Oncology Flashcards
Immunohistochemistry
Antibody labeled with special stain applied to slide to test for presence of cell components
- Lights up when antibody reacts with specific surface
Flow Cytometry
Measurement of multiple antigenic/physical features at single cell level in suspension
- Antibodies labeled with fluorochromes
- Mix antibodies and cells and flow past laser
- Detect fluorescent emmision
(Ex: detect CD4 count with CD4 antibodies labeled with flourescent dye. Cells pushed through capillary at high speeds–> detects what fluoresces)
Chromosome analysis
Karyotyping
- Cells incubated in growth media with/without mitogen
- Spread on glass slides + stained
- Cells with metaphases IDed on light microscope
- Banding pattern reviewed
- Abnormal banding/duplicates/missing chromosomes noted
FISH
Fluorescent in Situ Hybridization
- DNA probes (ssDNA) labeled with fluorescent dye
- Probes applied to cells on glass slides
- Probes hybridize to DNA in target cells
- Can identify breaks in DNA/ translocations
(ex: 8; 14 translocation–> two fusion signals, two normal signals; increasing role in lymphoma diagnosis)
Mircroarray
Emerging tool for analyzing entire/section of genome in single test
- Multiple methods: expression array, array comparative genomic hybridization (aCGH), single nucleotide polymorphism (SNP)
- Evaluate entire genomes in submicroscopic level in single technology
- Entire genome in small fragments pre-arranged on small dots on glass slide
- Hybridizes to corresponding codes on carrier–> fluorescent signals collected–> microarray reader
ex: RNA expression pattern in diffuse B-cell lymphoma can be demonstrated by expression array
Molecular diagnostics
Detect changes at DNA, RNA, protein levels
- Mutations, translocations, deletion, amplification, methylation
Use:
- Southern blot
- PCR
- DNA sequencing
ex: detect point mutations (JAK2 V617F in myeloproliferative neoplasms)
Therapeutic intent
Curative vs Palliative
Curable cancers: testicular, lymphomas- treatment is curative
Palliative care: prostate, multiple myeloma (make patient feel better, live longer)
Systemic vs local therapy
Chemotherapy= systemic
- oral or IV
- Non-specific vs targeted
- Classic vs targeted agents
- Antibody therapies
- Immunologic therapies (antibodies such as CD-20)
- Radiolabeled antibodies
Radiation therapy= generally local
Surgery= local
Radiation therapy
Used in 60% of cancer patients: definitive treatment or palliation
- Primary use of RT for local/regional disease (effectiveness/toxicity should only be in irradiated area)
“Standard fractionation”= 5-9 weeks treatments M-F
- Total body irradiation (TBI) only used for certain conditioning regimens (BMT)
SI system (radiation prescribed in Gray)
- 1 Gray= 1 joule of absorbed dose/1 kg material
- 1 gray= 100 cGy= 100 rad
Teletherapy
External beam radiation
- External machine to deliver radiation through skin
Brachytherapy
Placement of radioactive bead/material in site of tumor
- “implants”
- temporary or permanent
- Radium, cesium, iridium, iodine
Proton Beam therapy
More specifically targets tumor with less surrounding damage
- No data of effectiveness/longevity over other forms of radiation
Gamma knife
Radiation used as knife
- Particularly used for brain tumors
Radiation therapy clinical applications
Definitive treatment: - Prostate, head and neck cancer Palliation of visceral metastases: - Bleeding, pain, obstruction, airway Palliation of CNS involvement - Brain metastases, cauda equina syndrome, spinal cord compression
Chemotherapy and radiation
Improve local control (organ preservation)
- Radiation sensitizer
- Can shrink tumor before operation
Adverse effects of radiation therapy
Acute:
- Dermatitis
- Esophagitis, mucositis
- Bone marrow suppression
Fatigue
Late effects:
- Secondary malignancy
- Thyroid disease
- Cardiac issues/ lung problems
Sources of hematopoietic stem cells (HSCs)
- Marrow= harvested in OR, iliac crest
- rich in stem cells - Peripheral blood= harvested in pheresis center after mobilization with growth factors (G-CSF, plerixafor)
- Umbilical cord= harvested at childbirth (only used for chidren)
HSC donor types
Autologous: self
- Rescue from chemotherapy (harvested before chemo started, give cells back)
Allogeneic:
- HLA identical sibling
- Syngenic= identical twin
Allogenic Alternative donors:
- HLA matched unrelated donors
- Partially matched (Haploidentical) family donors
Identifying donor:
- HLA matching
- Tie breakers: donor health, high risk behaviors, CMV status, ABO/Rh typing, sex matching, willingness to donate
Preparative regimen before graft
- Total body irradiaion
- High dose chemotherapy
- Myeloablative vs reduced intensity preparative regimens (older patients- avoid losing all myeloid cells)
Graft includes stem cells +/- mononuclear cells/ lymphocytes/ NK cells
Rationale for allogenic BMT
Increased dose intensity to treat resistant cancer–> produce long lasting/permanent myeloblation
- Applied to eradicate residual disease or resistant disease
Engraft normal blood forming elements to replace defective ones:
- Aplastic anemia, congenital disorders of hematopoeisis
- Congenital immunodeficiencies
- Metabolic/other disorders
- Thalassemia, sickle cell anemia
Diseases using allogenic BMT
Malignant disease:
- Leukemia
- Lymphoma
- Myeloma
- Lung, renal, breast, ovarian cancer
Non-malignant disease:
- Thalassemia
- sickle cell anemia
- aplastic anemia
- immunodeficiency disorders
Process of BMT
- Evaluation
- Admission for chemo/radiation?
