Cancer/Neoplasms Flashcards
Heritable cancers
- retinoblastoma: RB1
- hereditary breast and ovarian cancer: BRCA1, BRCA2
- Cowden syndrome: PTEN
- familial adenomatous polyposis (FAP): APC
- Lynch syndrome: MLH1, MSH2
- Li-Fraumeni syndrome: TP53
- multiple endocrine neoplasia type 1: MEN1
- multiple endocrine neoplasia type 2: RET
Cancer cachexia
wasting of tissues due to excess catabolism and/or decreased nutrition
mediated by tumor necrosis factor (TNF)
Carcinoma vs. sarcoma
Carcinoma:
- epithelial cell origin
- cohesive lobules, glands, reactive stroma
- spreads through lymphatic ducts into lymph nodes
Sarcoma:
- mesenchymal cell origin
- spindle cells, no lobular patterns, connective tissue tumors, elongated nuclei/cytoplasm
- spreads through vasculature and blood stream into lungs/veins
Stains and tumor types
- Carcinoma: keratin stain +
- Lymphoma: CD45 stain +
- Melanoma: S100 stain +
- Smooth muscle tumor: smooth muscle actin stain +
- Neuroendocrine tumor: keratin, synaptophpysin/chromogranin stain +
Keratin+
carcinoma, maybe neuroendocrine tumor
Smooth muscle actin+
smooth muscle tumor
CD45+
lymphoma
Synaphysin & Chromogranin
neuroendocrine tumor
S100+
melanoma
CDX2+
colorectal cancer
TTF1+
lung adenocarcinoma
Paraneoplastic syndrome
Signs and symptoms that occur in pts with cancer and cannot be explained by the tumor:
- unexplained anemia
- unintended weight loss
- hypercoagulable state => nonbacterial thrombotic endocarditis
- fatigue
- hypercalcemia: due to parathyroid hormone-related protein (PTHrP)
- Cushing syndrome: due to ACTH
- venous thrombosis (Trousseau syndrome)
Molecular changes associated with malignant tumors
CTLA4
- surface protein that binds to CD80/CD86 on APCs, turning them off
- early-acting in lymph nodes
PD1 & PD-L1/PD-L2
- PD expressed on activated T-cells, NK cells, B-cells, APCS
- PD-L1 expressed on tumor cells
- binding inhibits innate and adaptive immune responses
- late-acting in peripheral tissues
Tumor markers
- Prostate specific antigen (PSA)
- Carcinoembryonic antigen (CEA): colon, stomach, pancreas, breast
- Alpha-fetoprotein (AFP): hepatocellular carcinoma, yolk sac/embryonal
- Calcitonin: medullary carcinoma of the thyroid
- CA-125: ovarian cancers
- Syndrome of inappropriate antidiuretic hormone (SIADH), ADH: small cell lung carcinoma
Amyloidosis markers
- Ab2m: b2 microglobulin = renal failure
- AIAPP: islet amyloid = Type 2 diabetes
- ATTR: transthyretin = senile cardiac amyloid
- Acal: procalcitonin = medullary thyroid carcinoma
- AL: immunoglobulin light chains = plasma cell dyscrasias
- AA: serum amyloid associated = chronic inflammation
- Ab: cerebral amyloid b = Alzheimer’s disease
Acute myeloid leukemia (AML)
Pathology:
- neoplasm conposed of >= 20% myeloid blasts
- t(15;17)(q22;q12), PML-RARA gene
- myeloid lineage: CD13+, CD33+, CD117+, MPO+
Symptoms:
- no mature neutrophils; lots of immature myeloblasts
- Auer rods in blasts = crystalized granules
- anemia, neutropenia, thrombocytopenia
- Disseminated intravascular coagulation (DIC)
- Leukostasis when WBC > 100,000/uL
Treatment:
- t(15;17) has favorable prognosis after tx with ATRA (all-trans retinoic acid) and arsenic
Myelodysplastic syndrome (MDS)
- blast count < 20%
- dysplastic hematopoietic precursors, but there can be mature cells
