trioxide may be beneficial. Significant advances have been made in the treatment of APL. Once a patient has entered remission. and the addition of this biologic agent may be helpful in other cases as well.11). Patients who do not enter remission or who have high-risk cytogenetics (such as monosomy 7 and complex cytogenetics) do far more poorly and are rarely cured with chemotherapy. and chemotherapy. but is seldom seen in adults. postremission therapy should be given with curative intent whenever possible. a bone marrow study should be repeated in several days to see if maturation has taken place. either alone or in combination with other agents. but cure rates are only 20–30%. It may also be confused with the atypical lymphocytosis of mononucleosis and pertussis AML Most patients with AML are treated with a combination of an anthracycline (daunorubicin or idarubicin) plus cytarabine. and the risk factor profile of the leukemia. which has fusion genes involving the MLL gene at 11q23. This therapy will produce complete remissions in 80% of patients under age 60 years and in 50–60% of older patients (see Tables 39–3 and 39–4). with cure rates of 50–60% with chemotherapy and 70–80% with autologous transplantation. With this approach 90–95% of patients will achieve complete remission. The majority of cases of AML are of intermediate risk and have either normal cytogenetics or abnormalities that do not confer strong prognostic significance. Induction therapy should include an anthracycline plus all-trans-retinoic acid. APL is treated differently from other forms of AML. Only the uncommon group of high-risk patients (based on initial white blood cell count > 10. cure rates for postremission therapy are 35–40% for chemotherapy. and 50–60% for allogeneic transplantation. If the question is in doubt. ALL must be separated from other lymphoproliferative disease such as chronic lymphocytic leukemia. 40–50% for autologous transplantation. Within this large subgroup. termed the "core-binding factor" leukemias because of common genetic lesions affecting DNA-binding elements.q22) are seen in 15% of cases and are. Some types of AML whose cytogenetics involved core-binding factors have a more favorable prognosis. The optimal treatment strategy depends on the patient's age and clinical status. Allogeneic transplantation is the treatment of choice. With the use of all-trans retinoic acid. or complex cytogenetics with more than three separate abnormalities. arsenic trioxide. Favorable cytogenetics such as t(8. For patients with highrisk APL based on an initial white blood cell count > 10. and hairy cell leukemia. and myelodysplastic syndromes.000/mcL. lymphomas.and long-term disease control. For intermediate-risk patients with AML.Among the other types of AML. cytogenetic studies are the most powerful prognostic factors.
These stages can be collapsed in to low-risk (stages 0–I). Information about CLL is now evolving rapidly. and asparaginase. After achieving complete remission. Intermediate-risk patients have a 30–50% chance of cure with chemotherapy. With advanced disease. transplantation (autologous or allogeneic) offers a 20–40% chance of cure. Treatment decisions are made based on patient age and risk factors of the disease. vincristine. a variant. prednisone. Remission induction therapy for ALL is less myelosuppressive than treatment for AML and does not necessarily produce marrow aplasia. Clinical Findings Symptoms and Signs CLL is a disease of older patients. is more aggressive. Low-risk patients with ALL may be treated with chemotherapy with a 70% chance of cure. stage II. ALL Adults with ALL are treated with combination chemotherapy. patients may be treated with either chemotherapy or highdose chemotherapy plus bone marrow transplantation. High-risk patients with adverse cytogenetics or poor responses to chemotherapy are best treated with allogeneic transplantation. CLL is manifested clinically by immunosuppression. Those patients with Philadelphia chromosome-positive ALL (or bcr-abl plus ALL) should have imatinib (or dasatinib) added to their initial chemotherapy. with slowly progressive accumulation of long-lived small lymphocytes. lymphocytosis only. patients receive central nervous system prophylaxis so that meningeal sequestration of leukemic cells does not develop. On examination. General Considerations Chronic lymphocytic leukemia (CLL) is a clonal malignancy of B lymphocytes. but some subtypes behave more aggressively. Immunodeficiency is also related to inadequate antibody production by the abnormal B cells. The long-standing Rai classification system remains prognostically useful today: stage 0. CD5 on lymphocytes. • Coexpression of CD19. 