- Several days of therapy followed by stem cell infusion
- may be given unmanipulated or manipulated product - Follow for side effects of therapy, infection, transfusion need
- Discharge 2-6 weeks later
- Follow closely for months to years
Toxic side effects of BMT
Immunologic
- Rejection
- Graft vs host: skin, gut, liver, other (eye, oral, etc)
- Graft vs leukemia (GOOD)- cures disease
Non-immunologic:
- Heart – cardiomyopathy from cyclophosphamide
- Lung
- Liver – veno-occlusive disease
- Bladder – hemorrhagic cystitis (cyclophosphamide, BK virus)
- Kidney
- Fertility
- Hematologic
- Dermatologic
- Mucositis
Long-term risk of cancer, infection
Graft vs Host disease
Risk increases with increased HLA disparity
Older donors/patients have higher risk
T-cell containing transplants have more GVHD risk than T-cell depleted transplants
Non-Hodgkin Lymphoma staging: Ann Arbor System
Ann Arbor:
- A or
- B= “B symptoms”: fever (> 38C), weight loss (> 10%), night sweats
Stage I: Involves single lymph node/region or single extralymphatic site
Stage II: 2+ lymph nodes on same side of diaphragm (could have localized extralymphatic involvement)
Stage III: involves lymph nodes on both sides of diaphragm, spleen, localized extranodal disease
Stage IV: diffuse extra-lymphatic disease (liver, bone marrow, lung, skin)
Prognosis in aggressive lymphomas (index)
APLES (apples):
- Age > 60
- Performance status (>= 2)
- LDH elevated
- Extra-nodal sites (> 1)
- Stage (Ann arbor stage III or IV)
Risk: Low= 0-1 Low-Intermediate= 2 factors High-intermediate= 3 factors High= 4-5 factors
Pathology of Chronic Lymphocytic Lymphoma (B-CLL): Diagnosis and genetics/immunophenotype
aka Small Cell Lymphocytic Lymphoma:
Diagnosis:
- Malignant clone (small, mature) with lymphocytes > 5000/uL
- Frequent bone marrow involvement
Immunophenotype/genetics:
- CD5+, CD19+, CD20+/-
- 40% have v-region mutations in H chain gene
Prognosis based on genetics/immuno:
BAD= CD38+, trisomy 12, Bcl-1
Good= abnormal 13q
Chronic Lymphocytic Leukemia (B-CLL): Presentation and testing
Presentation:
- May be on routine labs
- Seen in elderly
- Male > Female
- Lymphadenopathy
- Splenomegaly/hepatomegaly
- Fatigue
Labs:
- Smudge cells
- Lymphocytosis
- Cytopenia
- Monoclonal protein
- Hypogammaglobulinemia
- Autoimmune cytopenias
Complications:
- Autoimmune hemolytic anemia (tx: corticosteroids)
- Immune thrombocytopenia (tx: corticosteroids)
- Red cell aplasia (tx: corticosteroids)
- Infections
- Hypogammaglobulinemia
- Transformation to large cell lymphoma (Richter’s transformation)- poor prognosis
Staging of B-CLL
Rai classification: Stage 0 -- lymphocytes >15,000/ml and >40% marrow Stage 1 -- enlarged lymph nodes Stage 2 -- enlarged liver and/or spleen Stage 3 -- anemia (< 100,000/l)
Therapy and prognosis for B-CLL
Combination:
- monoclonal antibody (Rituximab)
- Purine analog (fluarabine, pentostain)
+ Allogenic stem cell transplant (curative)
Prognosis:
- Only curative with stem cell transplant
- Can live many years without transplant
Extranodal marginal zone B-cell lymphoma (MALT type): Presentation and Pathology
Often related to chronic infections/inflammatory states
Presentation= Extranodal; May be associated with:
- h. pylori
- Chronic lung infections
- autoimmune disease (thyroid, Sjogren’s)
- 1/3 multifocal
Pathology:
- Tumors derived from cells surrounding germinal centers (B memory cells)
- Larger than small lymphocytes, have more cytoplasm
- Admixed with plasma cells- can be benign (reactive) or derived from tumor cells
Extranodal marginal B-cell lymphoma: Immuno/genetic
Immunophenotype (not specific):
- sig+ (M>G or A)
- IgD- some cig +
- CD19+, CD20+, CD22+, CD79+, CD5-, CD10-, CD23-, CD43-/+, CD11c +/-
Genetics:
- bcl-2 and bcl-1 negative
Extranodal marginal zone B-cell lymphoma (MALT type): therapy, prognosis, complications
- Triple antibiotic therapy for H. Pylori
- Cyclophosamide-based therapy with Rituximab
- Radiotherapy for early stage disease
Prognosis: good; may recur
- Response to therapy (antibiotics) less likely with deeper invasion, lymph node metastases, or t(11;18) found
Complications: related to organ involved/therapy
Follicular Lymphoma: Presentation and Pathology
One of most common indolent lymphomas (22% non-HL)
Presentation: enlarged lymph node; asymptomatic. Common marrow involvement
Pathology:
- Tumor enlarges, fills entire lymph node with neoplastic follicles, obliterates normal architecture
- Recapitulates nodal germinal center arrangement, germinal center cells
- May transform into larger, more aggressive lymphoma
- Involvement: lymph nodes, neoplastic follicles in extranodal soft tissue
- Stains for Bcl-2
Follicular lymphoma: Immuno/genetics
Immunophenotype:
- sig+ = IgM+/-, IgD > IgG > IgA
- CD10+ CD25-, CD2-/+, CD42-, CD11c-
- * Bcl-2
Genetics:
- t(14;18)(q32;q21): bcl-2 rearrangment–> IgH control–> overexpression of anti-apoptotic Bcl-2
Follicular lymphoma: therapy, prognosis, complications
Therapy: Chemo, rituximab
- ONLY cure is allogeneic stem cell transplant
- Remission with autologous stem cell transplant
Prognosis: FLIPI score
- Localized disease: 50% 10-year disease free survival; overall 60-70% survival
- Advanced disease: over 10-year median survival
- Elderly patients: watch and wait
Complications: infections, complication of chemo; can have normal life w/o therapy for several years
Mantle Cell lymphoma: Presentation and Pathology
Seen in Adults only (more common in males): frequently involves extranodal spaces
Presentation: presents SICK: can be v. aggressive with tumor lysis syndrome; not cured with standard therapy
- Usually seen in advanced disease
- Bone marrow, Waldeyer’s ring (tonsillar) and GI tract involvement
- Found in peripheral blood
Pathology:
- Most aggressive small cell lymphoma;
- Derives from pre-germinal center (antigen-naive) B lymphocytes in zone around germinal center (mantle zone)
- Cells small to medium
- Irregular nuclei (larger= more aggressive)
- Widespread involvement at diagnosis (bone marrow, GI tract)
- Colon involvement–> polypoid lesions (lymphomatous polyposis coli)
Mantle cell lymphoma: immunophenotype and genetics
Immunophenotype:
- slgM+, IgD+,
- CD 19+. 20+, 22+, 5+, 10-, 23-, 43+, 11c-
- Nuclear Bcl-1+
- Like B-CLL this B-cell tumor expresses a T-cell marker
Genetics:
- t(11;14) involving Bcl-1–> cyclin D1 overexpression
- Mutation drives cell cycling
Mantle cell lymphoma: therapy, prognosis, complications
