- 1 in 2 for men --> Prostate, lung, and colorectal are the most common

- 1 in 3 for women --> Breast, lung, and colorectal are most common

- Lung has the highest mortality rate

- 1 in 300 people on chemotherapy will develop a secondary cancer

- Uses high-energy radiation to shrink the tumor and kill cells

- Kills cancer cells by damaging their DNA --> Creates dsDNA breaks

- Therapy either damages DNA directly or creates free radicals that damage DNA

- Radiation biology --> Know the biological effects of radiation and side effects --> Carciongenesis, genetic changes, etc

- Radiation physics

- Radiation protection techniques for workers the general public and different body parts

- Consultation --> Planning --> Treatment

1. Consultation: Discuss the role of RT with the patient and discuss side effects, obtain consent, and set up planning appointment

2. Planning

3. Treatment: Radiation dosage is given in very directed ways using a linear accelerator (LINAC)

- 3D administration of radiation dosage to administer to the entire tumor and prevent exposing surrounding structures

- 3D administration via cyberknife

- Radioactive source in direct contact with the tumor

- Examples --> Interstitial implants, intracavitary implants or surface molds

- Greater deliverable dose --> Don't have to worry about exposing surrounding structures

- Continuous low dose rate

- Shorter treatment time --> Higher dose for a shorter time

- Seeds are radioactive after you leave the office depending on the half-life of the isotope

- Gyn cancer require internal seeds --> Small bowel can only take a little bit of radiation so can't give much externally

- Trans-perineal approach

- Small tumors (<60 cc)

- Low grade

- Small volume

- Patients with no voiding dysfunction

- Seeds implanted throughout organ/prostate

- Need to protect the urethra in the middle 

- Tobacco: Lung, mouth, pharynx, larynx, esophagus, stomach, pancreas, bladder, kidney, renal, pelvis, and cervix

- Secondary smoke: Skin and lung

- Alcohol: Liver, esophagus, pharynx, larynx, and breast

- Wood dust: Nasal sinuses

- Betel quid: Mouth

- Coal tars and radon: Lung

- Hot tea: Esophageal

- Mineral oils: Skin

- Salted fish: Nasopharynx

- Shale oils: Skin

- Soot: Skin and lung

- Obesity: Breast, colon, rectum, prostate, pancreas, and kidney

- Nickel: Lung and nasal sinuses

- Arsenic: Lung, skin and bladder

- Mustard gas: Lung and pharynx

- Beryllium, chromium, radon, and silica: Lung

- Asbestos: Lung, mesothelioma, and larynx

- Vinyl chloride: Liver (angiosarcoma)

- Aflatoxins: Liver (especially with HBV infection)

- Dioxin: Lymphoma and sarcoma

- Benzene: AML

- Ethylene oxide: Leukemia

- Cadmium: Prostate, GU, and respiratory tract

- Sunlight (UV): Skin, melanoma and eye

- Therapeutic radation

- Chemotherapy drugs

- Estrogens and tamoxifen

- Psoralen plus Ultraviolet A (PUVA)
- Phenacetin: Bladder cancer 

- 1 in 2 for men and 1 in 3 for women

- 47% lifetime risk for men

- 38% lifetime risk for women

- Cancer is now the #1 cause of death worldwide

- Death rates have decreased since the 1990s --> Lots of people quit smoking

- Men quit smoking before women did because women were more concerned about gaining weight than they were about the health risks of continuing smoking

- Incidence of cancer spiked in the 1990s for men due to the advent of the PSA test

- Higher risk of getting cancer or dying of cancer if you are African American

- Higher risk of cancer death in men vs. women

- Liver cancer: Due to Hep. B and C infections --> Highest in Asia and Africa

- Esophageal cancer: Due to consumption of hot tea --> Highest in the middle east and Asia

- Cervical cancer: Due to HPV infection --> Lowest in the US and other developed countries due to papsmear and HPV vaccine --> Highest in areas where HPV infection is most common

- Lymphoma: EBV infection

- Stomach cancer: H. pylori infection

- Bladder cancer: Schistosomiasis infection and phenacetin exposure

- Colon Cancer: Due to the amount of vegetables you eat and the amount of vitamin D the body has

- Delayed childbearing age

- Obesity after the age of 18

- Alcohol consumption --> Both in college and during adulthood matters --> 3-6 drinks/week (RR 1.15) and >18 drinks/week (RR 1.5)

- Estrogen/progesterone use --> Hormone replacement therapy

- Early puberty

- Less breast feeding

- Inverse risk with the amount of carotenoids in patient's diet

- Age > 65

- Family history

- African American descent

- BRCA1 or BRCA2 genes

- Vasectomy

- NOT associated with smoking, alcohol, BPH, STDs, obesity, lack of exercise or a diet high in animal fat/meat

- Leukemia --> ALL

- Brain and CNS cancer

- Hodgkin lymphoma

- Much higher incidence than mortality in children

- BRCA1: 90% breast and 24% ovarian --> Prostate cancer in men

- BRCA2: 40% breast and 4% ovarian --> Breast cancer in men

- New growth

- Uncoordinated cell growth exceeding normal barriers to give rise to a neoplasm (tumor/mass)

- Reversible change from one adult cel ltype to another adult cell type

- Will be reversed if stimulus for change is removed --> Adaptive

- Loss of the normal orientation of one cell to another in a particular tissue

- Pre-neoplastic lesion

- Cells within dysplastic tissue will be anaplastic

- Change in cell morphology from normal to abnormal

- Anaplastic cells are present in dysplastic tissue

- Cellular and nuclear pleomorphism

- Atypical mitosis --> Cross-looking mitosis

- Increased N/C ratio

- Prominent nucleoli

- Giant cell formation

- Lack of differentation of cells

- Aneuploidy

- Hyperchromasia of nuclei

- Well circumscribed

- Cells resembling normal cells

- Localized --> Do not spread

- Amenable to surgical excision

- Problomatic benign tumors: Myxoma and meningioma

- Lymphoma

- Mesothelioma

- Melanoma

- Hepatoma --> Hepatocellular carcinoma

- Seminoma

- Not well circumscribed

- Cells exhibit varying degrees of anaplasia

- Must be graded --> Well, moderately or poorly differentiated

- Malignancy of mesencyme --> Sarcoma

- Malignancy of epithelium --> Carcinoma

- Arborizing system of ducts lined by cuboidal epithelium

- Ducts open into acinar/glandular structures

- Glands grow once a women becomes pregnant

- Tumors of the breast develop from ductal and lobular epithelium

- Non-proliferative breast disease --> Benign

- Results from ductal dilation, cyst formation, metaplasia and fibrosis

- "Breast lumps"

- Not associated with increased risk for breast cancer unless associated with ductal proliferation

- Apocrine metaplasia occurs in the ducts

- Fibrosis occurs if the cyst ruptures

- Microcalcification is common 

- Moderate to marked cellular hyperplasia

- Without cellular atypia

- Rarely causes palpable masses --> Detected by mammogram

- Types of lesions: Sclerosing adenosis, radial scar, and ductal papilloma

- Sclerosing adenosis: Reactive response

- Papilloma: Can cause nipple discharge or bleeding

- 1.5-2x risk for developing breast cancer

- Increase in cells within the ducts and lobules

- Cells are cytologically atypical --> Anaplastic cells in dysplastic tissue

- Atypical ductal hyperplasia (ADH)

- Atypical lobular hyperplasia (ALH)

- Mass almost fit the criteria for carcinoma but falls short

- 4-5x relative risk for developing breast cancer

- Most common benign tumor

- Encapsulated benign tumor --> Both epithelial/ductal and mesenchymal tissue

- Multiple and bilateral tumors are often present

- Usually occurs in young women (<30)

- Tumors are hormonally responsive and regress with onset of menopause

- No increased risk for cancer

- 75% are ductal

- 10-15% are lobular

- The remaining are medullary, colloid, and tubular (10%)

- Ductal carcinoma --> Carcinoma in-situ

- Neoplastic cells confined to the ducts --> Basement membrane still intact --> Does not invade

- Types: Solid, cribriform, papillary and comedo

- Cribriform: Cookie cutter spaces

- Comedo form: Associated with carcinoma --> Area of central necrosis 

- Good prognosis --> ~28% will develop invasive carcinoma

- Masses 1-4 cm in diameter,  firm and gritty masses with fibrosis, calcifications and chalky white necrosis

- Not well circumscribed

- Retraction of surrounding tissue

- By the time the mass is palpable, ~50% of patients will have metastasis to axillary nodes

- Anaplastic cells with haphazard infiltration of involved tissues

- Well differentiated --> Estrogen (ER) and progesterone (PR) receptor positive and HER2neu negative --> Treated with tamoxafin (estrogen inhibitor)

- Poorly differentated --> ER/PR negative and HER2neu positive --> Treated with herceptin (antibody against HER2neu receptor)

- 2/3 of breast cancers are estrogen receptor positive

- Metastasis: Lung and pleura

- Triple negative breast cancers are VERY hard to treat!!

- ~1% of breast carcinoma

- Well circumscribed, soft and fleshy on gross exam

- Little stroma and cells grow in sheets

- Brisk mitotic rate

- Distinctive infiltration by lymphocytes

- High nuclear grade, absence of ER/PR receptors, and high proliferation rate

- Slightly better prognosis than typical ductal carcinoma

- AKA mucinous --> Soft gelatinous masses

- Generally presents in older women

- Characterized by excessive mucin production

- Tumor may or may not form glands

- Better prognosis than typical ductal carcinoma

- ~10% of ductal carcinomas

- Detected as an irregular mammographic density

- Most common in women in their 40s

- Metastasis seen in <10% of cases

- Seen in 1-2% of breast cancers

- Erythematous eczematous erosion of the nipple

- Malignant cells extend upward from the underlying ducts to the nipple epidermis

- Cells don't cross the basement membrane

- 50-60% of patients with Paget's Disease have a palpable mass indicating an invasive carcinoma

- Presence does not alter the prognosis of underlying cancer

- Usually detected incidentally

- Cells are monomorphic looking

- Cells confined to lobular acini and distend the acini

- No invasion of surrounding tissue

- 30% of patients with LCIS go on to develop invasive carcinoma

- Invasive carcinoma can develop in the same or contralateral breast over the next 20 years

- 5-10% of carcinomas of the breast

- May present as a palpable mass

- 25% of cases have little stromal reaction --> Very difficult to palpate

- Metastasis: Peritoneum, retroperitoneum, meninges, GI tract, and ovaries/uterus --> Less likely to the lungs and pleura

- Small bland cells --> Infiltrate singly and line up in sheets

- Often multicentric and bilateral (20%)

- Often very hard to kill with chemotherapy

- Tend to lead to relapse of disease if it occurs

- Cancer stem cells/tumor initiating cells --> 1-2% of tumor cells

- Identified as CD44+ and CD24-

- Stage

- Histological subtype --> Tubular, medullary, and mucinous/colloid

- Estrogen-progesterone receptor presence

- DNA content --> Proliferation rate

- Oncogenes --> HER2neu presence

- Cathepsins --> Proteinases

- Growth factors --> EGF receptor

- Angiogenesis

- Increased detection of in-situ cancers

- Decrease in the proportion of invasive cancers at the time of detection

- Invasive cancers that are found are smaller than they would be

- Overall reduction in mortality

- 90-95% bronchogenic

- Usually occurs between ages 40-70

- Association with cigarette smoking --> 20-40x increase

- Assocation with radiation, asbestos, and possibly air pollution

- Types: Adenocarcinoma, squamous cell carcinoma, small cell carcinoma, and large cell carcinoma

- Most common cancer is NOT a primary tumor --> Metastasis from other cancers

- 40-60% of lung cancers

- Bronchial derived --> Due to oncogene activation

- Most common type in women and non-smokers

- Tumors are peripherally located --> Tend to be smaller

- Tend to present at a later stage

- Morphology: Acinar/glandular

- Associated with mucin production

- Poorly differeniated types --> Not associated with gland formation

- Type of adenocarcinoma of the lung --> Trying to drop BAC terminology and now should be called carcinoma in-situ

- Arises from the terminal bronchioles/alveolar ducts

- Lepidic type

- Almost always peripheral --> >3cm in diameter

- Presents as a nodule or pneumonia-like consolidation

- Tumor cells line up along alveolar septa

- Cell types: Mucin secreting bronchial cells, Clara cells, and rarely type II pneumoncytes

