Myeloproliferative disorders, multiple myeloma, leukemia, lymphoma (Week 8) Flashcards
Acute vs. chronic leukemias in general
Acute leukemias involve blasts (immature cells); generally worse prognosis (short and drastic course); blocked differentiation; children or elderly
Chronic leukemias involve more differentiated cells (mature cell); generally better prognosis (longer, less devastating course; midlife age range
Myeloproliferative disorders
Clonal disorder of hematopoiesis characterized by excessive growth and differentiation of blood cells
Excessive production of mature blood cells, all of which are derived from single hematopoietic progenitor
1) Polycythemia rubra vera
2) Essential thrombocythemia
3) Myelofibrosis (agnogenic myeloid metaplasia with myelofibrosis)
4) Chronic myelogenous leukemia (CML)
Philadelphia chromosome
Over 90% of patients with CML have Philadelphia chromosome (in all cancer cells!)
Shortened chromosome 22 has bcr (breakpoint cluster region) plus long arm of chromosome 9 with abl oncogene
Fusion product P210 has tyrosine kinase activity (constitutive) and cells with the fusion protein grows out of control (unresponsive to suppressive elements)
Results in constitutive activation of bcr-abl tyrosine kinase which leads to intracellular signaling pathway going to nucleus and activating altered proliferation, adhesion and survival
Myelodysplastic syndromes (MDS)
Dysplastic and ineffective blood cell production –> decreased WBC, RBC, platelets
NOT a subset of myeloproliferative disorders (duh…this is decreased everything) but usually in the bone marrow have hypercellular hematopoiesis produced by few clones of cells with dysplastic characteristics
Typically have chromosomal abnormalities
Often called “preleukemia” but remember that some subtypes of myelodysplasia rarely evolve into leukemia while others are very close to leukemia
Clonal disorders of hematopoiesis
Acquired
Expansion of pluripotent hematopoietic stem cell
Abnormal production of mature blood cells
Predisposition to leukemia transformation
Myeloproliferative syndromes
Includes 4 myeloproliferative disorders plus more
CML
PV
ET
Myelofibrosis
Chronic monocytic leukemia
Chronic neutrophilic leukemia
Characteristics of chronic myeloproliferative disorders
Hepatosplenomegaly (clones go to embryonic sites of bone marrow production!)
Hypermetabolism
Clonal increase in number of one or more circulating mature blood cell types
Clonal hematopoiesis without dysplasia
Predisposition to evolve to acute leukemia
Atypical myeloproliferative diseases
Not the main 4!
Chronic neutrophilic leukemia
Chronic eosinophilic leukemia and hypereosinophilic syndrome
Systemic mastocytosis
Chronic myelogenous leukemia
Defined by Philadelphia chromosome: short chromosome 22; translocation of bcr from chromosome 22 and abl from chromosome 9
Over 90% patients have Philadelphia chromosome in all clonal cells
Usually in people 30-60 but can happen at any age; slightly more common in males; no heredity
Get hyperleukocytosis which causes rheologic (flow) problems which manifests as dyspnea, dizziness, slurred speech, visual blurriness, diplopia, decreased hearing, tinnitus, confusion, retinal hemorrhage, paiplledema, priapism, neuro findings, hepatosplenomegaly
Also get fatigue, anorexia, abdominal discomfort, early satiety, weight loss, diaphoresis, arthritis, leukostasis, urticaria (basophils and mast cells), pallor, sternal tenderness
Clone cell of CML makes all cells: lymphoid, myeloid, erythroid, megakaryocytic cells
Increased basophils seen in CML (especially at terminal stage), hypersegmentation (ran out of folate), anemia
Hypercellular bone marrow, reticulin fibrosis
Accelerated phase of CML
Transformation to more malignant phenotype
Additional chromosomal abnormalities cause disordered growth, diminished maturation
Clinical features: fever, diaphoresis, weight loss, splenomegaly, adenopathy, extramedullary blast crisis
Treatment: supportive care, chemotherapy, interferons, leukapheresis, splemectomy, radiotherapy, bone marrow transplantation
Should you give a healthy-seeming CML patient bone marrow transplant?
Hard to do, but yes because 70% cure rate if treated during chronic phase but only 15% cure rate if wait until blast crisis (even after phase)
Unsure about this…
Three phases of CML
1) Chronic phase
2) Accelerated phase
3) Blast crisis
Predictors of adverse outcome after allogenic transplant for CML
Advanced age of recipient
Prolonged duration of CML
Advanced stage of CML
T-cell depletion
Persistence of molecular positivity after transplant
Absence of a/c GvHD (?)
Imatinib mesylate (Gleevac)
Targets and inhibits product of brc-abl gene, P210 tyrosine kinase (the cause of CML)
Fits into ATP binding site of P210 and disrupts tyrosine kinase activity (doesn’t allow P210 to add phosphate to the substrate)
Completely gets rid of cells with Philadelphia chromosome in 68% of people! And reduces Ph+ to <35% in 15%
Response occurs quickly, after only 3 months
Therapeutic milestones in management of CML
Hematologic remission
Cytogenetic remission
Molecular remission
Monitoring during therapeutic management of CML
Hematologic monitoring weekly until stable, every 2-4 weeks until complete cytogenetic response achieved, then 4-6 weeks until molecular response, then every 6 weeks
Cytogenetic motoring every 3-6 months until complete cytogenetic response (CCyR = no cells contain Ph chromosome)
Molecular monitoring every 3 months
Polycythemia vera
Hematopoietic stem cell disorder with sustained erythrocytosis, increased RBC mass, cellular proliferation
Peak onset 50-60; males more than females; less common in Asians, more common in Ashkenazi Jews
Clinical features: headache, dizziness, vertigo, visual disturbances, angina, claudication, early satiety, abdominal pain, pruritus, thrombosis (Budd-Chiari syndrome), hemorrhages, plethora, retinal hemorrhages, hepatosplenomegaly
Lab findings: high B12, hyperuricemia, decreased erythropoietin, acquired mutation in JAK2
Treatment: phlebotomy (to decrease hematocrit), radioactive phosphorus, other myelosuppressive agents, Jakafi (ruxolitinib; Janus kinase inhibitor; doesn’t work as well as Gleevec does for CML), Hydroxyurea, alpha-interferon, anagrelide, treat symptoms (antihistamine, allopurinol, aspirin)
Prognosis: 30% evolve to spent phase (marrow completely scarred); only 1% evolve to leukemia
What else other than PV can cause increased erythrocytosis (DDx for PV)
Relative (stress) erythrocytosis
Secondary erythrocytosis (anything that causes hypoxemia): cardiopulmonary disease, high-affinity hemoglobin, decreased FiO2, COPD
Malignant neoplasm (CO poisoning, endocrine disorder)
Cerebellar hemangioma
Uterine myoma
Rheologic problems in CML vs. PV
in CML, white blood cells stick to each other
In PV, just too many red cells but not sticking to each other
Essential (primary) thrombocythemia
Excessive bone marrow production of platelets; have leukocytosis and marrow fibrosis as well
Presents age 50-70, usually asymptomatic
No chromosomal findings
Lab features: increased hematocrit, increased RBC mass, normal/increased plasma volume, occasionally microcytosis, neutrophilia, basophilia, thrombocytosis, hypercellular marrow, increased megakaryocytes, myeloid/erythroid hyperplasia (increase in all cell lines), absent stainable iron
Pathophysiology of ET: haven’t found mutation yet but JAK2 mutation in 30-50%, MPL 515 mutation in 1% (often with JAK2 mutation), endogenous erythroid colony (EEC) growth
What else other than essential thrombocythemia (ET) can cause increased platelets (DDx for ET)
Reactive thrombocytosis due to:
Iron deficiency
Splenomegaly
Malignant neoplasms
Chronic inflammatory diseases
Polycythemia vera
CML
Agongenic myeloid metaplasia
Clinical course of ET
Predictors of adverse events: age over 60, leukocytosis, smoking, DM
Thrombohemorrhagic risk: age over 60, platelets >1,500,000, cardiovascular risk factors
Risk of AML transformation
Rare to go to acute or blast crisis
Other myeloproliferative diseases
Chronic idiopathic myelofibrosis
Hypereosinophilic syndrome
Chronic eosinophilic leukemia
Mastocytosis (cutaneous, systemic, or aggressive systemic)
Hypereosinophilic syndromes
Sustained eosinophilia (>1500), typically in absence of clonality
Chronic eosinophilic leukemia if >5% marrow blasts or >2% circulating blasts
End-organ manifestations of tissue infiltration
Absence of secondary causes of eosinophilia (allergy, metazoan parasitic infection, hypersensitivity pneumonitis, collagen vascular disease, neoplasia, CML, mastocytosis, AML, other myeloproliferative disease)
Chromosomal abnormalities (interstitial deletion of chromosome 4q12, FIP1L1-PDGFRalpha fusion tyrosine kinase)
Clinical manifestations if untreated: infiltrative cardiomyopathy, peri-myocarditis, intramural thrombi, mononeuritis multiplex, peripheral neuropathy, central and cerebellar dysfunction, pulmonary infiltrates/fibrosis/effusions/emboli, GI, arthritis, myositis
Mastocytosis
Distinguished by site and degree of involvement (cutaneous, systemic, aggressive systemic)
Somatic clonal mutations may involve c-kit (D816V) of FIP1L1-PDGFRalpha
Clinical manifestations
Elevated serum tryptase
Acute myelogenous (non-lymphocytic) leukemia
AKA acute non-lymphoblastic leukemia
Increased myeloblasts in marrow (>20% needed for diagnosis but usually >50%)
AML more common in older people (60 median); more male
Clinical findings: fatigue, infection, bleeding, adenopathy, LUQ discomfort, leukostasis, rectal lesions, splenomegaly, lymphadenopathy, gingival hypertrophy, ecchymoses, neuro abnormalities, granulocytic sarcoma neutrophilic dermatosis, CHF
Lab findings: high WBC, blasts in peripheral blood, low hemoglobin, low platelets, high LDH, hypercellular marrow, marrow blasts >20%; possibly hyperuricenia, renal insufficiency, hypokalemia, hyper/hypocalcemia, CSF pleocytosis, coagulopathy, anergy
Possible causes of acute leukemias
Viruses (HTLV-1 with adult T-cell leukemia/lymphoma)
Drugs and radiation cause increased risk of leukemia (usually AML)
Cytotoxic chemotherapy or immunosuppression increases risk for leukemia
Genetic disorders with chromosomal instability (Klinefelter’s, Fanconi’s anemia, Down’s syndrome) increase risk for development of leukemia
Symptoms of acute leukemias
Result of failure of normal hematopoiesis: malaise, fever, infections, bleeding
Fever, pallor, petechiae, possibly hepatosplenomegaly, skin infiltrates or nervous system disease
Lab findings: hypercellular bone marrow with blast cells, blasts in peripheral blood but pancytopenia of mature blood elements
Histology and cytochemistry to use for AML
Use to distinguish different types of AML (from ALL too):
Wright’s stain
Peroxidase
Sudan Black B
Periodic acid (Schiff)
Esterases
Muramidase
Different types of AML
M1-7
Clinically distinct with unique drivers/mutations and maybe unique therapies
There are favorable and unfavorable genotypes
M1: deletion on 5 or 7 (bad prognisis); no differentiation
M2: deletion on Y; with differentiation
M3: acute promyelocytic leukemia (APL) with t(15;17) involving retinoic acid receptor-alpha binding protein
M4: trisomy 4 and trisomy 8 (good prognosis); acute myelomonocytic leukemia
M5: trisomy 8 (good prognosis); acute monocytic leukemia
M6: acute erythroid leukemia
M7: acute megakaryocytic leukemia
Acute promyelocytic leukemia
M3 type of AML
DIC
Distinct cytogenetic features = t(15;17) or t(11;17)
Distinct histological features = azurophilic granules, Auer rods
Distinct molecular features = PML (oncogene)-RARalpha
Treatment: all trans retinoic acid (which makes cells differentiate into neutrophil which die), arsenic trioxide, anthracycline-based chemotherapy (might not be used soon)
Chemotherapy stages
Induction: remission is induced by cytotoxic chemotherapy (this is hard for patient!)
Consolidation: sustains remission
Maintenance
Prognostic factors for remission and/or survival
Age
Prior radiation or chemotherapy
Karyotypic abnormalities, especially chromosomes 5 and 7
History of preleukemia
Gender
Leukocyte count at presentation
Acute lymphoblastic leukemia
Lymphoblasts of B cell type (null pre-pre B, Pre-B, B, and sometimes T cell)
Most common cancer in children
High N:C ratio
Characteristic pre-B cell markers: CD10 (CALLA), tDt (remember, this DNA enzyme induces hypervariability in immunoglobulin so tells you this cancer cell evolved early in development)
Sanctuary disease sites: CNS, testis
Treatment: survival only 3-6 month with no therapy but with maintenance antimetabolite therapy have >50% chance of 5 year survival; corticosteroids and vinca alkaloids, anthracycline antibiotics, L-asparaginase, CNS prophylaxis, cyclophosphamide
Distinct subtypes of ALL
Childhood ALL: L1 phenotype; CD10+, hyperdiploid
Adult ALL: L2 phenotype; 30% are Philadelphia chromosome +
Burkitt’s lymphoma/leukemia: L3 phenotype; c-myc juxtaposed to IgH or kappa or lambda; t(8;14) or t(2;8), t(8;22)
Do ALL and AML to the meninges/CNS?
ALL can enter spinal fluid since lymhpoid cells (B cells) go to meninges
AML cannot enter spinal fluid because myeloid cells don’t usually go to meninges
Graft vs. leukemia with bone marrow transplant
No single population of immune cells identified (CD4, CD6, NK) that does the attacking
Introduction of autologous graft vs. leukemia (interferons, interleukins)
Why do people with leukemia get back pain?
Back pain is bone pain and this is because expansion of marrow pushes on periosteum which is innervated and creates pain
Where can you get lymphomas?
Anywhere in the body that there is a lymphocyte, which is anywhere in the body!
Lymph nodes, spleen, bone marrow, thymus, Peyer’s patches, MALT, even extralymphatic sites because there are lymphocytes there!
However, most begin in lymph nodes (where there are most lymphocytes)
What does a benign, reactive lymph node look like?
Widely spaced irregularly shaped follicles with distinct darkly stained mantle zones and pale, expanded germinal centers
Follicles aren’t packed together, they’re respecting their neighbors
Normal parts of a lymph node
Paracortex has B cells in follicles and T cells in interfollicular zones
Medulla has T cells, plasma cells, histiocytes and B cells
Paracortical area has mostly T cells
Secondary follicle has mostly B cells
B cell markers
CD19
CD20
T cell markers
CD3
What are most common lymphomas derived from?
B cells which have passed through germinal centers of lymph nodes or spleed, where immunoglobulin genes complete diversification
Hodgkin’s Lymphoma
Usually begins in lymph nodes in neck or chest and then spreads to adjacent nodes then to liver, spleen and bone
Bimodal age distribution (20’s then 60’s) = “disease of young and old”
Slow, continguous progressive lymphadenopathy
Only a few malignant Reed-Sternberg cells amongst other inflammatory cells (this is different from other tumors)
First cancer found to be curable in advanced stages using combination chemotherapy
Reed-Sternberg cell
Malignant cell of Hodgkin’s disease
Large, binucleate or bilobed with 2 halves as mirror images with prominent nucleoli (owl’s eyes)
Transformed B cell, crippled by bad immunoglobulin gene rearrangements but rescued from apoptosis by multiple mutations/activations promoting cell growth and survival (NFkB or EBV!)
