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
Plasma cell myeloma: lab diagnosis
Serum Protein Electrophoresis (SPEP) and Immunofixation (IF) of M-protein
- SPEP: Electrical field used to separate serum proteins (on cellulose acetate)
- Separated proteins fixed to membrane, stained with protein-binding dye
- Normal: should see smooth, broad gamma globulin distribution
- Myeloma: sharp, dominant monoclonal band (M-spike)–> homogenous Ig (with lower than normal levels of other Ig)
- Infections: excess polyclonal Ig - Immunofixation (IF): proteins separated by electrophoresis incubated with monoclonal antisera
- Membranes removed, gels washed
- Proteins precipitating with antisera remain in gel–> dried and stained
- Typically IgG elevated (then IgA, light chains) with other Ig levels lower
* More sensitive than SPEP (used in combination most times) - Can also measure concentration of unbound (free) kappa and lambda light chains in serum and 24-hour urine
- Kappa:Lambda ratio helps diagnose MM
- > 4:1–> kappa population
- < 1:2–> lambda population
Plasma cell myeloma: staging and prognosis
Durie Salmon Myeloma staging system
Stage I: all of the following:
- beta-2 microglobulin < 3.5
- Mild anemia
- Normal calcium
- Few bone lesions
- Low M-protein (paraprotein) levels
- Good prognosis (low tumor mass)
Stage II= in between I and III
Stage III: 1+ of following:
- beta-2 microglobulin > 5.5
- Hg < 8.5 g/dL
- Elevated calcium
- Advanced lytic bone lesions
- High M-protein levels
- Poor prognosis (high tumor mass)
Subclassification:
A= normal renal function (serum creatinine < 2 mg/dL
B= Abnormal renal function (serum creatinine > 2mg/dL
* Renal failure= poor prognostic indicator
Beta-2 microglobulin and LDH levels have also been linked to prognosis
Plasma cell myeloma: cytogenetics
Bad prognostic indicators:
- Deletion 13, aneuploidy
- t(4;14) or t(14;16) or t(14;20) by FISH
- Deletion 17p13 by FISH
- Hypoploidy
- Median survival= 25-29 months
Good prognostic indicators:
- Absence of genetic markers above
- Hyperdiploidy
- t(11;14) or t(6;14)
- Median survival= 50-62 months
Plasma cell myeloma: treatment
Order of treatment:
- Induction phase
- Autologous stem cell transplant
- Maintenance phase
Chemo for MM:
- Lenalidomide, Thalidomide
- Bortexomib
HSCT:
- Autologous: improve quality of life, survival (even in elderly)
- Allogeneic: may be curative, but lack of donors, many co-morbidities
Treatment of complications:
- Vaccines (due to Ig disorder)
- Hydration (prevent renal failure)
- Avoid nephrotoxic IV contrast
- NSAIDs, bisphosphonates to prevent skeletal morbidity
- Calcium, vitamin D in non-hypercalcemic patients
- Radiculopathy
- Palliative radiation, dexamethasone-based therapy - Hydration, bisphosphanates to correct hypercalcemia
- Pamidronate, zoledronic acid (bisphosphanates) to prevent fracture
Monoclonal Gammopathy of Undetermined Significance (MGUS)
Precursor lesion in all MM patients= M-protein in patients without evidence of:
- plasma cell myeloma
- Waldenstrom macroglobulinemia
- Primary amyloidosis
M-protein elevations also seen in lymphoproliferative diseases, CLL (with no effect on clinical course)
See expanded clone of Ig-secreting cells
MGUS: Epidemiology
- Discovered on routine blood work
- Increases with age (3% of people over 50, 5% over 70 years)
- More common in men than women (1.5:1) and African Americans than caucasians (2:1)
MGUS: prognosis
May never advance to MM: 20 years after diagnosis: 50% patients die of unrelated causes 25% have no M-protein change 25% develop plasma cell neoplasm/lymphoproliferative disease: - IgA progression > IgG progression - Increased risk with increase M-protein - Increased with abnormal free light chain ratio (Kappa:lambda)
- Constant 1% progression rate to malignancy (vs variable progression rate of smoldering multiple myeloma)
- NO TREATMENT for MGUS
MGUS: clinical picture
- M-protein present at lower levels than in myeloma (M-protein < 30g/L), other Ig normal
- Bone marrow plasma cells < 10%
- NO lytic bone lesions
- NO end-organ damage (CRAB)
- No evidence of other B-cell lymphomas
Plasma cell leukemia
RARE (need > 20% peripheral blood cells to be plasma or 2x10^9 plasma cells/L)
Clinical features:
- Renal failure
- Lymphadenopathy
- Organomegaly
Labs:
- See higher proportion of light chain, IgD, IgE myelomas
- More unfavorable cytogenetic abnormalities
Non-secretory myeloma
3% of plasma-cell myelomas have no M-protein on IF
- Seen within cytoplasm in 85%
- Remaining 15%–> no Ig synthesis (non-producer); light chain gene mutations implicated
Plasmacytoma
Localized tumors of neoplastic plasma cells
- Seen in bone (solitary lesions) or soft tissues (extraosseous, extramedullary)
- Solitary or part of systemic plasma cell myeloma
- Occur without other features of plasma cell myeloma
4 criteria must be met:
- Biopsy-proven solitary lesion with evidence of clonal cells
- Normal bone marrow.
- No anemia, hypercalcemia, or renal disease. (No other evidence of disseminated multiple myeloma.)
- Normal levels of immunoglobulins.
Waldenstrom’s macroglobulinemia: criteria
- IgM monoclonal gammopathy (with lower than normal levels of other Ig)
- > 10% bone marrow lymphoplasmacytic infiltration exhibiting:
- IgM+
- CD19+
- CD20+
- CD22+
- CD5 +/-
- CD10-/+
- CD23-
Waldenstrom’s macroglobulinemia: clinical manifestations
Symptoms:
- Weakness
- Fatigue
- Bleeding (oronasal)
- Vision changes
- Dyspnea
- Weight loss
- Neurologic symptoms
- Recurrent infections
- Heart failure
- Retinal hemorrhages, exudates, venous congestion with vascular segmentation
- Sensorimotor peripheral neuropathy
Signs:
- Pallor
- Hepatosplenomegaly
- Lymphadenopathy
Rare:
- Bone lesions, renal insufficiency, amyloidosis
Waldenstrom’s macroglobulinemia: labs
- Anemia (moderate to severe)- normocytic, normochromic
- Elevated IgM (on IF)
- Rouleau formation, increased ESR
- Dutcher bodies (IgM inclusions)
Waldenstrom’s macroglobulinemia: treatment
Similar to treatment of MM Only treated if they have symptoms: - Anemia - Weakness, fatigue, night sweats, weight loss - Hyperviscosity - Hepatosplenomegaly - Lymphadenopathy
Plasmapheresis, autologous HSCT, lanolidomide (chemo)
Symptoms of hyperviscosity
- Chronic nasal bleeding, oozing from gums
- Post-surgical, GI bleeding
- Retinal hemorrhages
- Sausage-like segmentation of vessels in eye, papilledema–> vision issues
- Dizziness, headache, vertigo, nystagmus, decreased hearing, ataxia, parasthesias, diplopia, somnolence, coma
Treatment:
- Plasmapheresis for symptoms (may need more than one treatment with IgG M-proteins as they extravasate)
- Chemotherapy for underlying malignancy
Amyloidsosis: summary
Plasma cell dyscrasia - related to myeloma
- Light chain misfolding–> beta-pleated sheets (instead of normal alpha chains)
- Leads to insoluble protein deposits in tissues
- Stains with Congo red (apple-green birefringence under polarized light)
Three types:
- Systemic light chain amyloidosis (most common)= AL
- Amyloidosis due to chronic infection, inflammatory arthropathies= Secondary AA
- Tuberculosis, Osteomyelitis - Inherited familial cardiomyopathies/neuropathies (familial AA or AF)
Symptoms:
- organ infiltration of heart, nerves, kidneys, autonomic dysfuction, gut involvement
Workup:
- SPEP/IEP (immuno electrophoresis)
- Light chains
- Marrow biopsy
- Fat pat biopsy
Amyloidosis: clinical manifestations
Signs:
- Tongue enlargement with dental indentations
- “pinch” or periorbital purpura due to vascular fragility
- hepatomegaly
Symptoms:
- Fatigue
- Edema
- Dyspnea
- Anorexia
- Parasthesias
Syndromes:
- nondiabetic nephrotic-range proteinuria
- Cardiomyopathy (“hypertrophy” on ECG)
- Peripheral neuropathy (4% patients)–> bowel dysfunction
Amyloidosis: Heart involvement
Up to 50% of amyloidosis patients effected
