Increase in bicarb = increase pH = metabolic alkalosis Decrease in bicarb = decrease pH = metabolic acidosis
C. Suppressor genes
Suppressor genes suppress, therefore if knocked off, whatever they were suppressing keeps on going. Key suppressor genes: p53, Rb gene, adenomatos polyposis coli (familial polyposis), neurofibromatosis, wilm’s tumor gene, brca1 and 2 (both involved in DNA repair, and one is on c’some 13 while the other is on c’some 17); brca1 can be breast cancer, ovarian cancer, or others; brca2 is TOTALLY related to breast cancer. Only 15% of breast cancers have genetic assoc with these genes, therefore, most cases are sporadic.
X. Common things that predispose mutations:
Protooncogenes are activated, while suppressor genes are inactivated 3 main ways this occurs: chemicals, viruses, radiation
A. Chemicals:
Which of the three is most common in initiating a cell producing a mutation? Chemicals – smoking = MCC death in USA due to polycyclic hydrocarbons.
By itself, smoking is MC than virally induced or radiation induced cancers. Smoking causes lung cancer, squamous cancer of the mouth, larynx, lung, pancreas, bladder, and if it’s not the #1 cause, it’s often #2, such leukemias, cervical ca, and colon.
MCC papillary tumor of the bladder = transitional cancer (smoking) What if you worked in a dye industry? Aniline
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What if you had Wegener’s granulomatosis, put on a drug and got hematuria, did cytology and saw cells, what drug is pt on? Cyclophosphamide (hemorrhagic cystitis); prevent with mesna, and can cause transitional cell carcinoma (therefore acts as a carcinogen!)
Lung cancer – MCC = polycyclic hydrocarbons from smoke; most often assoc with smoking is small cell and squamous;
B. Viruses:
Virus assoc cancer: a virus with nonpruritic raised red lesions. Dx? Kaposi’s sarcoma (due to HHV 8)
26. Kaposi sarcoma
Burkitts; due to Epstein barr varies which also causes nasopharyngeal carcinoma, esp. in Chinese
25. Burkitt's lymphoma
liver – Hepatocellular carcinoma due to hepatitis B from Asia; also due to a mold – aflatoxin B; combo of hep B, cirrhosis, plus aflatoxin makes is common in Asia; can also be caused by hep C
HIV is assoc with primary CNS lymphoma. They will ask: the rapidly increasing incidence of primary CNS lymphoma can be directly attributed to what?
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HIV
HPV causes squamous cancer of cervix, vagina, and vulva, and anus of homosexuals due to unprotected intercourse; due to HPV 16, 18, 31. This virus causes anal squamous cell carcinoma in homosexuals. The virus works by making two proteins, E6 which knocks off p53, while E7 knocks of Rb.
C. Radiation
MC cancer assoc with radiation = leukemia
MC leukemia assoc with radiation = CML (9, 22 translocation of abl)
Papillary carcinoma of thyroid is also commonly seen as a result of radiation. Example: pt had radiation in head and neck, and has nontender nodular masses in cervical region = metastatic papillary carcinoma of the thyroid related to ionizing radiation.
Example: osteogenic sarcoma
Example: which medical profession is most subject to leukemia? Radiologist, leukemias are commonly caused by radiation and it’s the radiologist that are commonly involved with this.
Example: if you have Jacob Crutzfelt dz, what dr are you? Neuro-Pathologist (bc work with brains and prions)
Example: basal cell carcinoma (pic), multifocal; this is non ionizing radiation (ionizing radiation is the bad stuff). This is UV B light (b is bad); UV A light is for fluorescing
superficial dermatophytes (wood’s light) or green’s patches in tuberous sclerosis (therefore used by dermatologists), aka black light. UV B light is what you protect yourself from to prevent getting skin cancers (basal cell = MC, then squamous cell, then melanoma). UV D
= thymidine dimmers
Example: lesion in sun exposed areas that is scraped off and grows back – aka solar (actinc) keratosis; it predisposes to squamous dysplasia. Arsenic is a metal that is associated with skin cancer. Bangladesh has bad water supply which contains
arsenic, therefore they have a high number of squamous skin cancers, and with time it can lead to cancer of the lung, and angiosarcoma of the liver.
