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126 Cards in this Set

  • Front
  • Back
  • 3rd side (hint)
Estrogen receptor and breast cancer tumorigenesis
-ERa vs ERb
-what pathway does it effect?
-prognosis vs HER2/neu
-Rx
Estrogen receptor:
-Estrogen stimulated signaling through the estrogen receptor. This is a steroid signaling pathway.
Once estrogen binds to its receptor it then will bind estrogen responsive elements in the nucleus
-The ER-a is expressed in 70% of all breast cancers and it is an important factor in development of the disease
-ER+ breast cancers are on average better differentiated, grow more slowly, are not strongly aneuploid, and have a slightly better prognosis than ER- breast cancers.
-Tumors that are ER+ remain dependent on estrogens for growth.
-ER+ and PR+ (progesterone receptor) tumors are more likely to be hormonally regulated.
-Therapeutically these tumors are treated using drugs that suppress ER activity
-Selective estrogen receptor modifiers (SERMs) are compounds with structural similarities to estrogen that bind with the receptor, but antagonize its activity. SERMs used in treating breast cancer include tamoxifen and toremifene.
-Raloxifene has demonstrated activity in breast cancer prevention.
-In ER- tumors tend to be more aggressive and proliferation is stimulated through the ErbB proteins.
-ERa- mediates proliferative effects in femal repro tissue
-ERb- inhibits ERa (often lost in breast cancers, but ERa most important)
-ER bound to HSP90 in cyto
-Activates AP-1 (activator protein-1) can turn on MAP kinase pathway> proliferation
Her2/neu receptor and breast cancer tumorigenesis
-what pathway does it effect?
Rx- 2 categories of drugs
-important oncogene in breast cancer
>>>>HER2 activates MAP kinase, HER3 activates PI3K
-EGFR family
-binding of ligand causes receptor to dimerize with HER3> activates PI3-K pathways> altered gene expression and increased cell growth
RX
-Anti-ErbB therapeutic agents can be classified into two catagories based on their actions.
1) Kinase inhibitors are agents that can bind with the kinase domain and antagonize activity of the receptor. These are logically being tested as treatments in cancers in which the receptor has a mutation that renders the kinase constitutively active.
-ERbB inhibitors include erlotinib (Tarceva) and gefitinib (Iressa).
2) Humanized monoclonal antibodies constitute the second category. These agents are antibodies that bind to the extracellular domain of the receptor and prevent interaction between the receptor and its ligand.
The EGFR monoclonal antibody is Cetuximab (Erbitux)
The HER2/neu monoclonal antibody is trastuzamab (Herceptin)
Primary Biliary Cirrhosis vs Primary Sclerosing cholangitis
-Primary Biliary Cirrhosis
Autoimmune with most of them with anti-mitochondrial antibody
Common in middle aged female
Jaundice is a sign of progressive/advanced disease
Portal inflammation is cholangiolytic and granulomatous
-Primary Sclerosing Cholangitis
1. Autoimmune.
2. Often associated with inflammatory bowel disease.
3. Elevated serum IgM, hypergammaglobulinemia.
4. Extrahepatic and intrahepatic bile duct inflammation.
5. Predispose to cirrhosis and cholangiocarcinoma.
70% in association with chronic ulcerative colitis
Similar to primary biliary cirrhosis but involves larger bile ducts both in and out of the liver
Higher incidence of cholangiocarcinoma
BRCA1 and BRCA2 in breast cancer
-compare function of BRCA1 and 2 in DNA
-Both BRCA1 & BRCA2 are caretaker tumor suppressors whose function is to repair DNA, prevent chromosome breaks and activate checkpoint signaling.
-The main function of BRCA2 in HR is to serve as a scaffold for the assembly of large protein complexes that participate in repair of DSBs.
-A key role of BRCA2 is regulation of the Rad51 protein.
-BRCA1 functions upstream of BRCA2 by acting in conjunction with other protein factors as a sensor for DNA damage and regulator of cell cycle checkpoints.
-Loss of BRCA1 or BRCA2 leads to a profound sensitivity to radiation and anticancer agents that cause DNA damage
-other genes associated w/ breast cancer
i. BRCA1
ii. BRCA2
iii. PTEN
iv. TP53
v. MLH1, MSH2
vi. LKB1
>>>BRCA1 & BRCA2 have distinct but related functions. Both play important roles in the repair of DNA double stranded breaks (DSBs) that are repaired through homology-directed repair.
1. In homology-directed repair (HR) the sister chromatid is utilized to ensure that the appropriate ends of two DNA strands are rejoined and to reconstruct missing genetic information.
2. The main function of BRCA2 in HR is to serve as a scaffold for the assembly of large protein complexes that participate in repair of DSBs. A key role of BRCA2 is regulation of the Rad51 protein.
Loss of BRCA1 or BRCA2 leads to a profound sensitivity to radiation and anticancer agents that cause DNA damage.
Gorlin's Syndrome
Inherited form of basal cell carcinoma
-hereditary mutations in PTCH1 gene
-aka Nevoid basal cell carcinoma syndrome (NBCCS)
•Characterized by multiple BCCs
–High incidence of other neoplasms
•Meduloblastomas
•Ocular abnormalities
•Odontogenic keratocysts
•Autosomal dominant
•Prevalence of 1 in 56,000
•Gene mapped to chromosome 9q22-31
–Gene identified
•Patched
–Key signaling receptor in the hedgehog signaling pathway
Understand the 3 major mechanisms of molecular genetic changes associated with colon tumorigenesis
Progression along the adenoma/carcinoma sequence is accompanied by the accumulation of more genetic abnormalities. Specific gene alterations have been determined to occur at specific stages of tumorigenesis. The three most frequent mechanisms by which genetic alterations occur are:
a Chromosomal Instability (CIN)- Widespread imbalances in chromosome number
characterized by
gain or loss of whole chromosomes or fractions of chromosomes
b Mismatch Repair (MMR) deficiency leading to Microsatellite Instability (MSI) - Microsatellites (repeated DNA units of 1‐6 bp) are misread during
DNA replication due to a
failure to repair replication‐associated errors.
c CpG Island Methylation Phenotype (CIMP) by which epigenetic gene inactivation of tumor suppressor genes occur- most strongly, but not exclusively, associated with
methylation inactivation of tumor suppressor genes
- Role of JC Virus in initiating mutations in these three mutational models.
Xeroderma Pigmentosum
-hereditary syndrome caused by defects in DNA repair genes> exhibit increased risk for epithelial skin cancers (SCC and BCC)
5. There are no hereditary SCC syndromes. However, xeroderma pigmentosum (XP) exhibits elevated levels of both SCC and BCC.
a. The disease is associated with skin cancer and extreme sensitivity to sunlight. It is also associated with other defects including developmental defects, immunological defects, neurodegeneration, and reginal degeration.
b. XP is due to germline mutations in genes that are involved in nucleotide excision repair. Since there are many different proteins involved in this process, mutations in several different genes can give rise to the same syndrome.
c. A related syndrome is Cockayne’s syndrome. It is also caused by mutations in genes involved in nucleotide excision repair.
Radiology
Gamma Rays (Nuclear medicine)
-name the 2 most common radioisotopes
-limitations
Nuclear Medicine utilizes the injection of radioactive isotopes that emit gamma rays. The emitted gamma rays are captured using a gamma camera. The radioactive isotopes can be attached to a substrate that is normally present in the organ or disease process of interest. The most commonly used radioisotope in medical imaging is Tc99m and F-18.
Trace amounts of radioactive atoms attached to other molecules to form radiopharmaceuticals
Distribution of radiopharmaceuticals imaged with Gamma Camera or PET scanner
Evaluates function rather than structure
Diagnostic and therapeutic modalities
LIMITATIONS
Radiation
Poor anatomic definition
Time
Allergic reactions extremely rare except antibody studies, Persantine/adenosine reactions
Understand the interactions between CIN, MSI, and CIMP in colorectal cancer
Chromosomal Instability (CIN):
T‐antigen (TAg), through its interactions with p53 and pRB, abrogates the G1/S cellcycle
checkpoint that censors the replication of damaged DNA, leading to CIN.
CpG Island Methylator Phenotype (CIMP):
Genomic methylation is a host defense mechanism that silences the transcription of
transposons and retroviruses that have accumulated in the mammalian genome.
TAgs from other viruses can elicit a host‐mediated hypermethylation response that
targets genes across the genome.
Microsatellite Instability (MSI):
Through CIMP, JCV’s TAg may cause MLH1 methylation inactivation, resulting in
sporadic MSI.
Conventional X-ray
-limitations
Image formed is related to tissue density
Five Densities (in order)
Metal
Bone
Soft tissue (water)
Fat
Gas
2) Limitations
Radiation
Low yield - limited information about soft tissues
Understand the potential role of viral infection in initiation of the 3 mechanisms of colon cancer (CIN, MMR/MSI, CIMP)
• Most human CRC have JCV infection
• About half express JCV T‐Ag
• JCV associates with methylation inactivation (CIMP) in CRC
• JCV infection of cultured cells increases chromosomal instability (CIN)
• No correlation or evidence for JCV association with MSI
Basal Cell Carcinoma molecular biology
-describe the role of PTCH1
1. Basal cell carcinoma is the most prevelant epithelial skin cancer. It tends to be slow growing and usually is only locally invasive. Metastasis to distant sites is exceedingly rare.
2. There are no precursor lesions that have been identified for this tumor.
3. BCCs originate from basal kertinocytes associated with hair follicles.
4. A frequent genetic change that occurs during BCC tumorigenesis is mutation of the PTCH1 tumor suppressor gene
a. PTCH1 is located on chromosome 9q. Chromosomal loss at 9q has been observed in both sporadic and hereditary BCC.
b. PTCH1 is a large membrane receptor that normally suppresses the activity of another receptor smoothened (SMO)
c. When active, the SMO receptor stimulates expression of the N-myc oncogene which induces cell proliferaton
d. Loss of PTCH1 allows the SMO pathway to remain active resulting in uncontrolled cell proliferation.
5. Grolin’s syndrome is a hereditary BCC cancer syndrome that is characterized by hereditary mutations in the PTCH1 gene
Fluoroscopy
-limitations
Fluoroscopy – visualization of processes or procedures in real time
Injection, ingestion or placement of radiopaque material within the body
Increases inherent contrast
Sometimes can demonstrate functional anatomy and pathology
2) Limitations
Allergic reactions
Radiation exposure
Bowel perforation & Barium impaction
Aspiration of contrast media
Squamous Cell Carcinoma molecular biology
-what is the precursor lesion
-what is the molecular process of tumorigenesis?
1. Squamous cell carcinomas (SCC) are the second most prevalent epithelial skin cancer representing about 20% of the total. Although infrequent, these cancers do metastasize at a rate of 1%-2%.
2. Precursor lesion is the actinic karatosis (AK) that frequently presents as a rough, dry, red/brown scaly patch on the skin. Treatment for AKs is by topical application of growth inhibitors (5FU), photodynamic therapy, and cryosurgery.
3. Increased incidence of SCCs is seen in immunosuppressed patients. Interestingly stimulation of an adaptive immune response is used to treat both BCC and SCC.
4. Molecular genetic changes that occur in SCC include:
a. Activation of the ras oncogene with stimulates the MAP kinase pathway and induces cell proliferation
b. Activation of the epidermal growth factor receptor. This also results in activation of the MAP kinase pathway.
c. The NF-B signaling pathway is also activated. Activation of this pathway results in altered prolifearation and is associated with invasion, angiogenesis and inflammation.
d. Several tumor suppressor including p53 and INK4a are inactivated.
Molecular Biology of Skin Cancer: 4
5. There are no hereditary SCC syndromes. However, xeroderma pigmentosum (XP) exhibits elevated levels of both SCC and BCC.
a. The disease is associated with skin cancer and extreme sensitivity to sunlight. It is also associated with other defects including developmental defects, immunological defects, neurodegeneration, and reginal degeration.
b. XP is due to germline mutations in genes that are involved in nucleotide excision repair. Since there are many different proteins involved in this process, mutations in several different genes can give rise to the same syndrome.
c. A related syndrome is Cockayne’s syndrome. It is also caused by mutations in genes involved in nucleotide excision repair.