- Poor filling in diastole
- Poor stroke volume despite normal EF
- ECG: thickening of heart walls due to infiltration of amyloid appears like Left Ventricular hypertrophy (LVH)
Heart Failure due to:
- silent hypertension
- hypertrophic cardiomyopathy
*Prognosis of disease depends on cardiac involvement
Amyloidosis: liver involvement
13% of patients
- Hepatomegaly
- Increased serum alkaline phosphatase
- Deficiency of coagulation factor X
Amyloidosis: diagnosis
Must perform SPEP with IF
- Monoclonal proteins very small–> not detectable on SPEP alone
Confirmatory diagnosis (needed due to complications):
- Biopsy with congo red stain
- Subcutaneous fat aspiration (fat pat): recognizes 70% amyloid deposits
- Bone marrow biopsy (to rule out multiple myeloma)- 50% sensitive
- BOTH: 87% recognition
Localized amyloidosis
Much better prognosis Seen commonly in: - Ureter - Bladder - Urethra - Prostate - Brain (Alzheimer's)
Senile systemic amyloidosis
Transthyretin (normal serum protein) deposited on myocardium
Familial Amyloidosis
Only 3% of cases
One variant has transthyretin amino acid substitution (122: Val–> Ile)
- 3.9% of blacks in USA
- Heterozygotes: late onset cardiomyopathy with wall thickening
- Mild heart failure
POEMS syndrome
Polyneuropathy Organomegaly Endocrinopathy M-protein Skin changes
High levels of VEG-F–> sclerotic bone lesions (similar to clubbing)
- Associated with polyneuropathy, organomegaly, small plasma cell clone
Timing of Cancer therapy toxicity
- Immediate: hours to days
- N/V, flushing, hemorrhagic cystitis (cyclophosamide), fever and chills (bleomycin) - Early effects: days to weeks
- Hematopoietic depression, alopecia, stomatitis, cerebellar ataxia (5-FU), pancreatitis (L-asparaginase), pulmonary infiltrate (MTX) - Delayed effects: weeks to months
- Anemia, Azoospermia, hepatocellular damage, skin hyperpigmentation, pulmonary fibrosis (bleomycin, busulfan), cardiotoxicity (anthracyclines), SIADH (cyclophosamide, VCR), cholestatic jaundice (6MP) - Late effects: months to years
- Sterility, hypogonadism, second malignancies, hepatic fibrosis, encephalopathy
Grading of treatment toxicity
Grade 0= no harm
Grade 1= no interference with activity (unnoticed)
Grade 2= interferes with activity; outpatient treatment
Grades 3, 4= Hospitalization, change in functional status
Grade 5= fatal
Hypersensitivity reaction
1: Bronchospasm, wheezing, agitation, angioedema (starts within minutes)
2. Delayed; includes hemolytic anemia
3. Interstitial pneumonitis and vasculitis (ex. from methotrexate toxicity)
Caused by:
- L-asparginase
- Paclitaxel, docetaxel (vehicle causes reaction–> premedicate with steroids)
- Procarbazine
- Teniposide
Vomiting from chemotherapy
Most chemo causes N/V
- May see anticipatory emesis (Pavlovian)
Neurotransmitters 5HT3 adn NK1–> medullar, nucleus tractus solitarus, cerebral cortex, GI tract afferent stimuli, vestibular stimuli
Treatment of Nausea (from highest level):
- 5HT 3 receptor antagonist and steroid
- Phenothiazine, steroid, benzodiazepine
- Phenothizines, corticosteroids (delayed antiemetic)
Mucositis from cancer treatment
Radiation and chemotherapy
- 5 days after therapy with cytotoxic agent: recovery within days of cessation
- May require narcotics for relief
- Bacterial/fungal superinfection common
Bone marrow changes in cancer treatment
Bone marrow depression: 7-10 days after therapy
- neutropenia: susceptibility to infection
- thrombocytopenias: hemorrhage
- Recovery by 3-4 weeks post-treatment (some can cause long-term dysplasia)
Treatment: cytokines, GCSF, GMCSF, EPO, oprevleukin
- Epoetin alfa (procrit)
- Oprelvekin
- G-CSF
- GM-CSF
Reproductive impairment related to cancer therapy
- Alkylating agents:
- Progressive ovarian follicle loss–> menopause
- Prolonged azoospermia
Radiation:
- Ovarian and testicular failure
Endocrine disturbances related to cancer therapy
- Must evaluate pituitary-gonadal axis (FSH, testosterone, estradiol, prolactin, TSH)
- May also see Addisonian like syndrome from Busulfan use
- Hyperpigmentation, malaise, fatigue, anorexia, weight loss
- NO adrenal failure labs
Hyperglycemia: steroids, pazopanib
Ipilumumab, pazopanib–> hypothyroidism
Neurotoxicity due to cancer therapy
Chemo causing neuropathy: numbness, tingling, weakness, footdrop, autonomic neuropathy (cramping, constipation)
- Vinca alkaloids, vincristine, vinblastine, taxanes (paclitaxel, docetaxel)
- Heavy metal drugs (cisplatin)
Cisplatin–> high tone hearing loss (damages organ of Corti)
Ara-C–> cerebellar toxicity (Purkinje fiber drop out)
Reversible posterior leukoencephalopathy
Peripheral neurotoxicity:
- Taxanes
- Vincas
- Platinum-based compounds
Central neurotoxicity:
- Ifosphamide
- high dose methotrexate
- 5-FU
- Procarbazine
- ara-C
- Fludarabine
Reversible posterior leukoencephalopathy
Brain-capillary leak due to HTN, fluid retention, cytotoxicity on vascular endothelium
Symptoms: acute bilateral loss of vision, headache, confusion
Caused by: tacrolimus, cisplatin, epoetin, immune globulin, VEGF-inhibitor
Diagnostics: white matter changes
Treatment: reversible with control of BP, fluid status
Late encephalopathy from cancer therapy
Seen long after treatment (ex. CNS prophylaxis for childhood leukemias
Symptoms:
1-year post-cranial RT:
- Confusion, drooling, somnolence, irritability, ataxia, dementia, tremors, quadriparesis, slurred speech
Diagnosis:
- Abnormal CT: ventricular dilatation, subarachnoid space dilatation
- Significant cognitive defecits
- Path: demyelination, multifocal necrosis, astrocytic reaction, axonal damage
Causes:
- Cranial radiotherapy, intrathecal methotrexate, intravenous MTX
Pulmonary fibrosis from cancer therapy
Classic: Bleomycin pulmonary fibrosis
- Also associated with mitomycin, alkylating agents, methotrexate, ara-C
- ATRA: respiratory distress
- Taxol/Taxotere: bronchospasm, anaphylaxis/pulmonary edema
Dose-related
Pathophysiology:
- Decreases in DLCO, +/- change in FVC, decreased O2, CO2
- aggravated by high dose inspired O2 and previous/concomittant radiation
- Free radical formation, activation of inflammation–> upregulated collagen synthesis, cytokines
Symptoms: dry cough, exertional dyspnea, rare chest pain or hemoptysis
Path: Type 1 pneumocyte decrease, Type 2 pneumocyte increase–> migrates into alveolar sacs, sepate become thicker
Cardiotoxicity from cancer therapy
1 example: Dose-limiting effect of anthracyclines (lifetime dose limit)
- Occurs within 3 years (typical): increasing tachycardia, fatigue, pulmonary edema, CHF
- Due to mitochondrial injury, depletion of ATP/phosphocreatine, depression of contractility, free radical formation/lipid peroxidation
- Add dezrazoxone for cardioprotection
Cardiotoxicity also seen with:
- cyclophosphamide, ifophosphamide (high doses)
- Paclitaxel (arrhythmias, sinus bradycardia)
- Vincristine, vinblastine (autonomic dysfunction)
- 5-FU (chest pain, atrial arrhythmia, ventricular dysfunction, cardiac failure, coronary artery spasm)
- Ondansetron (antiemetic), pazopanib
- Herceptin (traztuzumab
Renal toxicity from cancer therapy
Cisplatin= prototype nephrotoxic drug
- Heavy metal–> acute proximal tubular necrosis (weeks post-therapy)
- Given with forced hydration to prevent high concentrations in tubule
- Can also cause K+, Mg+2 wasting
Methotrexate, mitomycin C= also nephrotoxic
Tumor lysis syndrome–> urate nephropathy
Hepatotoxicity from cancer treatment
Mild transaminitis from agents excreted in biliary tree
- Anthracyclines
- Anti-tumor antibiotics (actinomycin D)
Hepatic fibrosis:
- Chronic methotrexate
Veno-occlusive disease:
- Chemo in transplants
- See fluid retention, painful hepatomegaly, elevated bilirubin, high mortality
Neoplasms due to cancer treatment
Carcinogenesis from therapy (could also be due to environmental trigger):
Acute leukemia:
- radiation exposure
