Epidemiology, Predispositions and Clinical Course of Cancer Learning Objectives 1. US risk and relative rank of cancer. 2.

3 most common cancer sites in men and women, mortality trends. 3. 3 patterns genetic risk and examples. 4. 4 categories of paraneoplastic syndrome. 5. Tumor stage and grade, and explain which is more important clinically.

Mon. 10/11/10
In this period well answer 3 questions: Who gets cancer and what types? Are there patterns of genetic predisposition to getting cancer? And how do we predict how bad a particular case of cancer will be?

Caption: Our goal with this lecture is to equip you to answer 5 questions, which are chosen for their clinical relevance and likelihood of helping you in clinical rotations, The first is, What is the risk of getting or dying from cancer in the US, and where does that rank among major causes of mortality?

US Cancer Overall 1 in 4 chance of cancer death (23%) 1500 deaths per day males have 1 in 2 chance of getting CA (44%) females have 1 in 3 chance of getting CA (38%) survival rates improved significantly since 1974 for all body sites (SEER P<.05 1975-77 vs 1999-2005) New cases (incidence rate) decreasing Men 1.3 %/yr (2000-2006) Women 0.5 %/yr (1998-2006) Cancer death rate decreasing Men 2.0 %/yr (2001-2006) Women 1.5 %/yr (2002-2006)
Caption: Individuals living in the US have a 23% chance of dying from cancer, which comes to about 1500 deaths from cancer throughout the country every day. When looking at cancer statistics, we must always pay attention to whether the number is talking about dying from cancer, mortality, or being diagnosed with cancer, incidence. If we look at the lifetime probability of getting a lifethreatening cancer, we see that 44% of men and 37% of women will have a diagnosis of cancer at some point. Nevertheless, the news is not all bad. Mortality from all cancers except head and neck, and liver cancers has been steadily declining since 1974. There are indications that survival from head and neck cancer, too, is improving now with combined chemotherapy and radiation treatment. Because public awareness of cancer causes, the success of cancer screening programs and social pressures reducing risk factors, the incidence of new invasive cancers has been decreasing in both men and women since the beginning of the new millinium. For these reasons as well as improved treatments, survival from cancer has been improving as well.

US Mortality Causes 2007 Cause of Death No. of deaths 1. Heart Diseases 616,067 2. Cancer 562,875 3. Cerebrovascular diseases 135,952 4. Chronic lower respiratory diseases 127,924 5. Accidents (Unintentional injuries) 123,706 6. Alzheimer disease 74,632 7. Diabetes mellitus 71,382 8. Influenza & pneumonia 52,717 Relative Importance of Cancer nd 2 overall cause of death after Heart Disease before CVA, COPD, Accidents rd 3 cause of death before age 19 after Accidents and Homicide before Suicide and Congenital Anomalies nd 2 cause before age 14 Exclusions Non-melanoma skin cancers (1,000,000) CIS except bladder (115,400 breast & melanoma)

% of all deaths 25.4 23.2 5.6 5.3 5.1 3.1 2.9 2.2

Caption: Cancer is approaching cardiovascular causes for mortality in this country, and is already the number 1 killer for individuals under the age of 75. Stroke, chronic lung disease, accidents, diabetes and senile dementia are also significant causes of mortality, but lag far behind the leading two.
Test q: In the US in 2007, the leading causes of death in the overall population are: heart disease and cancer (From 2007 test)

Caption: Even in people under age 19, cancer is the third leading cause of death. But in these individuals accidents and homicide are the leading causes, rather than heart disease. Allocation of resources to prevention and treatment for all 3, as well as toward suicide prevention, is warranted because of the number of years of life lost and important social impact when someone in this age group dies. Since homicide is less of an issue, cancer again becomes the second killer below age 14. It should be mentioned in passing that virtually all statistics about cancer refer to potentially lethal cancers, and not such infrequent killers as squamous cell carcinoma and basal cell carcinoma of the skin, or in situ carcinoma such as breast intraductal carcinoma or skin melanoma-in-situ. Since in situ tumor cells are, by definition, not invasive and cannot access the vasculature to metastasize, they are usually cured by local excision or ablation.