No B cell (CD20) or T cell (CD3) markers but do have CD15 and CD30
Subtypes of Hodgkin lymphoma
1) Nodular sclerosis Hodgkin lymphoma
2) Lymphocyte rich (predominant) classical Hodgkin lymphoma
3) Mixed cellularity Hodgkin lymphoma
4) Lymphocyte depleted Hodgkin lymphoma
[5) Nodular lymphocyte-predominant Hodgkin lymphoma]
Nodular sclerosis Hodgkin lymphoma
Most common (75%)
Partially nodular pattern with fibrous bands separating nodules
Rare RS cells often of the “lacunar” variant with partial cytoplasmic loss when fixed
Women > men
Primarily young adults
Excellent prognosis
Lymphocyte rich (predominant) Hodgkin lymphoma
5%
RS cells in background of predominantly lymphocytes, with rare or no eosinophils
May have nodular pattern without fibrosis
<35 year old males
Excellent prognosis
Mixed cellularity Hodgkin lymphoma
10%
More abundant RS cells and lymphocytes, epithelioid histiocytes, eosinophils and plasma cells
Intermediate prognosis
Lymphocyte depletion Hodgkin lymphoma
5% (rare)
Presence of fibrosis, necrosis and paucity of inflammatory cells
Large numbers of RS cells (25%), at times in sheets and bizarre forms
Older males with disseminated disease
Poor prognosis
Nodular lymphocyte predominant Hodgkin lymphoma
5%
Not a standard Hodgkin lymphoma, more like indolent non-Hodgkin lymphoma and that’s how it’s treated
Partially nodular growth pattern with many lymphocytes and distinct type of cells (L&H variants with popcorn shaped nucleus)
CD20+ (unlike other Hodgkin lymphomas!)
Clinical presentation of Hodgkin lymphoma
Painless adenopathy in neck or axilla
Systemic complaints (fever, fatigue, night sweats, weight loss, pruritus)
Chest symptoms from mediastinal mass (chest pressure, pain, dry cough) that can extend into lung parenchyma
Adenopathy with rubbery textured, firm, nodes (only tender if grew fast)
Pain and itching at tumor sites with alcohol ingestion
Hepatosplenomegaly in advanced cases
Most advanced: lung, bone marrow, destructive bony lesions
DDx of painless lymphadenopathy
Hodgkin/Non-Hodgkin lymphoma
Metastases from other primary tumors
EBV (mononucleosis)
Toxoplasmosis
Tuberculosis or atypical mycobacterial infection
Systemic lupus erythematosis
Drug reactions causing lymph node hyperplasia
Diagnosing Hodgkin lymphoma
Do excisional biopsy, not fine needle aspiration because need larger sample (only a few RS cells!)
Immunohistochemistry for CD3, CD15, CD20, CD30, kappa and lambda light chains
History of “B symptoms” (fatigue, night sweats, weight loss)
Physical exam: lymph nodes, tonsils, base of tongue (Waldeyer’s ring), spleen, liver, chest
Lab studies: CBC, differential count, platelets, ESR, LDH, hepatic panel, albumin, BUN, creatinine
Radiographs: CT of neck, chest, abdomen, pelvis; PET
Bone marrow biopsy (if advanced stage cytopenias present)
Fertility: pregnancy test, cryopreservation of semen
Ann Arbor Staging System for Hodgkin and Non-Hodgkin lymphoma
Stage I: involvement of a single lymph node (I) or involvement of a single extralymphatic organ or site (IE; spleen, thymus, Waldeyer’s ring)
Stage II: involvement of two or more lymph node regions on the same side of the diaphragm alone (II) or with involvement of limited contiguous extralymphatic organ or tissue (IIE)
Stage III: involvement of lymph node regions on both sides of the diaphragm (III) which may include spleen (IIIS) and/or limited contiguous
Stage IV: multiple or disseminated foci of involvement of one or more extralymphatic organs or tissues with or without lymphatic involvement
A: asymptomatic
B: fevers > 38 C, drenching night sweats, loss >10% body weight
Bad prognostic factors affecting outcomes in Hodgkin lymphoma (international prognostic score; IPS)
IPS is 1 point per adverse factor:
Male
>45
Stage IV
Anemia (<10.5)
Elevated WBC (>15 x 109)
Low lymphocytes (<0.6 x 109 or <8% of WBC diff)
Low serum albumin (<4)
How does Hodgkin lymphoma cause its effects?
Affects inflammation locally and at a distance: attracts eosinophils, neutrophils, mast cells, fibroblasts (to lay down fibrous stroma causing nodular sclerosis)
Attracts lymphocytes (T cells) and then inactivates them via PDL1/PD1 (this is why patients are immunosuppressed)
Chemokines and cytokines at a distance mess up function of the liver, cause anemia even if bone marrow not infiltrated
What does blocking PD1 do?
Causes regression of solid tumors of Hodgkins lymphoma
Causes strong immune response against tumor cells because tumor cells express PD1 which dampens the immune response (normally on APCs) to allow RS cells to “hide” from immune system
Treatment for Hodgkin lymphoma
Early stage disease (Stages I-IIA): 4 cycles of ABVD chemotherapy + involved field radiation
Advanced stage disease (Stages IIB-IV): 6-8 cycles of ABVD; or BEACOPP for high-risk cases (IPS>4) which adds etoposide (topoisomerase inhibitor), cyclophosphamide (alkylator), oncovin, procarbazine (alkylator), prednisone (corticosteroid)
Relapsed/refractory disease: “salvage” chemotherapy and autologous or allogenic stem cell transplantation; can be curative in 25-50%
ABVD chemotherapy
Adriamycin: anti-tumor antibiotic, anthracycline, causes DNA strand breaks
Bleomycin: anti-tumor antibiotic, can cause pulmonary toxicity
Vinblastine: vinca alkaloid, microtubule inhibitor
Dacarbazine: alkylating agent
What is the overall cure rate for Hodgkin lymphoma?
85% of everyone
What’s the problem with treating Hodgkin lymphoma too aggressively?
Too much radiation causes secondary malignancy (leukemia, lung cancer, breast cancer)
We want to give just enough treatment to cure
Non-Hodgkin lymphomas
8x as common as Hodgkin lymphoma
Youngest median age of all common cancers (42 years)
Fatal in many cases, but about half can be cured with modern chemotherapy and anti-CD20 antibody therapy
More than 30 sub-types (includes B cell, T cell and NK cell mature (peripheral) neoplasms)
Ways that Non-Hodgkin lymphomas are classified and named
1) Appearance of nodal architecture
2) Appearance of cells; what they look like compared to cells in normal lymphoid tissue compartments; stage of differentiation
3) Immunophenotype (B cell, T cell, NK cell)
4) Anatomic location where they arise and reside
Why do we get non-Hodgkin lymphoma?
When rearranging immunoglobulin DNA (rearrangements and hypermutations) we can make mistakes that cause non-Hodgkin lymphoma
Immunoglobulin promoter/enhancer elements brought next to genes controlling cell growth
Faulty translocations activate proto-oncogenes
Proto-oncogenes activated by faulty translocations causing non-Hodgkins lymphoma
1) Transcription factors: c-myc in Burkitt’s lymphoma; bcl-6 in diffuse large B cell lymphoma
2) Cell cycle regulators: cyclin D1 in mantle cell lymphoma
3) Anti-apoptotic proteins: bcl-2 in Follicular lymphoma
Mutations involved in Burkitt’s lymphoma
Translocation of heavy chain IgH on chromosome 14 in front of c-myc on chromosome 8 = t(8;14)
Or could be lambda light chain from chromosome 22 = t(8;22)
Or could be kappa light chain from chromosome 2 = t(8;2)
Rapidly growing tumor
Clinical features of non-Hodgkins lymphoma
Painless enlargement/lump, sweats, fatigue
Aggressive: (ex: diffuse large B cell lymphoma) rapid growth, maybe pain, extranodal site (lung, kidney, stomach, bones), acute illness, impaired functional status
Indolent: (ex: follicular lymphoma, small lymphocytic lymphoma, marginal zone lymphoma) slow insidius growth, often asymptomatic, usually limited to nodal sites, cytopenias from bone marrow involvement is common
Prognosis/outcomes in aggressive vs. indolent non-Hodgkin lymphoma
Aggressive: curable in half of cases, or death within 1-3 years
Indolent: responds to therapy initially but nearly always recurs, so “incurable” but average survival ~13 years
International prognostic index (IPI) for DLBCL non-Hodgkins lymphoma
Bad for prognosis:
Age > 60
LDH > normal
Performance status >/= 2
Ann Arbor stage III or IV
Extranodal involvement > 1 site (not independent predictor in age <60)
Note: number of points here can predict survival time
Diffuse large B cell lymphoma
Most common subtype of non-Hodgkin lymphoma (34%)
60% present with nodes only; 40% have extranodal involvement
Cells are large, have open chromatin pattern
CD20+ in virtually all cases
Half cured by R-CHOP; recurrent cases treated with autologous stem cell transplantation
Gene expression profiling defines distinct biologic and prognostic categories
Gene expression profiling for Diffuse Large B cell Lymphoma
Did gene expression study and found that DLBCL fell into 2 subtypes: germinal center type and activated B cell type
Germinal center type had better outcome
Don’t routinely do whole genome study for patients, but can look at a few markers to decide what category they fall into and change treatment (aggressive therapy vs. rituximab-CHOP)
Follicular lymphoma
Indolent non-Hodgkin lymphoma
Asymptomatic at diagnosis, grows slowly
CD20+ in virtually all cases
Highly responsive to rituximab anti CD20 antibody therapy
Despite good response to initial therapy, usually “incurable” median survival 13+ years
Approximately 25% experience “transformation” to higher grade lymphoma with poor prognosis
Follicular lymphoma International Prognostic Index (FLIPI)
Poor prognisis if:
Age >60
Ann Arbor stage III, IV
Hemoglobin level <12
Serum LDH level >ULN
Nodal sites > 5
Note: number of factors predicts risk group
Marginal zone lymphoma
3rd most common non-Hodgkin lymphoma
Indolent, slow-growing, asymptomatic at diagnosis, good prognosis
Small to medium-sized cells that infiltrate around “marginal zone” of reactive B cell follicles
“Triple negative” lymphoma because CD5, 10, 23 negative
CD20+ and highly responsive to rituximab anti-CD20 antibody therapy
Gastric MALT lymphoma (driven by cytokines released during H. pylori infection –> promote B cell proliferation and survival –> MALT lymphoma –> treat H. pylori infection –> lymphoma goes away!)
Other MALT sites: salivary glands, lung, head and neck, conjunctiva, skin, thyroid, breast
Small lymphocytic lymphoma
Only 6% of non-Hodgkin lymphomas
Nodal/solid tumor counterpart to chronic lymphocytic leukemia (CLL)
CD20 low, CD5+, CD23+
Typically widespread involvement of nodes, liver, spleen, bone marrow, peripheral blood
Treated with rituximab anti CD20 antibody but less responsive than follicular lymphoma
Richter’s transformation in approximately 5% (survival less than 1 year)
Mantle cell lymphoma
6% of non-Hodgkin lymphoma cases
Cells resemble normal mantle zone B cells that surround germinal centers (small, monotonous, are CD20+, CD5+, CD23-)
Characteristic t(11;14) Ig heavy chain gene translocation activates cyclin D1 oncogene which promotes cell cycle progression
Often involves extranodal sites: bone marrow, spleen, liver, GI tract; lymphomatous polyposis (submucosal nodules on colon)
5 year survival is 50%, but improved with new therapies
Burkitt’s lymphoma
Only 3% of non-Hodgkin lymphoma cases
Driven by Ig/c-myc oncogene chromosomal translocation: t(8;14) or others
High-grade, very rapid growth
Cells medium-sized, diffuse, monotonous with numerous mitoses and infiltrating macrophages giving “starry sky” pattery at low power
sIgM+, CD20+, CD10+
Endemic form from Africa, in jaw and EBV+
Sporadic form from North America, extranodal/abdominal mass and only 30% are EBV+
Presents in young patients or HIV+
Requires immediate hospitalization and chemotherapy, including intrathecal methotrexate
Treatment often complicated by tumor lysis syndrome (hyperuricemia, uric acid nephropathy, hyperkalemia, hyperphosphatemia, hypocalcemia
3 year overall survival 50%
T cell lymphomas (includes NK cell cases)
11% of non-Hodgkin lymphoma cases
Over 20 different subtypes
Most are CD3, 4, 5+
Tend to be more aggressive with extranodal involvement and poorer survival than B cell non-Hodgkin lymphomas
Most are cutaneous T cell lymphomas (CTCL)
Ex: mycosis fungoides (MF)/Sezary syndrome (leukemic phase, when cells get into blood)
Mycosis fungoides/Sezary syndrome
Type of T cell lymphoma
Diffuse erythroderma because cells spread out and home to skin and cause itchy flaky skin
Form mushroom-like tumors
Sezary syndrome is just the point where the cells get to the blood, so you have diffuse erythroderma PLUS 20% of lymphocytes are sezary cells (have cerebreform/brain-like nuclei)
CHOP treatment for non-Hodgkin lymphoma
Cyclophosphamide (DNA alkylating agent)
Doxorubicin (Hydroxydaunomycin; DNA strand breaks)
Vincristine (Oncovin; disrupts microtubules and mitosis)
Prednisone (corticosteroid; pro-apoptotic to lymphocytes)
How have we changed CHOP treatment in the past few decades?
We added anti-CD20 Rituximab to CHOP therapy
Made treatment much better
What is the idea behind using drug combinations for treatment?
Agents with different mechanisms of action but non-overlapping toxicities
CHOP is an example
Rituximab (Rituxan)
Genetically engineered chimeric murine/human antibody (IgG1)
Binds the CD20 antigen on surface of normal and malignant B cells
First FDA-approved monoclonal antibody for treatment of cancer
Minimal toxicity
50% have remission that lasts at least 1 year
Giving rituximab with CHOP chemotherapy was very good
R-CHOP
Rituximab plus CHOP
Standard therapy for non-Hodgkin lymphoma
Other than lymphoma, what can rituximab be used for?
Kills B cells, so can be used in autoimmune diseases that are the result of over-active B cells (antibody-mediated auto-immune diseases: ITP, hemolytic anemia, RA, SLE, pemphigus, cryoglobulinemia, organ transplantation)
However, sometimes the auto-antibodies are so well established that rituximab doesn’t work that well
Most important in vivo mechanism we have against lymphomas
Antibody-dependent cellular cytotoxicity (ADCC): antibody binds tumor cell, then binds Fc portion on NK cell and NK cell carries out perforin-granzyme-mediated lysis of tumor cell
Some apoptosis and antiproliferation and complement-mediated cytotoxicity used to kill tumor cells, but these are just minor mechanisms
T cell immunity probably not involved in killing lymphoma tumor cells
Note: ritubimab uses ADCC because is an antibody that binds tumor cell and then the NK cell to cause perforin-granzyme-mediated lysis of tumor cell
Treatment for non-Hodgkin lymphomas
Follicular lymphoma 1st line: watch and wait, rituximab, R-CVP, R-bendamustine, R-fludarabine
Follicular lymphoma 2nd line: one of above, radioimmunotherapy (Zevalin, Bexxar), R-CHOP
Follicular lymphoma 3rd, 4th line: one of above, investigational agents, salvage regimen, autologous or allogenic stem cell transplant
DLBCL 1st line: R-CHOP, R-EPOCH (high-risk), CODOX-M/IVAC (for c-myc translocation in Burkitt’s)
DLBCL relapse/2nd line: R-ICE, R-ESHAP, R-EPOCH, Gemzar/navelbine, oxaliplatin (if respond, autologous transplantation; if no response or BM+ consider allogenic transplant), investigational agents
Autologous stem cell transplantation
Used to treat recurrent aggressive lymphomas after failure of R-CHOP
1) Collect stem cells from patients bone marrow or blood when they are in remission
2) Cryopreserve stem cells
3) Give patient very high dose chemotherapy to try to kill cancer cells
4) Reinfuse thawed stem cells into patient, and they populate empty bone marrow to regenerate blood and immune cells
What are new drugs for non-Hodgkin lymphoma targeting?