- up to 40% of pts progress to AML
Myeloproliferative neoplasms (MPNs)
- proliferation of one or more hematopoietic lineages, not necessarily immature blasts
- mutation leading to constitutively active tyrosine kinase
- splenomegaly and hepatomegaly common due to extramedullary hematopoiesis
Chronic myeloid leukemia (CML)
Pathology:
- t(9;22); BCR-ABL1 gene on Philadelphia chromosome
- tyrosine kinase always turned on ==> proliferation of mature and immature myeloid elements
Symptoms:
- seen in older patients
- peripheral blood leukocytosis: neutrophils and immature granulocyte precursors
- basophilia
- splenomegaly
Treatment:
- Imatinib, tyrosine kinase inhibitor
- chronic ML can become acute leukemia if blasts > 20%
Acute lymphoblastic leukemia (ALL)
- proliferation and accumulation of neoplastic, immature lymphoid cells
- B-cell ALL & T-cell ALL
- CD34+, TdT+, CD10+
B-cell ALL (B-ALL)
- most common childhood leukemia (80%)
- t(12;21) ETV6-RUNX1 has good prognosis
- arises in bone marrow; peripheral blood usually involved
- CD10+, TdT+, CD19+, CD79+
- serum lactate dehydrogenase (LDH) and uric acid commonly increased
T-cell ALL (T-ALL)
- presents in adolescence
- involves bone marrow and thymus (mediastinal mass)
- CD10+, TdT+, CD1+, CD2+, CD3+, CD4+, CD5+, CD7+, CD8+
- mutations in NOTCH1, FBXW7
Polycythemia vera (P. vera)
- proliferation of erythrocytes (can also see panmyelosis)
- increased Hgb and RBC mass; RBCs are normocytic and normochromic
- mutations in JAK2 kinase
Primary myelofibrosis
- megakaryocytic hyperplasia and bizarre dysplasia => eventual marrow failure due to fibrosis => hematopoiesis moves to spleen (extramedullary hematopoiesis) => splenomegaly
- peripheral: teardrop RBCs, immature granulocytes, atypical platelets
- bone marrow: tightly clustered megakaryocytes with cloud-like nuclei, increased marrow fibrosis, intrasinusoidal hematopoiesis
- mutations in JAK2, CALR, MPL
Essential thrombocytothemia (ET)
- proliferation of platelets (up to millions/uL)
- bone marrow: clusters of “staghorn” megakaryocytes
- mutations in JAK2, calreticulin, thrombopoietin receptor
Chronic lymphocytic leukemia (CLL)
- most common leukemias of adults in the West
- most of cancerous B-lymphocytes are in the blood
- peripheral blood: small lymphocytes with scant cytoplasm, nucleus with clumped chromatin, smudge cells
- lymph nodes: pseudofollicles with proliferation centers
- CD19+, CD20+, CD22+, CD23+, CD5+
- Richter transformation: when CLL transforms into more aggressive ALL
Small lymphocytic lymphoma (SLL)
- just like CLL, but most of cancerous B-lymphocytes are in lymph nodes and lymphoid tissue
- 4% of non-Hodgkin’s lymphoma
Hairy cell leukemia (HCL)
- rare B-cell neoplasm: infiltration of lymphoma cells into bone marrow, blood, liver, spleen
- hair-like projections on lymphoma cells
- pancytopenia, splenomegaly (obliteration of white pulp), diffuse interstitial infiltrate of lymphoma cells in bone marrow
- CD19+, CD20+, CD11c, CD25+, CD103+
- BRAF oncogene mutation
- Tx: alpha-interferon, purine analogues; good response to chemotherapy
Multiple myeloma (MM)
- > 10% clonal plasma cells in bone marrow
- serum M-protein > 30g/dL
