Quiz #2 - Malignant Heme Flashcards

Question

Essential thrombocythemia

Answer 1

Characterized by massive proliferation of megakaryocytes and platelets. Symptoms include bleeding and thrombosis. Blood smear shows markedly increased number of platelets, which may be large or otherwise abnormally formed B. Erythromelalgia may occur.

Answer 2

Obliteration of bone marrow with fibrosis due to increased fibroblast activity. Often associated with massive splenomegaly and “teardrop” RBCs . “Bone marrow is crying because it’s fibrosed and is a dry tap.”

Answer 3

t(8;14) Burkitt (Burk-8) lymphoma (c-myc activation) t(9;22) (Philadelphia chromosome) CML (BCR-ABL hybrid), ALL (less common, poor prognostic factor) Philadelphia CreaML cheese. The Ig heavy chain genes on chromosome 14 are constitutively expressed. When other genes (eg, c-myc and BCL-2) are translocated next to this heavy chain gene region, they are overexpressed. t(11;14) --> Mantle cell lymphoma (cyclin D1 activation) t(14;18) --> Follicular lymphoma (BCL-2 activation) t(15;17) --> APL (M3 type of AML) Responds to all-trans retinoic acid.

Answer 4

Collective group of proliferative disorders of dendritic (Langerhans) cells. Presents in a child as lytic bone lesions and skin rash or as recurrent otitis media with a mass involving the mastoid bone. Cells are functionally immature and do not effectively stimulate primary T cells via antigen presentation. Cells express S-100 (mesodermal origin) and CD1a. Birbeck granules (“tennis rackets” or rod shaped on EM) are characteristic B.

Answer 5

Oncologic emergency triggered by massive tumor cell lysis, most often in lymphomas/leukemias. Release of K+--> hyperkalemia, release of PO43– --> hyperphosphatemia, hypocalcemia due to Ca2+ sequestration by PO43–. increased nucleic acid breakdown --> hyperuricemia --> acute kidney injury. Prevention and treatment include aggressive hydration, allopurinol, rasburicase.

Answer 6

all act on S phase --> DNA synthesis Azathioprine, 6-mercaptopurine - mach: Purine (thiol) analogs --> decrease de novo purine synthesis. Activated by HGPRT. Azathioprine is metabolized into 6-MP. - use: Preventing organ rejection, rheumatoid arthritis, IBD, SLE; used to wean patients off steroids in chronic disease and to treat steroid-refractory chronic disease. - AEs: Myelosuppression; GI, liver toxicity. Azathioprine and 6-MP are metabolized by xanthine oxidase; thus both have increased toxicity with allopurinol or febuxostat. Cladribine - mech: Purine analog --> multiple mechanisms (eg, inhibition of DNA polymerase, DNA strand breaks). - used in Hairy cell leukemia. Myelosuppression, nephrotoxicity, and neurotoxicity. Cytarabine (arabinofuranosyl cytidine) - mech: Pyrimidine analog --> DNA chain termination. At higher concentrations, inhibits DNA polymerase. Use: Leukemias (AML), lymphomas. AEs: Myelosuppression with megaloblastic anemia. CYTarabine causes panCYTopenia.

Answer 7

5-fluorouracil - mech: Pyrimidine analog bioactivated to 5-FdUMP, which covalently complexes with thymidylate synthase and folic acid. Capecitabine is a prodrug with similar activity. This complex inhibits thymidylate synthase ---> decresed dTMP --> decreased DNA synthesis. - Use: Colon cancer, pancreatic cancer, actinic keratosis, basal cell carcinoma (topical). Effects enhanced with the addition of leucovorin. - AEs: Myelosuppression, palmarplantar erythrodysesthesia (hand-foot syndrome). Methotrexate - mech: Folic acid analog that competitively inhibits dihydrofolate reductase --> decreased dTMP --> decreased DNA synthesis. - use: Cancers: leukemias (ALL), lymphomas, choriocarcinoma, sarcomas. Non-neoplastic: ectopic pregnancy, medical abortion (with misoprostol), rheumatoid arthritis, psoriasis, IBD, vasculitis. - AEs: Myelosuppression, which is reversible with leucovorin “rescue.” Hepatotoxicity. Mucositis (eg, mouth ulcers). Pulmonary fibrosis. Folate deficiency, which may be teratogenic (neural tube defects) without supplementation. Nephrotoxicity (rare).