122. Actinic Keratosis
Example: kid with white eye reflex – retinoblastoma – c’some 13. This dz is sporadic and familial. It takes the sporadic dz 2 separate mut’n to become retinoblastoma (knock off on each c’some 13). If it is familial, which is Autosomal dominant it takes just one mut’n, b/c you are born with one already inactivated, therefore only need one more mutation on the other chromosome in order to develop retinoblastoma. White eye reflex is not MC due to retinoblastoma – the MCC is congenital cataract (which can be due to CMV, rubella,
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or any congenital infections). Which drug predisposes to cataracts? Corticosteroids;
therefore a person with Cushing’s dz may develop cataracts.
24. Retinoblastoma
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Audio file : 4 Neoplasia
XI. Genetic dz
Xeroderma pigmentosa – sun exposed areas, auto recessive, can cause all skin cancers (BCC, SCC, and melanomas), and the defect is in DNA repair enzymes. Other DNA repair defects are associated with BRCA1 and BRCA2, p53, they splice out the defects, this group is called the chromosomal instability syndromes – wiskott Aldrich, Blooms, Ataxia Telangiectasias, and Fanconi’s, all have probs with DNA repair.
27. Xeroderma pigmentosum
Basic rule of thumb for BCC and SCC:
Upper lip and up is basal cell carcinoma;
lower lip and down is squamous cell
(therefore, lesion on lower lip = sq cell; lesion on upper lip = basal cell)
Example: inside nose is BCC, b/c above the upper lip
Example: keloid – sq cell carcinomas and 3rd degree burns and sq cell carcinoma developing in areas of drainage from the sinus and ulcer that doesn’t heal from antibiotics. So, wherever there is constant irritation, and division of cells related to irritation, there is an increase susceptibility to cancer. This does not hold true for scar cancer tissue related cancers of the lungs or adenocarcinoma (just applies to things on the skin – ie burns and draining of sinus tracts).
Only bacteria assoc with cancer? H. pylori – adenocarcinoma and low grade malignant lymphomas.
XII. Grade vs Stage
A. Grade = what does it look like? The term well differentiated means that the tumor is making something like keratin or glands, and if it’s identifiable it’s called low grade. When the cells are anaplastic, poorly differentiated under the microscope, and if you cannot tell what it is, then it’s called high grade.
Example: sq cell carcinoma can see keratin pearls; can ID it, so it’s a low grade cancer.
Example: see gland like spaces, can ID so its low grade
B. Stage = (TNM) MC staging system; goes from least imp to most imp (TNM)
Example: breast cancer with axillary node involvement; therefore, the N=1, but the “M” is worse, b/c it indicates that cancer has spread to other organs like bone, etc.
Just b/c it goes to lymph nodes doesn’t mean it is the most imp prognostic factor.
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T=size of tumor; if tumor is over 2 sonometers, it has a chance of mets N=nodes (next most imp for prognosis)
M=mets outside of nodes (most imp prognostic factor)
Stage is more important than grade for prognosis; and within staging, M is the most imp factor for prognosis
Example: pt with prostate cancer, which of following has it the worst? The answer choices were cancer limited to prostate, it went into seminal vesicles, it involved the wall of bladder, went to lymph nodes, or bone? Answer = bone (bone represents the “M” of the TNM system – this ie is stage 4 by definition=mets)
Example: a slide of a colon cancer and a lymph node: what is most important – size of tumor or lymph node involvement? Lymph node. If it was also in the liver, what is most imp? Liver specimen is the most imp prognostic factor.
XIII. Host defenses – most important is Cytotoxic CD8 T cell Others – NK cells, Ab’s, macrophages, type 2 HPY
In hospital, they look for altered MHC class I Ag’s in the cancer pt, b/c cancer wants to kill T cells;
they do this by putting in perforins, which activate caspasases, and this leads to apoptosis (the signal, from the perforins, activate the caspasases, which have proteases, which break down the nucleus and mitochondria, and cell dies, without any inflammatory infiltrate).
XIV. Other diseases seen in malignancy: