LYMPHOPROLIFERATIVE DISORDERS FARIDA OESMAN DEPARTMENT OF CLINICAL PATHOLOGY FACULTY OF MEDICINE, UNIVERSITY OF INDONESIA

LYMPHOPROLIFERATIVE DISORDERS HEMATOPOETIC CHRONIC LYMPHOCYTIC LEUKEMIA HAIRY CELL LEUKEMIA PLASMA CELL MYELOMA MACROGLOBULINEMIA WALDENSTROM’S LYMPHORETICULAR HODGKIN’S DISEASE NON HODGKIN’S LYMPHOMA

CHRONIC LYMPHOCYTIC LEUKEMIA CHARACTERIZED BY ACUMULATION OF MATURE B LYMPHOCYTES USUALLY COEXPRESS CD5 & CD23 IN PERIPHERAL BLOOD, BONE MARROW SPLEEN, LIVER, LYMPH NODES

CLASSIFICATION OF CLL ACCORDING TO FRENCH AMERICAN BRITISH (FAB) CLASSICAL CLL >90% SMALL LYMPHO-CYTES CLL/PLL 11-54% PROLYMPHO-CYTES ATYPICAL CLL >15% LYMPHOPLAS-MOCYTOID <10% PROLYMPHO-CYTES

EPIDEMIOLOGY A PEAK AT 60 - 80 YEARS RARELY OCCUR AT <40 YEARS IS THE MOST COMMON LEUKEMIA OF ADULTS A PEAK AT 60 - 80 YEARS RARELY OCCUR AT <40 YEARS MALE TO FEMALE RATIO IS 2 : 1

CLINICAL FeatureS MOST PATIENTS ARE ASYMPTOMATIC, BUT SOME PRESENT WITH SYMETRICAL ENLARGMENT OF LYMPH NODES SPLENOMEGALY & HEPATOMEGALY ARE COMMON IN LATER STAGES FEATURES OF ANEMIA (PALLOR, WEAKNES) AND FEATURES OF THROMBOCYTOPENIA (BRUISING, PURPURA) DUE TO MARROW REPLACEMENT RECURRENT INFECTIONS BACTERIAL INF IN EARLY DISEASE VIRAL & FUNGAL INF IN ADVANCED DISEASE DUE T0 IMMUNOSUPRESSION AS RESULTS OF HYPOGAMMAGLOBULINEMIA CELLULAR IMMUNE DYSFUNCTION

LABORATORY FINDING PERIPHERAL BLOOD BONE MARROW ABSOLUTE LYMPHOCYTOSIS AT LEAST 10.000/uL 70-99% OF WBC ARE SMALL LYMPHOCYTES VARYING NUMBERS OF SMUDGE CELLS NORMOCYTIC NORMOCHROME ANEMIA, NEUTROPENIA & THROMBOCYTOPENIA DEVELOP WITH DISEASE PROGRESSION AUTOIMMUNE HEMOLYTIC ANEMIA IN  10% POSITIVE DIRECT COOMB’S TEST BONE MARROW FOCALLY OR DIFUSELY INFILTRATED BY LYMPHOCYTES >90% OF CASE ARE B CELL ORIGIN  CD19+, CD20+, CD23+, CD5+

PERIPHERAL BLOOD

DIAGNOSIS OF CLL ACCORDING TO INTERNATIONAL CLL WORKSHOP NATIONAL CANCER INSTITUTE WORKING GROUP 1989 1. LYMPHOCYTES ≥10.000/uL ESPECIALLY MATURE LYMPHOCYTES 2. LYMPHOCYTES IN BONE MARROW ≥30% 3. LYMPHOCYTES IN PERIPHERAL BLOOD SHOWED B CELL PHENOTYPE (CD19, CD20, CD23, CD5) DIAGNOSIS IS ESTABLISHED IF 1 + 2 or 1 + 3 or 2 + 3

LEUKEMIC RETICULOENDOTHELIOSIS HAIRY CELL LEUKEMIA IS ORIGINALLY REFERRED TO A LEUKEMIC RETICULOENDOTHELIOSIS IS AN UNCOMMON B CELL LYMPHOPROLIFERATIVE DISORDERS MATURE B CELL WITH OVAL NUCLEI, ABUNDANT CYTOPLASM WITH HAIRY PROJECTIONS  HAIRY CELLS INVOLVING PERIPHERAL BLOOD DIFFUSELY INFILTRATING IN BONE MARROW AND SPLEEN

MALE TO FEMALE RATIO IS 5 : 1 EPIDEMIOLOGY IS A RARE DISEASE COMPRISING 2% OF LYMPHOCYTIC LEUKEMIA PREDOMINANTLY IN MIDDLE-AGED TO ELDERLY ADULT WITH A MEDIAN AGE OF 50 YEARS MALE TO FEMALE RATIO IS 5 : 1