Answer 8

Bleomycin - Induces free radical formation --> breaks in DNA strands. - use: Testicular cancer, Hodgkin lymphoma. - AEs: Pulmonary fibrosis, skin hyperpigmentation. Minimal myelosuppression. G2 phase: blocks double check repair Dactinomycin (actinomycin D) - Intercalates into DNA, preventing RNA synthesis. - Use: Wilms tumor, Ewing sarcoma, rhabdomyosarcoma. Used for childhood tumors. - AEs: Myelosuppression. Doxorubicin, daunorubicin - Generate free radicals. Intercalate in DNA --> breaks in DNA --> decreased replication. Interferes with topoisomerase II enzyme. - Use: Solid tumors, leukemias, lymphomas. - AEs: Cardiotoxicity (dilated cardiomyopathy), myelosuppression, alopecia. Dexrazoxane (iron chelating agent), used to prevent cardiotoxicity.

Answer 9

Busulfan - Cross-links DNA. Used to ablate patient’s bone marrow before bone marrow transplantation. - Severe myelosuppression (in almost all cases), pulmonary fibrosis, hyperpigmentation. Cyclophosphamide, ifosfamide - Cross-link DNA at guanine. Require bioactivation by liver. A nitrogen mustard. - Solid tumors, leukemia, lymphomas. - Myelosuppression; SIADH; hemorrhagic cystitis, prevented with mesna (thiol group of mesna binds toxic metabolites) or adequate hydration. Nitrosoureas - Require bioactivation. Cross blood-brain barrier --> CNS. Cross-link DNA. - Brain tumors (including glioblastoma multiforme). - CNS toxicity (convulsions, dizziness, ataxia). Procarbazine - Cell cycle phase–nonspecific alkylating agent, mechanism not yet defined. - Hodgkin lymphoma, brain tumors. - Bone marrow suppression, pulmonary toxicity, leukemia.

Answer 10

Paclitaxel, other taxanes Hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down (anaphase cannot occur). Ovarian and breast carcinomas. Myelosuppression, neuropathy, hypersensitivity. Taxes stabilize society. Vincristine, vinblastine - Vinca alkaloids that bind β-tubulin and inhibit its polymerization into microtubules --> prevent mitotic spindle formation (M-phase arrest). - Solid tumors, leukemias, Hodgkin (vinblastine) and non-Hodgkin (vincristine) lymphomas. Vincristine: neurotoxicity (areflexia, peripheral neuritis), constipation (including paralytic ileus). Crisps the nerves. Vinblastine: bone marrow suppression. Blasts the bone marrow.

Answer 11

Cisplatin, carboplatin - mecHanism Cross-link DNA. clinical -Use Testicular, bladder, ovary, and lung carcinomas. adVeRse eFFects Nephrotoxicity, peripheral neuropathy, ototoxicity. Prevent nephrotoxicity with amifostine (free radical scavenger) and chloride (saline) diuresis. Etoposide, teniposide - mecHanism Inhibit topoisomerase II --> increased DNA degradation. - clinical Use Solid tumors (particularly testicular and small cell lung cancer), leukemias, lymphomas. - adVeRse eFFects Myelosuppression, alopecia. Irinotecan, topotecan - mecHanism Inhibit topoisomerase I and prevent DNA unwinding and replication. - clinical Use Colon cancer (irinotecan); ovarian and small cell lung cancers (topotecan). - adVeRse eFFects Severe myelosuppression, diarrhea. Hydroxyurea - mecHanism Inhibits ribonucleotide reductase --> decreased DNA Synthesis (S-phase specific). - clinical Use Myeloproliferative disorders (eg, CML, polycythemia vera), sickle cell (increased HbF). - adVeRse eFFects Severe myelosuppression.