Therapy: multiple options:
- Chemo, rituximab
- ONLY cure is allogeneic stem cell transplant
Prognosis:
- Poor without allogeneic transplant
- High M&M with transplant
Complications:
- Infection
- Complications of chemo
- Tumor lysis syndrome
- Rare visceral perforation
Diffuse large B-cell lymphoma: presentation
Most common aggressive lymphoma (31% non-HL)
- Variant= mediastinal large cell (younger women with good prognosis)
Presentation:
- Presents sick; aggressive in tumor lysis syndrome at diagnosis
Often has splenogmegaly
Diffuse large B-cell lymphoma: pathology
Pathology:
- Arise de novo (most common)
- derive from lower grade tumor (less common)
- Nodal/extra-nodal
- Large cells
- Bizarre nuclei, big nucleoli
Immuno: slg+, Cig +/-, CD19, 20, 22, 79a, 5+
Genetics:
- Some positive for bcl-2 rearrangement (follicular cell lymphomas)
- some c-myc positive (gene rearrangment)
- bcl-6 rearrangment
Therapy for diffuse B-cell lymphoma
Rituximab Cyclophosphamide Doxorubicin Vincristine, prednisone (R-CHOP)--> nothing better to date - Autologous HSC transplantation with relapse
Prognosis: based on IPI
Complications: infections, complications of chemo, tumor lysis syndrome
Burkitt lymphoma: presentation
Caused by Epstein Barr Virus HIV= risk factor More common in men Endemic variant in West Africa with jaw involvement Non-endemic may have abdominal disease - Involve kidneys, ovaries, breasts - 1/3 bone marrow involvement
Presentation:
- Presents sick
- Aggressive tumor lysis
Burkitt Lymphoma: pathology
Pathology:
- Small, primitive B-cells
- High mitotic rate
- Basophilic cytoplasm with lipid vacuoles
- Starry sky pattern (=> macrophages ingesting apoptotic debris)
Immuno: slg+, Cig +/-, CD19, 20, 22, 79a, 5+
Genetics:
* t(8;14)(q24;q32)–> MYC, IgH*
t(8;22)(q24;q11)–> MYC IgL
t(2;8)(p12;q24)–> IgK, MYC
Burkitt Lymphoma: treatment
CNS prophylaxis with intrathecal chemo/high dose methotrexate
2nd line: Rituximab Cyclophosphamide Doxorubicin Vincristine, prednisone (R-CHOP)
Prognosis: based on IPI
- Children do better than adults
Complications: infections, complications of chemo, tumor lysis syndrome
T-cell non-Hodgkin Lymphoma
- T-cell acute lymphoblastic leukemia
- Cutaneous T cell lymphoma/mycosis fungoides
- HTLV1 + Adult T-cell lymphoma:
- Rare
- Associated with hypercalcemia, high EBC (w/o anemia, thrombocytopenia) and opportunistic infections - Anaplastic large cell lymphoma:
- treated like diffuse large B cell lymphoma (without rituximab)
- children do well, adults need stem cell transplant
Hodgkin Lymphoma: presentation
Nodes enlarge over months
- Starts in neck and works its way down body
Bimodal age distribution (15-30 years, very old)
Presentation:
- B-symptoms (fever, weight loss, night sweats) more common than in non-Hodgkin’s
- Pruritis
- Adenopathy : cervical, axillary, mediastinal
- Nodal pain on alcohol ingestion
- Enlarged mediastinal mass (SVC syndrome, cough- tracheobronchial compression)
- Bone pain (metastatic involvement)
- Marrow depletion with metastases
Hodgkin Lymphoma: Pathology
See “Reed Sternberg” (RS) cell variant:
- Owl’s eye appearance
- Stains positive for CD30 (80-100%), CD15 (75-85%), BSAP (B-cell specific activating protein, PAX5 gene product- 90% cases)
RS cells seen with polyclonal lymphocytes, eosinophils, neutrophils, plasma cells, fibroblasts, histiocytes
- High number of associated macrophages
- Need biopsy (open) NOT FNAB
Unable to make intact antibodies
Two types:
- Nodular lymphocyte predominant HL
- Classical HL: subtypes:
- Nodular sclerosis
- Mixed cellularity
- Lymphocyte-depleted
- Lymphocyte-rich
(Nodular) lymphocyte predominant (NLP) HL
Tumor effaces lymph nodes
- Vaguely nodular
Pathology:
- Popcorn cells
- Lobated nuclei
- Lacks CD30 and CD15
- Expresses sig, other B cell markers
- EBV negative
- Skips lymph node groups, does not involve solid organs
- Excellent prognosis
- Uncommon disease
Nodular sclerosis classical HL (NS-HL)
70% of cases
Characteristic Mononuclear CD30+ RS-like cells (lacunar cells)
- Mediastinal involvement
- Favorable prognosis
Broad bands of fibrosis separating:
- lymphoplasmacytic reactive cells
- occasional eosinophils
- neutrophils
- classic RS cells
Mixed cellularity classical HL
Seen in HIV+ individuals Reactive cellular infiltrate with: - Eosinophils - small lymphocytes - histiocytes - abundant RS cells, variants
Resembles NS-HL without fibrosis
- Less mediastinal involvement
- Seen in cervical lymph nodes
- EBV+
Lymphocyte depleted classical HL
Rarest
- Few lymphocytes in infiltrate
- Lots of fibrosis, RS cells/variants
- Seen in higher stages, poorer prognosis
Lymphocyte-rich classical HL
Classical RS cells in sea of lymphocytes
- Infrequent to see other inflammatory cells
Hodgkin Lymphoma: treatment and prognosis
ABVD: Doxorubicin (Adriamycin) Bleomycin Vinblastin Dacarbazime - 90% cure rate with chemo \+ radiation in advanced disease
- *EXCEPT NLP: Chemo, rituximab
- ONLY cure is allogeneic stem cell transplant
Prognosis: good
Index for prognosis (each decreases likelihood of remission):
- serum albumin < 4 g/dL
- hemoglobin < 10 g/dL
- male
- age >= 45 years (elderly who receive similar doses of chemo have same outcomes)
- Stage IV disease (Ann Arbor)
- WBC >= 15,000
- Absolute lymphocyte count < 600/mm3 or < 8% total lymphocyte count
Complications of Hodgkin Lymphoma
- SVC syndrome
- Infection
- Interstitial pneumonitis (Bleomycin treatment)
Late complications:
- Infections (esp. strep pneumo)- vaccinate!
- Cardiac (CV disease)
- Pulmonary
- Infertility
- Second malignancies (AML, MDS, solid tumors)
- Thyroid disease
- Reduced saliva (head and neck radiation)–> dental problems
CD antigens in lymphoma (rule of thumb)
CD1- CD8: Mainly T-cell
CD11-CD15: Mainly myeloid
CD19-23: Mainly B-cell
CD 30: R-S cells (Hodgkin)
Tumor Lysis syndrome
Tumors with high tunover/ tumor burden:
- related to rapid turnover and destruction of cells.
- hyperkalemia (and associated arrythmias);
- hypocalcemia;
- hyperphosphatemia,
- acidemia;
- hyperuricemia (and uric acid nephropathy);
- high LDH (may be >100X normal).
Treatment:
- Prophylaxis and therapy with vigorous hydration and allopurinol.
- Monitor labs every 6-8 hours or more often as needed.
- Seen in high tumor burden with:
- acute leukemias
- lymphoblastic lymphomas
- Burkitt lymphoma
- mantle cell lymphoma
- diffuse large cell lymphoma.
Major cause of morbidity and mortality.
Complications of Lymphoma therapy
- Cytopenias – infections, bleeding, anemia (multiple agents
- Cardiac – decreased ejection fraction (anthracyclines – doxorubicin)
- Secondary malignancies – radiation and alkylators (cyclophosphamide) – breast, lung, bone, hematologic
- Neuropathy – vinca alkaloids
- Infertility – patients need counseling up front and discussion of fertility preservation
Lymphomas
Solid tumor
Caused by anything that suppresses the immune system (incidence on rise with AIDS)
HTLV-1
Human t-lymphtrophic virus type-1
- Associated with ALL cases of adult T-cell lymphoma/leukemia (3% lifetime risk)
Infectious agents associated with Lymphomas
EBV HTLV-1 HHV-8 C virus H. pylori: gastric lymphoma (cured with infection!)
Clinical presentation of non-Hodgkin’s Lymphoma
B Symptoms (fever, chills, weight loss, night sweats) Palpable, hard, nontender lymph nodes Immunologic abnormalities: - AIH (autoimmune hemolytic anemia) - Immune thrombocytopenia
Peripheral neuropathies (due to overproduction of monoclonal proteins)
Paraneoplastic neurologic complications
Diagnosis of Non-Hodgkin’s lymphoma
- Biopsy to establish diagnosis
- History, exam
- Labs:
- CBC
- Chem screen (LDH) - Imaging studies:
- CT of chest, abdomen, pelvis
- PET scan - Additional biopsies:
- Bone marrow
- Any other suspicious site
Primary mediastinal large B-cell lymphoma
LARGE mass (> 10 cm) Similar pathology, treatment to large B-cell lymphoma
Seen in younger women
Prognosis similar to Large B-cell lymphoma
- Relapses seen in CNS, lungs, GI tract, liver, ovaries, kidneys
AIDS and non-Hodgkin’s/Hodgkin’s lymphoma
Non-Hodgkin’s Lymphoma:
AIDS-defining illness (in HIV-infected)
- More aggressive than in others
- Involve CNS, GI tract, anus, rectum, skin, soft tissue
- Poor prognosis with: low CD4=, low performance, older age, advanced stage
Chemo + HAART= good control
Hodgkin’s lymphoma:
- Increased 5-10-fold incidence
- Associated with EBV within Hodgkin-Reed-Sternberg cells
- Mixed Cellularity or Lymphocyte Depleted types
- Involves bone marrow most commonly
- 80% seen in late stage (B symptoms)
Post-transplantation non-Hodgkin’s Lymphoma
Marked increase in risk for solid organ transplant patient
- Receive aggressive immunosuppression after transplantation
- Use acyclovir/ganciclovir to reduce risk of EBV development post-transplantation
Tests for staging Hodgkin’s Lymphoma
- Complete history (B symptoms)
- Physical exam
- CBC, ESR, liver/renal function tests, hepatitis, HIV
- Serum creatinine, alk-phos, LDH, bilirubin, protein electrophoresis (+serum albumin)
- Chest x-ray (PA and lateral)
- CT scan of neck, thorax, abdomen, pelvis
* PET more sensitive/specific than CT/gallium- no improvement in outcome
Ann Arbor staging with Cotswold modification
Staging Hodgkin’s Lymphoma:
Stage I: Single nodal
Stage II: 2+ nodal areas on one side of diaphragm
Stage III: nodal disease on both sides of diaphragm
- Spleen, lymph of Waldeyer’s ring= nodal sites
Stage IV: extranodal disease
Indolent NHL
Grow and spread slowly, respond to therapy (radiation, chemo) but always come back
- SLL
- CLL
Aggressive Lymphomas
Grow rapidly, may be cured with standard chemo +/- radiation
- Diffuse Large B cell lymphoma
Very aggressive lymphomas
Grow and spread very rapidly, often cured with chemo
- Patients may die at time of presentation.during therapy from tumor lysis syndome, other complications
- Acute Lymphocytic Leukemia (ALL)
NHL Treatment
- Chemo: CHOP, purine analogs, bendamustine
- Radiotherapy
- Monoclonal antibodies
- Radiolabelled monoclonal antibodies (target CD20)
- Stem cell transplantation (allogeneic or autologous stem cell rescue)
Myelodysplastic syndrome: Pathophysiology and prognosis
MDS= clonal hematopoietic stem cell disorders characterized by marrow failure, peripheral cytopenias, dysplastic morphology
- Ineffective hematopoiesis: increased apoptosis of progenitors, limited response to growth factors
- Abnormalities in proliferation, differentiation, apoptosis of precursors and progeny
High grade: genetically unstable (mutator)
- Increased risk of transformation to AML (increased blasts–> increased transformation)
- Survival: 6-30 months
- 7q- genotype
Low grade (lack mutator phenotype)
- More stable
- Survival: 6-8 years
Myelodysplastic syndrome: epidemiology/ predisposing factors
- Men, > 70 years
- Sporadic
- Risk factors: previous chemo (solid tumor < lymphoma), radiation, toxic exposures (pesticides, benzene)
- Genetic syndromes: Diamond-Blackfan, Schwachman-Diamond, Fanconi’s anemia, Dyskeratosis congenita, congenital neutropenia
Myelodysplastic syndrome: lab features
Peripheral blood:
- Anemia (normocytic or macrocytic)- acclerated apoptosis of increased progenitor cells
- dual RBC population (may be transfusion related)
- +/- Neutropenia, thrombocytopenia
- Low reticulocyte count
- Dimorphic red cells on histology
- Dysgranulopoiesis (pseudo-Pelger-Huet cells= hyposegmented neutrophils): abnormal granulocyte nucleus, staining, shape
- Dyserythropoiesis (dysplastic erythroid lineage)
- Ringed sideroblasts in RBC precursors (iron accumulation in mitochondria)
- Dysplastic megakaryocytes
- Dacrocytes (teardrop cells), red cell fragments, rouleaux formation, helmet cells
Bone marrow (perform aspirate and biopsy)
- Hypercellular
- Dysplasia (10% cells in lineage show dysplastic features)
- +/- increased blasts (myeloblasts, monoblasts)
Myelodysplastic syndrome: Cytogenetic abnormalities
Clonal abnormalities seen in: 5q deletion (-5) IMPORTANT - Seen in elderly women - Macrocytic anemia, nL/high platelet count, increased megakaryocytes (hypolobulated nuclei) - Mild clinical course