Tyrosine kinases that are active in cancerous B cells
CAL-101 is a new drug that inhibits PI3 kinase delta
Summary of therapies for aggressive vs. indolent B cell non-Hodgkin lymphomas
Aggressive: rituximab+CHOP, stem cell transplant, investigational
Indolent: rituximab alone, rituximab+bendamustine, soon PI3 kinase delta/Btk inhibitors
Multiple Myeloma
Multifocal neoplastic proliferation of plasma cells (clonal)
Crowding out of normal marrow cells causes pancytopenia, anemia, infections (with encapsulated bacteria if asplenic), bleeding
(Don’t need to know this but also the plasma cells produce IL-6 which causes anemia of chronic disease)
Bone lesions are “punched out” (tumor causes bone resorption by growing but also making IL-1 and other bone resorbing factors)
Increased cell turnover (uric acid and calcium phosphate deposits)
At least one CRAB end-organ manifestation
Criteria for diagnosis of MM
Monoclonal plasma cells in bone marrow
Monoclonal protein present in serum and/or urine
At least 1 CRAB organ dysfunction (calcium increase, renal insufficiency, anemia, bone lesions)
Lab findings in multiple myeloma
Elevated serum protein (+/- hyperviscosity)
Hyperglobulinemia (but effective hypoglobulinemia and increased infections)
Monoclonal spike on SPEP and IEP
Rouleaux formation of RBCs on smear (Ig stacks on RBCs, no more negative charge to repel each other)
Ig coats coagulation factors (get excess bleeding)
Excess light chains in urine and serum (Bence Jones protein) may cause renal failure and amyloidosis
Different types of multiple myeloma
IgG: most common, classical findings
IgM: hyperviscosity; usually Waldenstrom’s Macroglobulinemia which is NOT multiple myeloma
IgA: may have flame cells (secretory part)
IgD: may not detect globulin on routine protein electrophoresis so need to do immune electrophoresis with IgD (rare)
IgE: may present with plasma cell leukemia (very rare)
Light chain only: usually missed on serum electrophoresis so need to do urine protein electrophoresis and light chain typing to see monoclonal light chain
Null chain: no production or secretion of abnormal antibody but have neoplastic proliferation of plasma cells in marrow (usually hypogammaglobulinemic)
Plasmacytoma
Isolated collection of plasma cells, plasma cell tumor
(NOT multiple myeloma)
Plasma cell leukemia
Neoplastic plasma cells in the blood
M protein
M protein = paraprotein = immunoglobulin that is over-produced by plasma cells of multiple myeloma
Found in serum or urine or both at time of diagnosis in 97% of patients
Amount of M protein correlates with number of malignant cells in the body
Serum protein electrophoresis
Test done to investigate multiple myeloma
Can determine amount of M protein (paraprotein, immunoglobulin) in blood
With MM, have spike at m, and no broad gamma peak like usual
Clinical findings in multiple myeloma
Pathologic fractures
Pancytopenias
Increased infection
Renal failure
Hyperviscosity
Why do you get more infections with multiple myeloma?
Lack of effective antibodies (only 1 kind made!)
Decreased opsonization
Neutropenia from marrow myeloma
Chemotherapy (steroids, neutropenia)
Why do you get renal failure in multiple myeloma?
Myeloma kidney: light chains inhibit renal tubular function (Bence Jones protein)
Amyloidosis (light chain deposits)
Uric acid and calcium deposits
Renal infiltrates by plasma cells
Infections (?)
Therapies for multiple myeloma
Bisphosphonates
Immunomodulatory drugs (thalidomide, lenalidomide)
Proteosome inhibitors
Others (HSP90 inhibitors, histone deacetylase inhibitors, anti-IL6 monoclonal antibodies)
Waldenstroms Macroglobulinemia
Lymphoid-plasmacytoid cells (look like combo between plasma cell and lymphocyte) in bone marrow and/or blood that clonally produce IgM pentamers
Hyperviscosity (large amounts of IgM pentamer in plasma): fatigue, malaise, SOB, neuro symptoms, bleeding, headache, vision
No bone lesions
NOT multiple myeloma
Top 5 cancer types in men and women
Men: prostate, lung/bronchus, colon/rectum, urinary bladder, melanoma of skin
Females: breast, lung/bronchus, colon/rectum, uterine corpus, thyroid
Top 5 types of cancer killers in men and women
Men: lung/bronchus, prostate, colon/rectum, pancreas, liver/intrahepatic bile duct
Women: lung/bronchus, breast, colon/rectum, pancreas, ovary
Which cancers do we screen for?
Established: colon, breast, cervical
Controversial, but supported by ACS: prostate
Not established: lung, ovarian
Screening for breast cancer
Self breast exam optional
Clinical breast exam every 3 years starting at age 20 and every year after age 40
Mammogram yearly after age 40
Women at high risk (>20% lifetime) should get yearly MRI and mammogram
Why shouldn’t younger women get mammograms?
Because younger women have dense breast tissue because of estrogen
Dense breast tissue can look like tumor on mammogram so get false positives
MRI for breast cancer screening
More sensitive than mammogram but less sepcific
Since more false positives, only want to do this on high risk patients because don’t want to do useless biopsies for confirmatory testing
Screening for colon cancer
Start at age 50
Yearly fecal occult blood and flex sig q5 years
Double contrast barium enema q5 years
Colonoscopy q10 years
If high risk (family hx, personal hx polyps, IBD), more frequent and may start younger
Screening for cervical cancer
Pap smears start yearly 3 years after vaginal intercourse and no later than 21yo
Yearly screening regular pap or q2 years with liquid based pap
Age 30 and 3 normal pap in a row, can screen q2-3 years or every 3 years if add HPV DNA test
If DES (diethylstilbestrol) exposure before birth, HIV, immunosuppression, continue annual screening
If 70+ yo with 3 normal paps in a row and no abnomal in last 10 years can stop screening
Prostate cancer screening
PSA blood test and digital rectal exam (DRE) yearly starting at age 50
High risk men (AA, family history) start screening at age 40-45
Discuss risks/benefits (limitations to testing) but should offer to patients
Do most people with cancer have a family history?
No, only 5-10% of cancers are familial
Familial cancers
Li Fraumeni (chk2, p53): sarcoma, breast, brain, leukemia
Cowden (PTEN): multiple hamartomas, breast, thyroid
BRCA1 (chrom 17): ovarian and breast; prostate/colon?
BRCA2 (chrom 13): breast (males), pancreatic
MEN I (chrom 11): pituitary, thymic, pancreatic islet cell
MEN II (chrom 10, RET): medullary thyroid, pheo
FAP/Gardner’s syndrome: colon
HNPCC/Lynch syndrome (chrom 3): colon, uterine, GBM?
Von Hippel Lindau (VHL): hemangiomas, renal cell
Ataxia-telangiectasia: lymphoma, gastric, brain, uterine, breast?