Answer 12

Cisplatin/Carboplatin ototoxicity Vincristine peripheral neuropathy Bleomycin, Busulfan pulmonary fibrosis Doxorubicin cardiotoxicity Trastuzumab (Herceptin) cardiotoxicity Cisplatin/Carboplatin nephrotoxicity CYclophosphamide hemorrhagic cystitis

Answer 13

the study of heritable changes in cellular function or gene expression that can be transmitted from cell to cell (and possibly even generation to generation) as a result of chromatin- based signals that do not alter the nucleotide sequence of the DNA. The main currencies of epigenetic information = enzymatic chemical modifications on the DNA and histones Transcriptional coactivators have activities that modify chromatin, to increase access to the DNA

Answer 14

Disorganization of epigenetic information is prevalent in leukemia, leading to changes in gene expression. i.e. global DNA demethylation and increased DNA methylation in promoters of tumor suppressor genes. • Leukemias also have altered histone modification and microRNA modulation. • Many leukemias have mutations in the enzymes that regulate epigenetic information. • Epigenetic changes, unlike genetic changes, can be reversed by therapeutics. AML and CLL have one of the lowest number of mutations per case of any adult cancer HDAC inhibitors also reactivate gene expression MLL protein fusions target the super elongation complex (SEC) or DOT1 complex (DotCom) to MLL target genes, leading to expression of pro-leukemia genes AFF1