Change in US Death Rates* 1950 & 2004

Cancer Incidence Rates in Men and Women (1975-2006)

Caption: Compared to the rate in 1950, the cancer death rate decreased slightly in 2004, while rates for other major chronic diseases decreased substantially during this period. There is still room for improvement in cancer prevention, detection and treatment. Above: Annual Age-Adjusted Cancer Incidence Rates for Selected Cancers by Sex, United States, 1975 to 2006. Prostate cancer has the highest incidence rate in males, and breast cancer has the high incidence rate in females.

Cancer Mortality Trends (1975-2006):

Figure 6: Figure 7:

Figure 2:

Caption: FIGURE 2. Annual Age-Adjusted Cancer Incidence and Death Rates* by Sex, United States, 1975 to 2006. FIGURE 6. Death Rates* For Cancer and Heart Disease for Ages Younger Than 85 Years and 85 Years and Older, 1975 to 2006. *Rates are age adjusted to the 2000 US standard population. Cancer is the leading cause of death among men and women aged younger than 85 years (Fig. 6). A total of 475,211 persons aged younger than 85 years died from cancer in the United States in 2007, compared with 380,791 deaths from heart disease, which is the leading cause of death overall in the United States. FIGURE 7. Total Number of Cancer Deaths Avoided From 1991 to 2006 in Males and From 1992 to 2006 in Females. The blue line represents the actual number of cancer deaths recorded in each year, and the bold red line represents the expected number of cancer deaths if cancer mortality rates had remained the same since 1990 and 1991.

Five-year Survival Rates 30-yr Increase by Site:

Improvements in diagnosis and treatment have led to improved 5year survival for all the major sites when we compare the mid-70s, early-90s and the late-90s. Overall, the improvement in 5-year survival from 1976 to 2002 was over 30%.

3 most common cancer sites in men and women, mortality trends. What are the organs most frequently involved by cancer, and what malignancies are most common in male and female patients? Which organs are showing the most favorable trend in mortality? 2010 Estimated US Cancer Cases*
Caption: Prostate cancer in men and breast cancer in women show many parallels in their epidemiology. Both are the most frequently diagnosed cancers in their respective sexes. Lung and colorectal cancer are the second and third most common cancers in both men and in women. Bladderl cancer in men is comparable in incidence to endometrial and cervical cancer in women. Frequency of hematopoietic malignancy and melanoma is similar for both, and kidney cancers in men are about as common as invasive thyroid cancers in women.
Test q: Malignant tumors w/the highest incidence in men and women in the US as of 2009 are __ and __, respectively. Prostate and breast

2010 Estimated US Cancer Deaths*

Caption: When we look at mortality, however, lung cancer is, by far, the most common fatal cancer in men (30%), followed by prostate (9%), and colon & rectum (9%). In women, lung (26%), breast (15%), and colon & rectum (10%) are the leading sites of cancer death. So we see that one is more likely to die from some cancers than from others.
Test q: In the US in 2007, the most common cancer causing death in women is cancer of: lung. (From 2007 test) Test q: In 2006, the most common cause of cancer death in the US in men and women respectively is: Men/lung; women/lung. (From 2006 test)

Cancer Death Rates* 1930-2006

Caption: Most of the increase in cancer death rates for men prior to 1990 was attributable to lung cancer. However, since 1990, the age-adjusted lung cancer death rate in men has been decreasing. Stomach cancer mortality has decreased considerably since 1930. Death rates from prostate and colorectal cancers have also been declining, mostly because of earlier detection.

Lifetime Probability of Cancer Men 2003-2006* Site Risk All sites 1 in 2 Prostate 1 in 6 Lung and bronchus 1 in 13 Colon and rectum 1 in 19 Urinary bladder 1 in 26 Non-Hodgkin lymphoma 1 in 44 Lifetime Probability of Cancer Women 2003-2005* Site Risk All sites 1 in 3 Breast 1 in 8 Lung & bronchus 1 in 16 Colon & rectum 1 in 20 Uterine corpus 1 in 40 - Cervix 1 in 145 Non-Hodgkin lymphoma 1 in 52 Cancer 5-Yr Survival by Site and Race, 1999-2005: Site White African American All Sites 69 59 Breast (female) 91 79 Prostate (male) 100 98 Uterine cervix 73 65 Colon 67 56 Kidney & Renal Pelvis 69 66 Liver & Bile Duct 13 10

Lifetime probability of developing cancer and relative survival rates of cancer. Presently, the risk of an American man developing cancer over his lifetime is one in two. The leading cancer sites are prostate, lung, and colon and rectum.

Approximately one in three women in the United States will develop cancer over her lifetime. The leading sites are breast, lung, and colon and rectum.

% Difference 10 12 2 8 11 3 3

Test q: In an African American male whose father died of prostate cancer, annual screening should begin at age: 45. (Was this ever said in class?)

Caption: The 5-year relative survival rate from cancer is 68% for whites and 57% for African Americans (taking normal life expectancy into consideration). For many sites, survival rates in African Americans are 10% to more than 20% lower than in whites. This is due, in part, to African Americans being less likely to receive a cancer diagnosis at an early, localized stage, when treatment can improve chances of survival. Additional factors that contribute to the survival differential include unequal access to medical care and tumor characteristics. This slide shows that the death rate from cancer is higher in African Americans than for whites for almost every site. Mortality from cancer, however, is lower in other minorities than for whites. Many of these differences have not yet been adequately explained.

Cancer Survival by Site, Stage and Race

FIGURE 8. Five-Year Relative Survival Rates Among Patients Diagnosed with Selected Cancers by Race and Stage at Diagnosis, United States, 1999 to 2005.

Caption: This cartoon is to help remember that the most common cancer diagnosis is prostate or breast in men and women, followed by lung and colorectal in both sexes. For mortality, lung replaces prostate or breast as the leader, and colorectal is still in third place. These three together account for 50% of al cancer deaths in men and for 51 % in women.

Cancer Mortality by Age and Type:

Caption: We noted earlier that cancer is the third cause of cancer in patients under age 19. This chart shows that different cancers are responsible for deaths in different age groups. The first set of bars shows the big three, lung, breast or prostate and colorectal, with significant overall contributions from pancreatic and hematopoietic malignancies, In children under age 15, however, hematopoietic malignancy is the leading killer, with brain cancers and sarcomas causing significant mortality in this age group. Sarcomas disappear in young adults, and leukemia or lymphoma account for a smaller and smaller proportion of cancers as we advance in age. The big 3 reappear by middle age, and pancreatic cancer begins to make an important contribution beginning at age 55.

Stomach Carcinoma Geographic Variation: 8x more common in Japan than US Incidence in Japanese immigrants to US decreases with each generation rd Same as US by 3 generation Iiver CA also decreases, colon and prostate increase after moving to US Possible environmental factors Food (Sushi?) Refrigeration (Why not South America?) Helicobacter (Related to lymphoma, not CA)
Caption: The gastric adenocarcinoma tumor occurs at a rate 8 times higher in Japan than in the US. However, if Japanese immigrate to the US and begin eating american food, then by the third generation the grandchildren have an incidence of gastric carcinoma the same as other Californians. A similar pattern is seen with hepatocellular carcinoma, but colorectal and prostatic carcinomas increase in frequency in immigrants to approach the average incidence rate for these carcinomas in the US. What environmental factor in Japan could cause the incidence of gastric cancer to be higher? Is it the high fish diet, or raw fish often eaten in Japan? But this diet is also consumed by many Japanese even after immigrating to the US. Is it because of better refrigeration in the US than in Japan? Then why is the rate of gastric carcinoma almost as low in South America as it is in the US. Is it because of the higher prevalence of Helicobacter in Japan? But other epidemiologic studies have associated Helicobacter with gastric MALT lymphoma, not adenocardinoma.

Robbins Immigrant Carcinoma Mortality:

Caption: Here we see a graphic representation of gastric, hepatocellular, colorectal and prostatic cancer mortality in Japan and the US. The rate in the US has been set at 1, and the other bars are relative to this baseline rate in the US for each site. Immigrants already show a decrease in mortality from stomach and liver cancer, and a rise in the frequency of deaths from colon and prostate cancer. By the second generation, stomach and liver have come down significantly and the rates of colon and prostate cancer death are almost the same as the general US population.

3 patterns genetic risk and examples: Are there genes or familial traits that increase the risk of getting cancer? How would we recognize them and how frequently are they associated with cancer? Are there patterns or classes of risk? What are some examples of these? Hereditary Predispositions: Dominant Inheritance Pattern Relative risk 100 10,000 Marker phenotype in affected individuals Multiple generations, many family members DNA Repair Defects Relative risk 10 100 Sensitive to environmental carcinogens Fail to detect or repair mutations Familial Cancer Pattern Relative risk 2 - 10 No marker phenotype 2 or more close relatives, early onset Retinoblastoma 40% familial, 60% sporadic Mutant Rb gene 10,000 fold risk Bilateral tumors in infancy Increased risk of osteosarcoma in childhood

Neurofibromatosis: Caf-au-lait spots and Lisch nodules Hyperpigmented patches increase with age Pigmented hamartomas of iris seen with slit lamp Plexiform neurofibromas Sarcomas, esp. neurogenic Two genetic types NF1: gliomas and MPNST NF2: early mortality of spinal astrocytomas and ependymomas DNA Repair Defect: High spontaneous mutation rate Chromosomal instability Environmental carcinogen sensitivity Four original clinical syndromes Xeroderma pigmentosum Ataxia-telangiectasia Blooms syndrome Fanconis anemia Familial Pattern: No marker phenotype Two or more close relatives Early occurrence of malignancy Multiple or bilateral tumors Examples BRCA-1 and BRCA-2 Lynch Syndrome (HNPCC Hereditary Non-Polyposis Colon Cancer)

4 categories of paraneoplastic syndrome: Paraneoplastic Syndromes Symptoms unexpected for tumor type 10% of patients with advanced malignancy may be first sign of occult malignancy may be lethal or most debilitating of symptoms may mimic metastatic disease, cause overstaging Endocrinopathies Hypercalcemia in SCCA, breast Cushings in oat cell Neuromuscular Antineuronal antibodies in oat cell Dermatologic Acanthosis nigricans (pictured). 50% familial 50% paraneoplastic. Gastric adenocarcinoma Coagulopathies Trousseaus syndrome in GI adenocarcinoma Test q: A 51M has an annual physical exam. Tumor stage and grade, and explain which is more important clinically:
Acanthosis nigricans is noted and you suspect: Colon cancer (Other choices: Melanoma, Dysplastic nevus syndrome, Seborrheic keratosis, Hodgkins disease.)

Tumor Prognosis: Grading degree of differentiation or proliferation Staging degree of invasion and metastasis Prognostic markers Gene expression array (Van de Vijver, MP, et al, NEJM 347:1999-2009, 12/19/02) estrogen and progesterone receptor in breast CA aneuploidy by flow cytometry or image analysis cytogenetic molecular, eg. p53, HER2-neu, N-myc Tumor Grade: Subjective nuclear features, necrosis, mitotic index many different systems of criteria for many organs poor reproducibility Important for some tumor types non-Hodgkins lymphomas (Working Formulation) soft tissue sarcomas Useless for some tumor types neuroendocrine neoplasms Figures: Well-differentiated Squamous carcinoma pearls (top) versus poorly-differentiated Gastric adenocarcinoma (bottom) Tumor Stage: Clinical or Pathologic both correlate better with survival than grade used for therapy selection Size of primary tumor TX = dont know or cant tell T0 or Tis = in situ (T0 no evidence of primary) T1-T4 = increasing size or depth of invasion Lymph node metasteses N0 = absent N1-N3 = increasing number and range of nodes Hematogenous metastases M0 = no distant metastases M1 = distant organ metastasis

Test q: A 55F has ductal adenocarcinoma of breast. Which of the following features/findings are used for tumor staging: Tumor diameter. (Other choices: Presence of glands, mitotic rate, nuclear atypia, presence of necrosis)

Answers to Learning Objectives: nd 1. US risk and relative rank of cancer: 1,479,350 new cases, 562,340 deaths; 23% all deaths; 2 after cardiovascular 2. 3 most common cancer sites in men and women, mortality trends: Lung, Breast/Prostate, Colorectal 3. 3 patterns genetic risk and examples: Dominant Rb, NF-1; Familial BRCA-1,2; DNA Repair XP 4. 4 categories of paraneoplastic syndrome: Unexpected: Endocrinopathy, Neuromuscular, Dermatologic, Coagulopathy 5. Tumor stage and grade, and explain which is more important clinically: Stage invasion & metastasis, Grade microscopic appearance. Stage more important clinically.

PEDIATRIC NEOPLASIA: (Tumors and Tumor-like Lesions of Infancy and Childhood) Objectives: - Spectrum of diseases and key diagnostic entities - The significances: prognostic implications.

Tues. 10/12/10

Definition of Neoplasia: - Greek: new growth - Benign, pre-malignant or malignant - Synonymous with tumor, but tumor more implies of mass lesion. Leukemia not a mass lesion but considered neoplasia. - Neoplasia clonal population expansion out of control - Clonality demonstration is not always possible.
Test q: Which single manifestation of neoplastic growth is the most certain evidence that it is malignant? Metastasis.

Tumor-like Lesions: Choristoma - Choristoma (heterotopia): histologically normal tissue present in abnormal locations. i.e. pancreatic rests in stomach, adrenal rests in kidney, liver, testis, ovary
Test q: Tumors that usually present w/distant metastases are: ovary and pancreas.

Tumor-like Lesions- Hamartoma - Hamartoma (abnormal pattern): normal degree of differentiation but excessive, focal growth of cells and tissue native. i.e. hemangioma, lymphangioma, adenoma of liver, rhabdomyoma of heart. - Can also be clonal. - Relatively benign in terms of prognosis. Malignancy: - Benign and malignant in histopathology and clinical senses are different. - In medical science, benign and malignant are for the most part defined by histopathology parameters. - Ultimately it is prognosis that we care about. - Benign and malignant are relative terms. MALIGNANT PEDIATRIC TUMORS: - The leading natural cause of death between 4-14 (accidents are #1) - Brain tumors and leukemia/lymphoma account for about two-thirds - Pediatric and adult tumors are different st - Tumors in perinatal and 1 year of life are different CNS tumors/lymphoma/leukemia = ~2/3 of childhood cancers.
Test q: The leading cause of death in children aged 1-14 in the US is: Neoplasia. Test q: Two-thirds of all childhood deaths secondary to cancer are due to tumors of: brain and white blood cells Test q: In the US in 2009, the most common malignant tumors in children younger than 15y/o are: leukemia, brain tumors, sarcomas Test q: The most common malignancies in children are: hematologic and brain tumors.

Common Malignant Neoplasms of Infancy and Childhood: 0-4 Years Leukemia Retinoblastoma Wilms Tumor Hepatoblastoma Soft tissue sarcoma (especially rhabdomyosarcoma) Teratomas CNS tumors Neuroblastoma 5 to 9 Years Leukemia Retinoblastoma Hepatoblastoma Soft tissue sarcoma Soft tissue sarcoma 10 to 14 Years In first year of life, neuroblastoma is #1. Teratomas are #2.

CNS tumors Ewings tumor Lymphoma

Osteogenic sarcoma Thyroid carcinoma Hodgkins disease

DIFFERENCES IN PEDIATRIC CANCER: 1. Site of origin different (In adults, tend to be from GI tract, breast, pancreas, GU tract, etc. In kids, from adrenal gland, CNS, soft tissue.) 2. Type sarcomas, blastomas, small round blue cell tumors. Mostly see carcinomas and melanomas in adults.
Test q: Tumors that are exceptionally rare in children are: carcinomas. (Other choices: sarcomas, lymphomas, blastomas, brain tumors)

3. 4. 5. 6.