Environmental/industrial carcinogens
Arsenic: lung/skin
Asbestos: pleura, peritoneum, lung
Benzene: lymphoid tissue
Aminobiphenyl: bladder
Cadmium, Beryllium: lung
Hairdyes: bladder
Formaldehyde: nose/nasopharynx
Vinyl chloride: liver
Carcinogenic medical agents
Estrogens: endometrial/breast
Anabolic steroids: liver
Tamoxifen: endometrium
Melphalan: lymphoid tissue
Busulphan: bone marrow
Viruses associated with cancer
Kaposi’s sarcoma (HIV, HHV-8)
Non-Hodgkin lymphoma (EBV and HIB for Burkitt’s; HIV and HHV-8 for primary effusion lymphoma)
CNS lymphoma
Hodgkins lymphoma (EBV)
Nasopharyngeal carcinoma (EBV)
Cervical cancer (HPV 16, 18, 33, 39)
Liver cancer (Hep B and C)
H pylori (gastric lymphoma and cancer)
Adult T cell leukemia/lymphoma (HTLV-1)
Lifestyle factors that are carcinogens
Tobacco: lung, bladder, esophagus, mouth, larynx
Betel nut: oral cavity
Alcohol: esophagus, orla, pharynx, liver
UV radiation: melanoma, other skin cancer
Cancer staging
Cancer stage tells you degree of localization/spread
Helps determine prognosis (better than grade!) and thus treatment
Imaging modalities for staging: PET, CT (large mets and bleeds), MRI (catch more subtle findings), bone scan, ultrasound, plain X-rays
T (tumor size 1-4), N (regional lymph node involvement 0-3), M (metastases X,0,1)
Stage 0: Tis, N0, M0
Stage I: T1, N0, M0
Stage II: T0-2, N0-1, M0
Stage III: T0-3, N1-2, M0
Stage IV: anyT, anyN, M1
Tumor types not staged by TNM
Pediatric
Leukemia/lymphoma
CNS tumors
Factors that are important in treatment and prognosis other than stage
Grade and type of tumor
Presence of biomarkers, gene mutations, amplifications, deletions
Age of patient, other medical conditions
Clinical stage vs. pathologic stage
Clinical stage: PE and imaging (use little c); guides presurgical (“neoadjuvant”) chemotherapy choices
Pathologic stage: histologic examination of tissue (use little p); helps determine prognosis and guides whether patient should receive post-surgical (“adjuvant”) chemotherapy
Clinical exam might not identify pathologic disease
Treatment approaches
Surgery
Radiation: external beam, RFA, stereotactic radiosurgery/Gamma knife
Chemoembolization
Chemotherapy
Novel biological agents: immune therapy (interferon, vaccines, gene therapy), anti-angiogenesis, targeted agents (monoclonal antibodies, tyrosine kinase inhibitors)
Palliation
Judging response to therapy
Complete response (CR): disappearance of all lesions
Partial response (PR): >30% decrease from baseline (RECIST), >50% decrease from baseline (WHO)
Overall response rate (ORR): %PR + %CR
Progressive disease (PD): >20% increase over smallest sum observed or appearance of new lesions (RECIST), >25% increase in one or more lesions or appearance of new lesions
Stable disease (SD): neither PR nor PD criteria met
Oncologic emergencies
Superior vena cava syndrome
Spinal cord compression
Electrolyte disturbances (tumor lysis, low Na, high Ca, hyperuricemia, etc)
Cardiac tamponade (malignant effusion)
Venous thromboembolism
Febrile neutropenia
Spinal cord compression
Most commonly associated with prostate, breast, lung cancer (also renal cell, lymphoma and myeloma)
Most common and earliest symptom is pain (precedes neurological compromise by 7 weeks, worse lying down)
Motor weakness 60-85%
Sensory defects
Bowel/bladder incontinence or dysfunction (late sign)
Imaging (best is MRI, can also do CT myelogram)
Treatment: urgent surgical decompression and/or RT
New cancer drugs developed once we knew more about molecular underpinnings of cancer
ATRA: acute M3 leukemia (APL)
Gleevec: CML
Rituximab: non-Hodgkin lymphoma
Trastuzumab: Her2/neu + breast cancer
HER2 breast cancer
HER2 is overexpressed in 25% of breast cancers
HER2 is a protein on the surface of cancer cells
Functions: growth and proliferation, differentiation, cell survival, motility, angiogenesis
Trastuzumab (Herceptin)
Breast cancer drug that targets Her/neu protein expressed on surface of breast cancer cells
Is an anti-HER2 antibody that binds HER2 and kills cells that express it (possibly through ADCC, but also other mechanisms)
T-DM1 therapy for HER2 breast cancer
Trastuzumab with a very toxic chemical emtansine stably linked to it
Binds to HER2 using trastuzumab, then gets endocytosed and toxic emtansine is released into cell to kill it (inhibit MT polymerization, etc)
Things to think about if you see a solitary “spot” or “bump”
Melanoma
Basal Cell Carcinoma (BCC)
Squamous Cell Carcinoma (SCC)
Actinic Keratosis (AK)
Benign growths
Ephilides (freckles)
Lintigines
Nevi
Seborrheic keratoses
Acrochordons
Cherry angiomas
Dermatofibromas
Sebaceous hyperplasia
Keloids
Epidermal inclusion cysts
Milia
Lipomas
Actinic keratosis (AK)
Solar keratosis
Common cutaneous growth, seen in fair-skinned adults
Seen in sun-exposed areas
Potential to develop into squamous cell carcinoma (only <5% though)
Clinical features: rough, pink or tan scaly papules, 3-10mm, can become thicker or hyperkeratotic
Treatment: Cryotherapy, curettage, chemical peel, dermabrasion, topical chemo (5FU) or immunotherapy (imiquimod), photodynamic therapy
Basal cell carcinoma (BCC)
Most common malignancy in US
Areas of chronic sun exposure, lighter skin types
Can be locally destructive
Rare reports of metastasis but if leave alone for 10-20 years, will metastasize
General clinical presentation: telengectasias and blood vessels around nodule with round borders
Types: nodular BCC, pigmented BCC, superficial BCC
Pathogenesis: sporadic BCCs have mutations in p53 tumor suppressor gene; sporadic and hereditary have mutation in PTC tumor suppressor gene
Treatment: curettage, electrodissection, excision, Mohs micrographic surgery, radiation, cryotherapy, photodynamic therapy, topical 5FU or imiquimod, laser surgery
Different types of BCC
Nodular BCC: most common, usually on head and neck; firm, waxy papule or nodule, pearly border, can ulcerate, telangiectasias on surface
Pigmented BCC: common in asians, latinos, AAs; make melanin so brown or black and look a lot like melanoma; similar morphology as nodular BCC
Superficial BCC: scaly pink to red-brown patch, usually on trunk; can look like ecxema, psoriasis or Bowen’s disease, can ulcerate
Morpheaform or Sclerosing BCC: less common; poorly defined firm papules or plaque; scar-like appearance, usually not ulcerating; borders extend beyond what you can see
Squamous cell carcinoma (SCC)
Malignant skin tumor of keratinizing cells of epidermis or appendages
Second most common cutaneous malignancy
Metastatic potential
Risk factors: UV exposure, fair skin, radiation, arsenic, inflammation/burn scars, HPV, immunosuppression, history of actinic keratosis
Pathogenesis: defects in p53 tumor suppressor gene, 10-50% have mutation in RAS tumor oncogene
Treatment: excision, Mohs micrographic surgery, laser surgery, radiotherapy, cryotherapy, curettage and electrodessication, phototherapy, topical chemotherapy (5FU)
Types of SCC
SCC in-situ: Bowen’s disease, Erythroplasia of Queyrat
Keratoacanthoma
Verrucous carcinoma
High risk SCC tumors
Size >2cm
Recurrent
On ears, scalp, temple, lip
Histologic features: perineural invasion, poorly differentiated, increased depth of invasion
Melanocyte
Cell that produces pigment
Determines color of skin
They distribute melanosomes to keratinocytes; basal cells pick up melanin from melanocytes too
Derived from neural crest, migrate to skin (hair follicles), eye, inner ear, medulla oblongata
Normally located in basal layer of epidermis (1 for every 10 basal cells)
Everyone has same number, but melanocytes produce different numbers of melanosomes and that determines skin color
