Step 1 - Oncology (Path/Pharm)

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Hodgkin's lymphoma

B-cell lymphoma
-Affects localized, single group of nodes (extranodal is rare); contiguous spread (stage is strongest predictor of prognosis)
-Constitutional B symptoms: low-grade fever, night sweats, weight loss
-Mediastinal lymphadenopathy
-50% of cases associated with EBV (young & old people)
-Reed-Sternberg cells: B-cell origin, CD30+, CD15+; binucleate or bilobed with 2 halves as mirror images ("owl eyes")
-Prognosis worsens with dec. lymphocytes and inc. RS cells

Hodgkin's lymphoma: nodular sclerosing type

Nodules of mixed inflammatory cells
-Some RS cells & lacunar cells surrounded by bands of sclerotic fibrous tissue (collagen banding)
-Excellent prognosis

Hodgkin's lymphoma: mixed cellularity type

Numerous RS cells, more aggressive, usually found in older patients
-EBV+ (60-70%)
-Intermediate prognosis

Hodgkin's lymphoma: lymphocyte predominant type

Found in males 30-50 years of age
-Originate in germinal center
-Large nodules of small lymphocytes & macrophages ("popcorn" cells)
-Excellent prognosis

Non-Hodgkin's lymphoma

May be associated with HIV and immunosuppression
-Multiple, peripheral nodal involvement; extranodal involvement is common; non-contiguous spread
-Majority involve B-cells
-Fewer constitutional S/S
-Peak incidence 20-40 y.o.

Burkitt's lymphoma

Non-Hodgkin's B-cell lymphoma
-Occurs in adolescents or young adults
-t(8;14): C-MYC gene moves next to heavy-chain IgG gene
-"Starry-sky" appearance (sheets of lymphocytes with interspersed macrophages)
-Associated with EBV: infectious mononucleosis (high fever, cervical lymphadenopathy, splenomegaly)
-Jaw lesion in endemic form in Africa; pelvis or abdomen in sporadic form

Diffuse large B-cell lymphoma

Non-Hodgkin's B-cell lymphoma
-Usually affects older adults, but 20% in children
-Most common adult NHL
-May be mature T-cell in origin (20%)

Mantle cell lymphoma

Non-Hodgkin's B-cell lymphoma
-Occurs in older males
-t(11;14): overexpression of cyclin D1/Bcl-1 protein
-Poor prognosis
-CD5+

Follicular lymphoma

Non-Hodgkin's B-cell lymphoma
-Occurs in adults, most common indolent Non-Hodgkin's lymphoma
-t(14;18): overexpression of bcl-2 -> inhibition of apoptosis
-Indolent course with remissions and recurrence -> size fluctuates over time, difficult to cure
-S/S: painless lymph node enlargement, abdominal discomfort

Adult T-cell lymphoma

Non-Hodgkin's T-cell lymphoma
-Occurs in adults, especially in Japan, West Africa, and the Caribbean
-Caused by HTLV-1 infection: retrovirus integrates into T-cell DNA
-Presents with cutaneous lesions
-Aggressive course

Sezary syndrome

Non-Hodgkin's T-cell lymphoma
-Leukemic form of mycosis fungoides (cutaneous T-cell lymphoma)
-Generalized erythroderma ("red man syndrome"): hyperkeratosis of palms and soles, pruritis

Multiple myeloma

Malignant proliferation of plasma cells that replace bone marrow and secrete monoclonal IgG & IgA antibodies
-Cells have a "fried-egg" appearance & M-spike on protein electrophoresis
1. Signs/symptoms ("CRAB")
-hyperCalcemia: secondary to bone destruction
-Renal insufficiency: "myeloma kidney" with waxy Ab casts depositing in renal tubules and Ig light chains in urine (Bence-Jones proteins)
-Anemia: infiltration of marrow, dec. EPO secretion, hemolysis (rouleaux formation)
-Bone lytic lesions & Back pain: pathologic fractures, diffuse bone loss, osteoporosis (punched-out lesions on X-ray)
2. Associated with:
-Increased susceptibility to infx (encapsulated organisms)
-Primary amyloidosis (AL)

Waldenstrom's macroglobulinemia

Lymphoplasmacytic cells invade bone marrow and secrete IgM antibody (vs. IgG/IgA in MM)
-B-cell proliferation causes B-symptoms, infiltration of BM, lymph nodes, and organs
-M-protein production by plasma cells -> hyperviscosity syndrome, neuropathy, cold agglutinin disease, and Raynaud's phenomenon
-NO lytic bone lesions!