7q- (-7)
20q- (020)
+8
- 50% have normal karyotype
Myeloproliferative neoplasms
Acquired clonal hematopoietic disorders of pluripotent bone marrow stem cells
- See proliferation of 1+ myeloid lineages
Initially: BM proliferation effective–> neoplastic cells mature
- See increased RBCs, granulocytes, platelets in periphery
- EFFECTIVE hematopoeisis
Pathogenesis:
- Genetic stem cell abnormality
- Myeloid cell lineage proliferation/expansion
- See normal cell progression (initially) vs acute leukemia (arrested in one stage)
- Cells hypersensitive to cytokines
- Associated with TYROSINE KINASE constitutive activation: BCR/ABL fusion, JAK-2 mutations
- See SECONDARY non-clonal fibrosis
Epidemiology: 5th-7th decade of life
- BM hypercellularity–> increased granulocytes, PBC, platelets in periphery
- Can progress to:
1. Marrow failure or
2. Transform to acute blast phase
Presentation:
- Increased cellularity in peripheral blood
- Hepatosplenomegaly
Chronic Myelogenous Leukemia (CML): genetics
Philadelphia Chromosome: BCR-ABL1 positive t(9:22)
- 9= abl1
- 22= BCR (breakpoint cluster region)
- -> increased P210 protein leads to:
1) increased proliferation (constitutive tyrosine kinase activity)
2) MYC/BCL-2 transcription–> cells protected from apoptosis (MYC/BCL-2) - Translocation seen in 90-95% CML patients, some ALL (acute lymphoblastic leukemia)
Clonal evolution: 70% of patients in blast phase; relapse after BMT:
- +Ph (duplication of Ph chromosome)
- +8
- isochromosome 17q
Chronic Myelogenous Leukemia (CML): Clinical
MOST COMMON myeloproliferative disease (15-20% leukemias)
- Seen in 5th-6th decade
- more common in males
Bi or Tri-phasic disease;
Expansion in GRANULOCYTE pool
Chronic phase= insiduous, 2-8 years
- Bone marrow:
- Increased granulocytes (WBC precursors)
- Smaller megakaryocytes with hypolobated nuclei= “dwarf”
- decreased erythropoiesis
- elevated myeloid to erythroid ratio
- reticulin fibrosis - Peripheral blood:
- Increased WBCs (leukocytosis)
- Increased thrombocytes (+ abnormal platelets)
- Basophilia
- Anemia correcting on treatment
- Enlarged spleen due to red pulp infiltration by leukemic cells
Accelerated phase
- Increased blasts: 10-19% in PB or BM
- Increased PB basophils (>20%)
- Thrombocytopenia/thrombocytosis
- Increasing WBC/spleen size
- Clonal cytogenetic evolution
Blast phase= < 1 year survival
- Increased myeolobasts (20%) or extamedullary blast proliferation
- Abnormal platelets
- Blasts= myeloid (70%) or lymphoid (30%)
Polycythemia Vera (PV): criteria
Increased production of RBCs with normal arterial O2 saturation (no secondary polycythemia)
Clinical/lab criteria: BOTH major, 1+ minor:
Major:
- Elevated RBC mass (> 25% above mean) or Hb > 18.5 in men, > 16.5 in women
- Presence of JAK2 V617F (or similar mutation)
Minor:
- Bone marrow: hypercellular (pan-myelosis)
- Serum EPO below reference range
- Erythroid colony formation in vitro (endogenous)
Polycythemia Vera: path
JAK2 mutation
- Changes interaction between EPO receptor and JAK2
- Mutation in position 617–> constituitively active JAK–> clonal expansion
Bone marrow:
- Increased cellularity
- Panmyelosis with full maturation (no increase in blasts)
- Mild/moderate increase in WBCs, platelets
- No iron stain (all being used in RBC production)
- Increased reticulin fibers
Peripheral blood:
- Persistant leukocytosis (elevated WBC)
- Persistant thrombocytosis (elevated platelets)
Polycythemic phase= most patients
- 10% go to “spent” phase (anemia)
- 10% show myelofibrosis (with splenogmealy due to extramedullary hematopoieses
- 5-10% transform to AML
Polycythemia Vera: prognosis
Mean survival= 13 years
Terminal events: see cytogenetic abnormalities (trisomy 18, deletion 20q)
- Myelodysplastic transformation
- Leukemic transformation
- Postpolycythemic myelofibrosis
Essential Thrombocythemia
Megakaryocyte clonal, autonomous proliferation
- Must distinguish from inflammatory/malignant processes
Epidemiology:
- 1/100,000 individuals
- 55 years (M=W)
- Second peak in women ~30 years
- Usually incidental finding
Clinical presentation:
- may see life-threatening bleeding (common in GI tract)
- Erythromelagia (dramatic vasomotor symptoms)= warmth, pain in distal extremities
- Splenomegaly
- Large vessel thrombosis
- May progress to fibrotic phase (like PMF/AML)- rare
- Venous thrombosis to unusual sites or PE
Essential Thrombocythemia: Path
50% due to JAK-2 V617F mutation or MPL mutations
Proliferation of marrow megakaryocytes Peripheral: - Increased circulating platelets (abnormal morphology) - Normal Hb, WBC - Splenomegaly
Bone marrow:
- Increased in megakaryocytes
- Abnormal clustering of megakaryocytes
- Enlarged with hyperlobulated (stag-horn) nuclei, abundant cytoplasm
Essential Thrombocythemia: diagnostic criteria
ALL required for diagnosis:
- Sustained platelet >= 450,000/uL
- Megakaryocytic hyperplasia (enlarged and mature) in marrow
- Exclude other myeloproliferative disorders:
- CML (no BCR/ABL fusion)
- no PC
- no myelodysplasia
- no PMF (no collagen/reticulin fibrosis) - JAK2 V617F mutation or MPL (EPO receptor) mutation, or exclusion of reactive (secondary) thrombocytosis
Primary myelofibrosis (PMF)
Proliferation of Megakaryocytes and Granulocyte elements in bone marrow–> reactive fibrosis
- Fibrosis= response to growth factors produced by megakaryocytes (clonally abnormal hematopoietic cells)
1. See reticulin fibers
2. Later: overt collagen fibrosis
Marrow fibrosis–> extramedullary hematopoiesis (spleen, liver, etc.)