Diseases of defective melanocyte migration
Piebaldism (patches of white hair/skin)
Waardenburg’s syndrome (patches of white hair/skin, deafness, diff colored eyes, megacolon)
“Mongolian spots” = dermal melanocytosis (when dermal melanocytes don’t die like they’re supposed to and cause nevus of Ota on head and neck, blue nevi on distal extremities, presacral areas)
Oculocutaneous albinism
Defect in tyrosinase (produced by melanocytes and converts tyrosine to melanin)
Autosomal recessive
Normal number of melanocytes but no melanin
Get nystagmus, and white hair and light eyes
Vitiligo
Just a cosmetic problem
Acquired loss of melanocytes
Irregular patches of decreased pigment
Benign pigmented lesions
Flat lesions: ephelides (freckles), lentigines, cafe au lait macules, some nevi
Raised lesions: melanocytic nevi, congenital nevi, dysplastic nevi
Ephelides
Freckles
Normal number of melanocytes, increased melanin
Lentigo (lentigines)
Lentigo simplex if at birth
Solar lentigo (liver spots?) if from chronic sun exposure
Hyperpigmented macules and patches on skin or mucosa
May involve an increase in the number of melanocytes
Multiple lentigines can be marker for disease (Peutz-Jeghers Syndrome –> intestinal polyps and increased incidence of malignancies)
Cafe au lait macules
Seen in 10-20% of population
Often appear during early childhood
Smooth bordered, light to dark brown patch
Normal melanocyte density, increased melanin
No malignant potential
Multiple cafe au lait macules can be marker for disease (Neurofibromatosis type I)
Melanocytic nevus (“mole”)
May be flat or raised
Evenly pigmented (flesh to dark brown colored)
Even borders
Neoplastic collection of nested melanocytes
Hard to distinguish from seborrheic keratosis
Congenital nevus
Present at birth
Often larger than melanocytic nevi
Often have associated hair growth
Large or multiple congenital nevi may be associated with leptomeningeal involvement and resultant CNS defects
Large congenital nevi (>20cm) are associated with increased risk of melanoma
ABCDE of melanoma
Asymmetry
Border
Color
Diameter
Evolution
Dysplastic nevus
Clark’s or Atypical nevus
Melanoma can arise from dysplastic nevus (or de novo)
But dysplastic nevus is not necessarily a pre-cancer
Can be difficult to distinguish clinically and histologically from melanoma
Can be a marker for melanoma risk
Risk factors for melanoma
Intermittent high intensity UV exposure (history of sunburns)
>50 melanocytic nevi
Family or personal history of melanoma or dysplastic nevi
Giant congenital nevus
Lighter skin
DNA repair defects
Xeroderma pigmentosum
Autosomal recessive
Defective DNA repair
Numerous skin cancers at a young age
Genes involved in development of melanoma
BRAF mutations (80% of melanomas have activating mutation)
CDKN2A mutation (involved in regulating cell cycle; mutations can be familial)
Types of melanoma
Lentigo maligna and other melanomas in situ
Lentigo maligna melanoma
Superficial spreading melanoma
Nodular melanoma
Acral lentiginous melanoma
Lentigo maligna (a type of melanoma in situ)
Irregularly pigmented macule or patch (often fulfills ABCDEs)
Sun-exposed areas in elderly patients
Progresses to lentigo maligna melanoma in 2-5%
Thinned epidermis, solar elastotic changes in dermis
Proliferation of irregular and atypical melanocytes in epidermis
No invasion of atypical melanocytes into dermis
Lentigo maligna melanoma
5-15% of melanomas
Elderly patients with sun damaged skin
Identical to lentigo maligna but possesses vertical growth phase
Superficial spreading melanoma
Most common type of melanoma (60-70%)
Most frequently found on back in men and on legs in women
Fulfills ABCDEs
Nodular melanoma
Second most common type of melanoma (15-30%)
Rapidly developing nodule (may not satisfy ABCDs)
Can be ulcerated and bleed
Mostly in vertical growth phase
Acral lentiginous melanoma
Rarest type of melanoma (5-10%) but common in dark skinned patients
45% of melanomas in Asians
Occurs on palms and soles
Subungual melanoma
Variant of acral lentiginous melanoma
Can present as hyperpigmented streak on nail plate (longitudinal melanonychia)
Hutchinson’s sign: pigmentation of proximal nail fold
Amelanotic melanoma
Melanoma that stopped making melanin
Dangerous!
What determines prognosis of melanoma?
Breslow depth
Measured from stratum granulosum (down past epidermis)
Determines how likely it is to spread and what surgery they need
Note: Clark’s levels are NOT what determines prognosis
What do metastases tell you about prognosis?
Lymph node metastasis means 5 year survival is 66%
Extra-nodal metastasis means 5 year survival 10% (most often to lungs, liver, brain, or bone)
Management of melanoma
Surgical excision with margins dependent on thickness
Sentinel lymph node biopsy controversial but frequently done on tumors >1mm thickness
Elective lymph node dissection not performed routinely
Adjuvant or palliative chemotherapy (IFN-alpha, dacarbazine (DTIC) or temozolomide)
New treatments for melanoma
Ipilumimab: anti-CTLA4 antibody
Vemurafenib: B-RAF inhibitor
TLR agonists like imiquimod for lentigo maligna and cancer vaccines are experimental/off-label
Seborrheic keratoses
Very common
Waxy, scaly, greasy stuck on verrugous, papules to small plaques
Benign keratinocyte neoplasms
Everywhere except palms and soles
Sometimes become itchy/irritated or inflamed
Can look like nevi
Dermatofibroma
Common scar-like firm papules, mostly fibroblasts, often on limbs
Skin tag
Acrochodon
Two very common subcutaneous nodules
Lipoma: benign fat tumor; excise if symptomatic, patient worried or diagnosis unclear
Epidermoid cyst: “sebaceous cyst” or epiderman inclusion cyst (EIC); subcutaneous nodule with punctum; excise don’t drain; can ignore if diagnosis clear and patient unconcerned
Defining characteristics of marrow stem cell
1) Renewal capacity
2) Great proliferative and differentiative potential
3) Quiescent but easily induced into cell cycle
4) Capable of giving rise to variety of nonhematopoietic cells when microenvironment is altered
3 types of stem cell transplant
1) Autologous (own cells; just in order to be able to give high dose chemo then replace your bone marrow afterward)
2) Allogenic (someone elses; in order to give you a new immune system)
3) Syngenic (from identical twin)
Indications for stem cell transplantation
1) Restore hematopoiesis after myeloablative chemotherapy to intensify dose for chemotherapy responsive tumor (can use autologous tx)
2) Treat intrinsic bone marrow disorders (aplastic anemia, some metabolic genetic diseases)
3) Correction of immune defect (SCID)
4) Break tolerance to tumor by engraftment of donor immune system with graft versus tumor attack of malignancy
5) Break tolerance to autoimmune disease
6) Vehicle for gene therapy
7) Induce immune tolerance to permit solid organ transplantation
Conditions that can be treated with stem cell transplant
Leukemia/lymphoma: AML, ALL, CML, CLL, JMML, Hodgkin lymphoma, Non-hodgkin lymphoma
Multiple myeloma, amyloidosis
Marrow failure: aplastic anemia, Fanconi anemia
Immune deficiencies: SCID, Wiskott-Aldrich
Hemoglobinopathies: beta-thal major, sickle cell
Inherited metabolic syndromes: Hurler syndrome, adrenoleukodystrophy
Myelodysplastic syndromes: refractory anemias, CMML, IMF
Graft versus tumor effect
Donor cells attack recipient’s tumor
May be mediated by donor T cells attacking minor histocompatibility antigens (MHAs) on recipient tumor cells
CML has good GVT effect but ALL does not
Where does graft versus host disease occur?