Acute lymphoblastic leukemia (ALL)

Lymphoid leukemia
-Homogeneous proliferation of precursor B-cells or T-cells (lymphoblasts) with very high mitotic activity -> bone marrow is replaced by lymphoblasts
-Bone marrow involvement in childhood (B-cells)
-Mediastinal mass in adolescent males (T-cells): compresses great vessels, esophagus, and trachea -> superior vena cava syndrome, dysphagia, dyspnea/stridor
-Markers: TdT+ (blast marker), CALLA+ (CD10), CD19+ (B-cell), CD5+ (T-cell)
-May spread to testes or CNS
-t(12;21) -> better prognosis
-Most responsive to therapy

Chronic lymphocytic leukemia (CLL)

Lymphoid leukemia
-Mature B or T-cell lymphocytosis in peripheral blood and bone marrow
-Often asymptomatic, affects older adults
-Blood smear: smudge cells
-Labs: increased neutrophil alkaline phosphatase levels (vs. CML)
-Immune complications (warm antibody autoimmune hemolytic anemia)

Hairy cell leukemia

Lymphoid leukemia
-Mature B-cell tumor in the elderly, more often in males
-Pancytopenia and splenomegaly in an elderly man
-Labs: low leukocyte count, "hairy cells" on blood smear
-Stains TRAP+ (tartrate-resistant acid phosphatase)
-Indolent, slowly progressive disease w/bleeding and infection complications
-Tx: cladribine (purine analog; resistant to adenosine deaminase -> can reach high intracellular concentrations)

Acute myelogenous leukemia (AML)

Myeloid leukemia
-Malignancy of immature hematopoietic cells that also inhibit normal hematopoietic maturation
-Commonly affects adults
-Blood smear: increased number of circulating myeloblasts with Auer rods (stain with peroxidase)

Acute promyelocytic leukemia (APL)

Myeloid leukemia
-M3 variant of ALL
-t(15,17): PML-RAR-alpha fusion protein inhibits DNA transcription via abnormal retinoic acid receptor
-Blood smear: myeloblasts w/Auer rods
-Tx: all-trans retinoic acid (ATRA)
-Treatment may release Auer rods from cells -> DIC

Chronic myelogenous leukemia (CML)

Myeloid leukemia
-All levels of maturation of granulocytic cells are represented (neutrophils, basophils, eosinophils)
-t(9;22): Philadelphia chromosome -> bcr-abl tyrosine kinase fusion protein
-Splenomegaly
-May accelerate and transform into AML or ALL -> "blast crisis"
-Labs: very low leukocyte alkaline phosphatase (vs. CLL)
-Tx: Imatinib

Langerhans cell histiocytosis (histiocytosis X)

Proliferative disorder of dendritic (Langerhans) cells
-Defective cells express S-100 and CD1a
-EM: Birbeck granules ("tennis rackets")

Polycythemia vera

Chronic myeloproliferative disorder
-Absolute erythrocytosis; slight male predominance
-JAK2 V617F mutation -> tyrosine kinase is constitutively active -> BM trilineage proliferation -> hypercellular BM (erythrocytes, platelets, and leukocytes)
-S/S: aquagenic pruritus, gout, bleeding, erythromelalgia (burning, redness of the hands & feet)
-May cause abdominal vein thrombosis -> Budd Chiari Syndrome

Essential thrombocytosis

Chronic myeloproliferative disorder
-Proliferation of megakaryocytes and platelets; slight female predominance
-JAK2 V617F mutation -> tyrosine kinase is constitutively active
-Persistent thrombocytosis (>450k)
-BM: proliferating megakaryocytes with hyperlobated nuclei
-S/S: often asymptomatic; may have large vessel thrombosis, bleeding, splenomegaly, erythromelalgia

Myelofibrosis

Chronic myeloproliferative disorder
-Proliferation of megakaryocytes, granulocytes, and fibroblasts -> marrow fibrosis and angiogenesis
-JAK2 V617F mutation -> tyrosine kinase is constitutively active
-S/S: fatigue, weight loss, fever, night sweats, bone pain, marrow failure -> extramedullary hematopoiesis (splenomegaly)
-Blood smear: "tear-drop" RBCs (dacryocytes), hypercellularity and clustering of atypical megakaryocytes, reticulin

Methotrexate (MTX)

Antimetabolite
-Mech: folic acid analog that inhibits dihydrofolate reductase -> dec. dTMP synthesis -> dec. DNA and protein synthesis
-Clinical: cancer (leukemia, lymphoma, choriocarcinoma, sarcoma), abortion, ectopic pregnancy, rheumatoid arthritis, psoriasis
-Tox: myelosuppression, macrovesicular fatty liver, mucositis/stomatitis, teratogenic
-Leucovorin (folinic acid) rescue: replaces THF that was lost to MTX; used to treat myelosuppression

5-fluorouracil (5-FU)