CT
-limitations
Limitations
Radiation
Allergic reaction
Contrast induced renal failure
What are the types of polyps in the colonic epithelium
2) Tumorigenesis leads to a disruption of the normal functioning of the colonic epithelium.
a) Cells proliferate uncontrollably
b) Cells no longer die by apoptosis
c) Cells frequently remain in the crypt longer than is normal
d) This results in formation of a polyp which is an abnormal mass of cells that protrude from the surface of the colonic epithelium
e) Two types of polyps
Session Title: 3
i) Hyperplastic polyps – these are small polyps (<5mm in size) that show extensive cell proliferation, but retain many of the differentiated cell types including goblet cells.
ii) Adenomatous polyps – these are larger polyps (>5mm in size) with an abnormal structure and that show loss of differentiated cells are more likely to progress to cancers. These are the adenomatous polyps
(1) Three types of adenomatous polyps
(a) Pedunculated - left colon- associated with CIN
(b) Sessile- usually in right colon- associated with MSI
(c) Semisessile
(2) Size and degree of dysplasia is a key factor in classification of polyps and in assessing progression of the disease
(a) Larger more dysplastic polyps are indicative of more advanced disease.
Melanoma - general facts
1. Melanoma is the deadliest of the skin cancers and is responsible for almost 75% of all skin cancer deaths.
2. It is arguably the most malignant human cancer. It metastasizes to every tissue and death from melanoma is always due to metastases.
3. It is important to recognize that melanoma is not derived from a cell that is of epithelial origin.
a. Melanocytes originate from neural crest cells which migrate to the skin during development.
b. Neural crest cells migrate and give rise to structures in the peripheral nervous system and aid in formation of cartilage, muscle, and bone.
c. The ability of neural crest cells to migrate may be reactivated during melanomagenesis which is thought to be the reason for their ability to metastasize so readily.
4. Melanomagenesis occurs through a series of steps that include histopathological changes accompanied by distinct genetic mutations.
a. The precursor lesion is the dysplastic nevus or atypical mole with irregular boarders and variable color. However, approximately 70% of melanomas are considered to be “de novo”
b. There are four characteristics of a skin mole that are indicative of melanoma. The mnemonic for this is ABCD.
i. A = Asymmetrical mole shape
ii. B = mole with uneven Borders
iii. C = mole with varied Colors
iv. D = mole with a Diameter greater than 6 mm.
Ultrasound limitations
Limitations
Operator dependent
Unhelpful in non-localizable pain
Bone & bowel gas
Many artifacts
4 major pathways mutated in colorectal cancer
1) Loss of WNT signaling
a A key component of the Wnt signaling pathway is the APC tumor suppressor.
b APC controls proliferation of colon epithelial cells. APC is a gatekeeper TS gene.
c Loss or inactivation of APC is sufficient for the formation of adenomas. This is also the basis for several hereditary colon cancer syndromes.
d APC is mutated in 70% of all sporadic colon cancers.
2) RAS mutations
Session Title: 4
a RAS oncogene mutations result in a protein that is constitutively activated. This results in increase signaling through the MAP kinase and PI3 kinase signaling pathways. The result is increased cell proliferation and increased tumor growth
b Mutations in the ras oncogene occur in 30-70% of colon cancers. These mutations are frequently associated with intermediate stages of colon tumor development.
3) Loss of TGFβ signaling
a TGF encompasses many cellular, differentiation and homeostatic processes.
b TGFβ signaling molecules are mutated in ~30% of all human CRC.
c The role of these pathway mutations in CRC are not clear.
d The most common of these mutations (TGFBR2) results from MSI.
4) Loss of P53
a P53 is a caretaker tumor suppressor that has multiple functions in the cell. Mutations in the p53 gene are the most frequent genetic alteration found in human cancers.
b P53 functions include:
i) Inhibition of cell cycle progression in response to DNA damage
ii) Induction of DNA repair gene expression
iii) Induction of apoptotic cell death
iv) Loss of p53 results in increased genomic instability and increased frequency of genetic mutations.
Melanomagenesis
-name the 2 growth phases
-describe the progression and molecular biology
GROWTH PHASES
1) Radial growth phase (RGP)
-the tumor grows laterally along the plane of the epidermis. Tumors caught at this stage can be cured by surgical removal
2) Vertical growth phase (VGP)
-During this phase the tumor expands vertically and invades the dermis and underlying tissues. Depth of penetration of the tumor is highly predictive. The deeper the penetration the poor the prognosis.
GENETICS
d. Genetic alterations that occur during melanomagenesis include
i. Mutations in growth factor receptors such as the cKIT receptor. Melanoma cells also acquire the capacity to produce their own basic fibroblast growth factor. This is normally produced by keratinocytes. Growth of melanoma cells that produce their own bFGF is no longer controlled by keratinocytes and proliferate uncontrollably.
ii. The MAP kinase pathway becomes constitutively activated as a consequence of mutation in N-RAS and B-RAF genes which further stimulate cell proliferation.
iii. Loss of the PTEN tumor suppressor enables constitutive activation of the PI3K pathway.
iv. A key event is loss of the INK4A tumor suppressor
1. The INK4A gene is located at the CDKN2A genetic locus on chromosome 9p21.
2. Loss of the INK4A tumor suppressor occurs in 20% to 40% of melanomas. Notably, germ-line mutations are responsible for a hereditary form of melanoma.
Molecular Biology of Skin Cancer: 6
3. A key function of the INK4A protein is negative regulation of cell proliferation through the retinoblastoma tumor suppressor pathway. Conseqeuently, loss of INK4A results in uncontrolled cell proliferation.
4. The CDKN2A locus also codes for another protein p14ARF that regulates the p53 tumor suppressor. Hence, deletion of the CDKN2A locus results in a genetic aberration that disrupts the functioning of two important tumor suppressors.
MRI limitations
Limitations
Ferromagnetic displacement (eye debris, aneurysm clips, objects)
Electrical interference (pacemakers, defibrillators, neuro-stimulators)
Artifacts from metallic prostheses and debris
Subtypes of colorectal cancer
Actinic Keratosis
Actinic Keratosis:
I. Considered pre-cancerous, but only about 1% evolve to SCC.
II. Clinically scaly/hyperkeratotic lesions on sun exposed skin.
III. Histology
A. Atypical keratinocytes in lower epidermis
B. Underlying solar elastosis (bluish dermis)
C. Overlying parakeratosis (retained nuclei)
Cancer Cachexia
•Clinical Manisfestations
•Majority of patients develop weight loss during their disease course
•Cancers with the least weight loss are:
–Non Hodgkin’s Lymphoma, Breast cancer, Acute Leukemias, and Sarcomas
•Cancers with moderate weight loss
–Colon, prostate and lung cancer
•Cancers with Severe weight loss
–Pancreatic and gastric cancers
•Mechanisms:
–Loss of appetite
•Central component of cancer cachexia
–Serum from tumor bearing rats giving to normal rats causes anorexia Can Res 45:5547, 1985
•Also see altered taste and smell
–Increased energy expenditure / increased basal metabolic rate.
–Weakness
•Loss of both muscle and fat
–Increased cytokine production (TNF, IL-1, IFN-Υ)
–NOT caused by the nutritional demands of the tumor
Multistep model of colorectal cancer progression
Metabolic effects of cancer
(hypercalcemia)
•Cancerous growths can produce growth factors disrupting normal tissue function
–Cytokines leading to cancer cachexia
–Abnormal hormone levels leading to
•Hypercalcemia
•Tumor lysis and hyperuricemia
•Hypoglycemia
HYPERCALCEMIA
•Seen in many cancers
–Most common in:
•Myeloma and breast cancer
–Intermediate incidence in:
•Non small cell lung cancer
–Rare in:
•Colon, prostate and small cell lung cancer
•Much rarer with the use of bone targeting agents (bisphosphonates, denosumab)
iii. Causes of hypercalcemia in cancer patients
a) Bone metastases with direct bone destruction.
b) Parathyroid hormone and PTH related protein.
c) Tumor production of 1,25-dihydroxyvitamin D (calcitriol). Seen in
lymphoma.
d) Cytokines such as tumor necrosis factor and interleukin-1 appear to play
an important role by stimulating the differentiation of osteoclast
precursors into mature osteoclasts.
iv. Clinical Manifestations
a) Dehydration, weight loss, anorexia, polydipsia, fatigue, muscle weakness,
hyporeflexia, confusion, seizure, obtundation.
b) Nausea, vomiting, constipation
c) Polyuria, renal failure
Cancer Emergencies - 5
d) Shortened Q-T interval. In severe cases can see arrhythmia, ST segment
elevation mimicking acute myocardial infarction.
Coagulopathies in cancer
•Most patients with advanced cancers or leukemias have abnormal coagulation
–Individuals can be hypercoagulable
•Patients with cancer, particular adenocarcinoma have an increased risk of DVT and pulmonary embolism
–Highest incidence in pancreatic, breast, prostate and ovarian cancer
–Some Individuals can develop a consumption coagulopathy with low levels of platelets and clotting factors.
•Disseminated intravascular coagulation
•May see bleeding
•The coagulation abnormalities are due to release of procoagulants from tumor cells.
Organ rejection after transplant
-is it humoral or cell mediated?
-hyperacute vs acute vs chronic
-usually cell-mediated but can be humoral (rare)
-cell-mediated> recognition by both CD4 and CD8 cells
-humoral> preformed Abs
Types:
1) hyperacute- rapid thrombotic occlusion of graft vasculature within minutes to hours of restored blood flow> mediated by pre-existing Abs that bind endothelium and activate C'
2) Acute
a) Acute vascular- necrosis of individual blood vess cells> consistent with vasculitis rather than thrombosis
b) Acute cellular- necrosis of parenchymal cells caused by host lymphocytes and macrophages
-acute is within first week of transplant
3) Chronic- fibrosis with loss of normal organ structures> major cause of graph loss
Superior Vena Cava Syndrome
i. Superior vena cava syndrome: The thin walled SVC returns all blood from the
cranial, neck, and upper extremity vasculature to the right side of the heart. This
vessel can be compressed by primary or secondary tumors. Other nonmalignant
causes: massively enlarged thyroid, granulomatous disease, fibrosing
mediastinitis, thromboisis.
ii. Symptoms: Dyspnea, facial swelling / head fullness, cough, arm swelling, chest
pain, dysphagia / voice changes.
iii. Signs: Neck vein distention, distention of chest wall veins, facial edema,
plethora, cyanosis.
iv. Cancers associated with SVC syndrome:
a) Lung cancer (small cell, adenocarcinoma)
b) Breast cancer
c) Primary mediastinal lymphoma
d) Lymphoblastic lymphoma
e) Thymoma
f) Germ cell tumors
Cancer effects in bone
•Cancerous growths in bone can cause
–Structural failure leading to broken bones, and impingement on the spinal cord, brain or nerves
–Impaired blood production secondary to loss of bone marrow space to cancer and consumptive coagulopathies
–Release of calcium from bone leading to hypercalcemic states
EPIDURAL CORD compression
•Back pain – 90% of cases
•Weakness
–Usually in the lower extremities
–Can occur rapidly
–Common complaint is unsteady gait
•Sensory Disturbance
–Decrease in pain and temperature sensation
–Commonly in region distal to tumor level and then ascends
-can also cause cauda equina syndrome (see card)
Cancer effects in brain
Cancerous growths in the brain can disrupt critical neurologic functions even when small
–Paralysis
–Sensory loss
–Loss of Vital organ regulation
–Impaired higher center function
–Seizures
•Brain Metastases are the most common metastatic complication of systemic cancer
•15% of all patients who die of cancer have brain metastases at autopsy
•Of these, over 2/3rds had some neurologic symptom (only 1/3 are occult).
•The incidence of brain metastases is rising as the therapies of systemic disease improves.