CLINICAL FeatureS TYPICALLY PRESENT WITH FEATURES OF RECURRENT OPPORTUNISTIC INFECTIONS  FEVER ANEMIA  WEAKNESS & FATIGUE SPLENOMEGALY  LEFT UPPER QUADRANT PAIN

LABORATORY FINDING PERIPHERAL BLOOD PANCYTOPENIA IS USUAL AT PRESENTATION LYMPHOCYTE COUNT IS RARELY >20.000/uL MONOCYTOPENIA IS A DISTINCTIVE FEATURES A VARIABLE NUMBER OF LARGE LYMPHOCYTES WITH VILLOUS CYTOPLASMIC PROJECTIONS (HAIRY CELLS)

LABORATORY FINDING BONE MARROW FOCALLY OR DIFUSELY INFILTRATED BY HAIRY CELLS WITH B CELL ORIGIN (CD19+, CD20+) POSITIVE TARTRATE RESISTANT ACID PHOSPHATASE (TRAP) STAINING INCREASE OF RETICULIN FIBRES CAUSING DRY TAP WITH MARROW ASPIRATION IN PROPORTION OF PATIENTS, THE BM IS HYPOCELLULAR WITH A LOSS OF HEMATOPOETIC CELLS ESPECIALLY GRANULOCYTIC LINEAGE

PERIPHERAL BLOOD

PLASMA CELL MYELOMA CHARACTERIZED BY CLONAL PROLIFERATION OF PLASMA CELLS IN BONE MARROW PRESENCE OF MONOCLONAL (M) PROTEIN IN BLOOD AND OR URINE ASSOCIATED WITH ORGAN DYSFUNCTION

MALE TO FEMALE RATIO IS 1.5 : 1 EPIDEMIOLOGY COMPRISES 10-15% OF HEMATOPOETIC NEOPLASM USUALLY SEEN IN OLDER ADULTS 90% OF CASES OCCUR AT >50 YEARS A PEAK AT 70 YEARS MALE TO FEMALE RATIO IS 1.5 : 1

CLINICAL VARIANT SYMPTOMATIC MYELOMA DEFINED BY ORGAN DAMAGE ASYMPTOMATIC (SMOLDERING) MYELOMA SYMPTOMATIC MYELOMA DEFINED BY ORGAN DAMAGE  CRAB NON SECRETORY MYELOMA (3%)

CLINICAL FeatureS BONE PAIN AND PATHOLOGICAL FRACTURES DUE TO INFILTRATION OF PLASMA CELL INTO BONE FEATURES OF ANEMIA DUE TO BONE MARROW REPLACEMENT BY PLASMA CELLS RECURRENT INFECTION DUE TO DEPRESSSED OF NORMAL IMMUNOGLOBULIN PRODUCTION FEATURES OF RENAL FAILURE DUE TO TUBULAR DAMAGE RESULTING FROM MONOCLONAL LIGHT CHAIN PROTEINURIA (BENCE JONES PROTEIN)

CLINICAL FeatureS ABNORMAL BLEEDING TENDENCY DUE TO M PROTEIN INTERFERE WITH PLATELET FUNCTION OR COAGULATION FACTORS THROMBOCYTOPENIA IN ADVANCED DISEASE HYPERVISCOSITY SYNDROME IN 2% CASES  VISUAL FAILURE, CNS SYMPTOMS, NEUROPATHIES

LABORATORY FINDING PERIPHERAL BLOOD BONE MARROW NORMOCYTIC NORMOCHROMIC ANEMIA ROULEAUX FORMATION NEUTROPENIA & THROMBOCYTOPENIA OCCURS IN ADVANCED DISEASE PLASMA CELLS IN 15% OF CASES HIGH ERYTHROCYTE SEDIMENTATION RATE BONE MARROW INCREASE PLASMA CELLS USUALLY >20% OFTEN WITH ABNORMAL FORMS

BONE MARROW

LABORATORY FINDING OTHERS PRESENCE OF M PROTEIN IN SERUM  M SPIKE IN SERUM ELECTROPHORESIS IgG 50%, IgA 20%, LIGHT CHAIN 20%, IgM, IgD, IgE <10% URINE  BENCE JONES PROTEIN (2/3 CASES) INCREASED SERUM M PROTEIN LEVELS  IgG >30g/L, IgA >20g/L INCREASED OF SERUM CALCIUM (20%) INCREASED OF SERUM CREATININE (20-30%) DECREASE OF SERUM ALBUMIN IN ADVANCED DISEASE INCREASED OF SERUM 2 MICROGLOBULIN, USEFUL INDICATOR OF PROGNOSIS <4 mg/L  A RELATIVELY GOOD PROGNOSIS