Answer 15

``` Azacitidine(VidazaR): a CTP analogue that cannot be methylated DNA methyl transferase (DNMT) inhibitors FDA approved for myelodysplastic syndromes and AML treatment ```

Answer 16

Abnormal Blood Counts • Cytopenias (low blood cell counts) MDS, ALL, AML • Leukocytosis (high WBC count) some ALL & AML ✦ Incomplete or Aberrant Differentiation of hematopoietic cells. Cause of death: Related to the cytopenias resulting from the disease rather than as a direct effect of the neoplastic cells (in contrast to solid tumors). - Infection Neutropenia (v. common) Neutrophil Dysfunction (common) Other immune suppression (ALL) ✦ Bleeding Thrombocytopenia (v. common) Coagulopathy (less common)

Answer 17

The vast majority of AML is Sporadic (no causal linkage) ✦ Known Risk Factors - Ionizing radiation (occupational, therapeutic, atomic bomb) - Prior chemotherapy with DNA damaging agents (alkylating agents, topoisomerase II inhibitors) - Antecedent Hematologic Disorder (MDS, MPDs) - Certain Congenital disorders (Fanconi Anemia, Down Syndrome, Bloom Syndrome, Congenital Neutropenia) - Smoking (~2x risk) - Benzene exposure Most signs and symptoms are attributable to bone marrow failure/cytopenias. - Bleeding -Minor: skin, nose, gums; Major: GI tract, Lungs, CNS (thrombocytopenia) - Fevers, ﬂu-like symptoms, infections (neutropenia) - Palor/Fatigue/Generalized Weakness/ Shortness of Breath (anemia) Diagnostic Criteria: ✦ Blood or Bone Marrow with ≥20% Blasts - Blasts = Myeloblasts ~ Myeloid Blasts ~MPO+ Blasts ~ Sudan Black+ Blasts ~ NSE+ Blasts ✦ Blasts are cells with the Morphology of very immature hematopoietic cells. Normally, there are ≤ 3-5% in Bone Marrow and none in Blood. ✦ Major Diagnostic Branch: ALL vs AML - Flow Cytometry, Histochemistry and Immunohistochemistry used. M3: Acute Promyelocytic leukemia (APL) AML is highly aggressive and generally fatal. It is better to be young than old. Molecular Features are used for treatment decisions and predict survival

Answer 18

t(8;21) AML1-ETO & inv(16) CBFβ-MYH11 CBF is a heterodimeric transcription factor composed of α and β subunits. ‣ RUNX1 (aka CBFα, AML1 & PEBP2a)-Chr 21 ‣ CBFβ (aka PEBP2b) - Chr 16 ✦ Knockout Mice deﬁcient in either RUNX1 or CBFβ fail to develop deﬁnitive hematopoiesis & are non-viable. Essential for Hematopoiesis. ✦ Knockin Mice Engineered with AML1-ETO or CBFβ-MYH11 fusion genes are not viable due to hematopoietic failure. Fusions are dominant inhibitors of native gene function.

Answer 19

8% of AML (~25% in Latinos) ‣ ~1000 cases per year in US ‣ Younger patients (median age ~40), no increased incidence with age ✦ Fulminant DIC common at presentation ✦ Typically presents w/ pancytopenia ✦ Originally described in 1957 as a particularly lethal form of AML (survival months) ✦ Now ~80-90% patients cured with ATRAbased therapy ‣ APL is the most curable form of AML. ***All Phases of Treatment Differ from other AML ATRA syndrome: Fever, weight gain, dyspnea, hypoxemia, edema, pleuropericardial effusions. 3846 - treat with steroids - called differtiation syndrome

Answer 20

Clonal hematopoietic disorders characterized by: •ineffective myelopoiesis •progressive cytopenias •morphologic abnormalities of erythroid, granulocytic and megakaryocytic lineages •propensity to transform to AML (1/3 of cases) Median Age: 70 yrs (risk increases with age) - Most common heme malignancy of elderly - & likely vastly under-diagnosed. Patients typically present with cytopenias. - Mild Anemia is most common ✦ Years may elapse between the ﬁrst recognition of a cytopenia and an MDS diagnosis. ✦ When signs and symptoms are present they are generally attributable to cytopenias. - Bleeding -Minor: skin, nose, gums; Major: GI tract, Lungs, CNS (thrombocytopenia) - Fevers, infections (neutropenia) - Palor/Fatigue/Generalized Weakness/ Shortness of Breath (anemia) - Goals of Therapy ✓Improve Cytopenias ✓Reduce AML transformation ✓Improve Survival - New Drugs: ✓DNA Hypomethylating Agents (reactivate epigenetically silenced genes) ✓Lenalidomide for del(5q) ✓New growth factors (romiplostim - TPO to add to EPO and GCSF) ✓Kinder, gentler Allo-BMT methods

Answer 21

Most common type of leukemia in North America incidence: ~20,000 cases/year prevalence: ~ 200,000 cases • More common in Western Europe and North America • Median age = 72 years old • Peripheral blood smear demonstrates mature, resting B-cells and smudge cells Diagnosis: absolute B-lymphocyte count in peripheral blood >5,000/µl – small lymphocytic lymphoma (SLL) < 5,000/µl, with lymphadenopathy or splenomegaly • 30% of bone marrow involved with lymphocytes • co-expression of CD5, CD19/20, & CD23 surface proteins • Dim expression of CD20 and surface Ig(sIg) ˗ exception: Trisomy 12 Presentation: – Asymptomatic at diagnosis – Frequently diagnosed on “routine” blood work;; adds to shift towards earlier stage – Painless lymphadenopathy – Occasional B symptoms – Initial treatment strategy = Watch and Wait

Answer 22

Symptoms occur secondary to: 1. Accumulation of lymphocytes: lymphadenopathy, hepatosplenomegaly, anemia, thrombocytopenia 2. Immune dysregulation autoimmune complications in ~25% of patients: AIHA, ITP 3. Immunodeficiency hypogammaglobulinemia present in 75% of patients T cell defect present as well Richter’s Syndrome: – Evolution of CLL into an aggressive lymphoma – Occurs in ~10% of patients – Two types: • clonally related (80%): acquire TP53, c-myc • clonally unrelated (20%) – Risk Factors: NOTCH1 mutation, VH4-39 – Treated as if it were a large cell lymphoma: RCHOP

Answer 23

* progressive bone marrow failure (worsening anemia and/or thrombocytopenia, i.e. Rai Stage III or IV) * massive, progressive, or symptomatic LAD * massive, progressive, or symptomatic splenomegaly • lymphocyte doubling time of < 6 months * AIHA or ITP poorly responsive to steroids * disease related symptoms: weight loss, fevers, fatigue

Answer 24

1. Alkylating agents: • chlorambucil • cyclophosphamide • bendamustine 2. Purine analogues: • fludarabine (Fludara) • cladribine (Leustatin, 2-Cda) • pentostatin(Nipent) 3. Monoclonal antibodies: • rituximab (Rituxan) • alemtuzumab (Campath) • ofatumumab (Arzerra) • obinutuzumab (Gazyva) 4. BCR Antagonists: • ibrutinib (Imbruvica) • idelalisib (Zydelig) 5. Small Molecule Inhibitors • venetoclax (Venclexa) 6. CAR T cells Novel Treatment Tox: 1. BTK Inhibitors 1. Diarrhea 2. Bleeding 3. Thrombocytopenia 4. Atrial fibrillation 2. PI3 Kinase Inhibitors 1. Diarrhea 2. Colitis 3. Transaminitis 4. Pneumonitis 3. Bcl-2 Mimetics 1. Tumor lysis syndrome

Answer 25