•Symptoms
–Headache 53%
–Weakness 40%
–Behavior 31%
–Seizure 15%
–Ataxia 20%
•Signs
–Cognition 77%
–Hemiparesis 66%
–Sensory 27%
–Papilledema 26%
–Ataxia 24%
Forms of melanoma (4)
Forms of Melanoma:
I. Superficial spreading malignant melanoma
A. Radial Growth Phase
B. Frequency = 60-70%
C. Typically on intermittently sunburned skin.
II. Lentigo maligna melanoma
A. Radial Growth Phase.
B. Frequency = 5-15%
C. Typically on chronically sun damaged skin of the elderly.
D. May occur after years of Lentigo Maligna, a form of me-lanoma in situ
III. Nodular melanoma
A. Vertical growth phase
B. Frequency = 15-30%
C. Can be rapidly fatal.
IV. Acral lentiginous melanoma
A. Radial growth phase
B. Frequency = 5-10%, but is the most common form of melanoma in people with darker skin types.
Cancer and fluid accumulation
Cancerous growths can result in abnormal fluid production and collections of malignant fluids causing pressure on organs leading to dysfunction
–Pericardial fluid and tamponade
–Malignant pleural effusions cause lung collapse
–Malignant ascites can impair bowel function
Tumor lysis syndrome
•Caused by massive tumor cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation.
•Most often occurs after the initiation of chemotherapy in patients with high-grade lymphomas and acute leukemia.
•Can occur spontaneously in tumor types that have a high proliferative rate and large tumor burden.
•Hyperuricemia, acute renal failure.
-hyperphsophatemia and calcium phosphate deposition in renal tubules can also cause renal failure
Febrile Neutropenia (in cancer)
•An urgent condition
•Can be directly the result of cancer
–Leukemias
–Lymphomas
–Bone Metastases
•Much more commonly the condition is treatment related
–Leading cause is chemotherapy
–Rarely radiotherapy
•The association of neutropenia and infection was first published in the 1960’s as it occurred in children with leukemia.
•5 Factors effect a patient’s risk:
–The degree of neutropenia
–Phagocytic function
–Cellular and Humoral Immunity
–Altered Physical Defense Barriers
–Endogenous Microflora
–60-70% are gram positives
•Common gram-positive cocci include Staphylococcus aureus, Staphylococcus epidermidis, and streptococci.
–MRSA is common
–30-40% Gram negatives
–Candida is now being seen as a cause of primary infections
-Infection risk begins with absolute neut count (ANC) <1500 and dramatically <500
vii. Major Fungal pathogens are: Candida, Aspergillus, Cryptococcus and
Mucormycosis. Reactivation of endemic fungi (histoplasmosis, blastomycosis,
and coccidioidomycosis) especially in patients with prolonged glucocorticoid
exposure.
f. Broad-spectrum antibiotics should be given as soon as possible and at full doses. Early
studies documented mortality rates of up to a 70 percent if initiation of antibiotics was
delayed. The aim of empiric therapy is to cover the most likely and most virulent
pathogens that may rapidly cause serious or life-threatening infection.
Immunosuppression after organ transplant
-what are some infections to worry about?
-induction vs maintenance regimens
- Steroids (potent immunosuppressive and anti-inflammatory agents that inhibit T-cell activation and other activation signals. Side effects include diabetes, hyperlipidemia, GI toxicity, neurologic and psychiatric toxicity, and others).
- Azathioprine (an antimetabolite that interferes with the precursors of purine synthesis. Adverse events include myelosuppression and GI toxicity).
- Cyclosporin A (a calcineurin inhibitor which inhibits DNA, RNA and protein synthesis. Side effects include diabetes, hyperlipidemia, nephrotoxicity, neurotoxicity, and GI toxicity).
- Tacrolimus (like cyclosporine, a calcineurin inhibitor. Side effects include diabetes, hyperlipidemia, nephrotoxicity, neurotoxicity, and GI toxicity).
- Mycophenolate Mofetil (like azathioprine, an antimetabolite that interferes with the de novo purine synthesis. Side effects include GI toxicity, myelosuppression).
REGIMENS
1) Induction- immediately post transplant
Steroids
ATG/ IL 2 Blockers
2) Maintainance
Steroids
Tacrolimus/Cyclosporin
MMF
Infections due to immunosuppresion
Post operative bacterial
HSV
PCP
CMV
C.DIFFICILE
Calculate an insulin:CHO ratio for a patient who needs prandial insulin
Bolus Dose
Insulin:Carbohydrate (I:C) ratio
• Individually determined
based on insulin
sensitivity
• Based on amt of CHO in
meal
• Questions to ask:
– What am I going to eat?
– Certain? take
immediately before
– Uncertain? take
immediately after
• 500 Rule:
• 500/total daily insulin dose
= estimate of # CHOg 1
unit of insulin will ‘cover’.
• Mr Gonzales is taking 60
units of basal insulin.
• 500/60 = 8.3
• 1 unit of insulin would be
expected to ‘cover’ ~8g
CHO
2) Correction dose or sensitivity factor
• Individually determined
based on insulin
sensitivity
• Based on prevailing blood
glucose
• Questions to ask:
– What is the blood
glucose now?
– What is my target
glucose (eg, 100 mg/
dL)?
– How much insulin do I
need to reach my target?
1800 Rule:
1800/total daily insulin dose =
estimate of mg/dL 1 unit of
insulin will decrease Bg.
Mr Gonzales is taking 60 units
of basal insulin.
1800/60 = 30
1 unit of insulin would be
expected to decrease Bg by
30 mg/dL
Thrombocytopenia in cancer
•Caused by a wide array of benign and malignant conditions. Severe bleeding complications are rare.
•As with neutropenia, can be related to hematologic malignancy due to bone marrow involvement. Can also be related to the toxic effects of chemotherapy on the bone marrow.
•Prior to 1960: Bleeding was a major cause of death in children being treated for leukemia.
•Current recommendations:
»Threshold for transfusion is 10,000 unless infection, bleeding, anatomic defect. Threshold is then 20,000 to 30,000.
Relate how cancer and cancer treatments cause nutrition-related side effects
Tumor “Threat” Changes Metabolism
“Fight or flight” response
Decreased appetite
–Hunger is deferred when “attacked”
Protein Changes
–Increased breakdown for quick energy: glucose
–Changes in proteins produced
More help for clotting
Less production of proteins not involved in surviving attack
Adaptive changes for emergencies
Less adaptive with a long-term threat of cancer
1) Tumor derived factors mobilize lipids and promote proteolyis in muscle
2) Inflammatory response from tumor promotes decreased glucose utilization in muscle and decreased appetite
Nutrition related SE:
-anorexia
-Nausea/vomiting
-Mouth sores
-Taste Changes
-Dry mouth
-Constipation
-Diarrhea
Glycemic index vs glucemic load
1) glycemic index is the increase
above fasting in the blood glucose area over 2 hr after ingestion of a
constant amount of a particular food, divided by the response to a
reference food (usually glucose or white bread).
2) glycemic load of a
meal is calculated by multiplying the glycemic index of the constituent
foods by the amounts of CHO in each food and then totaling the values
for all foods.
i. Research results have not consistently shown benefit of low GI
diets in diabetic patients, except those with a baseline high GI
diet.
ii. Over and above limiting (or compensating for) total CHO, a low GI
diet may provide modest benefit.
Hyperleukocytosis in the setting of acute leukemia
•Defined as a white blood cell count >100,000 cells/mm3. Seen in hematologic malignancies, particularly acute leukemia. Also seen in chronic leukemias, lymphomas.
•Patients become symptomatic in acute leukemia because leukemic blasts are less deformable and larger than mature cells. Patients with more chronic conditions may not be symptomatic and treatment is not emergent.
•Complications occur secondary to:
–Microcirculatory plugs (hypoxia).
–Hypoxia is exacerbated by the high metabolic activity of the blasts.
•Common presentations:
–Hyperleukocytic intracerebral hemorrhage: stupor, delirium dizziness, tinnitus, visual changes. On physical exam may find ataxia, papilledema, retinal vein distention.
–Pulmonary vascular occlusion: dyspnea, tachypnea, hypoxemia.
–Less frequent: vascular insufficiency, claudication, priapism.
•Patients with acute leukemia and hyperleukocytosis are very high risk for tumor lysis (both with treatment and spontaneous), neutropenic fever, thrombocytopenia with bleeding. Must be managed in the hospital, generally in the ICU.
Describe types of nutritional changes that cause malnutrition in cancer patients
1) Mechanical- tumor obstruction of GI
2) Treatment related
Chemotherapy: N/V/D, mucusitis, anorexia
Radiation: anorexia, taste changes, dysphagia, diarrhea, mucositis, fistulas, strictures
Surgery: dumping, malabsorption, impaired intake
3) Tumor-related
-Cancer cachexia characterized by progressive weight loss, anorexia, generalized wasting, immuno-suppression, altered basal metabolic rate, and abnormalities in fluid and energy metabolism.
Causes of cancer cachexia include those associated with the inflammatory response as well as tumor derived factors.
Effective treatment of cachexia is difficult and probably needs multiple treatment strategies including calorie supplements/interventions, appetite stimulants, and a
means to target the underlying pathology such as cytokines, prostaglandins, and other mediators via NSAIDS, COX2 inhibitors and omega 3 inhibitors and omega 3 fats.
Pyoderma Gangrenosum
-associated with what dz?
Pyoderma Gangrenosum
I. Skin ulceration secondary to sterile neutrophilic infiltrates often due to trauma (pathergy).
II. Most commonly associated with inflammatory bowel disease, but can be associated with rheumatoid arthritis or IgA gammopathy.
III. Neutrophilic infiltrates can involve internal organs.
Sarcoidosis
Sarcoidosis
I. Erythermatous to violaceous plaques of nose (lupus pernio), but many other manifestations including erythema nodosum.
II. Non-caseating granulomas – most commonly African Americans.
III. Most commonly pulmonary, but skin affected in 15-30% and may be the presenting sign.
•Dermatological manifestations:
–Erythema nodosum may occur. A lower extremity panniculitis with painful, erythematous nodules. Associated with Löfgren syndrome but may be seen in other conditions
–HLA-DQB1*0201 is strongly associated with Löfgren syndrome.
–Lupus pernio is the most specific associated cutaneous lesion
–Osseous involvement may be present
–Maculopapular plaques are possible
Tuberous Sclerosus
Tuberous Sclerosis
I. Facial angiofibromas (adenoma sebaceum), periungual fibromas, connective tissue nevus of skin (Shagreen patch), and hypopigmented macules (ash leaf shape).
II. Greater than 90% of cases have skin involvement.
III. Multiple hamartomas found in other organs.
IV. Autosomal dominant usually diagnosed between age 2 and 6.
Two genetic loci for tuberous sclerosis have been identified so far.
–The first gene maps to chromosome 9, TSC1; Hamartin/may function as a tumor suppressor
–The second gene maps to chromosome 16, TSC2; Tuberin / homologic identity Rap 1 GAP. Rap 1 is a member of a group of proteins involved in the regulation of cell proliferation and differentiation.
Neurofibromatosis
(Von Recklinghausen's)
Neurofibromatosis (Von Recklinghausen’s Disease)
I. Numerous neurofibromas of skin with café au lait macules.
II. Lisch nodules of iris and acoustic neuroma.
III. Hypertension secondary to pheochromocytoma.
IV. Autosomal dominant disorder.
•Two major subtypes exist: type 1 neurofibromatosis, also known as von Recklinghausen neurofibromatosis, which is the most common subtype and is referred to as peripheral neurofibromatosis, and type 2 neurofibromatosis, which is referred to as central neurofibromatosis.