- alkylating agents for hematologic neoplasms
- Topoisomerase II inhibitors (myelodysplasia risk)
- Rare after solid tumors (ovarian ca, bladder ca, lymphoma)
- Seen after Hodgkin’s treatment
Lymphoma:
- Second neoplasm in Hodgkin’s treated with radiation, chemo
- B-cell lymphoma after transplant (can be reversed by withdrawing immunosuppressive therapy)
Cystitis from cancer therapy
May occur early or late: suprapubic pain, dysuria, urgency, hematuria
Caused by:
- Cyclophosamide
- Ifosphamide
- Mesna (mercaptoethanol)
Effects of angiogenesis inhibitors
ex: Bevacizumab
HTN Proteinuria Increased bleeding Clotting Bowel perforation
Effects of EFGR and Tyrosine Kinase inhibitors
ex: Cetuximab
Folliculitis
Diarrhea
Interstitial pulmonary fibrosis
Alkylating agents/radiation type neoplasms
5-10 years post-exposure
- See t-MDS and cytopenias
- Chromosomal abnormalities similar to MDS: -5/del(5q), -7/del(7q)
Topoisomerase II inhibitor neoplasms
1-5 years after treatment
- Presents as AML without MDS phase
- Translocation of MLL gene (11q23)
Tumor staging in GI cancer
T0= no evidence of primary tumor invasion (carcinoma in situ) T1= Tumor invades lamina propria, muscularis mucosa, submucosa T2= Tumor invades muscularis propria T3= Tumor invades muscularis propria into subserosa T4= Tumor invades adjacent organs, perforates viscera
Lymph node stage in GI cancer
N0= no regional lymph node involvement N1= 1-2 regional lymph nodes N2= 3-6 regional lymph node metastases N3= 7+ regional lymph node metastases
M stage: M0= no distance metastases
M1= distant metastatic sites
- Need to examine at least 15 lymph nodes to rule out metastases
R level
R0= all tumor cells removed (only in 50% of GE surgeries)- complete resection with 4 cm margins R1= some cells remain (microscopic residual) R2= macroscopic residual disease
Post-operative chemo/RT
Improves survival, but may be intolerable to patients
Peri-operative chemo/RT
Improved outcomes after peri-operative chemo
Risk factors for and Diganosis of GE cancer
Risk factors:
- Barrett’s esophagus
- H. pylori
- Smoking
- High salt diet
- Inherited syndromes (1-3%): diffuse, e-cadherin mutations, CDH1
UES + biopsy
- Stain specimen for HER2 (in 20% of cancer)
PET/CT
Risk factors for pancreatic cancer
Strong correlation: Cigarette smoking
Weaker:
- Diabetes
- Obesity
- Diet
- Chronic pancreatitis
Inherited pancreatic cancer syndromes
BRCA2 Familial atypical multiple mole-melanoma syndrome (p16 mutation) Peutz Jehers Familial pancreatitis HNPCC Ataxia-Telangiectasia (ATM) FAP- 4.5 relative risk
Clinical presentation of pancreatic cancer
Weight loss Jaundice Greasy stools Abdominal pain/back pain Nausea Anorexia Depression Sudden onset diabetes
Diagnosis of pancreatic cancer
CT scan (pancreatic protocol) - Triphasic, thin slices Endoscopic US with biopsy Histology: - 90% adenocarcinoma - 10% less common variants (neuroendocrine- better prognosis) CA 19-9: - Sialylated Lewis blood group antigen: not tumor specific but can be helpful with follow-up
Tumor stroma in pancreatic cancer
Makes it difficult to reach tumor with radiation
“soil in which tumor can grow”
- Provides nutrients, growth factors
Pancreatic cancer staging
T1= < 2 cm T2= > 2 cm T3= Extends beyond pancreas, NOT to celiac axis, SMA T4= involves celiac axis, SMA - Can cause lots of pain
Pancreatic cancer node stage
N0= no regional N1= positive regional lymph node metastases
M0= no distant metastases M1= distant metastases
Pancreatic cancer: prognosis
Only 20-25% have resectable disease
- Only 20-25% of these survive for 5 years
Overall, 5% 5-year survival rate
Pancreatic cancer: surgical criteria
Resectable:
- No distant metastases
- Clear fat plane around celiac, SMA
- Patent SMV, portal vein
Borderline:
- Severe uni/bilateral SMV/portal impingement
- < 180 degree tumor abutment on SMA
- If reconstructible, abutment or encasement of hepatic artery or SMV occlusion
Unresectable:
- Distant metastases
- Encases SMA by > 180 degrees
- Abuts celiac axis: unreconstructible SMV/portal vein occlusion
- Lymph node metastases beyond field of resection
Pancreatic cancer: surgery
Whipple procedure
- R0= complete resection with negative margins
- R1= incomplete tumor resection
- R2= Substantial remaining tissue
- Only 20% resectable
- < 5% mortality in experienced hands
- Median survival 15-19 months
- 5-year survival only 20%
Adjuvant therapy for pancreatic surgery
Chemo alone: Gemcitabine
Chemo + XRT:
- sandwich gem
- 5FU/XRT
- sandwich gem
Post-op XRT 45-54 Gy with chemo sensitizer
Clinical trial post-op
Neoadjuvant therapy for pancreatic surgery
Prolonged recovery from surgery prevents/delays post-op treatment
- Selects for patients with more stable, repsonsive disease for surgery
- More sensitive to treatment
- Can downsize tumor
Erlotinib
Orally bioavailable tyrosine kinase inhibitor for HER1/EGFR
- Used in post-op pancreatic cancer patients
10-day increase in survival (what?)
Supportive care: pain management
80% of patients have pain at presentation
Celiac plexus nerve block to manage pain + medications
Hepatocellular carcinoma
5th most common malignancy worldwide
< 30% cure rate with surgical resection
Risk factors for HCC development: Hepatitis
Hepatitis B and C infection
- 1.5 million people in US with Hep B
- 4 million with hep C
- Annual HCC is 0.5% in asymptomatic HBV, 2.5% in symptomatic HBV
- Annual HCC in HCV= 3-8%
Cirrhosis:
- Alcoholic
- NAFLD
- Autoimmune hepatitis
- Primary biliary cirrhosis
Risk factors for HCC; non-cirrhotic
Metabolic disorders:
- Herditary hemochromatosis
- Wilson’s disease
- alpha-1 antitrypsin
- Prophyria cutanea tarda
Environmental toxins:
- Arsenic
- Aflatoxin (aspergillus)
Viral carcinogenic mechanisms
Necroinflammatory changes/regeneration leading to accelerated turnover–> spontaneous mutations, DNA damage
HBV: x-protein inactivates p53 and interacts with transcriptional activation functions
HCV: activates NFkB to stimulate proliferation, inhibit apoptosis
Screening for HCC
Cirrhosis, alcoholics, HCV, HBV, NASH, primary biliary cirrhosis
Serial ultrasound, AFP testing every 6-12 months
- Follow-up CT/MRI is abnormal
Symptoms of HCC
RUQ pain Weight loss Early statiety Anorexia Jaundice Abdominal distension Weakness Bleeding
Signs of HCC
Hepatomegaly Splenomegaly Wasting Hepatic bruits Plummer erythema Fever Ascites Liver nodularity Spider angiomata
HCC: Paraneoplastic syndromes, laboratory abnormalities
Hyperbilirubinemia Abnormal liver function tests Prolonged coagulation parameters Thrombocytopenia Hypoalbuminemia Hypoglycemia Erythrocytosis Hypercalcemia Hypercholesterolemia
Workup for HCC
Hepatitis serology LFTs, CBC, chems, AFp PT/PTT Child-Pugh classification Imaging: CT of chest, bone scan
Diagnostic imaging in HCC
Ultrasound CT (triphasic) MRI (triphasic) Angiography PET: less useful (20-50% accuracy)
Radiographic diagnosis of HCC
Diagnosis of HCC can be made radiographically
- Lesions 1-2 cm in size: classic appearance on two different imaging modalities
- Lesions > 2cm or AFP > 200 with arterial enhancement on one imaging modality
Grading of HCC
Child-Pugh score
TNM (tumor, nodes, metastases)
Okuda
Cancer of the liver Italian program (CLIP)
Barcelona Clinic Liver Cancer (BCLC)
Chinese University Prognostic Index (CUPI)
Obstacles to systemic treatment:
- advanced Child-pugh score
- Poor performance status
- Thrombocytopenia
- Bleeding disorders
- Poor liver reserve
- Underlying liver dysfunction: change dosing
Surgery for HCC
Partial hepatectomy
< 1/3 patients are ideal surgical candidates
- Child-pugh class A
- Small < 5 cm tumors
- Encapsulated (50%)
- Unilobar disease
- No portal HTN
- No tumor in portal vein, IVC
- Minimal cirrhosis
- No distant metastases
- 5 yr Overall Survival (OS) 50-70%
Liver transplant for HCC
Solitary tumor < 5 cm No more than 3 tumors, each < 3 cm No vascular invasion No extrahepatic disease Childs-pugh B or C
4 year Disease free status (DFS): 92%
4 year OS: 85%
Embolization for HCC
Normal hepatic tissue= portal vein supply
Hepatic tumors= hepatic artery supply
- Gelatin sponge particles +/- chemo, radio microbeads delivered to tumor
- Ensure liver has adequate portal inflow/outflow
Chemoembolization= more effective than embolization alone
- 2-year survival= 63% vs 50%
HCC: follow-up
H&P, LFTs, AFP every 3-6 months
Imaging: dynamic CT, MRI q 6months
Sorafenib in HCC
* Experimental drug Multitargeted Tyrosine Kinase inhibitor - Targets Raf, VEGFR, etc. - Raf= overexpressed, activated in HCC - Raf/Ras/MEK pathway: hepatic tumorigenesis
Induces apoptosis in HCC xenograft models
- Phase II data promising
Esophagus benign tumors
Two types:
- Stromal tumors (leiomyomas): submucosal, benign
- Squamous papillomas (RARE): from HPV infection
Risk factors for Esophageal cancer
Squamous cancer:
- Smoking (5-10-fold risk)
- Alcohol (+ Smoking)
- HPV
- Chronic esophagitis
Adenocarcinoma:
- Barrett esophagus (10-fold)
- Obesity, male, heartburn, older age, white
Stomach physiology
cardia: Mucin-secreting
Gastric body: parietal cells (HCl), oxynitis cells (pepsinogen)’
Antrum/pyloris: Mucin-producing cells
Carcinoma of stomach: risk factors
H.pylori= greatest risk factor
- Cigarette smoking
- Dietary substances: nitrites
- Microbial contaminants in food (aflatoxin B)
- Incidence has decreased significantly
- Strophic gastritis
- Adenomatous polyps
- FAP
Early vs advanced gastric cancers
Early refers to size, not duration; early lesions may have spread to nodes
- No necessarily precursors
- Even with metastases, more curable
- “early” gastric cancer= misnomer, as it has different biological morphology
Small intestine tumors
Benign:
- Adenomatous polyps (uncommon)
- Peutz-Jehers polyps
- GISTs
Malignant:
- Adenocarcinoma (uncommon)
- NETs (carcinoid tumors): ileum= most malignant
- Lymphomas
Colon cancer
Adenomas: very common
- Tubular adenoma: on stalks, potentially premalignant, cancer probability depends on size
- Villous adenoma: Sessile, more malignant
- Tubulovillous: mixed histo (25-75% villous), intermediate cancer risk
Hyperplastic polyps
Familial polyposis coli
Juvenile polyps
Adenocarcinoma
Villous adenoma
Large broad-based cauliflower-liked lesion
- Finger-like processes with fibrovascular cores with hyperchromatic nuclei
- > 2 cm at time of discovery
Higher malignancy rates than tubular adenomas
- 50% of adenomas > 2 cm
HNPCC
Hereditary non-polyposis coli cancer (Lynch syndrome)
- AD inherited mutation in DNA mismatch repair (MSH2), MLH1 (40%), MSH6
- Predisposition to mutation in other allele
- Methylation can also decrease expression of mismatch repair genes
- 80% lifetime risk for colon cancer
- younger age (< 44 years)
- RIGHT sided
- Increased risk of endometrial carcinoma (80% lifetime in women)
- Digestive system cancer risk (pancreas, hepatobiliary, stomach, small intestine)
- Urinary tract cancers
Cholangiocarcinoma
Originates anywhere within biliary tree
- Age= 60 years
Causes:
- Chinese liver fluke (C. sinensis)
- Primary sclerosing cholangitis (PSC)
Increased colorectal cancer non-syndromic family history
Family history:
- 1st degree relative < 60 with colon cancer, adenomatous polyps
- two 1st-degree relatives with cancer at any age
Screen at 40 or 10 years prior to age of youngest individual (whichever is first)
- Surveillance at 5 year intervals
HNPCC: diagnostic criteria
3+ relatives with associated cancer (colorectal, cancer of endometrium, small intestine, ureter, renal pelvis)
2 successive generations involved
1 of cancers diagnosed before 50 (1 should be 1st degree relative of other 2)
- Criteria can miss 1/2 of all HNPCC families
Bethesda criteria:
- CRC in patient < 50 years
- Synchronous/metachronous HNPCC associated tumors (colon, small bowel, endometrial, GI/GU)
- CRC in patient= 1+ first degree relatives with HNPCC related cancer, one at < age 50
- CRC in patient with 2+ 1st or 2nd degree relatives with HNPCC related to cancer at any age
Polyposis cancer syndromes
FAP
Attenuated FAP
MYH associated polyposis
Peutz Jeghers
Non-polyposis cancer syndromes
HNPCC
Hereditary CRC variants
Muir-Torre syndrome:
- HNPCC with skin lesions (sebaceous adenoma/carcinoma)
- Genitourinary cancers
Gardner Syndrome
- FAP with cutaneous lesions (osteomas, epidermoid cysts), desmoid tumors
Turcot syndrome:
- HNPCC + glioblastoma
- FAP + medulloblastoma
Peutz-Jeghers syndrome
- Small bowel + colonic hamartomas
- Increased GI cancer risk (CRC, small bowel, pancreatic cancer)
- Perioral pigmentation
History of prior adenoma: risk stratification
Advanced lesion : screen every 1-3 years
- > 1 cm
- Villous
- High grade dysplasia
More than 2 lesions: screen every 3-5 years
1-2 lesions without advanced features: screen every 5 years
CRC and IBD
Increased cancer risk, esp in inflamed segments
Initiate screening after:
- Pancolitis: 8 years of disease
- Left-sided colitis: 8-15 years of disease
Biopsy 4 quadrants every 10 cm
Attention to strictures and polyps
Surveillance every 1-2 years
Principles of colorectal surgery
- Remove entire cancer with enough bowel proximal and distal: submucosal lymphatic tumor spread
- Remove regional mesenteric draining lymphatics (pedicle)
- Predictable lymphatic spread
- Regional mesenteric involvement without concurrent distant involvement - En bloc resection of involved structures
- Exploration: visual, tactile, ultrasound
- Minimize psychological/functional consequences without compromising first four concepts
FDA drugs approved for CRC adjuvant therapy
5FU: inhibits thimydylate synthase
Capecitabine: Metabolized to active 5FU within tumor
- Side effects; diarrhea, hand-foot syndrome (redness and blistering)
Oxaliplatin: Platinum derivative–: DACH adducts, impairs DNA synthesis; bulkier and more hydrophobic
- Pharyngolaryngodysesthesia
- Doubled remission rate, prolonged time to prognosis
Metastatic cancer therapies
Palliative therapy: increase lifespan, decrease side-effects of cancer
VEGF and oncogenesis
Key pro-angiogenic protein
- Helps tumor grow
- Increases vascular permeablity
- Tumor endothelial receptor expression > normal tissue endothelium
Bevacizumab= Anti-VEGF antibodies
- inhibits downstream VEGF signalling
Aflibercept= Part of human VEGF receptors 1 and 2 fused to Fc of human IgG1
- “trap” for VEGFR to prevent activation of VEGF receptors, inhibit angiogenesis
EGFR and oncogenesis
Overexpressed in 60-70% solid tumors
- ligands upregulated: EGF, TGF alpha
TK inhibitors= EGFR blockade
- Cetuximab (first generation)
- Panitumumab: fewer infusion reactions (human monoclonal)
- Regorafenib: small molecule inhibitor of VEGFR, FGFR, PDGFR, BRAF, KIT< RET
- all involved in tumor growth/angiogenesis
- Overall survival improvement: 6.4 months vs 5 months
- Can cause skin rash (acneiform)
Epidural spine compression: etiology
Breast and lung cancer
Epidural spine compression: signs and symptoms
Back pain, exacerbated by lying down, Valsalva
- Weakness below level where pain exists
- Bladder/rectum dysfunction
Epidural spine compression: diagnosis
Plain films: bony destruction
MRI: anatomic detail of involvement
Obtain pathologic specimen if patient does not carry a known malignant diagnosis
Epidural spine compression: treatment
Urgent high dose steroid administration (dexamethasone)
- Surgery due to progressive deficit
- Radiotherapy to shrink tumor in inoperable/less urgent cases
Malignant pericardial effusion causing cardiac tamponade
Sudden changes in hemodynamic function due to compression of myocardium by fluid around it
- Treated timely, can be fully resolved
- Need high index of suspicion: may have complex differential diagnosis (pulmoary parenchymal problems, TB infiltrate, etc.)
Pathophys:
- Sudden accumulation of fluid in pericardial space preventing full ejection
Etiology:
- Most common with lung, breast cancer, lymphoma, metastatic melanoma
- 10-15% autopsies
- Differential diagnosis: lymphangtitic spread, CHF, radiation pneumonitis, pulmonary toxicity
Signs/Symptoms:
- Insiduous
- Severe dyspnea, orthopnea, cough, fatigue, palpitations, dizziness, chest pain, Kussmaul’s sign, paradoxical pulse
- tachycardia/tachypnea
- XRAY: waterbottle heart
- ECHO
- RARELY need cardiac catheterization
Treatment:
- Acute: Pericardiocentesis, window
- Chronic: pericardiocentesis with sclerosing agent, chemo and surgery, radiation
Hypercalcemia of malignancy
Most common metabolic emergency in cancer patients
Due to:
- Excess bone reabsorption, calcium release, increased renal absorption of calcium
- Most common in lung, breast, hematologic malignancies
Clinical diagnosis:
- CNS, PNS symptoms, GI symptoms (dyspepsia, constipation, severe bone pain)
- May be due to skeletal invasion by humoral mechanisms–> osteoclast activation
- Classic neoplasms associated with it
Pathophys:
- Release of calcium from bone due to invasion
- Horomonal process causing calcium release
- PTH of vit-D mechanisms (T-cell lymphomas) increasing Ca absorption
Etiology:
- Lung, breast, renal, multiple myeloma, lymphoma (T-cell more common), breast cancer with skeletal metastases
Signs/Symptoms:
- N/V, dysphagia, anorexia, constipation
- polyuria, polydypsia
- muscle weakness, hyporeflexia, mental status changes, kidney stones
- Severe bone pain
- Pancreatitis/kidney stones= rare
- Serum Ca > 14
- EKG changes: prolonged PR, shortened QT interval
Treatment: Saline rehydration
- Diuresis with furosemide
- IV bisphophonates
- Calcitonin, steroids (v. effective in plasma cell dyscrasias), dialysis for renal dysfunction
Tumor lysis syndrome
Can be avoided by prepping for anti-tumor treatment
Pathophys/etiology:
- Rapid necrosis of bulky tumors after chemo and radiation therapy
- Acute cell destruction, release of intracell products
- URic acid, phsphates, calcium, potassium released
- Causes kidney damage–> hyperkalemia, hyperphos, hypocalcemia, uremia
Most common with:
- Acute leukemia, chronic leukemias, lymphomas, small cell lung cancer
Signs and symptoms:
- Uremia: lethargy, decreased sensorium
- Hyperkalemia: EKG abnormalities, arrhythmias
Treatment:
- IV hydration
- Allopurinol with alkalinization or urine
- Rarely need rasburicase
- Dialysis in rare occasions
Massive hemoptysis in oncologic emergency
Rare: usually have time for something to be done nonemergently (radiation, surgery)
Pathophys:
- Tumor-induced destruction with rupture of arteries–> hemoptysis
Etiology:
- Lung cancer
- Metastatic renal cancer
- Metastatic melanoma
- Bevacizumab (Avastin): block VEGF receptor- do not use in squamous cell carcinoma of lungs
Treatment:
- Surgical resection
- Radiation therapy
Chemotherapy extravasation
Destruction of skin, vessels, muscle, connective tissue–> ulceration
- Much more avoidable with access ports (ports can cause thrombosis and infection)
- Antidotes are marginally effective
- Careful documentation and notification of patients
Etiology:
- Drugs in chemo: Doxorubicin, vinca alkalyoids, nitrogen mustard, antibiotics for tumor
Signs/symptoms:
- Pain/erythema at site
- Rapid swelling of injection site
- thrombosis of vessels
Microangiopathic hemolytic anemia similar to TTP
Mitomycin, gemcitabine
- difficult to differential from DIC: plasmapheresis and steroids to treat
- Can present with excessive fibrinolysis due to hormone-refractory prostate cancer
See:
- Hemolytic uremia
- Kidney dysfunction
- Blood abnormalities (schistocytes, clotting, bleeding)
SVC syndrome
Only emergency with severe respiratory/neurologic symptoms
Pathophys:
- Compression of SVC by tumor- blood can’t get back to heart
Etiology:
- 70-75% due to lung cancer
- 15-20% due to lymphoma (mediastinal B-cell lymphoma, lymphoblastic lymphoma)
Signs/symptoms:
- Venous dilatation of arms/chest
- Facial flushing and swelling
- Dyspnea
- Cerebral edema
Diagnosis:
- High index of suspicion key
- CT/MRI can confirm
Treatment:
- High dose steroids
- Anti-coagulants
- Radiation/chemo if sensitive tumor (lymphoma, small cell lung cancer)
Risk factors for breast cancer
Breast cancer= #1 cancer risk in women (1 in 3), #2 killer
- Gender
- Age
- BRCA1/2
Previous history BrCA
Ovulation
Estrogen (start menstruating sooner, end later, nulliparous)
Alcohol
Race
Obesity
Radiation to chest
Family History
Genetic syndromes
- BRCA1/2
- Peutz-Jaegers
- Cowden syndrome
- Li Fraumeni
- Ataxia/telangectasia
Screening for breast cancer
Normal risk: annual mammogram starting at age 40
Increased risk: mutation carrier, strong family history, prior history of BrCa, history of premalignant lesion—annual MG starting age 35
Very increased risk—radiation to upper thorax–MG starting age 25 or 10 years after radiation
Ways to diagnose breast cancer
- Image guided needle biopsy:
- Adv: no surgery, fast, good for unresectable lesions, metastatic disease
- Disadv: less tissue, may miss spot - Excisional biopsy
- Adv: lesions far from surface, more tissue extracted
Disadv: requires surgery, more scarring - Biopsy with lymph node sampling:
- Adv: accurate staging, good for neoadjuvant therapy
- Disadv: Requires blue dye/radiation; must have strong pretest probability
Staging of breast cancer
Stage 0=DCIS/LCIS Stage I=T1, N0 Stage II=T0-2, N1 or T2-3, N0 **Stage III= T3, N1 or any T4 or any N2, 3** **Stage IV= M1**
T1= less than 2cm
T2 2-5cm
T3 more than 5cm
T4 chest wall or skin
N1 movable axillary *N2 fixed or matted* *N3 other nodes* M0 no mets *M1 mets*
Staging:
- Decide if a tumor is resectable
- Gives a rough estimate of ability to cure the patient
- Helps decide what treatment modalities are necessary
Staging does NOT:
- Determine longevity of patient
- Help decide type of chemotherapy
Local therapy for breast cancer
All gross tumor must be removed
Mastectomy and lumpectomy plus radiation are equivalent therapies
Radiation recommended for–
- Lumpectomy
- Positive lymph nodes
Sentinal lymph node biopsy
Advantages:
- Less risk of lymphedema
- Shorter OR time
- Pathology can section the most important node
- In most patients, this is the only positive node
Disadvantages:
- Number of positive lymph nodes not known
- Not indicated for clinically positive nodes
- Blue dye contraindicated in pregnancy
- Requires experience
Who needs chemotherapy in breast cancer?
- Patients with positive lymph nodes
- Triple negative
- Her-2 positive (receptive to herceptin)
- High oncotype score
- ER/PR: estrogen receptors present
- Her-2 neu
- “Triple negative”= worst prognosis (nothing to target)- no ER/PR, Her-2 neu
- Lymphovascular invasion
- Tumor grade
- Can use computer modeling to help with decision (based on population data)
- DNA microarray: tells person what her risk of relapse is without chemo based on tumor DNA
NOT contraindications to chemo:
- Being pregnant
- Being over age 70
- Having comorbid conditions
- Being a man
- Wishing to have children in the future
Contraindications:
- Benefit vs. risk not favorable
- Performance status greater than 2
- Patient is unable to consent
- Comorbid conditions—with caveats (ex. difficult with dialysis patients)
Who needs hormone therapy in breast cancer?
Anyone with positive hormone receptors and no contraindications
Targeted therapy for breast cancer
In general: less toxic, as effective or more effective
- Her-2 targeted therapies
- Tyrosine kinase inhibitors
- Parp inhibitors
- Bisphosphonates
Treatment of advanced breast cancer
- Use the least toxic therapy available
- Single agent is preferable to combination
- Tailor treatment to the histology
- Tailor treatment to the patient’s lifestyle
- Use monthly bisphosphonates for bone metastases
Breast cancer prevention
Gail score (women over 35 with 1.7% or greater risk:
Premenopausal—tamoxifen is the only choice
Postmenopausal can also use raloxifene
Congenital anomalies of breast
Amastia (no glandular tissue develops and no nipple areolar complex present)
Aplasia (nipple areolar complex present but no glandular tissue develops)
Hypoplasia (underdevelopment of glandular tissue)
Athelia (no nipple areolar complex)
Supernumary nipples or accesory breast tissues
Nipple inversion
Acute mastitis
Seen in nursing women, related to staph
Idiopathic granulomatous mastitis
Young females with mass lesion
Duct ectasia
Periductal mastitis with dilated ducts, foamy histiocytic lymphoid cell infiltrate
Fibrocystic changes in breast
Non-proliferative: production of cysts within breast (blue-domed), apocrine metaplasia (eosinophilic), stromal fibrosis
- NO increased risk in developing invasive carcinoma
Proliferative without atypia:
- Usual ductal hyperplasia
- benign adenosis, sclerosing adenosis (SA)
- Radial scars
- columnar cell change/hyperplasia
- Only small increased risk of breast cancer
Proliferative with atypia
- Atypia ductal
- Atypical lobular hyperplas (ADH, ALH)
- Flat epithelial atypia
- Need excision to determine what is occurring in lesion
- Significant risk of breast cancer risk
Pediatric brain tumors: Etiology
pediatric brain tumors as a group are becoming as common as acute leukemia
- incidence is increasing
- mortality is decreasing
Risk factors:
- More common in boys than girls
- More common in whites
- Ionizing radiation (tinea capitis, lice, leukemia treatment–> 1 Gy carcinogenic)
- Syndromes: NF-1, tuberous sclerosis (phakomatoses), Gorlin, Li-Farumeni
Most common types:
0-4 years: embryonal medulloblastoma
5+ years: pilocytic astrocytoma
Pediatric brain tumor: diagnosis
History:
- lethargy
- headaches
- declining school performance
- personality change
- nausea/vomiting, especially morning vomiting
- precocious puberty
- loss of milestones
Exam:
irritability
somnolence
macrocephaly: pediatricians check head circumference
cranial nerve palsies: double vision
seizures
papilledema: optic disc pushed forward
visual loss: not always obvious is the very young
precocious puberty
weakness
paresthesias
Syndromes:
- Gorland’s syndrome: skin and brain abnormalities
- NF-1 (prone to gliomas)
Sprengel’s deformity: failure of the scapula to descend to its normal position.