Primary Myelofibrosis (PMF): diagnostic criteria
Major (all 3 needed):
- Collagen fibrosis/prefibrotic disease in marrow
- Rule out: CML (no BCR/ABL), PV, other MDS
- JAK2 V617F mutation or other clonal marker (MPL)
Minor (2+ needed):
- Leukoerythroblastosis (low RBCs, WBCs)
- Increased LDH
- Anemia
- Splenomegaly
Primary Myelofibrosis: presentation
1/100,000
Most common in 6th-7th decade
60% have cytogenetic abnormality
- Unknown cause (could be radiation- seen in Hiroshima survivors, benzene)
Clinical:
- Anemia (due to ineffective hematopoeisis, hypersplenism)
- Marked splenomegaly (extramedullary hematopoeisis- also seen in liver)
- Fatigue, weight loss, night sweats, fever
- Peripheral edema, early satiety
- Portal HTN (varices, ascites)
- Bleeding and thrombotic events
Primary myelofibrosis: bone marrow changes
Early: - Hypercellular marrow - Prominent, abnL megakaryocytes - Increased reticulin Later: - Increased fibrosis (collagen) - Reduced hematopoeitic elements - End stage: osteosclerosis (thickened bony trabeculae--> decreased marrow space)
- Fibrosis in marrow also seen in: PV, CML
Primary Myelofibrosis: Peripheral blood
Leukoerythroblastosis= increased immature granulocytes and nucleated RBCs (normoblasts) due to:
- Extramedullary hematopoeisis
- Disruption of normal bone marrow-blood barrier (fibrosis)
- Can also be seen in metastatic solid tumors
Marrow fibrosis leads to:
- myelophthisic anemia (weird RBCs made in other parts of body)
- anisopoikilocytosis (abnL RBC shapes + sizes)
- Dacrocytes (teardrop-shaped cells)
- Giant platelets
- Megakaryocytes in circulation
Spleen:
- Red pulp expansion
- Extramedullary hematopoeisis
- Focal splenic infarcts
Primary Myelofibrosis: prognosis
Median survival= 3-5 years Poor prognosis: - age > 70 - Hg < 10g/dL - Leukocyte > 25 x 10^9 - Circulating blasts > 1% - Constitutional symtoms
Plus:
- Platelet < 100,000/uL
- Immature WBCs in peripheral blood
- Abnormal karyotypes
Polycythemia vera: clinical manifestation
Blood hyperviscosity (due to increased RBCs) causing: - Headaches - blurry vision - Altered hearing - Mucous membrane bleeding - Shortness of breath - Malaise Splenomegaly Thrombosis (arterial most common) - can be in unusual sites (mesenteric, Budd-Chiari) Pruritis (provoked by warm water) Vasomotor symptoms (paresthesias)
Secondary causes of polycythemia
- Hypoxia-driven:
- Chronic lung disease
- R to L cardiopulmonary shunt
- High-altitude
- Tobacco/CO poisoning
- Sleep apnea (hypoventilation)
- Renal artery stenosis - Hypoxia-independent
- Androgen use, EPO
- Post-renal trasnplant
- Cerebellar hemangioblastoma, meningioma
- Pheochromocytoma, uterine leiomyoma, renal cysts, PTH adenoma
- HCC, renal cell carcinoma
Congenital causes of erythrocytosis
Reduced p50 (partial pressure of O2 where Hg saturated):
- High-oxygen-affinity hemoglobinopathy (Autosomal dominant disease)
- 2,3 BPG deficiency (autosomal recessive)
- Methemoglobinemia
Diagnosis:
- Measure Serum EPO
- low EPO= mutation of EPO receptor
- normal/elevated? - Measure p50
- decreased p50= high-O2-affinity hemoglobinopathy or 2,3 BPG deficiency
- Normal p50–> VHL
Causes of Thrombocytosis
- Infection
- Rebound thrombocytosis
- Tissue damage (surgery)
- Chronic inflammation
- Malignancy
- Renal disorders
- Post-splenectomy status (see Howell-Jolly bodies)
- Primary thrombocythemia
Treatment of Polycythemia Vera and Essential Thrombocythemia and prognosis
Main objective=
- prevent thrombosis in high risk patients (> 60 years, history of thrombosis)
- Alleviate non-life-threatening symptoms:
- microvascular disturbance (headaches, acral parasthesia, erythromelalgia),
- pruritis (responds to JAK-inhibitor)
- symptomatic splenomegaly (hydroxyurea)
- Pruritis related to JAK-STAT signalling-related cytokines
3. Phlebotomy in all patients (target Hct < 50%–> 45% ideal)
Prognosis: Median survival ~20 years
Treatment for Primary myeloid fibrosis
Lack of drug therapy:
Bone Marrow Transplant in patients with median survival < 5 years and leukemia risk > 20%
De novo AML (acute myelogenous leukemia) mutation
MLL gene translocation:
t(11;16)(q23;p13)
–> leads to fusion between promoter of cyclic adenosine monophosphate response element binding protein (CBP) and MLL protein
> 20% blasts
Myelodysplastic syndrome: clinical manifestations
Peripheral blood:
- Persistent, progressive cytopenia
- Neutropenia (diabetic with infections, poor wound healing)
- Anemia (may see increased angina)
- Thrombocytopenia- petechia, bruising, frank hemorrhage
- 30% of patients will develop AML
- mainly in older patients
- See dysplasia in > 50% cells in at least 2 cell lines
- 20%+ blasts
Clinical signs/symptoms:
- Fatigue
- Weakness
- Infection
- Easy bruising
- Pallor, petechiae, purpura
- No lymphadenopathy, no hepatosplenogmegaly
Myelodysplastic syndrome: differential diagnosis
Seen in elderly predominantly:
- Polypharmacy
- Vitamin deficiencies (iron, folate, B12)
- Parvovirus 19
- HIV
- Viral hepatits
- Splenic sequestration due to portal hypertension, myelofibrosis, infiltrating lymphoma
- Alcoholism
Myelodysplastic syndrome: subtypes
- Refractory anemia
- Refractory anemia with ring sideroblasts (RARS)
- Refractory anemia with excess blasts (RAEB)
- CMML
- Refractory anemia with excess blasts in transformation (RAEB-t)
Myelodysplastic syndrome: treatment
- Hematopoeitic growth factors:
- Recombinant erythropoietic stimulating agent (ESA) - Best in patients with low EPO
- G-CSF - Epigenetic therapy:
- 5-AZA, decitabine - Immunomodulatory drugs:
- Lenalidomide (for 5q deletion, low risk pts) - Immunosuppressive:
- antithymocyte globulin plus cyclosporine - HSCT= ONLY cure for MDS
- Iron chelation (for iron overload in transfusion-dependent patients)
CML treatment
Tyrosine Kinase Inhibitor: Imatinib
- Blocks effects of BCR/ABL fusion protein
Acute Leukemia
20% or more blasts in bone marrow
Blasts= immature hematopoietic cells of myeloid or lymphoid lineage
- Monocytic leukemias= increased tissue infiltration, tumor lysis syndrome, bad cytogenetics
Clonal disorder (somatic mutation in hemoatopoietic precursor) of bone marrow–>
1) Accumulation of clonal abnormal blasts
2) Impaired production of normal blood cells
- leads to anemia, infection, bleeding
Two types:
1) Acute myelogenous leukemia (AML)
2) Acute lymphoblastic leukemia (ALL)
Causes:
- Clonal hematopoietic disorders: CML, PMF, ET, PV, MDS, PNH
- Ionizing radiation
- Oncogenic viruses: HTLV-1 (T-cell leukemia), EBV (mature B-cell ALL)
- Benzene
- Prior chemo with alkylating agents–> myelodysplastic syndromes 4-6 years later (chromosomes 5, 7, 8 abnormalities)
- Prior chemo with Topoisomerase Inhibitors: Epipodophyllotoxin (teniposide, etoposide): 1-2 years later, no myelodysplasia–> progresses right to monocytic leukemia (chrom 11 q23 or chrom 21 q22)
Genetics:
- 20% chance in identical twin with affected twin
- Trisomy 21
- Trisomy 13 (Patau)
- XXY (Klinefelter)
- Bloom’s syndrome
- Fanconi’s anemia
- Ataxia-telangiectasia
Clinical presentation: - Anemia - Thrombocytopenia - White blood count can be low or high - Neutropenia - Marrow expansion – bone pain - Leukostasis – high WBC modified by cell size and plasticity (Lung and CNS) - Tissue Infiltration; Granulocytic sarcoma (Gums, skin, testes, meninges, retina) - Organomegaly: Hepatosplenomegaly - Mediastinal mass or adenopathy - ALL - Tumor lysis syndrome: uric acid, LDH - Coagulopathy – especially in t(15;17) or with infection
Acute Myelogenous Leukemia: Epidemiology
Neonates= predominant leukemia form Childhood/adolescence= Less common than ALL Adults= 80% of leukemias (incidence increases with age, vs ALL)
Acute myelogenous leukemia: clinical manifestations
See symptoms due to:
1) Expansion of malignant clone (w/ or w/o organ involvement)
2) Deficiencies in normal blood cells
1. Leukocytes: low, normal, high High Leukocyte levels--> alterations in blood flow in organs/compromise function (cells sticker, larger, stiffer): - Respiratory failure - Stroke, cerebral ischemia - Infiltration different organs - Skin, CNS, gums
- Organomegaly with other myeloproliferative disorders
- Platelet deficiency (thrombocytopenia)–> bleeding, bruising
- Low granulocytes–> infections
- Suppression of RBCs–> severe anemia, cardiopulmonary symptoms
* See DIC in acute promyelocytic anemia (APL)
* Elderly at increased risk for pancytopenia
Acute Myelogenous Leukemia: Path, Labs
Labs:
- Decreased hemoglobin, platelets
- Stains for MPO, non-specific esterases
Path:
- Arrest of myeloid cells at blast phase (>20%): medium to large cells with abundant cytoplasm
- Cytoplasmic granularity:
- Neoplastic promyelocytes= high granularity
- Granulocytic blasts= present/absent
- Monoblasts= no granularity
- AUER RODS= condensed granules
- Seen in any AML, more numerous in neoplastic promyelocytes (APL)
- Stain red with Wright-Geimsa
- NEVER seen in normal myeloid/lymphoblastic precursors
AML: immunophenotype
- Stem cell marker (CD34) in myeloid or lymphoid basts
- Granulocytic antigens: CD117, CD13, CD15, CD33, MPO
- Monocytic antigens: CD14, CD64
- Erythroid marker: glycophorin A
- Megakaryocytic antigens: CD41, CD61
- TdT not usually seen in AML, usually in ALL
Genetics:
- t(8;21)–> core binding factor (transcription factor) abnormalities
- inv(16)–> core binding factor (transcription factor) abnormalities
- t(15;17)–> PML and RAR (= APL)
- t(9;11) due to chemotherapy
- t11q23: MLL
- trisomy 9
- trisomy 21, 11
- Deletion of 5, 7
- FLT3 mutation (20-40% AML): poor prognosis
AML: Therapy
CANNOT be cured without HSCT
- Admission: cultures, antibiotics if febrile
- Fluids, allopurinol to treat/prevent tumor lysis syndrome
- M0-M7 treated the same EXCEPT for M3
- Induction therapy: achieve hematological remission (peripheral blood normal)
- Anthracycline for 3 days
- Cytarabine for 7 days
ex: APL= t(15;17)–> retinoic acid + chemo + arsenic
- Retinoic acid induces maturation of tumor cells, prevents accumulation of granules that can cause DIC
- Consolidation therapy:
- High dose Cytarabine: particularly good in t(8;21) and inv16- use high dose ARA-C
- Autologous HSCT: after remission, store bone marrow stem cells–> myeloablative chemo–> rescue hematopoeisis with stem cells
- Allogeneic HSCT: replenish cells post chemo, allow for graft-versus-leukemia effect (less likely to be effective in older patients)
- Remission induction:
- Anthracycline, cytarabine - Maintenance therapy: APL ONLY
Side efects:
- Effects on proliferating cells (skin, gut, marrow)
- Cytopenias get worse before they get better
- Mucositis
- Infections and bleeding worsen - Anthracycline cardiac effects
AML: Prognosis
Good Prognosis:
- t(8;21), t(15;17), inv(16)
- trisomy 21
- NPM1 mutation (nucleophosmin)- normal karyotype
- Absence of myelodysplasia
- Younger age
- CEBPA mutation= normal karyotype
Poor prognosis:
- Unfavorable karyotypes: 5-, 7-, 5q-, trisomy 8, t(6,9), trisomy 11
- FLT3
- Multidrug resistant (MDR1)
- Pre-existing clonal hematological disorder
- Older age (> 60)
- Higher WBC (> 30,000/uL)
- Low platelet count (< 30,000)
- Co-morbidities
- Prior chemo/radiation therapy
Acute Promyelocytic Leukemia (APL)
APL: translocation t(15;17)(q22;q21)
Forms novel gene: PML-RARA= tumor suppressor (PML) + alpha receptor for nuclear transcription factor retinoic acid
- Chimera–> abnormal function–> can’t mature past promyelocytic stage
Highly responsive to all trans-retinoic acid (ATRA)
- dissociates nuclear repression factors (histone deacetylase)–> genes transcribed again
- Retinoic acid induces maturation of tumor cells, prevents accumulation of granules that can cause DIC
- Adverse effect of ATRA= ATRA syndrome (all cells pushed through maturity–> can cause organ infiltration, like lung failure)
+Arsenic= combination therapy that can cure disease
- ONLY AML that requires maintenance therapy
Acute lymphoblastic leukemia (ALL): epidemiology
12% of all Leukemias
60% of leukemias for people < 20 years
MOST COMMON malignancy in patients < 15 years (25% of all malignancies, 75% of all leukemias)
- Bimodal distribution: peaks at ages 2-5, again in 60s
Subdivided into B-cell and T-cell
Etiology:
- Down syndrome, Bloom syndrome, neurofibromatosis type 1, ataxia-telangiectasia
- Environmental exposures: ionizing radiation in utero, pesticides, solvents
ALL: clinical manifestations
Manifestations due to:
1) expanded malignant clone (may or may not involve organs)
2) deficiencies in normal blood cells
Manifestations similar to AML
May also involve:
- CNS/meninges