Antimetabolite
-Mech: pyrimidine analog that is bioactivated to 5F-dUMP, which covalently complexes with folic acid -> inhibits thymidylate synthase -> dec. dTMP -> dec. DNA and protein synthesis
-Clinical: colon cancer and other solid tumors, basal cell carcinoma (topical); synergy with MTX
-Tox: myelosuppression (NOT reversible with leucovorin; treat overdose with thymidine); photosensitivity

6-mercaptopurine (azathioprine)

Antimetabolite
-Mech: purine analog -> decreases de novo purine synthesis; activated by HGPRTase
-Clinical: leukemia, lymphoma (NOT CLL or Hodgkin's)
-Tox: bone marrow, GI, liver; metabolized by xanthine oxidase, so has increased toxicity with allopurinol
-6-thioguanine (6-TG): can be given with allopurinol

Dactinomycin

Antitumor antibiotic
-Mech: intercalates into DNA
-Clinical: Wilms tumor, Ewing's sarcoma, rhabdomyosarcoma ("children ACT out")
-Tox: myelosuppression

Doxorubicin (adriamycin)

Antitumor antibiotic
-Mech: noncovalently intercalates into DNA and generate free radicals -> DNA breaks -> dec. replication
-Clinical: Hodgkin's lymphoma, myelomas, sarcomas, solid tumors
-Tox: dilated cardiomyopathy, myelosuppression, alopecia

Bleomycin

Antitumor antibiotic
-Mech: induces free radical formation -> causes breaks in DNA strands
-Clinical: testicular cancer, Hodgkin's lymphoma
-Tox: pulmonary fibrosis, skin changes; minimal myelosuppression

Etoposide

Antitumor antibiotic
-Mech: inhibits DNA topoisomerase II -> increased DNA degradation
-Clinical: small cell carcinoma of lung and prostate, testicular carcinoma
-Tox: myelosuppression, GI irritation, alopecia

Cyclophosphamide

Alkylating agents
-Mech: covalently cross-link DNA at guanine N-7; requires bioactivation by the liver
-Clinical: non-Hodgkin's lymphoma, breast/ovarian carcinomas, immunosuppression
-Tox: myelosuppression, hemorrhagic cystitis
-Partially prevented with mesna

Nitrosureas

Alkylating agents (carmustine, lomustine, semustine, streptozocin)
-Mech: require bioactivation; can cross the BBB into the CNS
-Clinical: brain tumors (e.g. glioblastoma multiforme)
-Tox: CNS toxicity (dizziness, ataxia)

Vincristine, vinblastine

Microtubule inhibitors
-Mech: bind to tubulin in M-phase and block formation of mitotic spindle
-Clinical: Hodgkin's lymphoma, Wilms' tumor, choriocarcinoma
-Tox: neurotoxicity (areflexia, peripheral neuritis) and paralytic ileus (vincristine); BM suppression (vinblastine)

Paclitaxel

Microtubule inhibitor
-Mech: hyperstabilize polymerized microtubules in M-phase to prevent breakdown of the mitotic spindle
-Clinical: ovarian and breast carcinomas
-Tox: myelosuppression, hypersensitivity

Cisplatin, carboplatin

Platinums
-Mech: cross-link DNA
-Clinical: testicular, bladder, ovary, and lung carcinomas
-Tox: nephrotoxicity, ototoxicity (high-frequency hearing loss, tinnitus)
-Prevent with amifostine

Hydroxyurea

Inhibits ribonucleotide reductase -> decreased pyrimidine synthesis -> decreased DNA synthesis (S-phase specific)
-Clinical: melanoma, CML, sickle cell disease (increases HbF synthesis)
-Tox: bone marrow suppression, GI upset

Prednisone

Most commonly used glucocorticoid in cancer chemotherapy
-Clinical: CLL, Hodgkin's lymphoma (MOPP regimen), immunosuppression
-Tox: Cushing-like symptoms, immunosuppression, cataracts, acne, osteoporosis, HTN, peptic ulcers, hyperglycemia, psychosis

Trastuzumab (Herceptin)

Monoclonal antibody
-Mech: binds and kills breast cancer cells that overexpress HER-2 (antibody-dependent cytotoxicity)
-Clinical: metastatic breast cancer
-Tox: cardiotoxicity

Imatinib (Gleevec)

Tyrosine kinase inhibitor
-Mech: inhibits Philadelphia chromosome bcr-abl tyrosine kinase fusion protein
-Clinical: CML, GI stromal tumors
-Tox: fluid retention

Rituximab

Monoclonal antibody
-Mech: binds to CD20 on neoplastic B-cells
-Clinical: Non-Hodgkin's lymphoma, rheumatoid arthritis (w/MTX)

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