Vertebral anomalies: hemivertebrae (vertebral rings incomplete)
Scans:
- CT (quick look)
- MRI of brain, spine
- MR Spectroscopy: metabolic signature of tumor, central necrosis, etc.
Treatment of pediatric brain tumors
- Surgery
- Chemotherapy
- Radiation: Delivery:
- 3D conformal technique
- Intensity modulated radiation therapy (IMRT)
- Proton scatter beam
- Proton pencil beam
- **Protons specially beneficial for children*: no exit dose, more precise, less radiation to neighboring tissue
- Stereotactic radiosurgery/CyberKnife
Outcome of pediatric brain tumors
Dependent on location and pathology
Infants do worse because of the constraint of limited radiation therapy
Problem of late recurrences
- 5-10 years after diagnosis
ANC (absolute neutrophil count)
ANC= WBC x (polys + bands)
Neutropenia= low ANC
Neutropenia in children:
- Mild (1000-1500)
- Moderate (500-1000)
- Severe (< 500)
Neutropenia in childhood
- Viral induced:
- RSV, EBV, CMV, influenza A and B, varicella, hepatitis A, hepatitis B, parvovirus, HIV - Drug-induced:
- Ibuprofen, penicillin, cephalosporins, Bactrim, hydralazine, Zantac, phenytoin, carbamazepime
- May occur 1-2 weeks after exposure to drug; can last for months - Cancers: infiltration and replacement of normal marrow with malignant cells
- Leukemias: ALL, AML; rarely only presenting sign of leukemia, but can be only hematologic abnormality
- Solid tumors metastatic to bone marrow (rhabdomyosarcoma, retinoblastoma, neuroblastoma)
- Diagnosis: Bone marrow exam
Severe congenital neutropenia
ELANE-related:
(ELAstase, Neutrophil Expressed); neutropenias include congenital neutropenias and cyclic neutropenia
These are hematologic disorders with:
- recurrent fever
- skin and oropharyngeal inflammation
- mouth ulcers, gingivitis
- Sinusitis
- Pharyngitis
- cervical adenopathy
Infectious complications are generally more severe in congenital neutropenia than in cyclic neutropenia.
Infections are much more common in the ELANE disorders than in the common pediatric neutropenias
Symptoms:
- Typically presents at =5 g/kg/day (granulocyte colony stimulating factor) to boost ANC and decrease infections
Prognosis:
- ongoing risk of developing AML with or without the use of G-CSF
By age 15:
- 36% chance of developing myelodysplasia
- 25% chance of developing acute myelogenous leukemia
**Ultimate cure: allogeneic bone marrow transplant
Cyclic neutropenia
Rare, relatively benign disorder with periodic oscillations of ANC, often in remarkably regular 21 day cycles
Patients typically have periods of count dependent wellness alternating with periods of illness
Etiology:
- Autosomal dominant or sporadic
- Ask about family history
Signs and symptoms:
- fever, oral ulcerations, perianal cellulitis
Pathophys:
- ANC nadir is usually 90% of patients have mutations in neutrophil elastase (ELANE)
Treatment:
- daily G-CSF injections >=3 g/kg/day
Prognosis:
- NOT typically associated with an increased risk of malignancy/leukemia
- Neutropenia and associated morbidities typically lessen into adulthood
Shwachman-Diamond Syndrome
Very rare cystic fibrosis-like exocrine pancreatic insufficiency with neutropenia;
Etiology:
- Autosomal recessive inheritance
presents in early childhood
Symptoms:
- short stature, failure to thrive, infections, neutropenia (may be chronic or cyclic)
- may have anemia, thrombocytopenia as well
Diagnosis:
- test pancreatic enzymes
- check CBC twice weekly for several months to follow ANC
- bone marrow examination
Pathophys:
- 80-90% have mutations in SBDS gene
- undergoes recurrent mutations because of the presence of a nearby pseudogene, an inactive copy of the SBDS gene.
- Gene conversion: transfer pseduogene mutations to real gene
Treatment:
- enzyme replacements for pancreatic insufficiency
- G-CSF for neutropenia
- Ultimately, bone marrow transplant for marrow failure/transformation
Prognosis:
- increased risk of myelodysplasia/ malignant transformation
Fanconi Anemia
Autosomal recessive disorder: not uncommon, look for it, many cases not diagnosed until teenage years or later
- Initial hematologic problem is usually thrombocytopenia, not neutropenia
- 80% of patients have phenotypic anomalies
Symptoms:
- Bone problems: Absent bones from hands/thumbs, wrists, forearms; scoliosis
- Skin problems: Hyperpigmentation, cafe au lait spots, vitiligo
- Short stature
- Microcephaly
Autoimmune neutropenia (Chronic Benign neutropenia)
Common cause of chronic neutropenia in childhood; typically healthy and do not get invasive infections as a result of their neutropenia
- Often diagnosed incidentally on a CBC drawn for some other reason; panic often ensues
- Most cases resolve within 6-18 months
Etiology:
- Infections, drugs, other autoimmune disorders, cancer
- Disorders that can trigger AIN: ITP, Lupus, EBV infections, Hodgkin disease
Morbidity:
- Serious infections rare
- Primary morbidity is the onset of fever related to a minor coincidental viral infection
Diagnosis:
- Serial blood counts, ANC is usually 1000)
Transient Neonatal Hematologic Alloimmune phenomena (TNHAP)
Basic categories:
- Anemia: secondary to antibody mediated RBC destruction
- Neutropenia: secondary to antibody mediated WBC destruction
- Thrombocytopenia: secondary to antibody mediated platelet destruction
TNHAP: Hemolytic anemia
Alloimmune anemia of the newborn
Antibody mediated destruction of RBC; antibodies directed against:
- Rh antigens
- ABO antigens
- other minor antigens
Pathophys:
- maternal Immune system rejects fetal (paternal) antigens–> lysis
- rejection is humoral/IgG mediated; there is no direct cellular or IgM attack as these cannot cross the protective placental membranes
Hemolytic disease of newborn:
ABO incompatability
ABO incompatability:
- not as severe as Rh incompatable
- Infant= A or B, mother= O
- 20% of ABO incompatable–> clinical jaundice
Clinical presentation:
- can occur in first born child
- subsequent pregnancies less severely affected (opposite of Rh incompatibility)
- jaundice within first 24 hours (umbilical cord was clearing bilirubin before birth)
- typically milder than Rh incompatibility because the diffuse expression of ABO antigens on tissues absorb much of the harmful antibodies
Diagnosis:
- ABO set-up needs to be present
- anemia: mild or absent
- smear: reticulocytosis, NRBC, spherocytes present
- direct Coombs: can be + or – (Don’t be misled by negative Coombs test)
- may be difficult to definitively prove ABO hemolysis is occurring especially if the Coombs test is negative
Treatment:
- phototherapy in some
- aggressive therapy (transfusion, exchange) in the rare severe case
TNHAP: alloimmune neutropenia in newborn
Lytic maternal antibodies cross the placenta to attack baby’s paternal WBC antigens
NOT:
- autoimmune neonatal neutropenia
- neutropenia due to passive transfer of maternal autoimmune neutropenia antibodies
40% of mothers of these babies have had miscarriages possibly related to early fetal injury
Pathophys:
- antibody mediated destruction of WBC
like ABO/Rh, several common antigen targets identified
- maternal antibodies= NA1 and NA2
Clinical presentation:
- usually picked up incidentally in well babies