•Axillary freckling (as well as freckling on the perineum), known as the Crowe sign
•Neurofibromas are the most common benign tumor of type 1 neurofibromatosis. These tumors are composed of Schwann cells, fibroblasts, mast cells, and vascular components. Plexiform neurofibromas are noncircumscribed, and specific for type 1 neurofibromatosis
Describe the radiobiological basis of the effects of radiation on normal and tumoral tissue
•External beam radiation therapy is an ionizing photon beam
•The radiation beam is generated in a similar fashion to x-rays (using a linear accelerator) and both are photon beams, but the radiation beam has a higher energy than diagnostic x-rays
•“Ionizing” means the radiation beam has enough energy to remove orbital electrons from atoms in the cell (direct damage) or from water, which in turn creates free radicals (indirect damage)
•The highly reactive free radicals cause DNA damage
•The process of creating free radical requires oxygen
-the ultimate insult is a double strand break, can't repair> leads to apoptosis> the higher the dose the more double strand breaks
Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome)
Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome)
I. Numerous telangiectasias involving skin, oral and nasal mucosa, eyes, lungs, liver, spleen, brain, GI and GU tracts.
II. Pulmonary arteriovenous malformations associated.
III. Autosomal dominant disorder usually manifests by age 40.
IV. Epistaxis is the most common presenting symptom.
V. Spontaneous internal hemorrhage can develop and may be life threatening.
Reiter's syndrome
Reiter’s syndrome
I. Scaling plaques with occasional pustules involving palms, soles, and genital areas.
II. Associated with classic triad – urethritis, conjunctivitis, oligoarthritis which may occur sequentially.
III. Associated with HLA-B27.
Scleroderma
Scleroderma (progressive systemic sclerosis)
I. Symmetric thickening, tightening, and induration of skin.
II. May be more localized or diffuse with involvement of internal organs.
III. Can be associated with calcinosis, Raynaud’s, and ulcers.
IV. Autoimmune fibrotic sclerosis with eventual occlusion of microvasculature.
Electromagentic vs Particulate Radiation
1) Electromagnetic
-X-rays are produced artificially from an extranuclear process whereas gamma rays are produced intranuclearly from a decay process. In practical terms, x-rays that are produced by linear accelerators that accelerate electrons to high energy and then stops them abruptly into a target (usually made of tungsten). When the highly energetic electrons stop part of the kinetic energy of the electron is converted to x-rays.
-Gamma rays- emitted by radioactive isotopes and represent excess energy given off by unstable nucleus that breaks up and decays in effort to reach stable form
2) Particulate radiation
1. Electrons- are small, negatively charged particles that can be accelerated to very high energy to a speed close to that of light; they are widely used in cancer therapy for superficial tumors.
2. Protons- are positively charged particles with a mass almost 2000 times greater than that of electrons. They are produced by complex and expensive equipment called cyclotrons. They are only now starting to be widely used for cancer therapy.
3. Alpha particles- are nuclei of helium atoms composed of two protons and two neutrons. They are positively charged and therefore can be accelerated in large electrical devices, cyclotrons.
Principles of Radiation Therapy for Clinicians: 3
4. Heavy charged particles- are elements such as carbon, neon and argon that are positively charged by stripping atoms from the planetary electrons.
Define the risk factors associated with thyroid cancer
-Differentiated vs Anaplastic vs Medullary
Differentied= papillary, follicular, and Hurthle cell
Outline the work-up of thyroid nodules
1) Physical Examination:
Size
Consistency
Mobility
Multifocality
Lymphadenopathy
2) Ultrasound > High Risk Nodule:
>1 cm
Irregular margins
Hypervascular
Internal calcifications
Round, instead of oval or flat
3) Fine Needle Aspiration (FNA)
Benign (~70%)
Follicular Neoplasm (~15%)
Suspicious for Papillary (~10%)
Malignant (~5%)
Inadequate/Nondiagnostic (repeat FNA)
Sweets Syndrome
(Acute Febrile Neutrophilic Dermatosis)
Acute Febrile Neutrophilic Dermatosis (Sweet’s Syndrome)
I. Indurated erythematous to violaceous plaques on face, neck, and upper extremities – malignant form may be bullous.
II. Benign form most common in women following URI, but can be associated with connective tissue disorders, drugs, pregnancy, and coccidiomycosis in AZ.
III. Fever and leukocytosis accompany flares.
IV. Myelodysplasia, AML, and lymphoma may follow years later.
Lymphoma (as a thyroid cancer)
Lymphoma
1-2% of thyroid cancers
Most common is non-Hodgkin’s B-cell lymphoma
Associated with Hashimoto’s thyroiditis
Rapid enlargement of thyroid gland
Need to diagnose on FNA
Non-surgical treatment
Chemoradiation
Dermomyositis
Dermatomyositis
I. Periorbital heliotrope (violaceous) hue, poikiloderma (scaling erythema with atrophy and telangiectasia), Gottron’s papules of fingers, and proximal limb muscle weakness secondary to myositis.
II. Increased carcinoma of ovarian, cervical, lung, pancreatic, gastric, and lymphoma.
III. Can preceded malignancy by many years leading to debate on causal association.
•DM is a disease of presumed autoimmune pathogenesis that is manifested by a symmetric proximal, extensor, inflammatory myopathy and a characteristic cutaneous eruption
•Although the etiology of dermatomyositis remains unknown, there is evidence to support a pathogenesis based on lymphocyte-mediated muscle damage and cutaneous lesions that result from an apoptotic reaction
Associated Malignancies
•The reported frequency of an internal malignancy in adults with dermatomyositis varies from less than 10% to over 50%
•Patients with dermatomyositis without myositis also appear to be at increased risk for associated carcinomas. Genitourinary malignancies, especially ovarian cancer, and colon cancer may be over-represented
•Other commonly seen malignancies include breast, lung, gastric, pancreatic, lymphomas (including non-Hodgkin) and other female genital cancers
Identify 3 common examples of targeted therapies in cancer
•Fusion proteins made through genetic translocations in oncogene
– BCR-ABL in CML
–C-kit overexpression in “GIST” (gastrointestinal stromal tumors)
•Signaling pathways involved tumor new blood vessel formation
–Vascular endothelial growth factor (“VEGF”) and VEGF receptors in many solid tumors
•Membrane-based growth receptors, mutated or activated
–HER-2 in breast cancer, ovarian cancer
–EGFR in lung cancer, colon cancer, head and neck cancer, colon cancer
Define the treatment of thyroid cancer
1) Total Thyroidectomy
Malignant diagnosis on FNA
Neoplasm with bilateral thyroid nodules
Suspicious nodules with family history or radiation exposure
2) Thyroid Lobectomy
Neoplasm diagnosis on FNA
No associated risk factors
3) Lymph Node dissection
Indicated for palpable nodes
not necessary for non-palpable nodes, minimal disease not clinically significant and can be treated with radioiodine
non-palpable but US + node
Routine for aggressive cancers that do not take up iodine, such as medullary and Hürthle cell cancers
Central neck dissection
Hyoid to sternum, carotid to carotid
Modified radical lateral neck dissection
Preserve accessory nerve, internal jugular and SCM
4) Radioactive Iodine???
Paraneoplastic Pemphigus
Paraneoplastic Pemphigus
I. Oral and skin blisters, erosions, and sometimes targetoid lesions.
II. Histologic features of pemphigus combined with erythema multiforme.
III. Strongly associated with non-Hodgkin’s lymphoma and CLL.
-often fatal
Understand why the epidermal growth receptor pathway is a relevant drug target in lung cancer
EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AS A TARGET FOR LUNG CANCER TREATMENT
EGFR: membrane receptor, one of four of the “HER’ family of growth signaling receptors
EGFR is expressed in a variety of normal tissues
(skin, corneal epithelium, GI), but no critical function
Aberrancy of this signaling pathway is seen in some important cancers, including non-small cell lung cancer, other epithelial cancers (colon, head and neck, gastric), some sarcomas (including mesothelioma) and gliomas
Overexpression of EGFR has been associated with more aggressive behavior and worse prognosis
IDENTIFYING PATIENTS “SENSITIVE” TO EGFR INHIBITORS
Works best in persons with subtype of lung cancer (adenocarcinoma), neversmokers, women, Asians
This patient “phenotype” has been associated with both presence of EGFR activating gene mutations and EGFR gene amplification
When patients are selected for EGFR-based drugs based on testing tumor for these molecular lesions, can get response rates in 70-90% of patients, as compared to only 15% in unselected Caucasians and 25% of unselected Asians (predictive biomarker for response)
Types of Thyroid cancer (5)
-what is the most common?
1. Papillary thyroid cancer (80%)
2. Follicular thyroid cancer (10%)
3. Hürthle cell carcinoma (3%)
4. Medullary thyroid cancer (5%)
5. Anaplastic thyroid cancer (2%)
Amyloidosis
Amyloidosis
I. Cutaneous involvement may appear as purpura which develops after pressure/rubbing – sometimes as waxy periorbital papules with “pinch purpura”.
II. Macroglossia/smooth tongue
III. May be associated with multiple myeloma producing light chain amyloid (AL)
•The three major forms of primary cutaneous amyloidosis are:
–macular amyloidosis: confluent or rippled hyperpigmentation, often on the upper arm and back
–lichen amyloidosus: hyperpigmented papules, often in a rippled pattern and on the extensor surfaces of the extremities and back
–nodular amyloidosis: waxy skin-colored to pink nodules
Highlight the side-effect profiles of targeted therapies compared to non-targeted therapies
EGFR inhibitors: Toxicities
Skin: Acneiform rash face, upper torso, arms up to 75% in Phase II studies
Mostly mild to moderate in intensity, occasionally severe
Often improved with holding the dose, or dose reduction
GI: diarrhea, vomiting
Treated with dose reduction or oral medication
Neurologic: HA
Ophthalmic: keratoconjunctivitis
Constitutional: fatigue
Pulmonary: Interstitial pneumonitis
Incidence: <1% U.S., 3% Japan (database 39,000 patients)
Majority in Japan were males, current smokers, squamous cell histology
Targeted Cancer Therapy: 3
Can be fatal
Treated with high dose steroids, oxygen, +/- mechanical ventilation
Essentially no hematologic toxicity seen
No neutropenia (thus no neutropenic fevers), no anemia, no thrombocytopenia
Papilary thyroid cancer
Papillary thyroid cancer
Most common, best prognosis
Increased risk with radiation history, family history, breast cancer, colon cancer syndromes
Overall 10-year survival > 90%
20% to 30% recur
80% have lymph node metastases
Primary systemic amyloidosis
Primary Systemic Amyloidosis
•Mucocutaneous lesions are seen in 30-40% of patients with primary systemic (AL) amyloidosis and include waxy nodules and plaques, ecchymoses, pinch purpura, and macroglossia; carpal tunnel syndrome with the latter is a classic presentation
•In the absence of specific mucocutaneous lesions, aspiration of abdominal fat can be performed to detect amyloid deposits and confirm the diagnosis of primary systemic amyloidosis; once the diagnosis of AL amyloidosis is established, evaluation for systemic involvement is indicated
Account for the purpose and effects of fat in the liver cells
 Steatosis means abnormal accumulation of triglycerides in the liver
 It could also happen in the heart, muscle and kidney
 Causes include toxins, protein malnutrition, diabetes, obesity and anoxia
 Free fatty acid is esterified in the liver to triglyceride which is excreted as lipoprotein. Carbon tetrachloride and starvation can cause lack of apoprotein synthesis.
 Alcohol induces number of defects primarily by mitochondrial dysfunction
 Anoxia inhibits fatty acid oxidation.