- Associated with better prognosis than normal adenocarcinoma of the lung

- Most tumors are well differentiated

- Tumors occur at all ages --> Equally distributed between males and females

- Surgically resectabe --> 50-75% five year survival

- 20-40% of lung cancers

- Arise from the large central bronchi

- Tend to spread locally --> Metastasizes later than other subtypes

- Adjacent bronchi exhibit squamous metaplasia, dysplasia and carcinoma in-situ (BAC)

- Exhibit squamous pearl formation --> Squamous cell derived

- Loss of tumor suppressor genes

- Highly malignant lung cancer --> 20-25% of lung cancers

- Composed of small round to oval cells with little cytoplasm --> "Oat cell" --> Neuroendocrine origin

- Cells don't look that anaplastic on H&E --> Organoid growth patterns

- Other forms: Spindle shaped and polygonal

- Neither glandular nor squamous features

- Ectopic production of hormones is common --> Paraneoplastic syndromes are common

- Strongly associated with cigarette smoking

- Tend to be centrally located, metastasize widely and are incurable

- Activation of oncogenes

- 10-15% of lung cancers

- Large polygonal cells with vesicular nuclei

- Undifferentiated version of either squamous cell or adenocarcinoma

- Variants: Giant cell, clear cell and spindle cell

- Often hard to differentiate from metastasis from another primary tumor

- Activation of oncogenes

- Cough (75%)

- Weight loss (40%)

- Chest pain (40%)

- Dyspnea (20%)

- Bronchial obstruction

- Wheezing

- Hemoptysis

- Pleural effusion: Tumor invasion of the pleura

- Hoarsness --> Involvement of recurrent laryngeal nerve

- SVC syndrome: Compression of SVC by tumor

- Pericardial effusion: Involvement of the pericardium

- Paralysis of the diaphragm: Invasion of the phrenic nerve

- Horner Syndrome: Invasion of neural structures around the trachea --> Enopthalmias, ptosis, miosis, and anhidrosis on the side of the lesion --> Due to Pancoast tumors

- Very poor --> Overall 5 year survival is 15%

- 4 cm or less --> Surgical resection leads to 40-50% 5 year survival in squamous cell carcinoma

- 30% 5 year survival for adenocarinoma and large cell carcinoma

- EGFR mutated cancers --> Common in Asian non-smoking women --> Responds to EGFR inhibitors (Erlotinib and gefitinib) 

- EGFR mutations only in 15-20% of adenocarcinomas

- 1-5% of all lung tumors --> Benign usually

- Usually detected on routine CXR

- Neuroendocrine in origin --> Uniform and bland appearing cells

- Protrude into the bronchial lumen

- Rarely exceeds 3-4 cm in diameter --> Spherical polypoid masses

- Most patients are younger than 40 years old --> Not associated with cigarette smoking

- Carcinoid syndrome: Diarrhea, flushing and cyanosis

- Symptoms: Related to secondary infection, bronchiectasis and atelectasis

- 50-95% 5-10 year survival

- Solitary Fibrous Tumor

- Malignant Mesothelioma

- Metastatic Tumors

- Arise from the visceral or parietal pleura

- Highly associated with asbestos exposure

- Asbestos: Serpentine and amphibole forms --> Serpentine gets stuck in larger airways and amphibole goes down to distal airways

- Asbestos/Ferruginous bodies are formed by macrophages in response to the presence of the amphibole form in the lungs

- Lesions: Fibrous plaques, pleural effusions, interstitial fibrosis, carcinoma, and mesothelioma

- Lung parenchyma is spared by tumor

- Morphology: Epithelioid, sarcamatoid and mixed forms

- Epitheloid type: Looks like pulmonary adenocarcinoma --> Pseudoglandular structure and differentiated by special stains for TTF-1 and calretinin

- Presentation: Pain, dyspnea, and recurrent effusions

- Prognosis: 50% of patients die within 12 months

- Therapy: Aggressive therapy (pneumonectomy, chemotherapy and radiation) --> Moderately improves the poor prognosis

- 228,000 new cases in 2013

- 159,000 deaths in 2013

- >1.67 million deaths worldwide projected for 2015

- Annual low dose chest CT for high risk patients

- Reduced mortality due to implementation of LDCTs

- 25% false positive rate

- 8-51% of patients had solitary pulmonary nodules

- 1.1-12% of malignancy in these patients

- Probability of Cancer: Low --> Watch and wait and high --> Surgery to resect nodule

- Cigarette smoking --> Due to aromatic hydrocarbons and arsenic --> Risk back to normal 20-25 years after quitting smoking

- Industrial exposures --> Asbestos

- Genetic factors

- Environmental factors --> Radon

- Underlying COPD

- Scar carcinoma

1. Classical Model

- Tumors acquire mutations that promote the invasive behavior

- Normal epithelium --> Hyperplasia --> Dysplasia --> carcinoma in-situ --> Carcinoma --> Metastasis

- p53 mutation between hyperplasia and dysplasia

- K-ras activation between dysplasia and carcinoma in-situ

2. Alternative Model

- Metastasis is an inherent feature of the tumors

- Certain cells have inherent invasive properties

- Hepatic metastases: Weakness and weight loss

- Brain metastases: Headache, nausea and vomiting, seizures, confusion, and personality changes

- Bone metastases: Pain

- Hypercalcemia: Bony metastases related to the production of PTH hormone by tumor

- Hypertrophic osteoarthropathy: Clubbing of fingers and toes, enlargement of extremities, and painful swollen joints --> Common in adenocarcinoma

- SIADH: 5-10% of patients with small cell cancer

- Cushings: 3-7% of small cell cancer patients

- Eaton-Lambert: Myasthenic symptoms --> Most common in small cell cancer

- Chest X ray

- CT scan of the chest

- Confirmed by biopsy

- PET scan

- MRI

- Mediastinal sampling for lymph node involvement --> Mediastinoscopy

- Endobronchial Ultrasound (EBUS)

- Endoscopic Ultrasound Fine Needle Aspiration

- Surgical resection

- Radiation therapy

- Chemotherapy

- Targeted therapy --> EGFR inhibitors

- Minimally invasive techniques

- Palliative chemotherapy --> Stage IV disease

- Most common cancer in women --> Leading cause of death in American women 40-55 years old

- 12% of American women will be diagnosed with breast cancer during their lifetime --> 3.5% will die

- Incidence increases with age

- Highest incidence in white women

- Highest mortality in African American women

- 85% sporadic, 10% familial and 5% hereditary

- Higher rates of breast cancer in higher socioeconomic groups

- Age 20-39: Monthly breast self-exam and clinical breast exam every 3 years

- Age 40+: Monthly breast self-exam, annual clinical breast exam and annual mammogram

- Visual inspection: Changes in skin texture, retraction or indentation of the nipple, discharge from the nipple, and atypical fullness or puckering of the breast

- Breast enlargement or asymmetry

- Nipple changes, retraction or discharge --> Fibroadenoma is the leading cause but malignancy is second

- Ulceration or erythema of the skin of the breast

- Axillary mass

- Musculoskeletal discomfort

- Age > 60 years

- Personal history

- Lobular or ductal carcinoma in-situ (LCIS or DCIS)

- Family history --> BRCA1 or BRCA2

- Atypical hyperplasia

- Radiation exposure

- Early menarche

- Late menopause

- Nulliparity

- First live birth after age 30

- Previous breast biopsy

- High level of education/socioeconomic status --> Confounds other factors

- Diet

- Sedentary lifestyle --> Obesity --> Estrogen builds up in fatty tissue --> Higher estrogen levels leads to higher risk of breast cancer

- Alcohol consumption --> Moderate

- Environmental exposure

- Estrogen replacement therapy

- BRCA1: Hereditary Breast and Ovarian Cancer (HBOC) --> Chromosome 17q21 --> Very high frequency of breast cancer

- BRCA2: HBOC --> 13q12-13 --> High frequency of breast cancer

- p53: Li-Fraumeni syndrome --> Chromsome 17p13.1 --> High frequency of breast cancer

- PTEN

- ATM: Chromsome 11q22-23 --> Low to moderate association with breast cancer

- STK11

- 5-10% of cancers have BRCA gene mutations

- Breast cancer before age 50

- Ovarian cancer at any age

- Male breast cancer at any age

- Multiple primary cancers

- Ashkenazi Jews

- Multi-disciplinary care --> Surgery, chemo and radiation often all used

- Surgery: Very rarely are radical mastectomies performed today --> Conservative treatment more common --> Improved quality of life

- Chemotherapy: Herceptin, etc

- Hormone therapy --> Tamoxifen and aromatase inhibitors

- Radiation: External beam, brachytherapy, mammosite, 3D conformal RT, etc --> Standard of care to offer RT after lumpectomy --> 6 weeks of treatment with whole breast external beam --> Reduces recurrence by 66%

- Persistently positive resection margins after reasonable re-excision attempts

- Multicentric disease

- Diffuse malignant-appearing microcalcifications --> Multicentricity

- A history of prior RT to the breast or chest wall

- Pregnancy --> Possible in third trimester though

- Patients with a history of scleroderma or other connective tissue diseases --> Tolerate RT poorly and have a great possibility of dermal complications

- Other connective tissue diseases being associated with increased risk is controversial

- Breast size can be a relative contraindication --> Large tumor in a small breast --> Can't really save breast

- Used in order to stage and determine prognosis of breast cancer

- Minimally invasive

- Lower rates of complications

- Complications of surgery: Lymphedema, seroma, sensory complaints, and risk of allergic reaction

- Adjuvant therapy for post-menopausal patients with early stage cancer

- At least as good as tamoxifen

- Examples: Letrozole, anastrozole, exemestone, and androstenedione

- AKA herceptin

- Antibody against HER2 neu receptor

- Used to treat HER2 neu positive breast cancers

- Tumor size

- Grade

- Axillary lymph node status

- Patient age

- Presence of metastasis

- 6% of all female cancers --> 80% of masses are benign

- Fifth most common cancer in women --> Fifth leading cause of cancer death

- Risk factors: Nulliparity, FHx, and gonadal dysgenesis

- Genetics: BRCA1 and BRCA2 mutations --> 30% express high levels of HER2neu oncogene and 50% have p53 mutations

- Surface Epithelium Derived: 65-70% --> Serous, mucinous, endometrioid, clear cell, brenner tumor, and cystadenofibroma --> Most malignant tumors are serous derived

- Germ cell: 15-20% --> Teratoma, dysgerminoma, endodermal sinus tumor/yolk sac tumor, and choriocarcinoma

- Sex-Cord/Stroma: 5-10% --> Fibroma, granulosa-theca, and Sertoli-Leydig tumors --> Can occur in both men and women

- Metastasis: 5% 

- Malignant tumors are more likely to be bilateral

- Types: Serous, mucinous, and endometrioid

- Gross structure: Small to massively large --> Cystic or solid

- Pathogenesis: Derived from coelomic mesothelium --> Form Mullerian ducts which evolve into the serous, endometrioid, and mucinous epithelium of the normal female

- Ovarian cortext forms mesothelial inclusion cysts

- Sometimes associated with endometriosis

- 30% of all ovarian tumors

- Benign (serous cystadenoma), borderline, and malignant (serous cystadenocarcinoma)

- Benign --> 20% bilateral --> Sac filled with fluid lined by tall, columnar epithelial cells (fallopian tube)

- Borderline --> Increased number of papillary projections --> More solid but no nuclear atypia seen in cells and no infiltration

- Malignant: Solid and complex growth with necrosis --> Stromal involvement with high grade atypia

- 66% of malignant masses are bilateral

- 75% are benign/borderline

- Peritoneal spread via seeding

- 30% of all ovarian tumors

- Benign (mucinous cystadenoma), borderline, and malignant (mucinous cystadenocarcinoma)

- Malignant form is 5% bilateral --> Has necrosis in the center --> "swiss cheese" looking

- Multiloculated tumors --> Sticky and with gelatinous fluid

- Cervical type --> Tall columnar epithelial cells --> Associated with endometriosis

- Intestinal type --> Gland-like or papillary growth with stratified epithelium and atypical mucin --> Big Goblet cells

- Pseudomyxoma peritonei: Extensive mucinos ascites --> Associated with mucinous tumors --> Probably arise from the appendixe and involve the peritoneum and ovary secondarily