- atypical plasma cells: Mott cell (cytoplasmic inclusions), plasmablasts, Dutcher body (intranuclear inclusion), Rouleaux formation (linking of RBCs)
- plasma cells stain CD138
- IL-6, MLP1a => RANKL => bone lytic lesions
- produces free immunoglobulin light chains (Bence Jones proteins) that enter the urine
Asymptomatic/smoldering MM:
- absence of organ dysfunction
- 75% of pts progress from plasma cell myeloma to multiple myeloma (multiple tumors) over 15 years
Symptomatic MM:
- CRAB symptoms: hyperCalcemia, Renal dysfunction, Anemia, lytic Bone lesions
Monoclonal gammopathy of unknown clinical significance (MGUS)
- < 10% clonal plasma cells in bone marrow
- serum M-protein < 30g/dL
- no end organ damage
- precursor to multiple myeloma; risk of progression is 1% per year
Waldenstrom macroglobulinemia (Lymphoplasmacytic lymphoma)
- non-Hodgkin’s lymphoma associated with abnormal production of monoclonal IgM antibodies ==> increased serum protein level ==> hyperviscosity (decreased vision)
- > 10% monoclonal B cells
- seen in older adults
- agglutination of RBCs ==> hemolytic anemia
- Russell body inclusions in lymphocytes
- MYD88 mutations
- incurable
Acute T-cell leukemia
- caused by human T-cell leukemia virus (HTLV-1)
- endemic in Japan, Caribbean, Central Africa
- increased lymphocytes, skin rash, lymphadonepathy, hepatosplenomegaly, hypercalemia
- CD2+, CD3+, CD5+, CD25+
- clover-leaved lymphocytes
Sezary syndrome
- CD4+ T-cell lymphoma
- triad: erythroderma, generalized lymphadenopathy, neoplastic T-cell population with cerebriform nuclei
- CD2+, CD3+, CD5+, loss of CD7 and CD26
- mycosis fungoides = more prolonged cutaneous disease
Classical Hodgkin’s lymphoma (CHL)
- monoclonal lymphoid neoplasm composed of mononuclear Hodgkin cells and multinucleated Reed-Sternberg cells (owl-eyes)
- associated with EBV infection
- CD30+, CD15+, CD45-
- 95% of all Hodgkin lymphomas
Non-Hodgkin’s lymphoma
Follicular lymphoma
- most common indolent NH lymphoma
- painless generalized adenopathy (lymph nodes swollen)
- splenic expansion of white pulp
- t(14;18), BCL2
- CD19+, CD20+, CD10+, BCL2+, BCL6+, CD5-
- centrocytes: small cells with irregular/cleaved nuclear contours
Burkitt lymphoma
- post-EBV infection
- t(8;14)
- African (endemic): mandible, viscera-kidney, ovary, adrenal
- sporadic: ileocecum, peritoneum
- starry sky appearance: high proliferation, high mitotic rate with numerous apoptotic cells
- very aggressive, responds to aggressive chemotherapy
Diffuse large B-cell lymphoma
- most common form of NH lymphoma in USA (80% adults, 20% children)
- large lymphoid cells with large nuclei, prominent nucleoli, frequent mitotic figures
- rapidly enlarging mass
- aggressive tumor, can be cured by chemotherapy
- BCL-2/6 mutations
- CD19+, CD20+, BCL6+
MALT (marginal zone) lymphoma
- t(11;18)
- memory B cell hypermutation; marginal zones typically present in splenic white pulp and Peyer’s patches of colon
- mucosa-associated lymphoid tumors
- associated with inflammation
- H. pylori gastritis ==> gastric MALT
- CD19+, CD20+, CD3-
Anaplastic large cell lymphoma (ALK)
- ALK gene on chromosome 2p23
- large anaplastic cells
- horseshoe nucleus with voluminous cytoplasm
- CD30+, ALK+
- good prognosis
Mantle cell lymphoma
- B-cell lymphoma most common in adult men