SERUM PROTEIN ELECTROPHORESIS NORMAL M SPIKE MONOCLONAL PROTEIN IN GAMMA REGION  MONOCLONAL GAMMOPATHY

EVIDENCE OF SURROUNDING OSTEOBLASTIC REACTION RADIOLOGICAL FINDING REVEAL A BONE LESIONS OSTEOLYTIC AREAS WITHOUT EVIDENCE OF SURROUNDING OSTEOBLASTIC REACTION OSTEOPOROSIS

DIAGNOTIC CRITERIA ASYMPTOMATIC MYELOMA SYMPTOMATIC MYELOMA CLONAL PLASMA CELLS IN BONE MARROW ≥10% OR PLASMACYTOMA AND /OR M PROTEIN IN SERUM >30g/L SYMPTOMATIC MYELOMA CLONAL PLASMA CELLS IN BONE MARROW ≥10% M PROTEIN IN SERUM OR URINE HYPERCALCEMIA, RENAL INSUFFICIENCY, ANEMIA, BONE LESIONS (CRAB) NON SECRETORY MYELOMA CLONAL PLASMA CELLS IN BONE MARROW ≥30% OR BIOPSY PROVEN PLASMACYTOMA

MYELOMA STAGING SYSTEM MODIFIED FROM DURIE & SALMON STAGE I LOW M PROTEIN  IgG <50g/L, IgA <30g/L URINE BENCE JONES <4g/24 hours ABSENT OR SOLITARY BONE LESIONS NORMAL Hb, SERUM CALCIUM, Ig LEVEL (NON M) STAGE II OVERALL VALUES BETWEEN I & II STAGE III HIGH M PROTEIN  IgG >70g/L, IgA >50g/L URINE LIGHT CHAIN >12g/24 hours ADVANCED, MULTIPLE BONE LESIONS Hb <8.5g/dL, SERUM CALCIUM >12 mg/dL SUBCLASSIFICATION BASED ON RENAL FUNCTION A: SERUM CREATININE <2mg/dL B: SERUM CREATININE =>2mg/dL

MYELOMA STAGING SYSTEM INTERNATIONAL STAGING SYSTEM STAGE I SERUM β2-MICROGOBULIN <3.5mg/L SERUM ALBUMIN >3.5g/dL STAGE II SERUM ALBUMIN <3.5g/dL OR SERUM β2-MICROGOBULIN 3.5-5.5mg/L IRRESPECTIVE OF SERUM ALBUMIN LEVEL STAGE III SERUM β2-MICROGOBULIN >5.5mg/L

WALDENSTROM’S MACROGLOBULINEMIA WHO CLASSIFICATION OF TUMORS HAEMATOPOIETIC AND LYMPHOID TISSUE (2008) DEFINES AS A TYPE OF LYMPHOPLASMACYTIC LYMPHOMA IS A NEOPLASM OF B LYMPHOCYTE, PLASMACYTOID LYMPHOCYTE AND PLASMA CELL, USUALLY INVOLVED THE BONE MARROW

WALDENSTROM’S MACROGLOBULINEMIA INFILTRATION OF LYMPHOPLASMOCYTIC CELLS IN BONE MARROW OCCURANCE OF MONOCLONAL IgM PROTEIN IN THE BLOOD IS UNCOMMON CONDITION FREQUENTLY IN MEN >50 YEARS

CLINICAL FeatureS USUALLY INCIDIOUS ONSET WITH FATIGUE AND WEIGHT LOSS HYPERVISCOSITY SYNDROME (20-30%)  OCULAR & NEUROLOGIC MANIFESTATION IF MACROGLOBULIN IS CRYOGLOBULIN  FEATURES OF CRYOPRECIPITATION (5%) SUCH AS RAYNAUD PHENOMENON ANEMIA DUE TO INCREASED PLASMA VOLUME A BLEEDING TENDENCY DUE TO MACROGLOBULIN INTERFERENCE WITH PLATELET FUNCTION COAGULATION FACTORS

LABORATORY FINDING PERIPHERAL BLOOD BONE MARROW OTHERS NORMOCYTIC NORMOCHROMIC ANEMIA ROULEAUX FORMATION NEUTROPENIA, LYMPHOCYTOSIS AND LYMPHOPLASMOCYTOID CELLS HIGH ERYTHROCYTE SEDIMENTATION RATE BONE MARROW INFILTRATION OF LYMPHOPLASMOCYTOID CELLS OTHERS M SPIKE IN PROTEIN ELECTROPHORESIS  IgM BENCE JONES PROTEIN IN 10% CASES INCREASED SERUM/PLASMA VISCOSITY

MYELOMA WALDENSROM’S CLINICAL FEATURES Bone lesion (+) (-) Recurrent infection (+) (-) Bleeding tendency (+) (++) Organomegaly (+) (++) Hyperviscosity (+) (++) Renal failure (+) (-) LABORATORY FINDING Anemia (++) (+) LeucopenIa (+) / (-) (+) / (-) Thrombocytopenia (+) / (-) (+) / (-) Hypercalcemia (+) (-) Increase serum viscosity (+) (++)

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