- Benign and borderline are uncommon forms

- Malignant --> 20% of all ovarian carcinomas

- Resembles endometrial adenocarcinoma

- 15% are associated with endometriosis --> Usually a hormone related malignancy --> Pts are a decade younger

- Seeds the peritoneal cavity over time --> Massive ascites and numerous tumor implants/nodules --> Omentum

- Tumor marker: CA-125 and osteopontin --> Need baseline

- Prophylactic salpingo oophorectomy for patients with BRCA mutation

- 15-20% of all ovarian tumors

- 95% are teratomas in children and young adults --> Differentiation of totipotential germ cells --> Mature (Benign) or immature (malignant) forms

- Dysgerminoma --> Testicular seminoma --> Differeniates to oogonia

- Choriocarcinoma --> Placental tumor

- Endodermal sinus/yolk sac tumor --> Primative embryonal tissue

- Derived from ovarian stroma --> Derived from sex cords of the embryonic gonad

1. 75% are estrogen producing --> Endometrial hyperplasia, cystic disease of the breast, and endometrial carcinoma in adults --> 5% of all ovarian cancers

- Mostly unilateral

- 2/3 present in post-menopausal women

- High rates of recurrence after 10-20 --> Can become malignant

- Histology: Call-Exner bodies --> Central fibrin area

2. Sertoli-Leydic Tumors --> Produce androgens and can cause masculinization of women

- Most are bilateral

- Primary tumors are generally more common

- Commonly come from other gyn organs --> Also of Mullerian origin

- Extra-Mullerian primaries: GI (Krukenberg/gastric tumor), breast and lung

- Krukenberg tumor: Characterized by signet ring cells in the ovary seen with mucin stain --> Huge ovary develops

- Vascular tumors: Hemangiomas and lymphangiomas

- Fibrous tumors: Fibromatosis and congenital infantile fibrosarcoma (malignant)

- Teratomas: Sacrococcygeal teratomas

- Bone tumors: Giant cell tumor/osteoclastoma and osteochondroma (exostosis)

- Small round blue cell tumors: Neuroblastoma, Wilms tumor, retinoblastoma, rhabdomyosarcoma, and Ewing sarcoma/primitive neuroctodermal tumor

- Bone tumors: Osteosarcoma and Ewing sarcoma

- Must common tumor of infancy

- Capillary type: Skin, subcutaneous tissue, mucous membranes of oral cavity and lips, liver, spleen, and kidneys

- Small capillary vessels --> Strawberry angiomas

- Typically grow in the first year but regress by age 5-8

- Cavernous type: Less well circumscribed and located in deep structures --> More dilated vascular spaces filled with blood --> Locally destructive and no spontaneous regression 

- Associated with von Hippel-Lindau disease --> Autosomal dominant disorder

- Benign lymphatic tumors

- Cystic and cavernous

- Dilated lymphatic vessels lined by endothelial cells

- Simple/capillary: Composed of small lymphatic channels --> Predominantly in the head, neck and axilla

- Cavernous: Typically found in neck or axilla --> Associated with Turner's syndrome and rarely occur in the retroperitoneum --> Lymphoid aggregate

- Webbed neck of Turners is actually due to the regression of cavernous lymphangiomas

- Can also occur due to lymphatic obstruction post radical mastectomy

- Sparsely cellular proliferations of spindle shaped cells

- Cells look benign without lots of mitoses

- Good prognosis based on low rate of metastasis

- Can grow and obstruct structures

- Not malignant but can still be destructive

- Rare malignant tumor of mesenchymal origin

- Presents in young children

- Characterized by t(12:15) translocation --> ETV6-NTRK3 fusion protein

- Excellent prognosis due to its low metastatic rate

- Treatment: Surgical excision or amputation of the limb depending on location

- Mature --> Benign and composed of tissues derived from all three embryonic tissues

- Immature --> Indeterminate potential

- Malignant teratomas --> Admixed with another germ cell tumor (endodermal sinus/yolk sac tumor)

- Most common type of teratoma --> 75% mature and 12% malignant and lethal

- Malignant --> Have Schiller-Duvall bodies (vessel surrounded by immature cells) --> Representative of yolk sac tumors

- Immature teratomas --> Malignant potential dpends on the amount of immature tissue present in the mass --> Most commonly have neuroepithelial elements

- Incidence: 1 in 20,000 to 40,000 live births

- Four times more common in girls

- 10% associated with congenital anomalies --> Defects of hindgut, cloacal region, and other midline defects

- Tumors can be very large and somtimes require complete removal of coccyx

- Symptoms related to a space occupying lesion

- Sites: Testis, ovaries, mediastinum, retroperitoneum, head and neck

- Located at the epiphyseal end of long bones

- Locally aggressive --> Usually around the distal femur and proximal tibia --> Knee region

- X-ray: Double-bubble or soap bubble appearance

- Histology: Multinucleated giant cells with background mononuclear stromal cells --> Derived from osteoclasts

- Most common benign bone tumor

- Originates from metaphysis of long tubular bones

- presents as an outpouching of mature bone from the normal long bone

- Mature bone with cartilaginous cap

- Tumor of the sympathetic ganglia and adrenal medulla

- Most common tumor of the adrenal medulla in children

- Origin: Primordial neural crest cells

- Age of presentation: 18 months --> 40% diagnosed during infancy

- Mostly sporadic but 1-2% may be familial

- Neuroblastoma: Contains primitive stroma --> Homer-Wright Pseudorosettes --> Worse prognosis

- Ganglioneuroblastoma: Contains primitive stroma and ganglion cells

- Ganglioneuroma: Contains Schwannian stroma and ganglion cells --> Well differentiated ganglion cells present

- Metastasis: Local infiltration, lymph nodes, liver, lungs, bone marrow, bones, and skin

- "Blueberry Muffin Baby": Skin dissemination of disease

- Prognosis: Depends on age --> Younger the better, n-myc amplification --> Poorer risk, localized disease vs metastatic disease

- N-myc amplification has the most profound impact on prognosis --> Over-expression means rapid tumor progression

- Treatment: Retinoids to induce differentiation and TrkB signaling via small-molecule inhibitors/tyrosine kinase activity

- Most primary renal tumor in children

- Presentation: Huge, palpable flank mass with or without hematuria --> Often noticed by mother while bathing child

- Diagnosed between ages 2-5 (95%)

- 5-10% of tumors involve both kidneys --> Simultaneously or one right after the other

- Histology: Stromal, epithelial and blastemal tissue --> Triphasic

- Must determine if vessels are involved with the tumor --> Vessel involvement implies that clean margins will be hard to achieve during surgery

- Genetics: Deletion of WT1 tumor supressor (Chrom. 11)

- Part of Beckwith-Wiedemann/WAGR Syndrome: Wilm's tumor, aniridia, genitourinary malformation, and mental retardation

- Possibly associated with bone and soft tissue sarcomas, leukemia, lymphomas, brain tumors, and genitourinary tumors

- Prognosis: Very good

- Treatment: Nephrectomy and chemo

- Most common intraoccular tumor in children

- Origin: Neuronal cells

- Prognosis: Adversely affected by extraocular extension and invasion of the optic nerve

- Genetics: Inheritance of one germ-line Rb mutation (40%)

- Metastasis: Brain and bone marrow --> Seldom to lungs

- Histology: Areas of necrosis, calcification and Flexner-Wintersteiner rosettes (Small blue cells surrounding internal stroma)

- Gives a blurred/whitish appearance to the eye

- Treatment: Enucleation (surgical removal), radiation, cryotherapy, thermotherapy, and chemotherapy

- Most common soft tissue sarcoma in children and adolescents

- Usually appears before age 20

- Locations: Head and neck or genitourinary tract --> Vagina and penis, etc

- Histology: "Tadpole" looking cells

- Types: Embryonal, Alveolar, and botryoid

- Prognosis: Aggressive neoplasms --> Depends on location of tumor --> Good prognosis for botryoid but all others are often fatal

- Treatment: Surgery and chemotherapy with or without radiation

- 

- Most common type --> 60%

- Occurs in children under age 10

- Locations: Nasal cavity, orbit, middle ear, prostate, paratesticular region, vaginas of little girls, and penises of little boys

- Genetics: Allelic loss of chromsome 11 (11p15.5)

- Botryoides type: Develops in the walls of hallow, mucosa-lined structures --> Nasopharynx, common bile duct, bladder and vagina --> "Cluster of grapes" appearance

- Most common in early to mid-adolescence

- Arises in the deep musculature of the extremities

- Genetics: t(2:13) or t(1:13) translocations

- Prognosis: Worse prognosis for t(2:13) translocations --> PAX-3-FOXO1a fusion gene

- Ewings sarcoma: Undifferentiated

- Primitive Neuroendocrine Tumors: Derived from neural origin

- Malignant small round cell tumors of the bone and soft tissue

- 6-10% of primary malignant bone tumors

- Boys slightly more affected than girls --> Slight predilection for whites

- X-ray: Onion skin appearance of bone

- Genetics: t(11:22) translocation forming EWS-FLI1 --> 85% of Ewings sarcoma and PNETs

- Presentation: Diaphysis of long tubular bones --> Especially the femur, flat bones of the pelvis, scapula and ribs

- Metastasis: Extremely aggressive --> Bone and lung

- Treatment: Chemo and surgical excision with or without radiation

- Prognosis: Improved to 75% 5 year survival due to advent of chemo --> Amount of chemo-induced necrosis is important for prognosis

- Most common primary bone malignancy --> 75% <20 years old and second peak in the elderly

- Location: Metaphysis of long bones, often around the distal femur and proximal tibia --> Knee region

- X-ray: Codman's triangle and sunburst pattern

- Prevalence: Male > Female

- Risk factors: Paget's disease of bone, bone infarcts, radiation, and familial retinoblastoma (Rb mutation already)

- Metastasis: Lung, bone, and brain

- Treatment: Chemotherapy and limb salvaging therapy

- 1 in 20 people will develop colon cancer in their liftime (6%)

- 1 in 10 adenomas progress to cancer

- Smoking exposure

- Diet and sedentary lifestyle --> Obesity and diabetes

- Low NSAID use --> NSAIDs actually protective

- Even immigrants develop same risk after living in the US for some time --> Environmental factors > genetic factors

- Increased fat intake

- Increased red meat consumption

- Moderate alcohol use

- 75% sporadic

- 15-18% with family history --> 3-4 RR for 2 first degree relatives, etc --> Tend to develop cancers earlier too

- 5% Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

- 1% Familial Adenomatous Polyposis (FAP)

- 1% Inflammatory Bowel Disease (IBD)

- Autosomal dominant condition --> APC gene mutation (Chrom. 5)

- Multiple adenomas form

- Polyps are not present at birth but develop between ages 20 and 30

- Risk approaches 100% by age 40

- Locations: Fundic gland, gastric, duodenal, ampullary, jejunoileal, and coloretal polyps are possible --> Colorectal are more numerous

- Pre-cancerous lesions for gastric polyps 

- Extra-intestinal Features: Congenital hypertrophy of retinal pigment epithelium (CHRPE), abnormal dentition, epidermal cysts, brain tumors (Turcott's syndrome), thryoid  tumors, osteomas, and desmoid tumors

- Similar phenotypically to FAP --> Variant of FAP

- Autosomal recessive mutation in MYH

- MYH: Base-excision repair gene

- Genetic testing available

- Penetrance and average age of developing cancer still unknown

- In this case, patient wouldn't have a direct family history --> Parents would be carriers not symptomatic

- Primarily proximal colorectal cancer lesions

- Early age of onset of cancer --> <40 years old

- Risk: ~80% for lifetime

- Extracolonic lesions: Endometrial, stomach, biliary, urinary, and ovarian

- Acclerated rate of adenoma to cancer progression --> <2 years instead of 15-20 years

- Genetics: DNA mismatch repair gene mutation --> MLH1 and MSH2 mutations

- Diagnosis: Must rule out FAP and some family history

- Incidence of cancer increases with prolonged duration of IBD

- ~60% will develop cancer after 40 years with disease

- Pancolitis patients are at much higher risk of developing cancer than distal colitis

- Cause 80% of colorectal cancers

- Normal --> Small adenoma --> Large adenoma --> High-grade dysplasia --> Invasive cancer --> Metastases

- This process usually takes about 10 years but can take as long as 25 years

- This is where the recommendations for colonoscopy every 5 or 10 years comes from