``` Favorable (variable definitions exist) • No bulky disease • No B-symptoms • < 3 sites • No extranodal sites • ESR < 50 mm/h ``` ``` Unfavorable: – Age > 45 – Male sex – Stage IV – Serum albumin < 4 g/dL – Hb < 10.5 g/dL – WBC count > 15,000 cells/mm3 – Lymphocyte count < 600 cells/mm3 ``` ``` Treatment: • Early: – abbreviated chemo – XRT • Advanced – chemo alone • Chemo: ABVD ``` Problems: * AML—related to chemotherapy – Latency 3-5 years • Solid tumors—related to RT – Lung cancer. High risk in smokers – Breast cancer. Young women – Others: sarcoma, skin, salivary • Cardiac: – Doxorubicin and RT contribute • Infertility: – Uncommon with ABVD • Hypothyroidism – Cervical XRT • Xerostomia – XRT to salivary glands

Answer 26

* Second most common lymphoma in US and Europe * Usually occur in older patients * Indolent clinical course * Often disseminated, with lymphadenopathy, bone marrow, liver and splenic involvement * Propensity to transform to more aggressive subtype • Natural course of untreated disease is prolonged;; patients often die of other causes ``` Prongostic Factors: Age > 60 years Stage III or IV disease Serum LDH levels > ULN Hemoglobin levels < 12 g/dL Involvement of > 4 extranodal sites ``` Rituximab is a monoclonal antibody that targets CD20 on the surface of B-lymphocytes

Answer 27

• Pathology o CD19+, CD20+, CD25+, CD11c+, CD103+ o TRAP resistant o BRAF • Presentation o Splenomegaly o Cytopenias ``` • Treatment o Cladribine or Pentostatin +/-rituximab o Vemurafenib (BRAF inhibition) ```

Answer 28

* Most common subtype of NHL * Represents approximately 30% adult NHL * Aggressive clinical course if left untreated ``` Prognostic factors (APLES) • Age 60 years • Performance status 1 • LDH 1× normal • Extranodal sites 1 • Stage III or IV ``` Risk Category • Low (L) 0 or 1 • Low intermediate (LI) 2 • High intermediate (HI) 3 • High (H) 4 or 5 DLBCL Therapy: R-CHOP Side effects • Alopecia • Nausea/vomiting • Myelosuppression – Neutropenia • Cardiac toxicity • Neuropathy 5y OS = 60%

Answer 29

FOLLICLE Mantle zone: naïve cells meet antigen Germinal center: proliferating cells (centroblasts) differentiate into antigen-specific B cells (centrocytes) MARGINAL ZONE Memory B cells MEDULLA B cell area: accumulation of plasma cells PARACORTEX Mainly T cell area Site of entrance of all lymphoid cells and of accessory cells -T / B cell interaction SINUS Macrophage area: “sieve”functions follicles - B only Diffuse - T or B