 Small amounts of steatosis is ok but acute massive steatosis can be fatal
Follicular thyroid cancer
Follicular thyroid cancer
10% of thyroid CA
Worse prognosis than PTC
Up to 33% have distant metastasis
Average overall 10-year survival rate is 85% (range, 43% to 95%)
Cannot diagnose on FNA
Acanthosis Nigricans
Acanthosis Nigricans
I. Velvety hyperkeratotic and hyperpigmented plaques in intertriginous areas (axillae, neck, or groin)
II. Malignant form is rare, but can be associated with adenocarcinoma, especially gastrointestinal.
III. Benign form is common and is seen with obesity and diabetes.
Distinguish between alcoholic versus non-alcoholic fatty liver disease
A. Alcohol Related Steatohepatisis
 76% of US consume alcohol, 14 million are alcohol abusers (twice as common in men)
 200,000 deaths are alcohol related, mostly from automobile accidents
 Commonest cause of cirrhosis related deaths (40%)
 Liver can weigh as much as 6kg
 Fat can be micro- or macro vesicular
Steatohepatitis 2
 Hepatocyte swelling because of accumulation of fat, water and protein leads to ballooning degeneration
 Neutrophils are around ballooning hepatocytes and particularly where there is Mallory’s hyalin (deposited prokeration). Changes lead to fibrosis and cirrhosis
B. Non-Alcoholic Fatty Liver Disease
 Men and women are equally affected
 Associated with obesity, hyperlipedimia, and type 2 diabetes
 Changes are similar to alcohol related injury
 Patients are asymptomatic, abnormalities are biochemical
 70% of chronic hepatitis of unknown cause of which 10-30% will develop cirrhosis
 The commonest cause of cryptogenic cirrhosis
 Makes hepatitis C disease worse
Hurthle cell carcinoma (thyroid)
Hürthle cell carcinoma
3% of all thyroid cancers
10-20% have lymph node metastasis
15% have distant metastasis
65% of tumors > 4 cm are malignant, 17% < 1cm
35% of HCN are malignant; higher if male and XRT
10-year survival rate is 70%
Muir-Torre Syndrome
Muir-Torre Syndrome
I. One or more sebaceous neoplasms associated with one or multiple visceral malignancies.
II. Sebaceous Tumors = adenoma, epithelioma, carcinoma.
III. Visceral malignancy usually GI or GU.
IV. Keratoacanthomas frequently associated.
V. Autosomal dominant in 59% of cases
Summarize the biochemistry and circumstances behind Reye Syndrome and acute fatty liver of pregnancy
C. Reye Syndrome
 With very rare exceptions, occurs in children
 Usually precedes by viral type illness, e.g., influenza B, Varicilla, etc.
 Initial symptoms vomiting and lethargy, quickly can change into mental status changes including seizures with hypoglycemia
 Salicylates play a role, number of deaths has declined in the US (555 in 1980)
 Mitochondria are enlarged and misshaped
 Early diagnosis with biopsy confirmation will lead to monitored supportive cared
 All patients have a presumed metabolic disorder
 Transplantation is only a last resort
 Extremely elevated liver enzymes
 Extensive microvesicular steatosis
 Treatment is N-acetylcysteine, repletes glutathione
D. Acute Fatty Liver of Pregnancy
Steatohepatitis 3
 Majority of steatosis in pregnancy have a mild course, but acute fatty liver of pregnancy can progress to liver failure and death in days
 Rare instance where the fetus causes metabolic disease in mother. For example, heterozygous mother with mitochondrial hydroxylacyl CoA dehydrogenase deficiency can undergo liver dysfunction because of hydroxylacyl fetal metabolite
Medullary thyroid cancer
Medullary thyroid cancer
5% of thyroid cancers
Sporadic (75%): 85% are unilateral and unifocal
Inherited (25%): FMTC, MEN2A and MEN2B; 90% are bilateral and multifocal
Associated with RET proto-oncogene (10% of sporadic)
80% of palpable nodules have LN metastasis
60-80% ipsilateral
 40% contralateral
Treatment: Total thyroidectomy + BCND
Overall survival rate of 75% at 10 years after treatment and 50% at 15 years.
Men 2b
-multiple mucosal neuroma syndrome
Multiple Mucosal Neuroma Syndrome (MEN IIb)
•MEN 2B or 3 is a genetic disease that causes multiple tumors on the mouth, eyes, andendocrine glands. It is the most severe type of multiple endocrine neoplasia, differentiated by the presence of oral and submucosal tumors in addition to endocrine tumors
•95% of patients with MEN 2B have a single-point mutation of the RET proto-oncogene encoding a receptor tyrosine kinase in the neurotrophic factor family.
•Associated with medullary thyroid carcinoma and pheochromocytoma.
Explain the diversity in fat accumulation in drug toxicity (in steatohepatitis)
Steatosis Caused by Drug Toxicity
 A large number of agents can do it
 Zonal differences are massive, e.g., phosphorus in peripheral zone whereas tetracycline and alcohol are centrilobular
 Microvesicular steatosis is usually acute, nucleus is central. An example is tetracycline.
 Aflatoxin, Reye Syndrome and fatty liver of pregnancy are other conditions that cause microvesicular changes
 Necrosis and steatosis can occur together (e.g., CC/4, tannic acid, Tylenol)
 Phospholipidosis can cause a third type of steatosis. An example is amiodarone induced liver disease.
 Cytochrome system plays a key role to zone of injury
 Some agents produce more characteristic morphologic patterns of injury
o Steatosis
Microvesicular steatosis (valproic acid, tetracycline, azothiaprine, phosphorus, ethanol)
Macrovesicular steatosis (ethanol, methotrexate, tamoxiphen, valproic acid, organic compounds)
Steatohepatitis-like (amiodarone, tamoxiphen, methotrexate)
o Necroinflammatory
Acute coagulative (zonal) necrosis
Perivenular (centrilobular)(acetaminophen, halothane, CCl4)
Acute hepatitis-like (isoniazid, sulfonamides)
o Cholestatic (Erythromycin, estrogens, androgens, diphenylhydantoin)
Hepatic steatosis/steatohepatitis 5
o Vascular – sinusoidal dilatation (oral contraceptives, androgens, glucocorticoids, azothiaprine)Other etiologies of steatosis/steatohepatitis
Anaplastic thyroid cancer
Anaplastic thyroid cancer
-all anaplastic carcinomas are considered Stage IV
Least common (1%), but worst prognosis
Associated with cancer transformation
Up to 85% of patients have lymph node enlargement and 75% have systemic metastases
5-year survival rate of patients with ATC is 5% to 10%
Mean survival is 3 to 9 months
List other known etiologies of steatosis/steatohepatitis.
OTHER ETIOLOGIES OF STEATOSIS/STEATOHEPATITIS
 Metabolic disorders – total parenteral nutrition, rapid weight loss, acute starvation, hypothyroidism, hyperlipidemia, ? fatty liver of pregnancy
 Abdominal surgery – gastroplasty for morbid obesity, biliopancreatic diversion, jejuna bypass
 Miscellaneous – Wilson’s disease, Weber-Christian disease, abetalipoproteinemia, bacterial overgrowth
Urticarial Drug eruption
Urticarial
I. Rapidly appearing and migrating erythematous wheals.
II. May be associated with angioedema or anaphylaxis.
III. IgE / mast cell mediated.
IV. Most cases idiopathic rather than drug induced.
Type I HS
Compare histology of alcohol vs non-alcohol fatty liver sz
ALCOHOLIC
 Hepatocyte swelling and necrosis (balloon degeneration)
o Steatosis is initially microvesicular (small droplet) and with time, macrovesicular
o The cells swell with excess fat, water, and proteins (which are normally exported). There is accompanying necrotic damage. The cell swelling may block nearby biliary ducts, leading to cholestasis in surviving hepatocytes. There is mild deposition of iron in hepatocytes and Kupffer cells.
 Mallory’s hyaline
o Cytosolic keratin filaments accumulate and complex with ubiquitin. These are seen as eosinophilic (pink) clumps within the cytoplasm of hepatocytes. Mallory’s hyaline is characteristic of, but not s specific feature of, alcoholic liver disease.
 Neutrophilic inflammation
o Neutrophils invade the hepatic parenchyma and accumulate around degenerating hepatocytes, especially those with Mallory’s hyaline. Lymphocytes and macrophages are also present.
 Fibrosis
o The inflammatory process activates sinusoidal stellate cells as well as portal fibroblasts, giving rise to fibrosis. The fibrosis is usually sinusoidal and perivenular (centrilobular).
o Cirrhosis is the final, irreversible form of liver fibrosis. The cirrhotic liver consists of islands of surviving hepatocytes separated by bands of dense fibrous tissue.
NON-ALCOHOLIC
 Steatosis
o Involves at least 5% of hepatocytes and sometimes > 90%
o May be both small droplet (microvesicular) and large droplet (macrovesicular) triglyceride within hepatocytes
 Steatohepatitis
o Neutrophilic inflammation - Neutrophils invade the hepatic parenchyma and accumulate around hepatocytes containing fat droplets; multifocal
o Mallory’s hyaline
o Hepatocyte necrosis – both balloon degeneration and apoptosis
 Fibrosis
o Sinusoidal
o In portal areas
o Perivenular
o Cirrhosis
Explain how PTHrP can have similar effects as PTH without being detected by PTH assays
The HHM factor instead encodes a peptide, PTH-related protein (PTHrP) that only has significant
homology with parathyroid hormone in the most amino-terminal 13 amino acids, which is the receptor
binding region.

This is a classic case of hypercalcemia due to secretion of parathyroid hormonerelated
protein (PTH-rP) by a neoplasm. This condition is also called humoral
hypercalcemia of malignancy (HHM).
Hypercalcemia is commonly found in patients with osteolytic metastases, due to
high bone turnover. However, in HHM, the hypercalcemia is due to secretion of a
peptide that mimics the actions of parathyroid hormone on the kidney and skeleton.
In bone, the PTH-rP binds to the PTH receptor on the surface of osteoblasts,
causing secretion of a paracrine factor that induces the action of osteoclasts, as well
as secretion of osteoclast differentiating factor (ODF). The net effect is increased
bone resorption, due to increased numbers of osteoclasts and increased osteoclast
activity. In the kidney, the PTH-rP acts on the proximal tubule to reduce phosphate
absorption and increase calcium resorption.
Humoral hypercalcemia of malignancy has been described in association with
several different types of neoplasms, including renal cell carcinoma, adult T-cell
leukemia, and adenocarcinoma of the breast, esophagus and colon. However, most
cases are due to squamous cell carcinoma, most commonly of the lung. In some
cases, immunohistochemistry can be used to detect protein expression of PTH-rP in
tumor tissue. There is some evidence to suggest that PTH-rP may have added
actions in promoting tumor growth and in the development of bone metastases.
Although clinically significant due to the potential serious consequences of
hypercalcemia, HHM is rare, and is seen in only 2-3% of patients with pulmonary
carcinoma. Due to feedback inhibition, patients with HHC usually have normal or
decreased levels of circulating parathyroid hormone and histologic examination of
the parathyroid tissue is normal. Circulating PTH-rP can be detected in the blood
and confirms the diagnosis.
Vasculitic Drug Eruption
Vasculitic
I. Palpable purpuric papules, especially on legs.
II. Secondary to immune complexes lodging in small vessels producing leukocytoclastic vasculitis (LCV).
III. LCV also occurs with infections and connective tissue diseases.
Compare mechanism of alcohol vs non-alcohol fatty liver sz
ALCOHOLIC
 Exposure to alcohol causes steatosis, dysfunction of mitochondrial and cellular membranes, hypoxia, and oxidative stress
 Normal substrates are shunted away from catabolism and toward lipid biosynthesis
 The oxidation of ethanol by ADH (alcohol dehydrogenase) produces acetaldehyde, which is then metabolized by acetaldehyde dehydrogenase to acetic acid.
 NAD is used as an oxidizing agent and converted to the reduced form NADH in these reactions. Because NAD is required for the oxidation of fat, its depletion inhibits fatty acid oxidation, resulting in fat accumulation within hepatocytes (steatosis). Variations in ADH isoforms may account for differences in ethanol metabolism rates.
o Acetaldehyde is a reactive metabolite and induces lipid peroxidation and acetaldehyde-protein adduct formation, which further disrupts cytoskeletal and membrane function.
o The microsomal ethanol-oxidizing system (MEOS) uses NADPH and molecular oxygen to oxidize ethanol using cytochrome P-450 as the central enzyme. This enzyme is also involved in the biotransformation of other drugs such as acetaminophen. Ethanol upregulates P-450 and the proportion of ethanol metabolized via this pathway increases with the severity and duration of alcohol consumption. P-450 metabolism produces reactive oxygen species (ROS) that react with cellular proteins, damage membranes, and alter heptocellular function. Impaired metabolism of methionine results in decreased intrahepatic glutathione levels with resultant increased susceptibility to oxidative injury.
 There may be impaired assembly and secretion of lipoproteins.
 There is increased peripheral metabolism of fat.
 Fatty change can occur within days of alcohol consumption. With abstinence, the normal redox state is restored, the fat is mobilized, and steatosis resolves.
 Steatosis can be a benign and reversible condition. However, rupture of lipid-laden (fatty) hepatocytes may lead to focal inflammation, granuloma formation, and fibrosis.
NON-ALCOHOLIC
 Excessive triglyceride accumulation in the liver
o Excessive importation of free fatty acids (FFA) occurs with obesity and with excessive conversion of carbohydrates and proteins to triglycerides (as in overeating)
o Decreased hepatic export of FFA secondary to reduced synthesis or secretion of VLDL (patients with NASH may have a defect in postprandial ApoB secretion, leading to triglyceride accumulation).
o Impaired oxidation of FFA as seen in patients with the metabolic syndrome/obesity/insulin resistance (decreased aponectin, leptin)
o Insulin resistance
Common causes of hypercalcemia
CHIMPS - Mnemonic for Relative Frequencies of Causes of Hypercalcemia
Cancer – primary malignancies of bone marrow (myeloma, leukemia), osteolytic
metastases, or secretion of PTH - related protein by tumor cells (humoral calcemia of
malignancy)
Hyperparathyroidism (primary)
Intoxication with vitamin D
Milk-alkali syndrome – excessive ingestion of calcium or calcium carbonate (milk
antacids)
Paget's disease and immobilization – both cause accelerated bone turnover
Sarcoidosis – due to dysregulated production of 1,25(OH)2D3 by activated macrophages
Exanthematous (Morbilliform) drug eruption
Exanthematous (morbilliform)
I. Fine papules, symmetric and diffusely scattered – measle like.
II. The most common drug eruption.
III. Usually spares the palms and soles.
Type IV HS
Hemochromatosis
-incidence
-pathophys
-organs involved (5)
INCIDENCE
•Northern European
•Autossomal Recessive
•Variable Penetrance
•Most cases homozygous for mutation in the HFE gene
•Screening with serum transferrin - iron saturation
•Most common cause of primary iron overload
MECHANISM
•Pathophysiology- increased iron absorption by enterocytes in the duodenum
•Most important prognostic factor- fibrosis on liver biopsy
•Secondary Hemochromatosis- ineffective hematopoiesis: thalassemia major, myelodysplastic syndrome, sideroblastic anemia
Excessive iron is directly toxic to tissue:
1)Lipid peroxidation via iron free radical reactions
2)Stimulation of collagen formation
3)Interaction of reactive oxygen species and of iron itself with DNA, leading to lethal injury or predisposition to hepatocellular carcinoma.
MAJOR ORGANS INVOLVED
1) Pancreas
•Morphology
–Interstitial fibrosis
–Parenchymal atrophy
–Iron in acinar cells, islet cells (selective for b-cells) and interstitium
•Clinical
–Early
•Insulin resistance
b-cell dysfunction
–Late
•Insulin deficiency
–Diabetes
–Malabsorption
2) Liver
• Iron deposition, hepatomegaly
• Eventual fibrosis and cirrhosis
Hepatocellular Carcinoma
• 20 to 200-fold increased risk
• Risk greatest in males
3) Skin
•“Bronze diabetes”
–Hemosiderin deposition in skin
–Increased melanin production
4) Myocardium
•Morphology
–Iron deposition in myocytes
–Fibrosis
–Cardiomegaly
•Clinical features
–Restrictive (early) or dilated (late)
–Conduction system abnormalities
•Arrhythmia
–1/3 of these patients will die of cardiac causes
5) Testicle
•Morphology
–Testicular atrophy
•Interstitial fibrosis, thickened basement membrane, absent spermatogenesis
–Not significantly pigmented
•Clinical features
–Hypogonadism due to excess iron deposition in pituitary, selectively in gonadotropic cells
–Decreased LH, FSH
• Erythema Multiforme: Targetoid erythematous lesions – often present on palms and soles. Herpes and other infections also associated
• Stevens-Johnson Syndrome: Erythema multiforme major
involves mucosal surfaces and less than 10% body surface. Requires hospitalization for fluid management and urinary catheter.
•Toxic Epidermal Necrolysis: Acute epidermal exfoliation of more than 30% of body surface. Potentially lethal skin eruption requiring hospitalization for management of fluids and potential infection.
Adrenal incidentaloma
Adrenal incidentaloma
 Definition: An adrenal mass identified during radiologic examination for other reasons, excluding staging and work-up for cancer
 Incidence: 8.7%
 80% are nonfunctioning
 5% have subclinical Cushing syndrome
 5% have pheochromocytoma
 1% Aldosteronoma
 < 5% adrenocortical carcinoma
 2.5% metastatic lesions
 Others: ganglioneuromas, myelolipomas, or benign cyst
Management Guidelines
1.Determine FUNCTIONALITY
2.Assess RISK of malignancy
3.Select APPROPRIATE treatment
- Observe
- Surgery
- Medical management
Paraneoplastic syndromes
Paraneoplastic syndromes
•This type on clinical entities are comprised of non-metastatic systemic effects which accompany malignancy, presumably due to substances produced by a tumor resulting in cross reactions between normal antigens and tumor antigens during the immune response to the tumor.
•They may precede detection of internal malignancy and potentially aid in early detection if recognized.
Primary Hyperaldosteronism
1) Primary Aldsoteronism
•Mean age at diagnosis is 50 years
•Slight male predilection
•HTN is responsiveness to spironolactone
•Untreated has increased risk of:
–CVA
–MI
–Atrial fibrillation
–Left ventricular hypertrophy
•Occurs in 8 to 12% of hypertensive patients
•Suspect in:
–HTN of early onset
–Refractor HTN (3 Rx)
–HTN with hypokalemia (30-40%)
•Symptoms are nonspecific
–Hypokalemia: muscle weakness, cramps, fatigue, polydipsia, polyuria, nocturia, paresthesias
SUBTYPES
•Adenoma (30%)
•Idiopathic bilateral hyperplasia (65%)
•Adrenal carcinoma
•Familial hyperaldosteronism
–Type I (glucocorticoid remediable)
–Type II (aldosteronoma or carcinoma idiopathic)
DX
•Plasma aldosterone concentration (PAC) > 15 ng/dL
•Plasma renin activity (PRA) < 0.2 to 0.5 ng/mL/hr
•A PAC-to-PRA ratio > 20
•Rarely needed: Confirmation with salt test
–24-hour urine aldosterone >12 μg/24
–Plasma aldosterone levels > 10 ng/dL
RX
•Treatment:
–Unilateral adenoma: laparoscopic adrenalectomy
–Bilateral hyperaldosteronism: Spiranolactone or Eplerenone (less binding to androgen receptors)
–Not amenable or agreeable to surgical: mineralocorticoid receptor blockers
•Outcome:
–100% cure of hypokalemia
–> 90% have improved HTN
–30% to 60% can discontinue all Rx
Skin lesions associated with internal malignancy
Lesions associated with internal malignancy
•Muir-Torre Syndrome
•Multiple Mucosal Neuroma Syndrome (MEN IIb)
•Gardner Syndrome
•Cowden Syndrome (multiple hamartoma syndrome)
•Birt-Hogg-Dube Syndrome
•Paget’s disease of skin
•Sezary Syndrome
•Cutaneous Metastasis
Availability Heuristic
Availability Heuristic
Selecting diagnoses based on ease of recalling past cases
Estimating likelihood of disease by ease of recall is easier than systematically collecting and memorizing probabilities
Discuss the indications for surgery in patients with adrenal hormone diseases
When to operate:
•Functional tumors
•Tumors > 4 cm
•Tumors with CT features suggestive of malignancy
•Adrenal mass that is growing
Cutaneous Drug Eruptions
(Dermatitis medicamentosa)
-general
-name one for each type of hypersensitivity
Drug Eruptions (dermatitis medicamentosa)
General Rules for drug reactions:
I. Most drugs require a minimum of 5 days for allergic sensitization to occur.
II. Drug allergy can develop after prolonged use – never rule out drug allergy because a patient has taken a drug for many years.
III. Allergic reactions involving skin sometimes appear only after exercise or heat produces cutaneous vasodilation.
Hypersensitivity reactions:
Type I – Urticaria/Anaphylaxis
Type II – Drug induced pemphigus
Type III – Leukocytoclastic vasculitis
Type IV – Exanthems, lichenoid, fixed, erythema muliforme group
Anchoring Heuristic
Anchoring Heuristic
Premature closure
Relying on initial impressions for diagnosis
Not considering other possibilities once initial commitment to a diagnosis is made
Discuss the risk of malignancy in adrenal tumors
•Virilizing or feminizing
–1/3 of hormonally active ACC causes virilization
–1/2 of virilizing tumors are cancer
–10% of ACC are feminizing. Almost all feminizing tumors are malignant
•Rapid onset of Cushing’s
•Multiple or mixed hormone secretion
RISK
• Size is the best predictor
• CT Hounsfield unit >10
• MRI enhance on T2 wt
• Heterogeneous
• Growing
Erythroderma
Erythroderma (drug eruption)
V. Acute onset of total body erythema due to generalized exfoliative dermatitis – “red man” syndrome.
VI. Differential includes many causes other than drugs, the most important being Sezary’s syndrome, a form of cutaneous T-cell lymphoma.
4 types of adrenal tumors
1. Incidentaloma
2. Pheochromocytoma
3. Hyperaldosteronism (Aldosternoma, Conn’s Syndrome)
4. Hypercortisolism (Cushing Syndrome)
Gardner Syndrome
Gardner Syndrome
I. Early onset (puberty) of multiple epidermoid cysts including unusual locations (head and extremities).
II. Unusual variant of familial adenomatous polyposis syndrome (autosomal dominant).
III. Adenomatous polyps of colon have 100% risk of malignant transformation. 60% of patients develop colonic adenocarcinoma by age 40.
IV. Multifocal pigmented lesions of ocular fundus in 80% and often the first sign observed in the syndrome.
V. Variety of benign tumors also associated.
Cushings syndrome
•Most common cause is Rx
•Endogenous 1 to 10/million
– 75% Cushing's disease
– 15% adrenal
– <10% ectopic ACTH syndrome
Biochemical Workup
 Workup is based on (1) loss of a normal diurnal pattern, with abnormally high late-night cortisol secretion (latenight salivary cortisol test); (2) failure to discontinue the production of cortisol, despite the absence of ACTH stimulation (dexamethasone suppression test); and (3) excess production of cortisol (24-hour UFC test).
 Late-Night Salivary Cortisol:
o Saliva collected at bedtime
o Sensitivity and specificity near 95%
 Overnight 1-mg Dexamethasone Suppression Test
o 1-mg dexamethasone suppression at 11 pm
o Fasting plasma cortisol level at 8am
o Plasma cortisol level < 1.8 μg/dL has the best negative predictive value
o A positive test result (> 5) should be confirmed with 24-hour UFC, midnight salivary cortisol, or a 2-day low-dose dexamethasone suppression test
4
 24-Hour UFC
o Not affected by factors that influence corticosteroid-binding globulin
o A value > 4 times than normal is diagnostic of Cushing syndrome
o A value up to 3 times elevated needs confirmation
 Plasma ACTH
o A low or suppressed ACTH level confirms hypercortisolism of adrenal origin
Pagets Dz of skin
Paget’s disease of skin
I. Unilateral eczematous plaque of nipple/areola (mammary paget’s) or eczematous plaque of anogenital (extramammary paget’s).