- 20% of colorectal cancers

- Normal --> Microvesicular hyperplastic polyp --> Sessile serrated adenoma --> Serrated adenoma --> Serrated cancer --> Metastases

- This process takes about 15 years

- Colonoscopy are not as useful for these 

- Alot of cancers can be missed because they are flat and grow out instead of up first

- Can grow slowly and then rapidly once the lesions become obvious on colonoscopy

- 30% right colon

- 10% transverse colon

- 15% proximal left colon

- 25% sigmoid colon

- 20% rectum

- Both can present with anorexia, malaise, and weight loss

1. Rectosigmoid

- Visible rectal bleeding --> Bright red blood

- Change in bowel habits

- Pain relieved by passage of stool or flatus

- Obstruction

- Perforation

2. Cecum

- Occult bleeding --> Clotted blood

- Iron deficiency anemia

- Palpable mass

- Pain

- Acute appendicitis

- Digital rectal exam --> Low yield but really easy and cheap

- Fecal occult blood testing --> Not a diagnostic test but rules out the presence of occult bleeding

- Flexible sigmoidoscopy: Examines the left colon only

- Barium enema: Indirect --> Not really done anymore because you need a colonoscopy to confirm

- CT colonography and PET scan

- Colonoscopy --> Gold standard --> Examines entire colon

- CEA levels --> Can track these levels to see progression of disease and relapse --> Need baseline though

- Metastasis (liver met) shows more rapid rise of CEA than localized tumors

- Invasive cancer

- Transmural invasion

- Regional lymph nodes --> Periaortic nodes

- Liver

- Lung 

- Surgical excision if the tumor hasn't invaded into the submucosa

- Advanced disease: 5-FU plus leucovorin and oxaliplatin, 5-FU plus leucovorin and irinotecan or capecitibine plus oxaliplatin

- Adjuvant: 5-FU/leucovorin, oxaliplatin and oral capecitabine

- Age (>50)

- Personal history

- Family history of colon cancer or adenomas

- Genetic syndromes --> FAP and HNPCC

- Inflammatory bowel disease

1. Positive family history: Two or more first degree relatives with CRC at any age or single FDR with CRC or FAP diagnosed >60 years old

- Colonoscopy every 5 years starting at age 40 or 10 years before youngest affected relatives

2. Familial Polyposis

- Genetic counseling and flex sig. yearly beginning at puberty

3. HNPCC

- Genetic counseling and colonoscopy every 1-2 years beginning at age 25

4. Prior cancers: Colonoscopy 1 year after then every 3-5 years

5. Prior adenoma: Colonoscopy every 3-5 years

6. IBD: Colonoscopy every 1-2 years after 8 years of pancolitis or 15 years of left-sided disease --> Pancolitis more at risk

- Inhibits dihydrofolate reductase --> Caused dihydrofolate polyglutamate build up

- Side effects: GI ulceration, leukopenia, nausea, thrombocytopenia, generalized bone marrow toxicity, and UV sensitivity

- Essentially blocks folate production and halts DNA replication

- Drug resistance: Decreased drug transport, increased drug export, altered affinity of DHFR, decreased polyglutamate formation, and gene amplification of DHFR

- Suicide inhibitor of thymidylate synthase --> Pyrimidine analog

- Permanently derivitizes thymidylate synthase --> 1 molecule of 5-FU inhibits one molecule of thymidylate synthase

- Indications: Colorectal cancer, pancreatic cancer, melanoma, adenocarcinoma, and head and neck cancers

- Side effects: Nausea, GI ulceration and mucositis, bone marrow suppression, and increased risk of sunburn

- 

- Used for methotrexate rescue and overdose

- Calcium salt of folinic acid

- Restores single carbon metabolism immediately to reverse bone marrow suppression and anemia

- Does not require dihydrofolate reductase for conversion to tetrahydrofolate

- Can restart the cycle of metabolism even when methotrexate is on board

- Side effects: Typically none but may increase toxicity or effectiveness of 5-FU

- Recombinant enzyme

- Rapidly lowers blood levels of methotrexate

- Enzymatically hydrolyzes the peptide bone of methotrexate to release glutamate

- Nucleotide analogues --> Stops proper DNA replication

1. Cytarabine: Leukemias and non-Hodgkin lymphomas

- Side effects: Neutropenia

2. 6-thioguanine

3. 6-mercaptopurine

- Antibiotic that forms complexes with Iron (Fe2+) and DNA

- Free radicals form --> Single and double stranded breaks

- Strand breaks cause accumulation of cells in G2 phase

- Synchronizes tumor cells --> Can then induce combination chemotherapy to kill arrested cells

- Indications: Squamous cell carcinomas, testicular cancer, and lymphoma

- Side effects: Anaphylactic shock, fever, anorexia, and pulmonary fibrosis

- No myelosuppression results

- Topoisomerase II inhibitor

- Inhibits the ability to relieve supercoiling of DNA during replication --> Halts DNA replication

- Arrests the cell in late S phase through G2 phase

- Indications: Monocytic leukemia, small cell lung cancer, and testicular cancer

- Side effect: Secondary AML development

- Similar to irinotecan --> Used for colorectal cancer

- Vinca alkaloid --> Mitotic inhibitor

- Binds to microtubule dimers --> Interferes with microtubule polymerization

- Leads to arrest of chromosome movement at metaphase stage --> Cell arrest in M phase

- Indication: Leukemia, lymphomas, some other childhood cancers, and breast cancer

- Side effects: Hair loss and loss of appetite

- Similar agents: Vinblastine --> Breast, testicular cancers, and lymphoma, paclitaxel/taxol --> Breast, lung and ovarian cancer, and ixabepilone --> Metastatic breast cancer

- Work VERY well in breast caners

- Tyrosine kinase inhibitor --> Inhibits HER2 (ErbB2) and EGF receptor tyrosine kinase by binding the ATP binding pocket

- Blocks the constitutive activation of tyrosine kinases which stimulate proliferation

- Indications: Breast cancer and possibly for prostate, brain, liver and ovary in the future

- Side effects: Anemia, diarrhea, rash, and hand-foot syndrome (red, swollen, numb or painful hands and feet)

- mTOR inhibitor --> Further down the signaling pathway from tyrosine kinases associated with receptors (EGFR)

- mTOR still stimulates proliferation

- Leads to G1 arrest of the cell cycle --> Fails to transmit growth signal from EGFR

- Indications: Advanced renal cell carcinoma

- Side effects: Rash, weakness, nausea, oral mucositis, and rarely thrombosis and renal failure

- Dietary components will further reduce cancer risk particularly in colorectal cancer

- ECGC --> Green tea

- Resveratrol --> Red wine

- Other antioxidants --> Vitamin C

- Dietary fiber from raw vegetables and cereal bran

- Derived from nitrogen mustards

- Has multiple Cl leaving groups that help the compound alkylate and form bonds with DNA residues

- Cl groups leave --> Compound forms 3 membered ring --> Very unstable and reacts with DNA residues --> Permanently links DNA

- Cells can no longer undergo replication

- Activation to 4-hydroxy-cyclophosphamide by P450 in the liver

- Most effective in G1 and S phases

- Side effects: Nausea, vomiting, bone marrow suppressino, sterility, and possible acute leukemia

- Other aziridine alkylating agents: Thiotepa --> Ovarian and breast cancer and triethylenemelamine --> Retinoblastoma

- Contains sulfates that are also excellent leaving groups

- Allows for cross linking with DNA

- Mechanism: Toxicity to myleoid precursors

- Indications: CML

- Platinum based DNA alkylator

- Cl molecules are in the cis formation to the platinum molecule --> Hence the name

- Indications: Testicular, ovarian, and bladder cancers

- Side effects: Nausea (most potent), little myelosuppresion, and hearing loss

- Hearing loss more prominent with increased doses

- Anthracycline DNA intercalator

- Binds DNA with high affinity by intercalation with pi bonds --> Above and below

- Blocks DNA replication and transcription of mRNA

- Generates free radicals --> Lead to cardiotoxicity

- Daunorubin: Similar mechanism and useful in acute leukemia but NOT solid tumors

- Histone deacetylase inhibitor

- Deacetylation reduces the expression of antiproliferative genes

- Too much deacetylase activity leads to reduced antiproliferative gene expression and ultimately leads to proliferation

- Restores balance and allows negative regulatory proteins to the synthesized

- Indications: Cutaneous T-cell lymphoma

- Used to counteract bone marrow suppression also resulting from chemotherapy

- Erythropoietin: Stimulates RBC precursor formation --> Overstimulation can lead to thrombosis

- Granulocyte-Macrophage Colony Stimulating Factor: Stimulates granulocyte, erythrocyte, and megakaryoctye producation --> Used to reverse neutropenia

- Targeted adjuvant therapy --> Potently binds ABL protein and inhibits production

- Targeted kinase-specific inhibitor for CML --> Very specific competitive inhibitor --> Reversible binding

- Indications: CML --> BCR-ABL (t(9:22)) gene

- Unregulated ABL activation leads to cell growth, proliferation, and survival

- Imatinib inhibits the loop of ABL from flipping back and forth the way it needs to

- Resistance: Mutations to ABL/imatinib binding site --> Thr converted to Iso --> Unstable hydrogen bonding

- Primary: Innate or natural --> At birth

- Secondary/Acquired

- Development requires:

1. Mechanism to introduce frequent mutations

2. DNA replication to stabilize and perpetuate mutations

3. Adventitious mutations develop

4. Selection pressure for mutations

- Inhibitor of the NFkB pathway --> Crucial for growth in the immune system

- IkB is an inhibitor of NFkB pathway

- Mechanism: Inhibits the degradation of IkB --> Prolonged blockade of NFkB pathway --> Significantly reduced cell proliferation

- Indications: Multiple myeloma

- Similar compounds: Sulfasalazine

- Targeted monoclonal antibody inhibiting CD20 receptor --> Selectively depletes B cell population

- Indications: B-cell non-Hodgkin's lymphoma --> Relapsed or low grade NHL

- Resistance mechanism: Down regulation of CD20 receptor

- Humanized antibody against EGFR --> HER2neu receptor

- HER2neu amplified in 20-30% of breast cancer

- Indications: Ovarian and breast cancer

- Daclizumab: Anti-CD25 antibody --> Depletes activated T-cells which express CD25

- Muromonab: Anti-CD3 antibody --> Depletes T-cells expressing CD3

- Estrogen receptor antagonist

- Used in conjunction with surgery and radiotherapy

- Indications: ER/PR+ breast cancers

- Reduces mitogenic signal transduction of breast tissue --> ER/PR+ breast cancers grow with estrogen secretion

- Inhibition of estrogen signal transduction --> 10 fold lower affinity to receptor than endogenous estrogen

- Must reduce other sources of estrogen to improve prognosis of the tumor

- Side effect: 2-3x risk of endometrial cancer

- Androgen hormone antagonist --> Male hormones

- Indications: Advanced prostate cancer

- Side effects: Hot flashes with sweating and impotence

- Has NOT been tested in women and children

- Initially causes tumor regression but tumors can regress because they fail to express androgen receptors

- 75% of pancreatic cysts are pseudocysts

- Related to acute and chronic pancreatitis

- Lack of epithelial lining

- Lined by granulation tissue

- Most commonly identified incidentally during routine CT or MRI

- 25% of all cystic neoplasms of the pancreas

- Most common in women in their 70s

- Multilocular and sponge-like

- Contains clear straw colored fluid

- Lined by clear glycogen-rich cells

- Always benign

- Cured by surgical resection --> Resection necessary unless it causes symptoms

- Rare tumor of young women

- Solid and cystic on gross examination

- Solid and pseudopapillary microscopically

- Caused by a b-catenin mutation --> Cells migrate away from eachother

- Immunohistochemistry: b-catenin in the nucleus and losso f e-cadherin in the membrane

- Can be locally invasive

- Large multiloculated cystic lesion

- Cystic neoplasms of the body or tail of the pancreas

- Usually occur in middle aged women

- Lined by mucinous epithelium --> Large Goblet looking cells

- Ovarian stroma in the wall of the neoplasm

- May be either benign or malignant --> Aggressive if malignant

- Resection is always indicated

- Multifocal and cystic neoplasm

- Involves the main pancreatic ducts --> Head of the pancreas

- More frequent in men

- Patulous mucoid ampulla --> Hugely dilated main pancreatic duct seen on gross examination after Whipple