80% of patients will have lymphadenopathy and 50% will have enlargement of the liver or spleen. and high-risk patients are rarely cured with chemotherapy alone. stage III. prolymphocytic leukemia. the prognosis is much more guarded. CLL usually pursues an indolent course.Once leukemia has recurred after initial chemotherapy. The morphology of the latter is
. with 90% of cases occurring after age 50 years and a median age at presentation of 65 years. bone marrow failure. organomegaly. For those patients with APL who relapse. This treatment produces complete remissions in 90% of patients. arsenic trioxide can produce second remissions in 90% of cases. stage IV. Others present with fatigue or lymphadenopathy. These cells are immunoincompetent and respond poorly to antigenic stimulation. lymphocytosis plus lymphadenopathy. Autologous transplantation is a possibility in high-risk patients who lack a suitable donor Chronic Lymphocytic Leukemia Essentials of Diagnosis • Lymphocytosis > 5000/mcL. CLL may cause damage by direct tissue infiltration. with new findings in biology and new treatment options. intermediate risk (stage II) and high-risk (stages III–IV). Many patients will be incidentally discovered to have lymphocytosis. including daunorubicin. As with AML. stage I. thrombocytopenia. anemia. and organ infiltration with lymphocytes. The disease is usually indolent. and autologous transplant in second remission produces cure rates of 60–70%. For patients in second remission.
but smaller numbers of larger and activated lymphocytes may be seen. patients whose cells have unmutated IgV genes and high levels of ZAP-70 expression do less well. The finding of deletions of chromosome 17p or 11q confers a poor prognosis. an isolated lymph node transforms into an aggressive large cell lymphoma (Richter syndrome). The assessment of genomic changes by fluorescence in-situ hybridization (FISH) provides important prognostic information. Laboratory Findings The hallmark of CLL is isolated lymphocytosis. or lymphoma (especially mantle cell) in the leukemic phase are distinguished on the basis of the morphology and immunophenotype of circulating lymphocytes and bone
. Viral infections producing lymphocytosis should be obvious from the presence of fever and other clinical findings.000/mcL and may be markedly elevated to several hundred thousand. In 5–10% of cases. Pertussis may cause a particularly high total lymphocyte count. low expression of surface immunoglobulin and CD20. Usually 75–98% of the circulating cells are lymphocytes. and the absence of overexpression of cyclin D1. with condensed nuclear chromatin. Other lymphoproliferative diseases such as Waldenström macroglobulinemia.different. whereas those whose only genomic change is deletion of 13q have a very favorable outcome. CLL may be complicated by autoimmune hemolytic anemia or autoimmune thrombocytopenia. The hematocrit and platelet count are usually normal at presentation. while the systemic disease remains stable. Lymphocytes appear small and mature. however. these cells typically express low levels of the surface antigen CD38 and do not express the zeta-associated protein (ZAP-70). fever may occur in CLL from concomitant bacterial infection. (see micrograph). Patients whose CLL cells have mutated forms of the immunoglobulin gene (which can currently be tested only in research laboratories) have a more indolent form of disease. The bone marrow is variably infiltrated with small lymphocytes (see micrograph). hairy cell leukemia. In approximately 5% of cases. The white blood count is usually greater than 20. CLL is distinguished from mantle cell lymphoma by the expression of CD23. characterized by larger and more immature cells. Differential Diagnosis Few syndromes can be confused with CLL. Conversely. and are morphologically indistinguishable from normal small lymphocytes. this finding is commonly observed only in CLL and mantle cell lymphoma. The immunophenotype of CLL demonstrates coexpression of the B lymphocyte lineage marker CD19 with the T lymphocyte marker CD5.