II. Mammary paget’s is almost always associated ductal adenocarcinoma of the breast.
III. Extramammary paget’s is associated with underlying GU carcinoma in about 25% of cases.
Pheochromocytoma
Paroxysms of
▪Palpitations
▪Tremor
▪Headaches
▪Diaphoresis
▪Anxiety
Triad of Headache, Sweating, and Tachycardia in a HTN Pt has Sensitivity 90.9% and Specificity 93.8%
SYNDROMES
•MEN 2a
•50% Pheo (usually bilateral), MTC, HPT
•MEN 2b
•50% Pheo (usually bilatl), MTC, mucosal neuroma, marfanoid habitus
•Von Hippel-Landau
•50% Pheo (usually bilat), retinoblastoma, cerebellar hemangioma, nephroma, renal/pancreas cysts
•NF1 (Von Recklinghausen's)
•2% Pheo (50% if NF-1 and HTN)
•Café-au-lait spots, neurofibroma, optic glioma
•Familial paraganglioma
•Familial pheo & islet cell tumor
•Other: Tuberous sclerosis, Sturge-Weber, ataxia-telangectgasia, Carney’s Triad (Pheo, Gastric Leiomyoma, Pulm chondroma)
DX
Diagnostic
• 24-hour urine total metanephrine level > 1,800 μg
• Plasma metanephrine level > 3-4 times normal
RX
•Treatment: Surgical resection for all
–Preoperative α-adrenergic blockade for 1-3 weeks
–Phenoxybenzamine,10 mg twice daily titrated to 300 to 400 mg
–Treat until normotensive or develop side effects
–SE: orthostatic hypotension, tachycardia, nasal congestion, nausea, or abdominal pain
–β-adrenergic blocker if tachycardia
•Long-term follow-up: 10-15% recurrence
Sezary Syndrome
Sezary Syndrome
I. Acute onset of total body erythema due to generalized exfoliative dermatitis – erythroderma / “red man” syndrome.
II. Form of cutaneous T-cell lymphoma.
III. Marked leukocytosis with Sezary cells (hyperconvoluted lymphocytes).
Carcinoid tumor
Variable and indolent presentation typical
Primary tumors that are quite small can present with extensive metastatic disease
Carcinoid tumors can secrete a variety of gastrointestinal peptides including gastrin, somatostatin, substance P, vasoactive intestinal polypeptide, pancreatic polypeptide, and chromogranin A, as well as serotonin.
In the absence of metastatic disease, the venous effluent from the tumors is degraded by the first pass through the portal circulation
5-HIAA is the primary metabolite of serotonin
ETIOLOGY
Neuroendocrine tumors derived from the enterochromaffin cells of the intestinal crypts of Lieberkuhn
Share embryologic origins with other neuroendocrine tumors including pancreatic endocrine tumors, medullary thyroid carcinoma, melanoma, and pheochromocytoma
LOCATIONS
Appendix and colon
Small bowel
Rectum
Lungs
Ovaries and testes
PRESENTATION
Flushing and diarrhea are the two most common presenting symptoms
Diarrhea occurs when the liver can no longer metabolize serotonin due to the presence of metastases
Flushing is typically sudden in onset and lasts 2-5 minutes
Flushing thought to be caused by excess histamine release
Diarrhea typically occurs with flushing
Steatorrhea present in up to 67 % of cases
Flushing in conjunction with an increase in 5-HIAA on urinalysis occurs only in carcinoid syndrome
TREAT
Surgery, if feasible, is the only curative therapy
If metastatic is considered incurable
Some promising treatment modalities
◦Radiolabeled octreotide
◦131l-mlBG (meta iodo benzyl guanidine)
◦Arrests growth of tumors and can prolong survival
◦Currently considered experimental
Neuroendocrine tumors that cause diarrhea
Vitiligo
Vitiligo
I. Complete loss of skin pigment (hypopigmentation) due to loss of melanocytes – probably autoimmune.
II. Can be associated with thyroid disease, diabetes mellitus, Addison’s disease, pernicious anemia, and alopecia areata
HTLV
-epi
-types of cancer
-mechanism
-Sx
-labs
Human T-cell Leukemia Virus, Type 1
•Epidemiology:
–Endemic in Southwestern Japan, the Caribbean, and parts of central Africa.
–Similar to the human immunodeficiency virus (HIV) in that they both infect human CD4+ T-helper cells.
–Transmitted sexually, via blood transfusions, and through breast feeding
–Only 2-5% of infected people develop an aggressive form of leukemia, after a long latency of several decades.
•Types of cancer:
–Adult T-cell Leukemia, arising in T-helper cells.
•Unusual, floral-shaped lymphocytes
•Hypercalcemia
•Skin rash
–Also a smoldering leukemia and tropical spastic paraparesis.
MECHANISM
•Molecular events related to transformation:
•HTLV1 integrates randomly into the host genome, not adjacent to a particular oncogene.
•Integration is clonal, (HTLV1 is in the same place in all leukemic cells).
– Virus is integrated early and passed down during leukemic cell replication.
•The Tax protein is essential for viral replication, and
–Activates several host genes related to proliferation and differentiation,
–Activates NF-kappa-B, which regulates many pro-survival and anti-apoptotic genes.
•Infection causes expansion of a non-malignant polyclonal T cell population.
•Accumulated genetic abnormalities lead to a monoclonal neoplastic T-cell population.
-HISTO
-T-lymphocytes with lobulated nuclei
HPV
-epi
-types of cancer
-mechanism
-Sx
-labs
EPI
•Over 70 strains of HPV
–Common Warts:
•No malignant potential: HPV 1, 2, 4, 7
–Genital Warts, commonly cervical, also anal and laryngeal
•Low malignant potential, HPV 6 and 11
–Carcinomas and high risk precursor lesions (severe dysplasia and carcinoma in situ):
•Invasive potential: HPV 16, 18, 31, 33, 35, 51
•Most HPV infections are asymptomatic
•90% are cleared within 2 years
•Prevalence of new cases peaks in the early 20-30 age range ranging from 20-50%.
•Recently released HPV vaccine is expected to decrease the rate of infection and incidence of cervical cancer.
• HPV alone is not sufficient for cancer formation, but works together with environmental factors (cigarettes, infections, diet, hormonal changes
MECHANISM
•Molecular events leading to transformation:
•Integration in the genome disrupts the E2 viral repressor leading to ↑ viral proteins E6 and E7.
•E6 and E7
–enhance degradation of p53, causing a block in apoptosis and decreased activity of the cell cycle inhibitor, p21.
–E7 also prevents p21 from inhibiting the cyclin CDK4 complex
–E7 binds up retinoblastoma (RB) protein to remove cell cycle inhibition.
–↓ apoptosis and ↑cell proliferation. (Figure 7-43, p. 313)
•Strength of binding between the E6 and E7 with host proteins alters the risk of cancer development.
•Integration into the host genome is random, however the pattern is clonal-implying that the virus is important for transformation.
EBV
-epi
-types of cancer
-mechanism
-Sx
-labs
EPI
•Epidemiology:
–>90% of all adults world-wide are sero-positive.
–Most people asymptomatically infected in childhood
–Average age of seropositivity is inversely related to the socioeconomic status of the population.
•With lower socioeconomic conditions, seropositivity occurs at a younger age.
•In U.S., primary infections may occur in teens and adults giving rise to infectious mononucleosis (fever, sore throat, hepatosplenomegaly, lymphocytosis and lymphadenopathy).
–Virus then integrates into the host genome and remains in a latent state.
–Possible viral reactivation occurs later in life due to various triggers.
CANCERS
•Associated Cancers: EBV has a natural receptor on B cells in tonsils and the epithelium of the oropharynx.
•B-cell lymphomas:
–Burkitt’s lymphoma
•100% in African/endemic form, where malaria is a frequent co-factor.
•30-40% of sporadic Burkitt’s lymphoma in the United States
–Immunodeficiency associated lymphoma
•HIV-infected patients
•Patients treated with immunosuppressive drugs after organ transplant, or for autoimmune diseases, or for other reasons.
•Lymphomas in elderly patients--immune system senescence late in life leading to relative immunodeficiency.
–Hodgkin’s lymphoma
•Nasopharyngeal natural killer-T cell (NK/T) cell lymphomas
•Nasopharyngeal carcinomas, endemic in Southern China, parts of Africa, and Inuit population in the Alaska.
MECHANISM
•Molecular Transforming events:
–B cells are infected via complement receptor CD21
–LMP1
•Behaves like a constantly active CD40 receptor, which is on B cells and normally receives stimulatory signals from T-helpers
•Also activates the NF-kappa B and JAK/STAT signaling pathways and prevents apoptosis.
–EBNA2 activates several genes such as Cyclin D.
–Viral IL10 prevents macrophages from activating T cells that might try to react to the infected B cells → immune system evasion
•Co-factors are required. (Figure 7-44, p.374)
–In Africa, malaria impairs immune competence leading to sustained B-cell proliferation.
•Infected B cells down-regulate viral proteins allowing them to evade immune surveillance.
–Additional mutations or chromosomal translocations occur.
•t(8;14) leads to the translocation of the proliferation gene, MYC, next to the immunoglobulin gene promoter.
•Leads to over-expression of MYC and ↑ proliferation.
•Not directly oncogenic, stimulates B-cell proliferation, setting up acquisition of additional genetic abnormalities.
EBV encoded RNAs (EBER)
•Common stain used to demonstrate viral genome in tissue biopsies Intestinal biopsy with lymphoma: Dark blue stain demonstrates presence of viral transcripts
MYC Translocation in Burkitt’s Lymphoma
Hep B virus
-epi
-types of cancer
-mechanism
-Sx
-labs
•Epidemiology:
•HBV is endemic in countries of the Far East and Africa.
•An estimated one-third of the world population has been infected (2 billion people)
•400 million are chronically infected.
•75% of all chronic carriers live in Asia and the Western Pacific rim.
•Overall carrier rates range from 8% to <2% geographically.
•Transmission depends on the prevalence of the virus and may include perinatal, horizontal (through cuts, abrasions or mucous membranes), unprotected sexual contact, needle sharing, or blood products.
•In the U.S. @ estimated 46,000 new cases per year.
•Associated Cancers:
–Hepatocellular Carcinoma of the Liver.
–Majority of liver cancers world-wide are associated with the chronic hepatitis associated with these viruses and follow the geographic pattern of distribution.
•Molecular Transforming events:
–Do not encode any oncoproteins
–No consistent pattern of viral genome integration
–Chronic inflammation →hepatocyte death →hepatocyte regeneration.
–↑ growth factors, cytokines, chemokines and reactive oxygen species.
–↑ opportunity for genomic accidents.
–One altered pathway is that of NF-kappa-B which blocks apoptosis.
–In HBV, the HBx protein alters several transcription factors and signaling pathways.
Hep C
-epi
-types of cancer
-mechanism
-Sx
-labs
•Epidemiology:
•170 million people world wide
•4.1 million Americans or 1.6% of the population.
•Most common blood-borne infection
•Nearly half of all chronic liver disease.
•Almost 30% of all acute infections become chronic.
•Most common indication of liver transplantation.
•Transmission is through needle-sharing, unprotected sexual contact, perinatal, and transfusion with blood products.
•Due to blood screening, blood-product related transmission has dropped to nearly zero.
•Associated Cancers:
–Hepatocellular Carcinoma of the Liver.
–Majority of liver cancers world-wide are associated with the chronic hepatitis associated with these viruses and follow the geographic pattern of distribution.
•Molecular Transforming events:
–Do not encode any oncoproteins
–No consistent pattern of viral genome integration
–Chronic inflammation →hepatocyte death →hepatocyte regeneration.
–↑ growth factors, cytokines, chemokines and reactive oxygen species.
–↑ opportunity for genomic accidents.
–One altered pathway is that of NF-kappa-B which blocks apoptosis.
–In HBV, the HBx protein alters several transcription factors and signaling pathways.
Kaposi's Sarcoma Herpesvirus
(KSHV1)
-epi
-types of cancer
-mechanism
-Sx
-labs
•Epidemiology:
•Previously known as Human Herpes Virus type 8 (HHV-8)
•Associated with Kaposi’s sarcoma.
–Originally described in the 1800s in the lower legs of Eastern European men
•Red-purple maculopapular lesions
•cutanous sarcomas originating from endothelial cells.
–Also in Africa, in transplant patients, and in HIV patients.
•Still the most prevalent malignancy in AIDS patients in the U.S.
•Most common cancer in central Africa (up to 50% of all tumors in men).
•Can involve lymph nodes and internal organs in addition to skin.
•Associated Cancers:
–Found in nearly all cases of Kaposi’s sarcoma, whether in older European men, African children, or immunocompromised individuals.