Answer 30

``` CD45 All leukocytes Ig ( / ) B cells (surface); plasma cells (cytoplasmic) CD20 Most B cells PAX5 Most B cells CD10 Progenitors; Germinal center B cells CD3 All T cells CD5 All T cells; some B cells CD4/CD8 T helper / cytotoxic cells CD23 Activation / dendritic cells / CLL/SLL CD15 Granulocytes; Reed-Sternberg cells CD30 Act. lymphs; Reed-Sternberg cells BCL2 Anti-apoptotic protein BCL6 Germinal center cells Ki67 Proliferation ```

Answer 31

Clonal IgH rearrangement --- B cell lymphoma Clonal Ig Kappa rearrangement --- B cell lymphoma Clonal TCR rearrangement ---T cell lymphoma t(14;18); IgH/BCL2 ---- Follicular lymphoma t(11;14); CCND1/IgH --- Mantle cell lymphoma t(8;14); MYC/IgH ---- Burkitt lymphoma

Answer 32

Grade I (our case): Mostly centrocytes Grade II: Mixed centrocytes and centroblasts Grade III: Mostly centroblasts (MOST AGGRESSIVE) (CD20+, CD10+, BCL6+ CD21+ FDC meshworks) ``` Malignant Follicle: No tingible body macrophages No zonation (“montonous”) Loss of mantle cell zone No dark zone No light zone No tingible body macrophages Mantle zone – thin, attenuated Neoplastic B cells BCL2+ t(14;18) ```

Answer 33

Germinal center type (GCB) Translocations of BCL2 Ampliﬁcations of CREL Mutations in EZH2 and GNA13 genes Activated B cell type (ABC) Constitutive activation of the NF-κB pathway Chronic active B-cell receptor signalling by activating mutations in receptor constituents: CD79B, CARD11 or CD79A, and/or MYD88 L265P (implying TLR pathway activation) Gene Expression Profiling: GC vs non-GC (Prior to Rituxan) GC better !! Immunohistochemistry: - Non-GC: NFkB/Rel pathway inhibitors - GC: BCL6 inhibitors “Double Hit” Lymphomas (High-grade B-cell lymphoma with MYCand BCL2 and/or BCL6 rearrangements)

Answer 34

Folic Acid Analogs: MTX: a folic acid analog that binds with high affinity to the active catalytic site of dihydrofolatereductase (DHFR) and interferes with the synthesis of tetrahydrofolate(THF) THF: the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine. Inhibition of these metabolic processes interferes with the formation of DNA, RNA, and key cellular proteins. ``` Side Effects: Myelosuppression Mucositis Renal toxicity ``` Resitance: Decreased drug transport into the cell • Altered dihydrofolate reductaseenzyme -lower affinity for methotrexate • Quantitative increase in dihydrofolate reductase enzyme concentration in the cell (gene amplification, increased message)

Answer 35

pyrimidine analog: resistance: Alteration of drug influx • Efflux, enhancement of drug inactivation and mutation of the drug target • High-level expression of TS • Increased activity of deoxyuridine triphosphatase • Methylation of the miss match repair MLH1 gene • Overexpression of bcl-2, bcl-xl, and mcl-1 proteins (apoptosis proteins) ``` Side Effects: Myelosuppression Mucositis Diarrea Hand-‐Foot syndrome ```

Answer 36

DNA alkylating SEs: Myelosuppression Mucositis Diarrea Cystitis Resistance: • Increased DNA repair • Decreased drug permeability • Production of “trapping” agents (thiols) • Increased expression of the aldehyde- dehydrogenase (ALDH)

Answer 37

pulmonary fibrosis

Answer 38

``` estrogen receptor agonist: Increased risk for Endometrial Neoplasia ```

Answer 39

The clinical staging system: Stage Area of Involvement I Single lymph node group II Multiple lymph node groups on same side of diaphragm III Multiple lymph node groups on both sides of diaphragm IV Multiple extranodal sites or lymph nodes and extranodal disease X Bulk > 10 cm B symptoms: weight loss > 10%, fever, drenching night sweats

Answer 40

1. Splenicmarginal zone* lymphoma -20% 2. Extranodalmarginal zone B cell lymphoma (or MALT lymphoma for "mucosa-associated lymphoid tissue") - 70% 3. Nodalmarginal zone B cell lymphoma (NMZL) -10% * Mucosa-associated lymphoid tissue (MALT) can develop in nearly every organ as a result of chronic infection or an autoimmune process. If there is prolonged lymphoid proliferation, a malignant clone can emerge and a MALT lymphoma could follow. * Certain infections have been associated with MALT lymphomas: * There is H. pylori infection in 85-90% of gastric MALT lymphomas. * Chlamydophila psittaci has been identified as a possible causative agent in ocular adnexal lymphomas.[4] * Borrelia burgdorferi infection has been linked to skin MALT lymphomas. * Campylobacter jejuni has been linked to small bowel MALT lymphomas. * There is also a possible link between hepatitis C and HIV and MALT lymphomas. * Autoimmune diseases such as Hashimoto's thyroiditis and Sjögren's syndrome have also been linked to MALT lymphomas in the thyroid and salivary glands.

Answer 41

what is the typical rearrangement in MCL? t (11;14) IgH:Cyclin D1(BCL1) this results in inappropriate “on” status of cyclin D1 Non-nodal: Less often exhibits complex karyotype Non-nodal: More SHM TP53mutations: Worse Prognosis

Answer 42

* Diffuse large B-cell lymphoma (DLBCL), centroblastic * DLBCL, immunoblastic * Burkitt lymphoma