- May be benign, borderline, or malignant

- Can mimick mucinous cystic neoplasms clinically

- Papilla become enfolded in lesion

- High grade dysplasia present in the surrounding ducts

- Development of invasive cancer is possible but unlikely

- 2% of pancreatic tumors

- Uniform cuboidal cells with pattern variations

- Diagnostic neuro-secretory granules

- Prognosis is weakly related to histology --> Necrosis, invasion, and metastasis

- Tumors <2.5 cm --> Excision often leads to cure

1. Beta cell (insulin) tumors: Hypoglycemia and benign tumor

2. G-cell (Gastrin) tumors: Z-E syndrome and MEN1 and malignant

3. Glucagonoma: Mild diabetes and skin rash (necrolytic migratory erythema) --> Very subtle presentation

4. Somatostatinoma: Diabetes, cholelithiasis and steatorrhea

5. VIPoma: Watery diarrhea, hypokalemia, and achlorhydria

- 10th highest incidence and 4th highest mortality

- 5 year survival is <5%

- Usually presents in 60-80 year old patients and more prevalent in men

- Risk factors: Smoking, family history, and chronic pancreatitis

- Involves the head of the pancrease in 60% of times

- Usually diagnosed at a later stage --> Already metastasized

- Well, moderately, or poorly differentiated tubules are present

- Desmoplastic stroma

- Perineural and vascular invasion possible

- Associated with ductal atypia in 33% of cases

- Gross examination: Firm and hard

- Very hard to resect because they spread so frequently

- Can mimick chronic pancreatitis presentation

- Genetic mutations: kRAS mutation and telomere shortening --> p16 inactivation --> p53 inactivation and activation of SMAD4 and BRCA2 --> Invasive carcinoma

- Stage I: 80-95% 5 year survival

- Stage II: 55-80% 5 year survival --> Invasion of submucosa

- Stage III: 40% 5 year survival --> Regional node involvement

1. APC

- Tumor suppressor gene mutations

- Typically presents in 65-70 year olds

- c-myc activation

- Increased expression of COX2 in small adenomas

2. Serrated Polyp Neoplasia Pathway

- Oncogene mutation --> BRAF most common but kRAS also possible

- Important in elderly women

- Cancer occurs about 10 years after normal presentation --> 80 year olds

- More aggressive

- Easily missed by colonoscopy because they grow quickly

- Lobulatated and branched tubules are present

- Lesions in the right colon and serrated polyps grow into tubular adenomas

- Develops a kRAS mutation

- Most invasive and aggressive tumors

- Size determines risk

- Various levels of dysplasia are possible 

- Additional mutations: p53, 18q, 6q, 22q, and 8p mutations

- Additional mutations are responsible for the later stage

- Impossible to cure if it has metastasized to other organs

1. Goblet Cell Serrated Polyp (GCSP): kRAS mutation

- Predominance of Goblet cells

- Surface tufting and minimal serration

2. Microvesicular Serrated Polyp (MVSP): BRAF mutation

- Predominance of microvesicular cells --> Goblet cells

- Serration extending deeply but not to crypt bases

- Hasn't transformed yet

- Transformation: Oncogene induced senescence due to CpG island methylation

- Sessile serrated adenoma

- Polyps in the proximal part of the bowel are more likely to transform

- CpG island methylation occurs

- Shuts down control genes by methylation

- Loss of growth control

- Abnormal architecture of the crypt bases

- Inverted crypts and dystrophic Goblet cells

- Crypts: Hyperplastic --> Develop odd shapes

- BRAF mutation and CIMP-H mutation

- Becomes dysplastic due to BRAF mutation and CpG island mutation --> Turns off mismatch repair gene (CIMP)

- Myriads of new mutations may develop

- Additional mutations will occur with further division

- TGF-b becomes inhibited and no longer has effect on cells

- BRAF mutated MSI

- Looks alot like other colorectal cancers

- Glandular cancer

- Well differentiated, undifferentiated or mixed forms

- Polymorphous

- Imbalance of cell proliferation and cell death

- Increased rate of proliferation

- Decreased rate of cell death

- Formed by molds that grow on improperly stored grains and legumes

- Converted to epoxide by P450 in the liver

- Binds guanine in DNA

- Selectively binds p53 and kRAS genes --> mutations

- Chemical changes the structure of guanine --> Polymerase doesn't know what to do with it so it just stops replicating and transcribing

- Self-sufficiency in growth signals (Activation of h-RAS oncogene)

- Insensitivity to anti-growth signals (Loss of retinoblastoma suppressor)

- Evading apoptosis (Production of IGF survival factors)

- Limitless replicative potential (Activation of telomerases)

- Sustained angiogenesis (Production of VEGF inducer)

- Tissue invasion and metastasis (Inactivation of E-cadherins)

- Virus provides one or more of the steps involved in the multi-step carcinogenesis

- Virus integrates into genome and persists

- Cell only expresses a subset of viral genes --> Allows for escape from the immune system

1. Oncogenes

2. Cell-fusion toxins

3. Viruses in viral induced malignancies

4. Immune system

5. Anti-tumor vaccines and antibodies

6. Gene therapy

1. Complement fixation

- IgM > IgG at fixing complement

- Complement activation leads to permeabilization of mebranes

- Not an efficient process

2. Antibody Dependent Cell-Mediated Cytotoxicity

- Antibodies opsonize so phagocytes can kill

- IgG > IgM

- Cell mediated cytotoxicity occurs 4 hours after IgG binding

- Effector cells: Macrophages/monocytes, PMNs, and lymphocytes (K cells)

- Non-specific response

1. Macrophages: Distinguish tumor cells from normal cells

- No immunization is required

- Require activation by IFN-g/macrophage activating factor and BCG

2. PMNs:

- Mediates ADCC

- Cell contact is required

- Performs opsonization, phagocytosis and cell lysis

- No immunization with antigen required

- Recognize and lyse tumor or virus-infected cells

- Killer cell inhibitor receptors (KIRs) bind the MHC I molecules on cells and inhibits cellular killing

- Loss of MHC I molecules and loss of self leads to activation of cellular killing

- Killer cell activating receptors bind a ubiquitous molecule on all cells and helps to initiate killing

- Stimulated by IL-2 and IL-12

- Mechanism: Degranulation of perforins, granzymes, and nitric oxide --> Non-antigen dependent killing

- Amplified after the exposure to antigens present on tumor cells --> Immunization priming

- Dual restriction: Self MHC and antigen bound on cell surface

- Tremendous specificity --> Needs both self MHC and tumor antigen to be present together

- Major anti-viral and anti-tumor defense of the body

- Target adhesion molecules: CD8/MHC I, LFA/ICAM, and CD2/LFA3

- Target Recognition/Activation Molecules: T-cell receptor/Antigen+MHC I and CD28/B7

- Target lysis: Release of lytic granules and toxins that perforate the target cell membrane

1. Oncofetal antigens: CEA (GI, lung and breast cancers) and AFP (hepatomas and germ cell tumors)

- Tumor markers are shed into the blood, have uniform distribution in the blood and the levels reflect the tumor mass

- Generally need baseline levels to really follow levels

2. Differentiation Antigens

- B-cell differentiation and serial expression of CALLA, B4, B1, clg, slg, and antibody secretion

3. Tissue-Specific Antigens

- Melanocyte antigens/Tyrosinase --> Melanoma

4. Tumor specific antigens: Tumor-limited

1. Virus-Induced Tumors

- Virus-encoded antigens: EBV, HBV, HTLV-1 and HPV associated

- Cellular antigens induced by the virus

- Antigens are strong and often cross-react

2. Tumor Restricted antigens

- MAGE proteins: 30 kDa protein of melanoma cells --> Recognized in HLA-A1 positive patients

- MUC-1: "Bare" mucin protein produced by breast and pancreatic carcinomas

3. Oncogenes: P21 Ras, BCR-Abl, and p53 mutations

4. B-lymphomas: Cell surface epxression of a unique Ig molecule --> Create a personalized monoclonal antibody

1. Loss of antigen presentation

- Antigenic progression

- Heterogeneity of expression within the tumor cells

- Lack of access by the immune system --> Cells within the tumor mass and tumor stroma --> WBCs can't get into the entire tumor

2. Excessive Antigen

- Shedding of antigen to neutralize B-cells in circulation

- Membrane blebs with antigen and MHC --> Neutralize CTLs

- Antigen/Antibody complexes to neutralize phagocytes

3. Blockade of Tumor Antigens by Antibodies

- Tumor antigens are hidden by antibodies and render them incapable of fixing complement

- Blockade of accessory molecules

4. Loss of Recognition Molecules

- Adhesion molecules and co-stimulatory molecules

- Method of immune evasion

5. Loss of MHC antigens

- Result of expression of some oncogenes

- Tumor becomes invisible to CTLs by no longer expressing MHC I --> Now can be killed by NK cells though

6. Specific Suppression of Cellular Immunity

- Secretion of immunsuppresive cytokines by tumors --> TGF-b and IL-10

- Stimulation of suppressor T-cells: Can be inhibited by therapies to help treat cancers and allow the immune system to kill

7. Non-specific Mechanisms

- Malnutrition --> Impairs phagocytes

- Loss of lymphoid tissue --> From surgery, irradiation, or tumor infiltration

- Chemotherapy: B and T cell toxicity

- Phagocyte function is also impaired by radiation and infections

- Dysphagia: Begins with just solids and then progresses to liquids as well

- Weight loss

- No chest pain, vomiting, melena or rectal bleeding

- Squamous cell cancer is decreasing

- Adenocarcinoma is rapidly increasing in prevalence

1. Risk factors

- Alcohol and smoking (SCC)

- GERD and Barrett's esophagus (Adenocarcinoma) --> 0.1-0.5% cancer risk per year for Barrett's

2. Ethnicity

- SCC: African American

- Adenocarcinoma: Caucasians

3. Location

- SCC: Upper 2/3 of the esophagus

- Adenocarcinoma: Lower 1/3 of esophagus and gastric cardia

4. Geography

- Asian cancer belt --> Due to consumption of hot tea

5. Diet

- Aromatic hydrocarbons, nitrosamines and hot tea/coffee

6. Associated diseases

- Achalasia

- Caustic strictures

- SCC of the head and neck

- T1: Invasion of lamina propria or submucosa --> 46% survival

- T2: Invasion of muscular propria --> 30%

- T3: Invasion of adventitia --> 22%

- T4: Invasion of adjacent structures --> 7%

- N0: No nodal involvement --> 40%

- N1: One group of nodes involved --> 17%

- M1: Metastasis --> 3-5%

- CT scan

- PET scan 

- Endoscopic ultrasound: Best modality for determining T stage

1. Surgery: Subtotal esophagectomy --> Connects stomach up to the remaining healthy portion of the esophagus

- Stomach no longer has the same ability to churn

- Rarely curative

- 20% 5 year survival

2. Endoscopic therapy

- Resection

- Ablation with laser or argon coagulation

3. Chemoradiation for resectable tumors

- Carboplatin and paclitaxel plus XRT --> 92% with resectability and only 69% without

4. Chemotherapy for advanced disease

- 5FU and carbolatinum or capecitabine and oxaliplatin

5. Esophageal stenting

- Possible for non-resectable tumors that are affecting the ability to eat

- Epigastric pain

- Early satiety

- Anorexia

- Weight loss

- Positive stool guiac

- Anemia

- Nausea and vomiting

- Paraneoplastic conditions: Acanthosis nigricans, Trousseau's syndrome, and ascites

- Virchow's syndrome: Left supraclavicular node

- Blumer's shelf: Retroperitoneal spread

- Krukenberg tumor: Bilateral infiltration of gastric adenocarcinoma to the ovaries --> Signet ring cells seen

- Incidence is declining since the 1940's

- 2nd leading cause of cancer death worldwide

- No longer in the top 10 cancers in the US

- Highest incidence in Japan and East Asia --> Consumption of smoked meats

- Most prevalent in patients 65-74 years old

- 2-3% of gastric ulcers are actually malignant --> Must screen

- Chronic atrophic gastritis --> H. pylori and pernicious anemia

- Gastric polyps --> 1% of the population and 10% of gastric polyps are adenomas (pre-cancerous) with a risk of malignancy