Acute GVHD in skin, gut, liver
Brentuximab Vedotin
AKA Adcetris
Anti CD30 antibody
Drug used for Hodgkin lymphoma
Antibody is linked to MMAE which is a potent antitubulin agent
Ibritumomab
AKA Zevalin
First radio-immunotherapy treatment approved by FDA
CD20 antibody linked to radionucleotide that emits beta radiation
Approved for relapsed/refractory low grade follicular or transformed B cell non-Hodgkin lymphoma
Genetic changes leading to cancer
Oncogenes
Tumor suppressor genes
DNA hypomethylation
Remember, multi-step process
Infectious agents in carcinogenesis
HPV
EBV
HTVL1
HIV
Hep B and C
HHV8
H. pyori
Therapeutic targets of antineoplastic therapy
Cell differentiation (ex: all-trans retinoic acid or arsenic trioxide in PML)
Cell proliferation (ex: block cell division with antimetabolite, induce dormancy)
Cell death
Vascular proliferation
Unique molecular targets (“rational drug design”)
Sanctuary site
Chemotherapy from IV does not get to these sites
CNS, testes, ovary
Terminology of antineoplastic therapy
Adjuvant: given when you don’t see disease but hope to get rid of it (like consolidation in leukemia)
Neoadjuvant: give before definitive resection and radiation (cosmetically don’t want to remove huge tumor)
Salvage: attempt to alleviate, but probably not saving patient’s life?
Induction: induce remission–get as low cancer cell count as possible
Consolidation: keep giving chemo after induction even if don’t see the disease in order to hopefully get rid of it
Maintenance: maintain low level of cancer cells
Diseases for which chemotherapy is given with curative intent
Gestational trophoblastic disease, testicular cancer, Hodgkins lymphoma, diffuse large B cell lymphoma, Burkitt’s lymphoma, ALL, AML, pediatric tumors (Wilms, neuroblastoma, osteosarcoma), breast cancer
Diseases for which chemotherapy is given to prolong life or palliate symptoms
Small cell lung cancer, indolent lymphoma and CLL, metastatic carcinoma, endometrial carcinoma, Kaposi’s sarcoma, multiple myeloma, bladder cancer, mycosis fungoides, hairy cell leukemia, malignant melanoma
DIseases for which chemotherapy is not given
Adenocarcinoma of stomach, pancreas, liver, bile ducts, thyroid
Carcinomas of unknown primary origin
Alkylating agents as antineoplastic drugs
Highly reactive compounds with ability to add alkyl groups (carbon chains) to DNA (attack the nitrogen) –> breaks in DNA molecule or crosslinks DNA strands –> interferes with DNA replication
“Nitrogen mustard”
Cyclophosphamide, ifosfamide
Busulfan
Nitrosureas
Cisplatin, carboplatin
Toxicities: hair loss, nausea, vomiting, mouth ulcers
Specific toxicities of some alkylating agents
Cyclophosphamide, ifosfamide: hemorrhagic cystitis
Busulfan: pulmonary toxicity (all “B” drugs!)
Cisplatin: ototoxicity, nephrotoxicity
Carboplatin: myelosuppression
Antineoplastic antibiotics
Derived from soil fungus Streptomyces
Mechanisms: intercalate DNA to uncoil helix, form free radicals, chelate important metal ions, inhibit topoisomerase –> all decrease DNA replication/cell division
Dactinomycin
Doxorubicin, daunorubicin
Bleomycin
Etoposide, teniposide
Idarubicin, mitoxatrone, mitomycin C
Toxicities: cardiotoxicity, alopecia, myelosuppression, pulmonary (for B drugs)
Microtubule inhibitors
Vinca alkaloids: vincristine, vinblastine
Taxanes (from Yew tree): paclitaxel (Taxol), docetaxel (Taxotere)
Specific toxicities of microtubule inhibitors
Vincristine: neurotoxicity (areflexia, peripheral neuritis (because neurons are longest MTs in the body!)), paralytic ileus
Vinblastine: bone marrow suppression (blasts bone marrow)
Specific toxicities of epipodophyllotoxins
Remember, these are topoisomerase II inhibitors (etoposide, teniposide)
Myelosuppression, GI irritation, alopecia
Can induce acute lymphoblastic leukemia (ALL)!
Camptothecins
Inhibit topoisomerase
Topotecan, irinotecan
Toxicities: myelosuppression, cholergic
Antimetabolites as antineoplastic drugs
Structural analogues of normal metabolites that are required for cell function and replication
Interact with cellular enzymes:
1) Substitution for a normal metabolite in key molecule making molecule function abnormally
2) Competition for active site to occupy/block active site of key enzyme
3) Competition at allosteric stie to alter catelytic rate of a key enzyme
Examples: methotrexate, 5-FU, 6-MP, 6-TG, ara-C
Methotrexate (MTX)
Folic acid analog that inhibits dihydrofolate reductase to decrease dTMP and DNA and protein synthesis
Rescue molecule leucovorin (analog of fully reduced folate) is absorbed by all cells except cancer cells (yay!)
Toxicities: myelosuppression (reversible with leucovorin rescue), fatty liger, mucositis, teratogenic, pulmonary
5-fluorouracil
Pyrimidine analog bioactivated to 5F-dUMP which inhibits thymidylate synthetase to decrease dTMP, DNA and protein synthesis
Uses: colon cancer
Toxicities: myelosuppression (rescue with thymidine), photosensitivity, GI and mucosal, hand-foot syndrome
Related drugs: FUDR, capecitabine
Note: can be used synergystically with MTX
Other antimetabolites
Gemcitabine
Cytarabine: pyrimidine antagonist to inhibit DNA; used for AML, ALL, non-Hodgkin lymphoma
6 mercaptopurine: purine (adenine) analog used for leukemia and lymphoma (not CLL or Hodgkin)
6 thioguanine: purine (guanine) analog used for ALL
Allopurinol: xanthine oxidase inhibitor for gout (not anticancer!)
Purine nucleoside analogues that operate on ribonucleotide reductase and adenosine deaminase
Fludarabine: inhibits ribonucleotide reductase and DNA polymerase alpha
Pentostatin: inhibits adenosine deaminase
Cladribine: causes DNA strand breaks and apoptosis
Potent marrow suppressants and immunosuppressants
Hormonal agents for antineoplastic agents
Appear to function by interacting and binding to specific receptors on cell membrane, in cytoplasm on in nucleus of target cell –> structural rearrangement –> bind to DNA –> not fully understood, but involve receptor transformation/activation, altering autocrine/paracrine survival mechanisms of cancer cells
Ex: tamoxifen, megestrol acetate, prednisone, dexamethasone, leuprolide and goserelin, arimidex, octreotide acetate
Tamoxifen
Multiple mechanisms of action
Liver biotransformation
SERM (selective estrogen receptor modulator): antagonist in breast and agonist in bone
Favorable side effect: prevent osteoporosis, prevent breast cancer?
Toxicity: may increase the risk of endometrial cancer, hot flashes
Corticosteroids
Complex mechanisms of intracellular activities
Lymphocytolytic
Potently immunosuppressive (duh)
Side effects: glucose intolerance (hyperglycemia), osteoporosis, opportunistic infection, fluid retention, fat redistribution, psychiatric
Antiandrogens
Direct: flutamide, bicalutamide
Indirect: LHRH/GnRH agonists (leuprolide, goserelin)
Aromatase inhibitors
Aminoglutethimide
Arimidex
All-trans retinoic acid
AKA Tretinoin, ATRA
Used to treat acute promyelocytic leukemia (APL; t(15;17) creates PML-RARalpha transgene and chimeric protein)
ATRA binds RARalpha and degrades this abnormal receptor, which induces differentiation of myeloblasts to neutrophils
May cause differentiation syndrome (huge increase in neutrophils)
High likelihood of long-term leukemia-free survival with this
Imatinib (Gleevec)
Tyrosine kinase inhibitor that acts specifically on the Philadelphia chromosome bcr-abl tyrosine kinase that is constitutively active
Used to treat CML (obvi)
EGFR inhibitors
Small molecular inhibitors: gefitinib and erlotinib in lung cancer
Monoclonal antibodies: cetuximab and panitumumab in colon cancer
ErbB2 (Her2neu) inhibitors: trastuzumab and lapatinib
Conjugated antibodies
Radioimmunoconjugates: tositumomab and Iodine I 131 Tositumomab; Ibritumomab tiuxetan