- Bone marrow necrosis: pain, fever, high LDH levels
- Painless testicular enlargement
- Mediastinal mass (T-ALL) or adenopathy (B-ALL)
- No symptoms (v. rare)
ALL: labs
Labs:
Diagnose with peripheral blood, bone marrow morphology, flow cytometry, cytogenetics, molecular genetics
Peripheral blood:
- Decreased hemoglobin, platelets
- May or may not see leukemic cells
Bone Marrow:
- replaced by malignant clone
Immunophenotype:
- CD10+, CD19+, TdT, intracytoplasmic IgM+, CD22+, CD79a+, HLA-DR+
Genetics:
- t(1;19)(E2A-PBX1)
- t(9;22)= BAD prognosis (25% adult AML, 3% child AML)–> 190kD fusion protein
- t(12;21)(TEL-AML1)= most common childhood translocation- good prognosis
- 11q23 (MLL) abnormalities= BAD prognosis
- > 50 chromosomes= good prognosis
- < 49 chromosomes= bad prognosis
ALL: Path
85% of ALL cases= B-cell type
- Malignant cells= immature B-lymphoblasts (B-ALL/LBL)
- Lymph node involvement
- Leukemic cells smaller than AML blasts, no granules
Organ involvement:
- Kidney damage: spontaneous/therapeutic tumor lysis
- CNS involvement: assess CSF for leukemic blasts
- more organ infiltration than AML
ALL: Therapy
ALL in children= curable
- NOT in neonates, infants
- After 12, cure rate decreases with age
- Induction therapy:
- Glucocorticoids, vincristine, L-asparaginase
- CNS prophylaxis - Intensification consolidation therapy:
- Antimetabolite agents (methotrexate, 6-mercaptopurine) - Maintenance Therapy:
- Required for children with ALL (other than mature B-ALL): methotrexate, 6MP
- Unclear value for adults - Allogeneic HSCT:
- Children with high risk cases
- Less successful in adults
- Standard of care in Phl ALL t(9;21) - Tyrosine kinase inhibitor (Imatinib)
ALL: Prognosis
Good prognosis:
- Age > 1, < 12
- Hyperploidy > 50 chromosomes/cell
- ETV6-CBFA2 fusion
- t(12;21)
Poor prognosis:
- Phl chrom (esp in adults)
- CNS disease
- Age < 1, > 12
- Rearrangement of MLL gene (Chromosome 11q23)
- High WBC
- co-morbidities
AML with t(8;21)
- Maturation along neutrophil lineage (M2)
- Occurs predominantly in younger adults
- Good prognosis
- Therapy with high dose ARA-C may be curative.
- AML with t(8;21) and inv(16) cause alterations to proteins which are part of the Core Binding Factor transcription complex.
AML with inv(16)
Usually shows monocytic and granulocytic differentiation (myelomonocytic)
- Characterized by conspicuous presence of abnormal eosinophils (M4Eo)
Occurs predominantly in younger adults
- Good prognosis
Therapy with high dose ARA-C may be curative.
AML with t(8;21) and inv(16) cause alterations to proteins which are part of the Core Binding Factor transcription complex.
Alkylating agent/radiation-related AML
Occurs 5-10 years after exposure
- Patients present with t-MDS and cytopenias
Complex chromosomal abnormalities, frequently similar to those in MDS: -5/del(5q), -7/del(7q) etc.
Topoisomerase II inhibitor-related AML
Follows treatment by 1-5 years
- Presents as AML usually without a preceding MDS phase
Predominant cytogenetic finding involves translocation of MLL gene (11q23)
Multiple Myeloma: Epidemiology
Genetic predisposition:
- Higher incidence in blacks than whites (blacks have higher physiologic Ig levels)
- Familial clusters (>= 2 1st degree relatives with myeloma
Environmental:
- 3-4 times higher incidence in farmers, cosmetologists
- Higher incidence in exposure to pesticides, petroleum products, radiation, long-standing infections (chronic osteomyelitis), chronic antigen stimulation (RA)
93% have MGUS within 8 years of MM diagnosis (100% within 2 years)
Symptomatic Multiple Myeloma: diagnostic criteria
- M-protein in serum or urine (IgG, IgA, light chain)
- Bone marrow clonal plasma cells or plasmacytoma
- Organ/tissue impairment (CRAB= hyperCalcemia, Renal insufficiency, Anemia, Bone lesions)
C= Calcium > 11.5 R= Renal; Creatinine > 2mg/dL A= Anemia; Hg < 10 g/dL or 2 g/dL below lower end of normal B= Bone disease: lytic lesions or osteopenia
- MM treated on the basis of end-organ damage
- Bence-Jones Proteinemia= elevated free light chains
Symptomatic Multiple Myeloma: clinical presentation
Pain, fatigue, anemia, mental status changes, headaches, visual changes, CHF
- Bone lesions: pain
- Osteolytic lesions more common than osteoblastic
- plasma cells secrete IL-6–> bone breakdown
- MRI (or x-ray) shows “punched out” lytic lesions, osteoporosis, fractures
- Seen in vertebrae (MRI detection), skull, thoracic cage, pelvis, proximal humerus/femur
- Can also use PET CT (FDG= F- deoxyglucose bone uptake measured)
* Do NOT use bone scan - Kidney problems: fatigue (anemia)
- Cast Nephropathy (light chain deposition)
- Decreased EPO (kidney damage)
- Uremia/renal failure (light chain deposition= acquired Fanconi’s)
- Nephrocalcinosis (hypercalcemia from bone destruction)
- Amyloidosis (light chain deposition)
- Hypercalcemia: thirst - Bone marrow infiltration: anemia
- Plasma cells replace hematopoeitic cells
- Normocytic, normochromic anemia - Hypercalcemia: mental status changes, polydypsia/polyuria
- Blood hyperviscosity: mental status changes, headache, renal failure, visual changes, CHF
- Radiculopathy due to bone compression: pain
- Plasmacytomas
- Infections: s. pneumo, s. aureus, gram-negatives
- Impaired antibody response due to abnormal Ig production - Bleeding: M-proteins coat platelets
- risk of DVT
Smoldering Multiple Myeloma: diagnostic criteria
- M-protein in serum at myeloma levels (> 30 g/dL)
- Higher than in MGUS
- IgG, IgA, light chain most common
AND/OR
- 10% or more clonal plasma cells in bone marrow
* NO related organ/tissue impairment (end organ damage, bone lesions, myeloma-related symptoms
Smoldering Multiple Myeloma: progression probability
Progression to symptomatic disease:
- 51% at five years
- 66% at 10 years
- 73% at 20 years
Median time to progression= 4.8 years
Risk of progression related to amount of M-protein (>= 3 g/dL vs < 3 g/dL) and amount of plasma cells in bone marrow (> 10% or < 10%)
Plasma cell myeloma: gross specimen/staining diagnosis
Bone marrow infiltrated with plasma cells (10+%)
- Sheets of plasma cells= suggestive of diagnosis
CD38+, CD138+, kappa, lambda chain
- Diagnose extent of plasmacytosis, light chain restriction
- Aberrancies in phenotype, amount of plasma cells exist