- occasionally present with invasive infections due to neutropenia: omphalitis, pneumonia, meningitis (Babies with omphalitis should have a CBC)
Diagnosis:
- CBC
- antineutrophil antibody studies on mother, child looking for lytic antibodies
- WBC typing on parents and child looking for incompatibility at the NA locus
Treatment:
- Neutropenic well baby: no therapy, follow counts
- Neutropenic sick/infected baby: IV antibiotics, G-CSF
TNHAP: Alloimmune thrombocytopenia of newborn
Also known as neonatal alloimmune thrombocytopenia (NAIT)
- rare, < 0.1% of all newborns have thrombocytopenia due to this, although 3% of pregnancies at risk due to tissue type incompatibility
NOT autoimmune neonatal thrombocytopenia (neonatal ITP)
Pathophys:
- Antibody mediated destruction of platelets
Clinical presentation:
- TNHAP that most frequently causes intrauterine morbidity/mortality (intracranial bleed)
- incidentally detected post-partum
- thrombocytopenia usually severe (<50,000)
- occasionally present with bleeding, petechiae (incidence of serious bleeds low)
Diagnosis: - Antiplatelet antibodies - Major platelet antigen is HPA-1 - demonstration of HPA mismatch: mother HPA-1 negative father (baby) HPA-1 positive
Treatment:
- prenatal interventions: maternal IVIg infusions; fetal platelet transfusion (tricky in a thrombocytopenic fetus)
- newborn interventions
- transfuse baby with washed, maternal (HPA-1 negative) platelets (convenient source)
- transfuse with non-maternal HPA-1 negative platelets (blood bank, often hard to get)
- IVIG infusions
Rhabdomyosarcoma
Malignancy in children
4 types:
- Botryoid: genital, young children
- Head and neck: children < 8 years
- Embryonal: orbital
- Alveolar: extremities; teens and young adults
Treatment: VAC:
- Vincristine
- Actinomycin-D
- Cyclophosphamide
+ Doxorubicin (anthracycline antibiotic)
+ Ifosfamide (cyclophosphamide analog)
+ Etoposide (topoisomerase I inhibitor)
Hemophagocytic lymphohistiocytosis (HLH)
Rare (1 in 3000 inpatient peds) potentially fatal syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme inflammation
- familial disorder (primary): fixed defects of cytotoxic function
- sporadic disorder (secondary): triggered by infections, malignancies, or rheumatologic disorders (EBV, CMV, parvo)
Pathophys:
Activated hematopoietic cells infiltrate target organs, leading to severe end organ damage
- Activated macrophages engulf healthy tissue
Symptoms:
- Fever
- Hepatomegaly (liver inflammation
- Splenomegaly
- Neurologic symptoms
- Rash
- Lymphadenopathy
Diagnosis:
- sCD5 (IL-2)
- Ferritin (v. elevated)
- Genes: PRF1, hMUNC13-4, Syntaxin 11
Risk factors for lung cancer
Smoking:
- Smoking accounts for 80-85% of bronchogenic cancer
- Risk related to number cigs/day, years smoked, depth of inhalation, age of initiation of smoking, amount of tar
Occupational:
- Asbestos: higher when combined with cigarette smoking; 50 times greater risk than non-smokers, non-asbestos exposed men
- Chloromethyl methyl ether
- Ionizing radiation
- Nickel, arsenic (glass, paints, pesticides)
- Aromatic hydrocarbons (petroleum industry)
Histologic types of lung cancer:
Small Cell Lung Cancer (SCLC):
- includes oat cell, intermediate and combined subtypes
Non-Small Cell lung cancer (NSCLC)
- squamous cell carcinoma
- adenocarcinoma (includes bronchioloalveolar subtype)
- large cell carcinoma
Mutations involved in lung cancer
"Driver" mutations: 1. EGFR: targeted by TKI 2 EML-4-ALK: fusion gene of EML4 and anaplastic lymphoma kinase: seen in non-smokers; - treated by Crizotinib 3. KRAS - Her-2 Neu (small number) - BRAF (rare) - MET - AKT1 - PIP3 Kinase - ERCC 1: Platinum - RRM-1: Gemcitibine
Chromosome 3, alterations in telomerase expression, KRAS mutations
“Passenger” mutations
EGFR in lung cancer
Mutations:
- Cluster in L868, exon19- sensitive to TKI
Overexpression:
- Not sensitive to chemotherapy drugs
Epidemiology:
- Asians
- Women
- Never smokers
- Independent predictor of response, progression free survival
Squamous cell carcinoma of lung
30-50% of US lung tumors; adenocarcinomas increasing in frequency
- Usually arise in the epithelium of proximal bronchi (but NOT always case)
Histo:
- Keratinization and “pearls” (flattened cells surrounding central core of keratin)
- intercellular bridges
- Cytokeratin
- EM: densely pack filaments
Labs:
- Hypercalcemia is common secondary to elaboration of PTH-like substance
Least likely to metastasize
- over 50% at autopsy are confined to the thorax
- brain mets only about 13%
Adenocarcinoma of lung
Precursor: Atypical Adenomatous Hyperplasia
- Usually are found peripherally
- Commonly metastasize (liver, adrenal, bone and CNS)
- At autopsy, brain is involved in over half of the cases
May secrete GH, corticotropin, calcitonin, FSH Hypertrophic osteoarthropathy (HO) more frequent with adenocarcinoma
M=F
More peripheral
May produce mucin
Contains cytokeratin
Immunohistochemical markers of lung adenocarcinoma
CK7+
CK20 negative (except mucinous)
TTF-1+: thyroid transcription factor-1
NAPSIN A+
Markers for squamous cell carcinoma
CK5/6
P63
Large cell carcinoma
NSCLC that is not classified as adeno or squamous by light microscope Variants: - Giant cell - Clear cell - Spindle cell
Grouped with adenocarcinoma, least common
Bronchoalveolar carcinoma
Difficult to diagnose based on symptoms, history and X-ray
- Non-smokers
- Resembles pneumonia (see infiltration on both sides)
- Oxygen-dependent, difficult to treat
Carcinoid tumor
Epithelial tumor with neuroendocrine markers
- NSE= neuron specific enolase
- Chromogranin, synaptophysin, CD56
- Centrally located
- younger patients, male=female, symptoms of bronchial obstruction
Low-grade malignant tumor Derived from neurosecretory line Atypical carcinoid has worse prognosis Cured by resection 2% of lung cancers
Small cell lung cancer
Neuroendocrine tumor: systemic illness at presentation
- 18% of all lung cancers
- Due to: heavy cigarette smoking, uranium miners, CMME (chloro methyl methyl ether) exposure
Histo:
- Small cell, classic oat, intermediate types
- 2X size of small lymphocytes
- Cells with very little cytoplasm thus appear small
- Nucleus occupies almost entire cell- v. little cytoplasm
- Usually manifested grossly by central masses and lymphadenopathy
- Mucosal and submucosal invasion appreciated bronchoscopically
- Staged and treated differently than NSCLC: radiation v. important part of control (25-30% cure rate if less extensive- can use chemo and radiation)
More malignant compared to carcinoid tumors--> still has neuroendocrine function Develop Paraneoplastic syndrome: - SIADH: low Na, altered mental status, urine/serum osmolality mismatch - Cushing's: hypokalemic alkalosis (someone NOT on diuretic with lung tumor) - Eaton Lambert syndrome - Never see elevated calcium - Gynecomastia - Hypoglycemia - Acromegaly - Hyperthyroidism - Clubbing of fingers - Pulmonary osteoathropathy
Systemic disease at outset:
- Treated with chemo
- Frequent metastases to endocrine organs (thyroid, pituitary testes, parathyroid)
- Moon metastases to elsewhere in lung, liver, bone, brain, adrenal, pericardium
- Brain metastases occur up to 40% of small cell lung cancers!!
Cytogenetics: - Deletion of 3q Abnormalities of Rb on Chrom 13 - Abnormal p53 on chrom 17 - cMyc amplification prominent
Lung cancer: presentation
Family history Chest pain Smoking history Recurrent nerve palsy Change in cough Superior vena cava syndrome New onset hemoptysis Airway obstruction Recurrent/refractory infections Pneumonia Atelectasis Exposure to environmental factors Pleural effusions
Lung cancer: prognosis
10% stage I disease; (60% 5yr survival) 20%, stage II; (40% 5-year survival) 15%, stage IIIA; (20% 5-year survival) 15% stage IIIB; (5% 5-year survival) 40%, stage IV. (2% 5-year survival)
NSCLC presenting signs and symptoms:
Locoregional disease: Cough Atelectasis/pneumonia Wheezing Pleural effusions Stridor Pleuritic pain Hemoptysis Shortness of breath
Advanced disease: Fatigue Decreased appetite Cough Weight loss Dyspnea
Lung cancer growth near hilum presentation:
Cough Hemoptysis Wheeze Dyspnea Post obstructive pneumonia
Lung cancer: peripheral growth
Cough
Restrictive dyspnea
Lung abscess
Lung cancer: mediastinal spread
- Tracheal obstruction: wheezing, stridor
- Dysphagia due to esophageal compression
- Hoarseness due to recurrent laryngeal nerve entrapment and paralysis
- Phrenic nerve paralysis: elevated diaphragm
- Superior vena cava obstruction
Lung cancer: apical spread
Generally seen with NSCLC (grows less rapidly):
Horner’s syndrome: ptosis, miosis, anhydrosis
- Cervical sympathetic chain trapped by tumor (Pancoast tumor)
Right shoulder pain
Pain, weakness in arms, back
Eaton Lambert Syndrome
Myasthemia-Gravis like syndrome (opposite)
- Muscle response gets STRONGER with stimulation
Tissue diagnosis in lung cancer
CT
MRI
Fine needle aspiration of tumors (CT, Bronchoscopy guided)
Bronchoscopy
Imaging in lung cancer
CT study of chest: lung, nodes, liver, adrenals
PET: NSCLC (and useful in SCLC)
- Inferior for CNS evaluation
- Mediastinal evaluation
- Stage I or II (extensive disease–> no surgery recommended)
- FALSE POSITIVES: infection, inflammation (will take up glucose- not specific)
- FALSE NEGATIVES: low-grade malignancy don’t pick up PET agent
Brain: MRI or contrast CT (needed for staging of SCLC)
Bone scan
Liver: MRI; clarification of PET scan for mets
Treatment of lung cancer
Early stage lesions, stages I and II: surgery preferred
- Chemo-radiotherapy for locally advanced disease
- Chemotherapy for systemic disease
- Radiation therapy for local palliation and control
- New paradigms in adjuvant chemotherapy for earlier stages are emerging
Stage II disease, early chemotherapy has been shown to have advantage as adjuvant therapy In recent trials
Stage II B: Pancoast tumors: radiation or radiation plus chemotherapy with surgery
Stage III: combined modality therapy: usually chemo-radiotherapy followed by chemotherapy
Stage IV (formerly IIIB): pleural effusion: chemotherapy
Stage IV: chemotherapy
Leukoplakia
WHITE premalignant neoplasia
- Hyperkeratotic epithelium
Erythroplakia
RED mucosa, fragile, easily traumatized
Oropharyngeal squamous cell carcinoma
- Includes tonsillar and base of tongue carcinoma
- HPV related (p16 positive)
- More common in young adults, male predominance
- Often presents as a “neck mass”
- Nonkeratininzing, poorly differentiated histology
- Good prognosis, better response to radiation therapy
Laryngeal squamous cell carcinoma
The most common malignant neoplasm of the larynx (95%)
Clinical presentation:
- Hoarseness or alteration of voice
- Throat pain, dysphagia
- Neck mass
- Airway compromise in large, bulky tumors (advanced cases)
Glottic carcinoma
- Most common
- Vocal cord involvement
- Early symptoms, while still curable
Supraglottic carcinoma
- Next most frequent
- Foreign body sensation, pain, hemoptysis, muffled voice
- Later symptoms than glottic carcinoma- takes longer for noticeable symptoms (spreads to glottis)
Tonsillar Squamous cell carcinoma
Tonsillar: don’t see nests as in normal squamous cell carcinoma- basilloid appearance (blue), no keratin production
- Majority HPV related
- Immunohistochemistry stains for p16 (HPV)
Salivary gland tumors: mucoepidermoid carcinoma
Mucoepidermoid carcinoma- most common
- Definition: tumor characterized by the presence of squamous, mucus-producing cells and cells of intermediate type
- 5th and 6th decades;
- most common salivary gland malignancy in children
Clinical presentation
- Low grade tumors: prolonged period of - painless enlargement (several years)
- High grade tumors: rapid growth, pain, ulceration
- Involvement of facial nerve in tumors of the parotid
Salivary gland tumors: Adenoid cystic carcinoma
Most difficult to manage
- Definition: malignant tumor with three growth patterns: glandular (cribriform), tubular or solid. It is composed of two types of cells: duct-lining cells and myoepithelial cells
- One of the most biologically deceptive and difficult to manage (bland histologic appearance and favorable short-term therapeutic results)
Clinical behavior:
- Slow, but relentlessly malignant natural course
- High incidence of local recurrence and distant metastases
- The success of treatment and ultimate prognosis must be considered in terms of 15-20 years.
- Distant metastases occur late in the course of disease (patients with distant metastases have uncontrolled disease in the primary site or neck)
- PERINEURAL INVASION**
Histo:
Tumor cells: small, round, with dark –staining nuclei and scant cytoplasm
Three basic patterns:
- Tubular = well formed ducts or tubules with central lumina, lined by 2-3 layers of cells
- Cribriform = classical pattern; “Swiss cheese” or “sieve-like” appearance
- Solid = solid epithelial islands completely filled with cells
Nasopharyngeal carcinoma
- Rare tumor in the general population
- Has striking and characteristic epidemiologic, virologic and pathologic characteristics
- “NPC” – refers to conventional squamous cell carcinoma and to nonkeratinizing or undifferentiated carcinoma arising from the surface of tonsillar crypt epithelium of the nasopharynx
Epidemiology:
- Common in Southern China and among Chinese in Taiwan, Singapore and Hong Kong
- First-generation Chinese immigrants to other countries maintain a high incidence of NPC
- Common among Alaskan, Canadian and Greenland Eskimos
- Twice more common in men than in women
Etiology:
- EBV-driven tumor (non-keratinizing forms)
- IgA and IgG EBV antibodies: Ab levels tend to increase in relation to tumor burden
- EBV-encoded RNA (EBER) is present in NPC cells
Clinical presentation:
- Most common – neck mass secondary to metastatic disease
- Unilateral hearing loss, otitis media
- Nasal obstruction, bleeding, pain or cranial nerve palsies
- Primary tumor: often small, difficult to visualize on clinical exam/exophytic
Histo: Keratinizing SCC Nonkeratinizing SCC (EBV related): - Differentiated - Nondifferentiated – syncytial growth of undifferentiated tumor cells, admixed with lymphocytes
Non-Keratinizing: better prognosis
more radiosensitive than keratinizing SCC; better prognosis
70% and 59% survival at 3 and 5 years for nonkeratinizing SCC
Sinonasal adenocarcinoma
Increased risk with exposure to wood dust, paints, varnishes, glues and adhesives
- Risk in woodworkers is 70-500 x non woodworkers
- High incidence in middle-aged and old men
Clinical presentation:
- Involvement of nasal cavity and maxillary sinuses
- Polypoid or papillomatous masses in the nasal cavity
- Destructive manifestations in the sinuses
- Unilateral nasal obstruction, epistaxis, pain, usually of a few months duration
Histo:
Origin – surface epithelium, accessory seromucous glands ducts, seromucous glands
Low grade – uniform glandular architecture, bland cytologic characteristics
High grade – necrosis, inflammation
- Subtypes: papillary, colonic, solid, mucinous, mixed
Prognosis:
- All grades of sinonasal adenocarcinoma tend to be locally aggressive, frequent invading orbit and the base of skull
- Distant metastases are rare
- Complete surgical removal with clear margins is the treatment of choice
Nasal type angiocentric cell lymphoma
NKT cells
- Aggressive type of lymphoma
- Insidious onset
- Ulcerations of nasal mucosa, erosion of the cartilage and bone
- Destructive lesions of the nasal septum, hard palate and nasopharynx
- Former designation “lethal midline granuloma”
Histo:
- Pleomorphic atypical lymphoid infiltrate
- Malignant lymphoid cells surround small to medium sized blood vessels, infiltrate through vascular walls and can occlude vessel lumens and cause necrosis in adjacent tissue
Olfactory neuroblastoma
Malignancy arising from the olfactory mucosa; no predisposing carcinogen known
Epidemiolgy:
Bimodal peak incidence in the 2nd and 6th decades of life
Symptoms:
Nasal obstruction, epistaxis
Prognosis: Locally aggressive tumor, low incidence of distant metastases
Histo:
- Polypoid, highly vascular tumor displaying diverse histologic patterns
- Lobular architecture
- Uniform tumor cells set in a neurofibrillary matrix
- Rosettes
- Intracytoplasmic dense core granules (by EM)
HPV and naso-oro-pharyngeal cancers
Better prognosis with HPV-caused cancers
HPV Related: based of tongue, tonsil, oropharynx
Younger patients
Better outcomes with radiation treatment
See p16 marker
Treatment of head and neck cancer:
Surgery
Radiation therapies
Chemo
Signs and symptoms and head and neck cancer
Neck mass Odynophagia, Disphagia Hoarseness Trismus (cant open mouth- muscle spasm) Otalgia, unilateral otitis media Loose teeth, ill-fitting dentures Cranial nerve deficits Non-healing oral/oro-pharyngeal ulcers
Muir-Torre syndrome:
- HNPCC with skin lesions (sebaceous adenoma/carcinoma)
- Genitourinary cancers
Gardner Syndrome
FAP with cutaneous lesions (osteomas, epidermoid cysts), desmoid tumors
Turcot syndrome:
- HNPCC + glioblastoma
- FAP + medulloblastoma
Peutz-Jeghers syndrome
Peutz-Jeghers syndrome
- Small bowel + colonic hamartomas
- Increased GI cancer risk (CRC, small bowel, pancreatic cancer)
- Perioral pigmentation
Oral squamous cell carcinoma
Tongue= most common site
Risk factors= Smoking, Betel nuts
- Male predominance
Pre-malignant lesions= leukoplakia, erythroplakia