- Prior partial gastrectomy

- Autoimmune disorder --> Antibodies against parietal cells and the intrinsic factor they produce

- Results in vitamin B12 deficiency

- Causes atrophic gastritis --> Increased risk of cancer

- Unsedated endoscopy performed routinely in high risk regions like Asia

- Japanese experience: 50% of cancers are identified at an early stage and ~50% mortality reduction due to screening

- Endoscopy with biopsy

- CT to identify metastasis

- Esophageal ultrasound for staging

- Who gets scoped?? --> >45 years old, anemic, signs of GI bleeding, and weight loss

1. Curative treatments

- Surgery: Total or subtotal gastrectomy

- Endoscopic mucosal resection --> For small T1N0 lesions

2. Advanced disease: 75% of gastric cancer patients

- Pre and post operative chemotherapy for resectable tumors --> 36% 5 year survival versus the previous 23%

- Mesenchymally derived tumors --> Resemble sarcomas

- 70% present in the stomach

- Slow growing tumors

- Symptoms related to mass effect --> Can grow to be 20-30 cm

- Large size and high mitotic rate are poor prognostic factors

- Surgery --> Definitive therapy

- Imatinib: KIT tyrosine kinase inhibitor --> Crucial in growth

- Clinical trials show partial responses or stabilization of growth due to imatinib therapy

- Makes the tumor more resectable

- 4th leading cause of cancer death in the US

- 85-90% due to ductal adenocarcinoma

- Rarely presents before age 45

- More common in men

- Usually diagnosed with advanced disease

- Overall 5 year survival is <5% --> Only 10-20% of lesions are resectable for cure

- Only 5-20% survival rate even with resection

1. Hereditary pancreatitis: Autosomal dominant

- Leads to 50-60% of pancreatic cancer

- Due to a trypsin inhibitor mutation --> Autodigestion of the pancreas due to autoactivation of trypsin

2. Chronic pancreatitis: Alcoholism and gallstones

3. Smoking

4. Family history: Very low level risk factor

- Positive in <10% of cases

- Abdominal pain: Invasion of the celiac and SMA nerve plexuses --> Poorer prognosis

- Back pain: Gnawing --> Due to nerve infiltration

- Weight loss

- Jaundice --> Painless jaundice --> Tumor in the pancreatic head, earlier presentation and slightly better prognosis

- Associated symptoms: Trousseau's syndrome and courvoisier gallbladder (Huge/dilated and palpable gallbladder felt on physical exam)

- CT scan: Predicts unresectability, distant metastases, and vascular involvement

- ERCP: Dilated common bile duct and pancreatic duct can be seen --> Biopsies have a low yield

- Endoscopic Ultrasound: Most accurate modality --> Perform fine needle aspiration of masses and lymph nodes

- Serum markers: CA 19-9: Poor accuracy --> Pancreaticobiliary tumor marker but not a useful screening tool

1. Resectable disease

- 15-20% are deemed resectable by CT

- 20-30% have peritoneal disease at laparoscopy

- Whipple procedure --> Most common surgical procedure

- 5-20% 5 year survival --> Micrometastatic disease is pretty common --> Commonly relapses

2. Metastatic Disease

- Palliative chemo with gemcitabine

- Median survival --> 3-6 months

3. Locally advanced disease

- Chemotherapy and radiation therapy

- Median survival --> 10-12 months

- Endoscopic biliar stents are useful to stent open the ducts and improve symptoms and jaundice for non-resectable tumors

- 4th leading cancer worldwide

- Highest incidence in Asia and sub-Saharan Africa --> Highest incidence of Hepatitis B infection

- Intermediate incidence: Eastern Europe and Alaska --> Hep B is endemic in the Inuit population of Alaska

- Low incidence: US and Western Europe

- Hepatitis B with or without cirrhosis --> Can develop even as a carrier

- Hepatitis C with cirrhosis --> Most common cause in the West

- Hemochromatosis

- Fatty liver

- Alpha-1 antitrypsin deficiency

- Alcohol induced cirrhosis

- Chronic inflammation and fibrosis

- Often asymptomatic

- Right upper quadrant pain --> Stretching of the hepatic capsule is painful

- Weight loss

- Fevers: Also possible in lymphomas and renal carcinoma

- May have a palpable mass on exam

- 15% may pesent with hepatic bruit

- Seizures --> Severe hypoglycemia due to release of insulin-like growth factor by tumor --> Rare paraneoplastic syndrome

1. Imaging: CT scan with IV contrast and MRI with IV gadolinium

- Characteristic arterial phase with washout in the venous phase --> Tumor recruits only arteries so tumor shows up brightly during arterial phase of contrast

- The rest of the liver will light up brightly during the venous phase because 2/3 of the liver is supplied by the portal vein

2. Alpha-feoprotein: >500 is diagnostic for either hepatic or germ cell tumors 

- Lower elevations in classic cirrhosis

1. Liver transplant

- Most effective therapy for a single tumor <5 cm or three individual tumors each <3 cm

2. Resection of tumor

- Can only be performed with adequat liver function of the rest of the liver

- Performed for tumors in a good location

- Untreatd large hepatomas have median survival of only a couple of months

3. Ablation: Can be a successful bridge to transplant

- Alcohol and radiofrequency catheter forms

- Can be curative in really small tumors

4. Transhepatic arterial chemoembolization

- Injection of chemo directly into the vessel and embolize vessel to eliminate blood supply

- Palliative treatment to bridge to transplant but CAN be curative

5. Sorafenib: VEGF and PDGF inhibitor

- VEGF and PDGF are crucial for angiogenesis and vascular growth

- Side effects: GI upset and hand-foot syndrome

- Improves survival to 46 weeks instead of 34 weeks --> 44% 1 year survival versus previous 33%

1. Hepatitis B patients >45 years old, females >55 years old in Southeast Asia, African Americans >20 years old, and patients with family history of HCC

2. Patients with cirrhosis of any etiology --> Hep B and Hep C are most common causes

- Ultrasound imaging and alpha fetoprotein levels every 6 months

- CT or MRI if either of the first tests are abnormal

- Biopsy necessary if CT or MRI are not diagnostic --> Uncommon though

- Benign lesions are relatively rare unfortunately

1. Renal cortical adenoma

- Most common benign lesion of the kidney

- Can potentially metastasize at any size but larger size increases the risk

2. Renal oncocytoma: 5-10% of lesions of the kidney

- Central scar is characteristic

- Oncocytes: Packed with mitochondria and highly eosinophilic

- Most common tumor of the kidney

- Arise from the tubular epithelium

- Large tumors --> Usually detected at later and larger stages

- Invasion: Collecting system, renal vein and even the IVC

- Histology: Clear cells forming small tubules --> May be granular or sarcomatoid

- Subtypes: Clear cell (From proximal tubule and 70-80%), papillary (5-15%), and chromophobe types --> Looks like oncocytoma

- Clear cell associated with loss of short arm chromosome 3 --> Highly vascular and overexpress VEGF

- Papillary associated with trisomy 7 --> More malignant transformation

- May elaborate hormones --> Erythropoietin and ACTH

- Poor prognosis

- Propensity for affecting one pole or the other

- Normal bladder: Lined by transitional/urothelium

- Lesions range from benign papillomas to papillary transitional cell carcinoma (TCC) to invasive carcinomas

- Graded 1-3 depending on differentiation

- Invasion of the muscle --> Poorer prognosis and higher risk of metastasis

- Invasive --> Invades into and beyond single muscle layer of the bladder

1. Carcinoma-in-situ (CIS): Loss of umbrella cells and hyperplasia with metaplasia --> Confined to mucosa

2. Papillary carcinoma: Confined or invasive forms

3. Flat carcinoma: Confined or invasive forms --> Harder to identify since they are flat and not as obvious as papillary

- Higher grade neoplasms have thicker cellular layers with very thin fibrovascular core --> Pleomorphism seen in cells and some cells have nucleoli

- Primary SCC due to schistosomiasis infection

- Parasites lay eggs in the bladder wall

- Inflammation due to the presence of the eggs leads to squamous metaplasia

- Impossible to tell if it's truly a primary tumor or if it's a metastasis from another site

- Uncommon cancer of the bladder

- Four anatomical zones: Peripheral (Cancer zone), central, transitional (BPH and urinary obstruction), and anterior fibromuscular stroma

- Gland histology: Lined by two cell layers (basal and secretory cells) surrounded by a fibromuscular stroma

1. Benign Prostatic Hypertrophy: Hyperplasia and hyperplasia of glands and stroma in the transitional zone --> Squeezes the urethra leading to trouble peeing --> Stimulated by DHT conversion from testosterone in stromal cells

2. Adenocarcinoma: Most common form of cancer in men

- Men >50

- Lethal form or latent incidental form

- Pathology: Gritty, gland forming tissue --> Cells slightly larger than normal often with prominent nucleoli

- Screening: Prostatic specific antigen (PSA)

- Perineural invasion is common

- Gleason Grading: 1-10 --> Lowest clinically is usually 6

- Staging: Tumor confined to gland versus extraglandular spread

- Metastasis: Lymph nodes --> Bone (vertebrae)

3. High grade Prostatic Intraepithelial Neoplasia: Essentially carcinoma in-situ form --> Confined to gland and defined low to high grade

- Clear cell renal cell carinoma: 75%

- Papillary RCC: 12%

- Renal pelvis urothelial cancer: 5%

- Chromophobe RCC: 4% (relatively benign)

- Oncocytoma: 4% (benign)

- Collecting duct RCC: <1% (aggressive)

- Angiomyolipoma: Quite rare

- Reninoma: Quite rare

- Neuroendocrine tumors: Quite rare

- von Hippel-Lindau Disease: ~70% risk

- Familial chromsome 3p translocation: High risk --> Loss of short arm of chrom. 3

- End-stage renal disease: 2-5% risk --> Patients on chronic dialysis develop cancers

- Smoking: 2-4x risk

- Cadmium exposure: 2-4x risk

- Obesity and hypertension: Increased risk but exact numbers not known

- Peak incidence: 60-70 year olds

- Slight male predominance (1.6:1)

- Flank pain, hematuria, and abdominal mass --> Classic triad

- Additional features: Anemia, weight loss, fever, reversible hepatic dysfunction, secondary amyloidosis, erythrocytosis, hypercalcemia, and left varicocoele (left testicular vein drains into left renal vein

- Can extend into the renal vein or even into the IVC

- 25% of patients have metastasis at time of presentation

- Lungs (75%), soft tissues/bone (20%), and liver, skin or brain (10%)

- Prognosis and survival determined by staging

- Treament: Largely surgical

- Stage I: <7 cm lesion --> >90% survival

- Stage II: >7cm lesion but confined to the kidney --> 80% survival

- Stage III: Lesion has extended through capsule but still within the surrounding fascia --> 60% survival

- Stage IIIa: Renal vein involvement --> 60% survival

- Stage IIIb: 1 lymph node involvement --> 20% survival

- Stage IV: Locally invasive or metastatic disease --> 10% survival

1. Surgery

- Radical nephrectomy: Remove kidney as well as the fascia, adrenal gland and surrounding nodes

- Nephron-sparing partial nephrectomy: <4 cm tumors

- Laproscopic nephrectomy: Quicker recovery

- Percutaneous ablation: Helpful for patients who are poor candidates for surgery

2. Medical

- Adjuvant: No real effective treatment

- Poor response to conventional chemo and RT

- High dose IL-2 --> 20% response --> Causes capillary leak syndromes so can be very dangerous

- IFN-a --> 14% response --> usually only provides 6 month response times

- Multitargeted kinase inhibitors (sunitinib, sorafenib, and pazopanib) --> 40% response

- Autosomal dominant disease --> VHL tumor suppressor (3p25.5) gene mutation

- VHL gene: Regulates hypoxia-inducible genes --> Mutation leads to increased VEGF transcription, proliferation signals and angiogenesis --> Responsible for sporadic cases of clear-cell RCC as well (80%)

- VHL gene also precipitates the build up of glycogen and lipids within cells that are characteristic of clear cell tumors

- Major features: Retinal angiomas, CNS hemangioblastomas, pheochromocytomas, and clear-cell RCC

- Minor features: Clear-cell renal cysts, pancreatic cysts, and epididymal cysts

- Multitargeted kinase inhibitors: Sunitinib (binds VEGFR signaling), sorafenib (inhibits PDGFR), and pazopanib

- 3:1 male predominance

- Most prominent in 70-80 year olds

- 4th leading cause of cancer in men and 7th in women

- Types: Transitional cell (95%), squamous cell (3%), and adenocarcinoma (2%)

- Transitional cell found from the renal pelvis to the urethra: 90% bladder and 8% renal pelvis

- Smoking: >4x risk --> Responsible for ~50%

- Chronic inflammation (2-10%): Indwelling catheters and schistosomiasis --> Leads to squamous cell and some transitional cell 

- Cyclophosphamide: 9x risk

- Aristolochic acid

- NSAID excess

- Aromatic amines

- Fast oxidizer or slow acetylator P450 mutations

- Hematuria (90%)

- UTI dysuria

- Obstructive uropathy

- Superficial (70% of cases): Can be surgically resected but often recurs

- Bladder musculature involvement: ~60% 5 year survival

- Beyond musculature or node involvement: ~10% 5 year survival

- Early event: Loss of chrom. 9q arm

- Late event: Rb and p53 mutations --> Poor prognosis

- Urothelial field defects due to smoking

- Fast oxidizer and slow acetylator phenotypes increase risk of exposure with aryl amines

- Direct correlation between urinary excretion time of carcinogens, bladder contact time, and bladder cancer development

1. Germ Cell Tumors

- Seminoma

- Nonseminoma

2. Sex Cord-stromal Tumors

- Leydig cell tumors

- Sertoli cell tumors

- Granulosa cell tumors

3. Paratesticular tumors

- Mesothelial tumors

- Epithelial tumors

- Lymphoma

- Leukemia/plasmacytoma

- Melanoma

- Germ cell cancers can occur as a primary cancer anywhere in the midline

- Testicle, retroperitoneum, mediastinum, and pineal gland

- Treated similarly to a testicular germ cell tumor

- ~8,000 men diagnosed and 370 will die

- Most common cancer in men 20-30 years old

- Only about 1% of all cancers in men

- 6% in kids/teens and 7% in men over 65

- HIGHLY curable --> Excellent salvage therapies with recurrence

- Personal history --> 1-5% will develop second cancer

- Family history --> 6-10x risk

- Cryptorchidism: Testicle doesn't completely drop

- Kleinfelter's syndrome

- Down's syndrome

- Intersexed individuals

- Intratubular germ cell neoplasia --> Pre-cursor lesion (carcinoma in-situ)

- HIV/AIDS --> Increased risk for seminoma

- Ethnicity: More common in whites, lower risk in blacks and increased mortality for non-Hispanic whites

- In-utero exposure to estrogen and diet (high saturated fat, cholesterol, and diary)

- Painless testicular mass

- Back pain

- Gynecomastia (5%)

- Infertility

- Sign of mets: Bone pain, abnormal lymphadenopathy, abnormal organ function, chest pain, shortness of breath, and weight loss

- Serum tumor markers: Alpha fetoprotein (AFP), beta human chorionic gonadotropin hormone (b-hCG), and lactate dehydrogenase (LDH)

- Unilateral radical inguinal orchiectomy

- CT of the abdomen and pelvis with contrast

- Chest X-ray

- Liver and renal function, CBC with differential and calcium levels

- Bone scan

- Brain MRI

1. Seminoma

- Usually no elevated markers

- Sometimes LDH is elevated

- AFP never elevated

- Slight elevation b-hCG possible

2. Nonseminoma

- Embryonal: b-hCG

- Yolk sac: AFP

- Choriocarcinoma: b-hCG --> Very high

- Teratoma: None or elevated LDH

- Mixed: Any can be elevated

- 95% of patients spread first to retroperitoneal lymph nodes

- 5% who don't --> Prior pelvic surgery, choriocarcinoma history (hematogenous spread), scrotal invasion, and simply being unlucky

- Left tumors --> Left para-aortic space

- Right tumors --> Interaortocaval space

- Stage I: 99% 5 year survival --> Localized and limited to the testis

- Stage II: 83-94% survival --> Limited to the retroperitoneal lymph nodes or low level tumor marker elevation after orchiectomy

- Stage III: Distant metastasis and/or high tumor marker levels --> Requires chemotherapy

- Seminoma: Good or intermediate risk --> 94% or 83% survival

- Nonseminoma: Good, intermediate or poor risk --> 94%, 83%, or 74% survival

- Radiation sensitive tumors

- Stage I: Cure is nearly 100% --> Orchiectomy, active surveillance (20% relapse), radiation (3-5% relapse), and 1-2 chemo cycles (5% relapse)

- Stage II: Radiation therapy

- Bulky Stage II or Stage III: Chemotherapy

- Negative tumor imaging but tumor markers --> Chemotherapy for micormetastatic cancer

- Not radiation sensitive tumors

- Teratoma doesn't respond to chemo or radiation --> Only option is surgery --> Teratomas can move to peritoneum and tumors of specific teratoma layers can develop

- Stage I: Active surveillance or retroperitoneal node dissection (RPLND) --> Unilateral dissection with nerve sparing technique

- Stage II: RPLND or chemo --> Full bilateral dissection with attempt at nerve sparing but not usually possible

- Stage III: Chemo

- Negative imaging but high tumor markers get chemotherapy for micrometastatic cancer

- Minimal morbidity if in the hands of a skilled surgeon

1. Retrograde ejaculation

- Nerves usually stimulate the closure of the bladder neck during ejaculation --> Loss of nerves due to dissection leads to inability to close bladder --> Sperm travels up into the bladder instead of out the penis

- Functional infertility results

- No erectile dysfunction or inability to orgasm tho

- 90% preservation if nerve-sparing technique performed --> Not always possible

2. Short bowel syndrome or ileus

3. Large incision

4. Bleeding

1. Nonseminoma

- Post RPLND: Teratoma --> Surveillance, no tumor --> Surveillance, and cancer --> Chemo

- Post chemotherapy with no residual masses --> Observation

- Post chemotherapy with residual mass --> Surgical resection/RPLND

2. Seminoma: No surgery possible

- Post radiation and chemo --> Observation unless residual mass is present

- Curative chemotherapy for testicular cancer

- 70% remission with chemo alone

- Another 11% were in remission after chemo with surgical resection

- 57% disease free at 13 year follow up

- Standard regimens: Bleomycin, Cisplatin, and Etoposide (BEP) and Etoposide and Cisplatin (EP)

- Fertility issues --> Usually preserved

- Minimal toxic exposures for radiation and chemo

- Cisplatin: Cardio, neuropathy, and renal toxicity

- Bleomycin: pulmonary risk and raynauds

- Secondary cancers: Etoposide --> Leukemia and radiation --> Solid tumors

- Dermatology: Dysplastic nevi

- Psychosocial effect of simply having testicular cancer

- 95% adenocarcinoma

- Most common cancer in American men --> 1 in 6 men

- 239,000 diagnosed and ~30,000 will die

- Men > 50 years

- More aggressive and earlier onset in blacks

- Lowest risk in Asians

- Family history: 5-10% are hereditary and due to BRCA2 and 2x increase with 1st degree relatives

- Serum Prostate Specific Antigen (PSA)

- Digital rectal exam: Limited utility

- Transrectal ultrasound guided prostate biopsy: Gold standard for diagnosis

- Imaging: CT scan, bone scan, and endorectal MRI

- Gleason score: Addition of 2 numbers detailing the histology present in the lesion --> Scores 6-10

1. Good risk: Normal rectal exam, Gleason score of 6 or less, and low PSA (<10 ng/dL)

- Active surveillance

- Radiation

- Prostatectomy

2. Intermediate risk: Normal rectal exam, Gleason score of 7 and PSA 10-20

- No active surveillance

- Radiation: External beam and brachytherapy

- Prostatectomy

3. High risk: Abnormal rectal exam, Gleason score 8-10, and PSA >20 ng/dL

- No active surveillance

- Radiation therapy with long course of hormonal therapy

- Prostatectomy

- Used for patients with localized disease in combination with radiation therapy for intermediate/high risk

- First line treatment for metastatic disease

- Highly effective --> Response doesn't last forever

- Androgens stimulate prostate cancer growth

- Medical: GNRH agonists (Lupron), GNRH antagonists, and adrenal gland blockers

- Surgical: Bilateral simple orchiectomy

- GNRH agonist

- Disrupts the normal pulsatile release of LH and FSH from the pituitary

- Release of LH and FSH is now constant

- Increased testosterone, LH and FSH now exerts strong negative feedback response on hypothalamus

- GNRH release is therefore reduced

- Overall reduction of LH and FSH production and reduced testosterone secretion

- After a while tumor learns to grow without exogenous testosterone --> Can also produce its own testosterone over time 

- Hot flashes

- Osteoporosis

- Anemia

- Loss of libido/erections

- Fatigue

- Liver failure

- Gynecomastia

- Loss of muscle mass

- Increased fat deposition

- Obesity --> Insulin resistance/diabetes, lipid alterations, and cardiovascular risk

- Antiandrogens: Bicultamide, nilutamide, flutamide, and enzalutamide

- Adrenal gland blockers: Abiraterone or high dose ketoconazole

- Chemotherapy

- Vaccine therapy

- Radioactive pharmaceuticals: Radium223

- Supportive medications to prevent skeletal related events --> Bisphosphonates and RANK ligand inhibitors

- Seizures

- Focal neurlogical defects: Slowly progressive due to the pressure effects or infiltration

- Headache

- Vomiting

- Dizziness

- Hydrocephalus

1. Adults

- Meningiomas and gliomas > Pituitary adenomas

- Glioblastomes are the most common gliomas

2. Children

- Gliomas and medulloblastomas > ependymomas

- Pilocytic astrocytomas are the most common gliomas

- Astrocytomas: Grades I-IV

- Oligodendrogliomas

- Ependymomas

- Choroid plexus tumors

- Neuronal tumors: Ganglioglioma and gangliocytoma

- Embryonal tumors: Medulloblastoma, pineoblastoma, and neuroblastoma

- Meningiomas

- Nerve sheath tumors (Schwannoma and neurofibroma)

- Blood vessel  tumors (Hemangioblastoma and hemagiopericytoma)

- Germ cell tumors

- Primary lymphoma

- Malformative tumors

- Amplification of oncogenes and loss of tumor suppressor genes

- Oncogenes: Platelet derived growth factor and receptor (PDGF and PDGFR), epidermal growth factor, CDK4, mdm-2, ras, gli, Akt, and mTOR --> Involved in membrane and internal transduction pathways

- Tumor suppressor genes: p53, p15, Rb and PTEN --> Turn on cell proliferation or inhibit internal message transduction

- Stepwise pattern

- Mutation or decreased expression of p53

- Glioblastomas/Type IV astrocytomas come from two cell lines

- Type 1: PDGF/PDGFR and chromsome 10 mutations

- Type 2: EPGF, PTEN, and chromosome 9 and 16 mutations --> Older patients, more aggressive, and less responsive to therapy

- Different from astrocyte transformation

- Intially doesn't involve p53 mutations

- Two paths to high grade tumors

- If EGFR present --> Chemorestitant and shows different suppressor gene changes

- EGFR negative --> 1p and 19q chromsome loss --> Chemosensitive

- Both lead to anaplastic oligodendrocytomas

- MGMT gene (DNA repair gene): Determines whether the tumor is responsive to chemo or not

- New chemo drug

- Effective only if DNA repair is damaged --> MGMT gene mutation

- Used in patients with methylated MGMT genes

- Most common form of glioma

- Most common is glioblastoma (grade IV)

- Anaplastic form (grade III) is the next most common

- Grades I and II are usually found incidentally

1. Grades I and II

- Increased cellularity

- No vascular hyperplasia

- No mitotic figures

- No necrosis

2. Grade III/Anaplastic

- Hypercellularity

- Mitotic figures

- Vascular proliferation

- Pseudopallisading

- No necrosis present

3. Grade IV/Glioblastoma

- Hypercellularity

- Mitotic figures

- Neovascularity

- Necrosis

- Treated with VEGF therapy --> Shut down leaky blood vessels to starve the tumor --> Also shuts off immune surveillance of the rest of the brain --> Other tumors pop up all over the place

1. Grade I and II

- No clear benefit for treatments

- Patients are observed and symptoms are treated

- Therapy: Excision, chemotherapy, radiation --> Reserved for lesions that become active

- Takes about 5-10 years for tumors to become active

2. Grade III

- Excision, chemotherapy (temozolamide), and radiation

3. Grade IV

- Surgery, radiation and temozolamide

- Life expectancy is 18 months to 3 years with chemosensitivity --> 6 week life expectancy without treatment

- Patients usually die from reccurence

- Targets VEGF

- Used successfully for breast and renal tumors

- Inhibits new blood vessel growth

- Efficacy depends on how quickly the tumor recruits blood vessels and performs angiogenesis

- Use for gliomas has been less successful --> Edema and radiation necrosis are reduced though

- Arise from ependymal cells

- Completely curable if diagnosed early

- Children: Posterior fossa

- Adults: Terminal cord

- Responds only to surgery

- Prognosis based on the location and degree of hydrocephalus

- Damage to the cord --> Gaze and balance problems

- Arise from cells of the choroid

- Most common in children and young adults

- Treatment: Surgery

- Prognosis is good as long as metastasis hasn't occurred

- Aggressive surgery --> 5 year life expectancy

- Rare tumors of neuronal origin

- Mixed with other types of cells

- Accounts for 10% of pediatric tumors

- Treatment: Surgery

- Ganglioglioma with neurons and glial cells

- Embryonal tumors

- Most common CNS tumor of children

- Usually occurs in the cerebellum

- Histology: Variable and may show differentiation to a variety of cell types --> Monotonous looking cells

- Treatment: Surgery and radiation

- Complications: Brain stem problems from radiation --> Fibrosis

- Radiation knocks out rapidly dividing cells

- Derived from the meninges --> Arachnoidal endothelial cells

- Benign tumors

- 15% of intracranial neoplasms

- Twice as common in females

- Slow progressive growth but possibility of malignant transformation

- Treatment: Surgery and radiation --> Sometimes difficult to remove (leather filled with sand)

- Neurofibromas and Schwannomas

- Rarely undergoes malignant transformation --> Neurofibrosarcoma

- Schwannomas --> CN VIII/Acoustic neuromas

- Neurofibromas --> Any peripheral nerve and may undergo malignant transformation

- Treatment: Surgery

- Non-Hodgkin's B-cell lymphomas --> Infiltrates into the white matter

- Immunocompromised patients --> HIV+ patients with CD4 counts <200

- Symptoms: Due to mass effect

- Treatment: Radiation and intrathecal chemotherapy if necessary --> High risk of infection

- Prognosis: 3-6 months --> Dismal

- Patients usually die from HIV before they die from lymphoma

- ~50% of malignant brain lesions and ~80% of cord lesions

- 50% are solitary

- Lung>breast>GI>GU>skin --> Adults

- Melanoma, breaset, and thyroid metastases are the most likely to bleed

- Prostate rarely if ever metastasizes to the brain

- Similar to primary tumors except the time course is faster --> Faster growing tumors

- Headache, focal weakness and seizures

- Cognitive dysfunction and gait

- Bleeding or herniation --> Acute deterioration

- Large masses --> Hydrocephalus or increased intracranial pressure

- Hernation --> Cerebellar and temporal lobes herniate through foramen magnum --> Initially compresses CN III (blown pupil)

- Cord compression: Acute neurologic problems --> Medical emergency --> Treated with steroids, radiation and surgery

- Auto-immune reaction to malignancy

- Treatment: IVIG

- Develops slowly --> Preceding the clinical presentation

- Signs of CNS inflammation in the CSF, with cells, and elevated antibodies

- MRI may show enhancement in affected areas

- Most common in adenocarcinomas and hematologic tumors

1. Cerebellar degeneration

- Associated with lung, ovarian, and Hodgkin's lymphoma

- Anti-Yo antibody --> Attacks Purkinje cells

- Ataxia and gait problems

2. Limbic encephalitis

- Associated with small cell lung cancer

- Patients develop confusion and lethargy

- MRI shows enchacement of limbic areas and CSF

- No known antibody associated

3. Sensory Neuropathy

- Most common paraneoplastic complication

- May precede malignancy

- Anti-Hu antibody --> Burning and numbness in distal limbs

- No weakenss but can progress acutely

4. Lambert-Eaton Syndrome: EXTREMELY uncommon

- Myasthenic syndrome --> Fluctuating weakness

- Antibody against pre-synaptic calcium channel --> Interferes ACh release

- Increased muscle strength with continued activity

1. Chemotherapy

- Peripheral neuropathy: Due to vinca, platinum, and taxol 

- Encephalitis, aseptic meningitis, and headaches

2. Radiation

- Radiation myelopathy: 5-10 years after therapy, transverse myelopathy due to fibrosis of the feeding vessels

- Radiation plexopathy: Usually painless, weakness greater than sensory loss, and may occur years after therapy

3. Surgery

- Traction injuries and injury to local nerves --> Chronic pain

4. Other complications: Hypercoaguable states, delirium, and depression

- 200,000 MW glycoprotein

- Embryonic gastrointestinal tumors

- Elevated 60-90% in colorectal adenocarcinoma

- Elevated 50-80% in pancreatic adenocarcinoma

- Elevated 25-50% of gastric and breast adenocarcinoma

- Can be elevated in IBD, liver disease, and smokers as well

1. CA-125

- Glycoprotein elevated in 80% of patients with ovarian cancer, normal in 50% of stages I and II cancers

- Also found in endometrial, breast, and colon cancers

2. CA-19-9: Present in pancreatic and other GI cancers

3. CA-15-3: Large mucin glycoprotein present in breast cancers

- Stem cells: CD34

- B-cell: CD10, CD19, CD20, CD21, CD22, and CD23

- T-cell: CD1, CD2, CD3, CD4, CD5, CD7, and CD8

- Monocyte: CD13, CD14, CD15, and CD33

- Cytokeratins: Epithelial and mesothelial tissues

- Vimentin: Mesenchymal, lymphoid, and endothelial

- Glial Fibrillary Acidic Protein (GFAP): Glial tumors

- Neurofilaments: Neuronal and neuroendocrine tissues

- Prostate: PSA

- Liver: HSA, alpha fetoprotein, and glycipan-3

- Thyroid: Thryoglobulin, TTF-1, and PAX8

- Lung: TTF-1 and napsin A

- Germ cell tumors: CD30, OCT3/4, CD117, and AFP

- Melonoma: S100, HMB45, and MART1

- Neuroendocrine: Chromogranin, synaptophysin, and NSE

- Vascular: Factor VIII, CD34, and DP-4

- Serine protease

- Synthesized by prostatic epithelium and secreted into semen

- Produced only by the prostate

- Normal and malignant prostatic epithelium produces PSA

- Normal males have serum values less than 4ng/mL

- PSA level is zero after prostatectomy

- Glycoprotein

- Major serum protein of the fetus --> Fetal albumin

- Synthesized by the liver, yolk sac, and gastrointestinal tumors

- Falls to undetectable leves at 1 year of life

- Elevated in HCC and non-seminomatous germ cell tumors (NSGCT)

- Mild to moderate elevated in benign conditions

- Used to screen and diagnose HCC

- Glycoprotein with alpha and beta sub-units

- Normally synthesized and secreted by the placental syncytiotrophoblast layer

- Used to diagnose prenancy and Hydatiform mole

- Highest levels in chriocarcinomas

- Elevated in germ cell tumors, even seminomatous type

- Calcitonin: Thyroid/Medullary cancer

- ACTH, GH, and PL: Pituitary adenoma

- Gastrin

- Somatostatin

- Insulin

- Pancreatic Polypeptide: Carcinoid tumors --> Can cause carcinoid syndrome

- p53 --> 50% of malignant tumors

- bcl2: FCCL (t(14:18))

- c-KIT: Gastrointestinal stromal tumors (GIST)

- ErbB2: Breast, gastric and prostate cancers

- pRb: Squamous cell carcinoma of the lung, osteogenic sarcoma, etc

- Npm-Alk fusion product: Anaplastic lymphom

- Cyclin D1: Mantle cell lymphoma (t(11:14))

- Ewings: t(11:22) --> FLI-1 and EWS

- Alveolar Sac: t(2:13) --> PAX-3 and FKHR

- Clear cell sac: t(12:22) --> ATF-1 and EWS

- Synovial sac: t (x:18) --> SYT and SSX

- Liposcarcoma: t(12:16) --> CHOP and TLS

- Non-small cell lung cancer shows ALK mutations

- Inhibits constitutively active ALK in tumors

- Section of surface cervical epithelium

- Extends between the original and the new squamous-columnar junction

- Onset of menarche --> Ovaries begin producing estrogen inducing epithelial maturation of the cervix

- Glycogen provides a good environment for bacteria

- Bacteria drops the vaginal pH

- Acidity induces metaplasia

- Trauma and other infections can induce metaplasia too

- Metastatic squamous epithelium obstructs crypt openings

- Accumulation of mucus in the glands (Nabothian cysts) develop

- Mucus retention induces acute and chronic inflammation

- Inflammation causes erosions of the surface epithelium

- Gonococci

- Chlamydiae

- Mycoplasmas

- Trichomonas vaginalis

- Fungal infection (candida)

- Herpes viruse --> Cellular inclusions

- Human papilloma virus

- Benign inflammatory tumors

- 2-5% of adult women

- Presentation: Irregular vaginal bleeding

- Present in the endocervical canal

- Size: Few mm - 7 cm

- Inflammed surface epithelium with squamous metaplasia and erosions --> Granulation tissue and loss of columnar epithelium at the tip

- Pre-cancerous

- Precedes the most invasive squamous cancers

- Doesn't definitely progress to cancer

- HPV infection

- Early age of first intercourse

- Multiple sexual partners

- Sexual partner with multiple previous sexual partners

- Infection with high risk viruses: HPV 16,18, 31,33,35,39,45,51,52,58,59,68,69 --> Associated with 100% of high grade and 80% of low grade

- Virus must be integrated into cellular DNA for malignant transformation to occur

- CIN-1: Atypical immature squamous cells limited to the lower 1/3 of the epithelium

- CIN-2: Limited to the lower 2/3 of the epithelium

- CIN-3: Full thickness of the epithelium

- Inflammatory cells surround cells with large nuclei, irregular morphology, and perinuclear necrosis

- All changes induced by viral DNA integration

- Cells with very large nuclei with very little cytoplasm surrounding the nucleus

- Most common in 40-45 year olds

- Nuclear inclusions seen on cervical smears

- Infiltration of epithelium with abnormal squamous cells

- Cells grow in patches

- HPV-related adenocarcinoma --> Associated with HPV 18

- Clear cell adenocarcinoma: Diethylstilbestrol (DES) exposed women --> DES was given to women for morning sickness ---> Mothers and their babies are not affected

1. Stage I: Carcinoma confined to the cervix

- Ia: <3 mm in depth and <7 mm horizontally --> 95% survival

- Ib: 3-5 mm and <7 mm --> 80-90% survival

2. Stage II: Extends beyond the cervix --> 75% survival

3. Stage III: Involvement of the pelvic wall or lower third of the vagina --> <50% survival

4. Stage IV: Extension beyond the true pelvis, mucosa of bladder or rectum --> <50% survival

- Exfoliative cytology: Fluid cytology and abrasive cytology (Passive and active)

- Fine needle aspiration cytology (FNA)

- Applications: Screening, diagnosis and staging, follow-up, hormone evaluation, and tumor prognosis

- Advantages: Less trauma, larger sample size, easier accessibility, rapid diagnosis, and cost effective

- Limitations: Extent and depth of invasion is hard to determine

- Requirements: Adequate cellularity, good fixation, and adequate reading

- Evaluation: Cellularity, cell arrangement, size and shape, cytoplasm, nucleus, mitoses, and extracellular material and background

- Contraindications: Patient's known to have abnormal bleeding issues

- Palpable breast masses

- Lesions detected by ultrasound, mammogram, or CT scan

- Follicular group of cells without nuclear atypia with macro/microfollicular patterns, abundant colloid material and macrophages --> Hyperplastic nodule (Goiter)

- Follicular groups of cells without nuclear atypia --> Follicular lesion

- Nuclear atypia --> Papillary carcinoma

- Hurthle cells --> Hurthle cell adenoma/carcinoma

- Follicular cells with Hurthle cells --> Chronic thyroiditis

- Bizarre large and spindle cells --> Anaplastic carcinoma

- Uniform oval or spindle cells with eccentric nuclei and amorphous background --> Amyloid deposition