–Relatively indolent in the classical European disease
–Aggressive and fatal in immunocompromised patients.
•Molecular Transforming events (Figure 6-49):
–Necessary requirement for development of Kaposi’s sarcoma
–Requires a co-factor such as HIV.
•In HIV, cytokines derived from infected T-cells or inflammatory cells produce a local proliferative environment.
–A viral-encoded protein induces local vascular endothelial growth factor (VEGF) which stimulates the endothelial cells that are part of the tumor.
–In latently infected cells, the virus produces inhibitors of the cell cycle checkpoint protein p53 and a viral homologue of Cyclin D.
HIV
-epi
-types of cancer
-mechanism
-Sx
-labs
•Associated Cancers
–With KSHV
•Kaposi’s sarcoma
•Primary body cavity Lymphoma (rare)
–With EBV
•Burkitt’s lymphoma (50% EBER+)
•Primary Central Nervous System Lymphoma
–100% EBER+
–1000X more common in HIV+ patients
–With HPV
•Cervical carcinoma
•Anal carcinoma
•Transforming Events:
•In Kaposi’s sarcoma,
–HIV-mediated immunodeficiency→ dissemination of the KSHV →infect more spindle-fibroblastic and vascular cells→ uncontrolled growth.
–HIV-infected T-cells produce cytokines→ cellular proliferation.
•In lymphomas,
–HIV-induced immunosuppression→ proliferation of a polyclonal B cell population (due to increased IL6 and other cytokines).
–During the uncontrolled proliferation, mutations or translocations that can occur causing transformation to malignancy.
•In Carcinomas, HIV immunosuppression leads to reactivation of HPV.
–HIV-infected women have 10X more cervical dysplasia than non-infected women.
DLBCL in brain from an HIV+ patient
OSTEOGENIC SARCOMA
1. Malignant neoplasm of osteoblasts
2. Teen-agers and young adults; other age group is >60 years (generally a complication of Paget disease)
3. Imaging findings:
a) irregular bone destruction which may include break-through of cor-tex and associated soft tissue mass
b) periosteal reaction “sunburst” (spiculated)
4. Most frequent location is about the knee (distal femur or proximal tibia)
5. Pathology:
Gross: gray-white mass; may be hard
Microscopic: malignant osteoblasts forming bone (usually in a lace-like or filigree pattern; rarely resembling normal bony trabeculae)
6. Lungs most frequent site of metastasis (If the number of lung metas-tases is small, may be resectable); metastasis to other bones common
7. Treatment: complete surgical resection; chemotherapy (may be given pre-operatively to reduce tumor volume)
CHONDROSARCOMA
1. Malignant neoplasm of chondrocytes
2. Patients usually adults (rarely seen before age 40)
3. Imaging findings:
a) irregularly destructive lesion within bone
b) generally lytic (radiolucent)
c) may have soft tissue extension which has radiodensity of cartilage with speckled calcification (not bone)
4. Pathology:
Gross: Often recognizable as cartilage, with translucent tissue and lo-bulated periphery (calcification frequently at the periphery)
Microscopic: varying degrees of differentiation: well-differentiated form looks much like ordinary hyaline cartilage, but cells have increased nuc-lear size; poorly-differentiated forms have greater numbers of cells, less
2012_0419_1300 GRAHAM Scarcoma LECT NOTES 3
matrix and increasing variation in nuclear size, shape and chromatin den-sity
5. Survival strongly inversely correlated with numerical grade (highest % survival for Grade I lesions)
6. Likelihood of malignant transformation closely related o anatomic loca-tion (more likely in axial skeleton or proximal portions of long bones, less likely in small bones of hands and feet)
EWING SARCOMA
1. Malignant neoplasm of primitive cells (current evidence favors a primitive mesenchymal cell line with neural features)
2. Children and young adults; distal femur/ proximal tibia
3. Imaging findings:
a) irregularly destructive, lytic lesion which may have a dispro-portionately large soft tissue mass relative to the amount of bone involvement
4. Pathology:
Gross:gray-white tumor
Microscopic: “round-cell” tumor of uniform cells with scanty cy-toplasm and moderate-sized, hyperchromatic nuclei; may grow in sheets, frequently filling up marrow space; no matrix produced by cells
5. Characteristic chromosomal translocation 11:22
a) this translocation also seen in primitive neuroectodermal tumor [PNET] which is felt to have similar origin as Ewing
b) fusion gene (FLI1-EWS)
6. Differentil diagnosis includes other “round-cell” tumors of child-hood or young adulthood: metastatic neuroblastoma or lymphoma
LIPOSARCOMA (fatty tissue origin)
1. Adults, principally 5th to 7th decade
2. Anatomic location chiefly retroperitoneum, deep tissues of thigh
3. Pathology
Gross: often more gray-white, myxoid (gelatinous) than mature fat (except for well-differentiated variant)
Microscopic variants -
a) Well-differentiated - may resemble benign lipoma
b) Myxoid - abundant mucopolysaccharide in stroma, "chicken-wire" vascular pattern
c) Round cell - may resemble other round cell tumors (lympho-ma, Ewing's sarcoma)
d) Pleomorphic - undifferentiated, anaplastic, bizarre cells
4. Myxoid and round cell variants have same chromosomal transloca-tions t(12;16)(q13;p11) and t(12;22)(q13;q12)
5. Best prognosis for well-differentiated variant; worst with pleomor-phic forms
6. Recurrence common (about 50%)
RHABDOMYOSARCOMA (skeletal muscle origin)
1. More common in children (except for pleomorphic variant)
2. Principally head and neck or urogenital sites (children and deep soft tissue (adults)
3. Pathology:
Gross: usually gray-white, infiltrative (exception is botryoid variant which is polypoid and has a grape-like texture)
Microscopic variants -
a) Embryonal - round to oval, generally small cells; some areas suggest skeletal muscle differentiation with larger, eosinophilic cells which may have cross-striations
b) Botryoid - small dark cells usually closely grouped beneath overlying normal mucosal epithelium (common form in uroge-nital tract)
c) Alveolar - primitive dark cells arranged among collagenous trabeculae with spaces suggesting alveolar spaces of lung
d) Pleomorphic - large, bizarre cells with abundant eosinophilic cytoplasm (more common in adults)
4. Immunohistochemical demonstration of muscle-related antigens (desmin, actin) or election microscopy (to demonstrate myofilaments) may be necessary to distinguish from other soft tissue sarcomas
5. Prognosis for subtypes in descending order (best to worst): Botryo-id, embryonal, pleomorphic, and alveolar
6. Clinical course: Success of surgical resection depends on anatom-ic site (surgery on sarcomas of extremities more likely to be complete than those involving the orbit or cranial foramina); 20-40% develop
metastases; about 65% cure rate (surgery, radiation and chemothera-py).
SYNOVIAL SARCOMA
1. Cell of origin uncertain, but probably not synoviocytes
2. Only 10% occur adjacent joints; most are deep soft tissue 3. Young adults, early middle-age (90% less than 50 years)
4. Males more often affected than females
5. Lower extremity most often involved (70%), commonly knee
6. Presents as mass lesion; may grow more slowly than other soft tissue malignancies, but intrinsically aggressive
7. Translocation t(X;18)(p11;q11); fusion gene SYT-SSX
8. Pathology:
Gross: Mass, usually tan to gray; may have calcification
Microscopic:
a) Typically biphasic, with glandular-type epithelial cells and spindled cells
b) Epithelial-type cells express cytokeratin; may have mucus
c) Spindle cells may also express cytokeratin (particularly helpful when tumor is the monophasic spindle-cell type)
9. Five year survival ~50% (only 20% at ten years)
10. Good prognostic features:
a) Tumor size less than 5 cm diameter
b) Early clinical stage
c) Age < 10 years at presentation
MALIGNANT FIBROUS HISTIOCYTOMA
1. High-grade, pleomorphic neoplasm without matrix production
2. Adults over 40 years; incidence greater with older age
3. Majority involve lower extremity
4. MFH in bone:
a) Lytic, irregularly destructive lesion
b) Frequently in femur
c) Pain is major presentation, less often swelling
d) Necrosis common, may be extensive
5. MFH in soft tissue:
a) Deep-seated tumor
b) More likely to present as mass than with pain
6. Pathology:
a) Gross: generally large, gray-white
b) Microscopic: mixed spindle cell and polygonal cell popu-lation, arranged in interwoven fascicles (storiform – “mat-like”)
2012_0419_1300 GRAHAM Scarcoma LECT NOTES 6
with conspicuously pleomorphic nuclei scattered throughout
7. Currently thought that many cases previously diagnosed as MFH may be pleomorphic, poorly-differentiated variants of other cell lineage (e.g., myogenic); however, the entity of MFH is still recognized
8. Still helpful as a diagnostic category, particularly for MFH of bone, which has a well-known association as a complication of bone infarct
What IHC markers may be useful in identification of an angiosarcoma?
CD31 and CD35
Markers helpful in ID of rhabdomyosarcoma
-desmin, Myogenin, MyoD1, and actin. Actin is not as specific because smooth muscle can also be positive.

What are the most common anatomic locations that these tumors arise in relation to age?
Children: Head and neck and the urogenital tract. (Botryoid variant often occur in the urogenital tract)
Adult: Deep soft tissues, more commonly the pleomorphic variant.
(However, these sarcoma types can still occur anywhere)
Is the prognosis good or poor in this case?
In order from good to poor prognosis:
Botryoid >Embryonal > Pleomorphic > Alveolar
Signs and Sx of malignant glioma
Signs and Symptoms:
a. Increased Intracranial Pressure
Headaches occur in approximately 50% of patients with primary brain tumors. Nausea, vomiting and lethargy can also be seen with increased intracranial pressure.
b. Focal Signs and Symptoms
Signs and symptoms are usually related to the location of the tumor. Hemiparesis, aphasia and visual-field deficits are not uncommon findings.
c. Seizures
Seizures are a common presenting symptom in patients with a primary brain tumor. Approximately 25% of patients with high grade gliomas and 50% of patients with low grade tumors may present with seizures.
d. Altered Mental Status
Patients with primary brain tumors may have impairment of consciousness or cognitive function. They may also have personality changes.
Radiographic features of malignant gliomas
3 major MRI findings:
a.Heterogeneous enhancing mass
b.Peritumoral edema
c.Central area of necrosis
MRI is the best imaging study to obtain to diagnose a brain tumor.
It is superior to CT. High grade gliomas appear on MRI as a heterogeneously enhancing mass that arises in the white matter and is surrounded by edema.
b. CT
A contrast-enhanced CT may be used if an MRI is not available or a patient cannot have an MRI. Tumor calcification is better seen on CT.
Treatment of malignant gliomas
-what are the complications of treatment?
MALIGNANT GLIOMA
Current Therapy
1.MAXIMUM FEASIBLE RESECTION
2.RADIATION THERAPY
Tumor portal plus margin
Tumor dose = 60 Gy
3. CHEMOTHERAPY (single or combination)
SUPPORTIVE CARE
-antiepileptics for seizures
-corticosteroids for peritumor edema
-anticoagulants for VTE
COMPLICATIONS
-some drugs alter p450s
-SE of steroids (cushings, osteoporosis, immune suppression, etc)
-suceptible to PCP because immunosuppressed
2 types of malignant gliomas
Pathology:
a. Anaplastic astrocytoma WHO grade III
b. Glioblastoma multiforme WHO grade IV

A staging evaluation is usually not done for known high grade gliomas. These tumors tend to involve the CNS and rarely metastasize to distant organs.
b. Prognosis
Adverse prognostic factors in patients with malignant gliomas include: advanced age, histologic features of glioblastoma, poor Karnofsky performance status and unresectable tumor.
With standard treatment including surgical resection, radiotherapy and chemotherapy, median survival is 3 years for patients with anaplastic astrocytoma and 15-18 months for patients with glioblastoma multiforme.
4 adverse prognostic factors for patients with malignant gliomas
•Adverse Prognostic Factors
a.Advanced age
b.Histologic features of glioblastoma multiforme
c.Poor Karnofsky performance status
d. Unresectable tumor