- lymphomatous polyposis = when mantle zone lymphoma involves the GI tract, typically presents as “polyps”
- t(11;14)
- CD5+, cyclin D1+
Treatable cancers important to know
Acute promyelocytic leukemia (APL):
- t(15;17)(q24.1;q21.1)
- PML-RARA gene
- responds to ATRA (all-trans retinoic acid) and arsenic
Chronic myeloid leukemia (CML):
- t(9;22)(q34;q11)
- BCR:ABL1 gene fusion
- responds to Imatinib, a tyrosine kinase inhibitor
Antineoplastic classes
- Alkylating agents: CCNS, work by adding alkyl to DNA ==> crosslinked DNA ; nitrogen mustards, nitrosoureas
- S-phase inhibitors: CCS, antimetabolites
- Anti-tumor antibiotics: CCNS and CCS
- Natural products
- Hormonal: gonadal antagonists, gonadotropin-releasing analogues, glucocorticoids, aromatase inhibitors
- Miscellaneous: L-Asparaginase, small molecule inhibitors, cytokines, monoclonal antibodies, bone marrow growth factors
Alkylating agents
Nitrogen mustards:
- cyclophosphamide
Nitrosoureas:
- carmustine
Misc. alkylating agents:
- cisplatin
- procarbazine
- busulfan
Cyclophosphamide
- alkylates DNA at N7 of guanine
- hemorrhagic cystitis (dysuria, hematuria)
- tx with mesna
“go to the cyclopHOSPhamide (hospital) if you get hemorrhagic cystitis”
Carmustine
- lipid-soluble, can cross blood brain barrier
- CNS toxicity
“carMUSTine cross BBB”
Cisplatin
- crosslink with DNA at N7 of guanine
- nephrotoxic; treat with mannitol
- neurotoxic: high-frequency hearing loss
“ciSPLATin goes your kidney and brain”
“CNN: cisplatin-nephrotoxity-neurotoxity”
Procarbazine
- generates free radicals
- CNS dysfunction, peripheral neuropathy, leukemogenic (AML)
- disulfiram-like reaction with ethanol
Busulfan
- crosslinks DNA
- pulmonary fibrosis
“pulmonary fibusulfan”
S-phase antimetabolites
- methotrexate
- 6-mercaptopurine (6-MG) & 6-thioguanine (6-TG)
- 5-fluorouracil (5-FU)
- cytarabine
- gemcitabine
Methotrexate
- binds to site of DHFR, inhibiting formation of THF and IMP (d.n. purine synthesis)
- hepatotoxicity
- tx with Leucovorin
- clearance depends on renal function
- resistance via increased expression of P-glycoprotein transporter
“meDHROotrexate”
6-Mercaptopurine & 6-Thioguanine
- purine analogue; inhibits de novo synthesis (HGPRT)
- 6-MP is inactivated by xanthine oxidase, which is inhibited by allopurinol
- when used concurrently with allopurinol, dosage of 6-MP must be reduced to 25-33%
“-purine = purine analogue”
5-Fluorouracil
- 5-FU ==> 5F-dUMP, which inhibits thymidylate synthetase ==> starves cells of thymine
- mucositis, hand-foot syndrome
- when used with Leucovorin, a smaller dose of 5-FU is needed
“FU = middle finger up”
“uracil = pyrimidine”
Cytarabine
- pyrimidine analogue
- inhibits DNA polymerase (most S-phase specific)
Gemcitabine
- inhibits ribonucleotide reductase
- blocks formation of dNTPs
Antitumor metabolites
CCNS:
- doxorubicin & daunorubicin
- dactinomycin
- mitomycin
CCS:
- bleomycin
Doxorubicin & Daunorubicin
- CCNS
- intercalates DNA, inhibits topoisomerase II
- cardiotoxic: dilated cardiomyopathy
- tx with Dexrazoxane
- multidrug resistance via P-glycoprotein
“ruby = heart = cardiotoxicity”
“Dexrazoxane for Doxorubicin”
Dactinomycin
- CCNS
- intercalates between GC base pairs
Mitomycin
- CCNS
- bioreductive alkylating agent generated via liver metabolism
- best drug for hypoxic tumors
Bleomycin
- CCS, G2-phase specific
- generates free radicals
- enzyme bleomycin hydrolase causes resistance to bleomycin
- pulmonary and skin toxicity because those areas are low in bleomycin hydrolase
- minimal myelotoxicity
“pulmonary fibleomycin”
“bleomycins = blisters”
Natural product antineoplastics
- vincristine & vinblastine
- paclitaxel (TAXOL) & docetaxel
- etoposide & teniposide
Vincristine & Vinblastine
- M-phase specific
- prevents mitotic spindle formation
- Vinblastine = bone marrow suppression, low neurotoxicity
- Vincristine = neurotoxicity, minimal myelotoxicity
- resistance via P-glycoprotein transporter
“Chris Christie is a neurotoxic mayor, blocked bridge”
Paclitaxel (TAXOL) & Docetaxel
- M-phase specific
- inhibits disassembly of microtubules
- peripheral sensory neuropathy
- multidrug resistance
“pacliTAXI drives you around blocked bridge”
Etoposide & Teniposide
- late S-G2 phase specific
- inhibits DNA topoisomerase II
- multidrug resistance
“teniPOSIde, etoPOSIde = posse, 2 or more people (topoisomerase 2)”
Hormonal antineoplastics
Gonadal hormone antagonists:
- tamoxifen: competes for binding at estrogen receptor site
- flutamide: binds to androgen receptor
Gonadotropin-releasing hormone analogues:
- leuprolide: short-term increases testosterone, long-term inhibits testosterone release
Glucocorticoids:
- prednisone: dissolution of lymphocytes (ALL, lymphomas, myelomas)
Aromatase inhibitors:
- anastrozole & letrozole: advanced breast cancer
Miscellaneous antineoplastics
L-asparaginase
Small molecule inhibitors:
- imatinib
- ibrutinib
- bortezomib & carfilzomib
- olaparib
Cytokines:
- alpha-interferons
- interleukin-2 (aldesleukin)
Monoclonal antibodies:
- rituximab: CD20
- trastuzumab: HER2
- cetuximab: EGFR
- bevacizumab: vascular EGF
- ipilimumab: CTLA-4
- pembrolizumab: PD-1 receptor
- atezolizumab: IgG Ab against PD-L1
L-Asparaginase
- CCNS
- used for cancers that require exogenous asparagine for growth
Imatinib
- inhibits tyrosine kinase activity of BCR-ABL1 oncogene in CML
Ibrutinib
- blocks Bruton’s tyrosine kinase signaling in B-cells
- mantle cell lymphoma, CLL, small lymphocytic lymphoma
Bortezomib & Carfilzomib
- 26S proteasome inhibitor
- multiple myeloma
Olaparib
- inhibits poly ADP ribose polymerase (PARP) used in DNA repair
Alpha-interferons
hairy cell leukemia, early CML, T-cell lymphomas
Rituximab
interacts with CD20 in non-Hodgkin’s lymphoma cells
Trastuzumab
- binds to human epidermal growth factor receptor 2 (HER2)
- female breast cancers that overexpress HER2
Aplastic anemia
Pancytopenia caused by bone marrow failure
- may be due to virus infections, Fanconi anemia: DNA crosslink repair defect ⇒ bone marrow failure
- toxic drug exposure
- Normocytic or macrocytic anemia
- Hypocellular fat-filled marrow
- splenomegaly (extramedullary hematopoiesis)
Pure red cell aplasia
Severe reduction in reticulocytes (immature RBCs) in circulation and bone marrow
- Abnormal T cell function
- IgG antibodies that target erythroblasts
- bone marrow: marked reduction or absence of erythroid precursors
Agranulocytosis
Absence of granulocytes or severe neutropenia
- drug-induced
- oral ulcers, sore throat, fever
- absolute neutrophil count < 500/mm3