Bulk typically greater but no cachexia (wasting metabolic syndrome) Prognosis often better (lot of exceptions) Neonatal tumors tend to be less aggressive (overstatement) Usually no precursor lesions in pediatric cancer (exception some Wilms tumors nephroblastoma)

Figure: Spindle cell sarcoma of a forearm removed immediately after birth. No bone is present except small masses near the wrist and elbow. The child survived after simple amputation. Microscopically, something like this looks VERY malignant. However, no remote metastasis. Patient was a newborn and survived. The point: biology in newborns is very different. Etiology Environmental factors: insufficient data (exceptions) Mechanisms of carcinogenesis: DNA point mutation, deletion, repair Chromosome translocation often associated with specific tumors. Oncogenes and tumor suppressor genes. Congenital malformation and syndromes. Selective pediatric tumors: - Teratoma - Small round blue cell neoplasms: Neuroblastoma Wilms tumor

Above: Congenital Sacrococcygeal Teratoma 1415 g Tumor. #1 location of teratoma in newborns.

Above: Preterm female with large sacrococcygeal teratoma, died at 7 days of age due to high output cardiac failure. Lots of chunks within the tumor babys heart had to have extremely high output. Histologically, looks very benign.

Above: Congenital Cervical Teratoma 1-day-old newborn. In cervical location, chance of malignancy is lower than in SC location. This patient would die because it compresses airway respiratory failure.

Teratoma - True tumor composed of multiple tissues foreign to, and capable of growth in excess of those characteristic of the part from which it is derived. - True tumor, but there can be borderline cases sometimes can be another fetus inside (so should it be called a tumor?) - Two peaks: perinatal (around birth), late adolescent/early adult.
Test q: A 32y/o woman has experienced dull pelvic pain for the past 2mo. Phys exam shows a right adrenal mass. An abdominal ultrasound scan shows a 7.5cm cystic ovarian mass. The mass is surgically excised. The surface of the mass is smooth, and it is nonadherent to surrounding pelvic structures. On gross exam, the mass is cystic and filled with hair. Microscopically, there is squamous epithelium, tall columnar glandular epithelium, cartilage, and fibrous connective tissue present. Which of the following is the most likely diagnosis? Teratoma (Review question from Exam 1, repeated on Exam 2)

Above: Newborn w/maxillofacial teratoma; survival was about 15 minutes. Because of the size and location, fetus cannot survive. Too big, not resectable, and extending intracranially.

Sacrococcygeal teratoma: prognostic factors: - Resectability if not resectable, fares badly. - Location if extends into pelvic region, bad. Very difficult to resect. - Age: neonatal 10% malignancy; 3 year approaching 100%. Age could be most important factor. - Histopathology: yolk sac tumor component translate into worse prognosis, not immature neuroglial component. - Complications: congestive heart failure, rupture and bleed and fetal exsanguination.
Test q: An infant is born w/a huge sacrococcygeal teratoma (15g) which is successfully removed a few days after birth. This tumor is: Benign.

BLASTOMA A neoplasm composed of embryonic cells derived from the blastema of an organ or tissue [Gr. BLASTOS = germ] BLASTEMA A primitive group of cells that give rise to an organ or part in development or regeneration. Important Pediatric Cancers Not Named as Blastomas: - Primitive neuroectodermal tumor (PNET) Central (medulloblastoma) Peripheral (bone and soft tissue) Not the same as neuroblastoma - Rhabdomyosarcoma - Ewings Sarcoma (now considered a PNET) - Lymphoma/leukemic infiltrates - Osteogenic Sarcoma - Other soft tissue sarcomas

The Important Blastomas: - Nephroblastoma (Wilms Tumor) Kidney - Neuroblastoma adrenal medulla and sympathetic nervous system - Hepatoblastoma liver - Pleuropulmonary blastoma lung/pleura - Pancreatoblastoma pancreas - Retinoblastoma neural retina - Medulloblastoma - cerebellum Small Round Blue Cell Tumors: - So-called because they consist of primitive blastema-like cells - Some adult tumors also have this appearance (oat cell carcinoma of lung) - Important to classify since treatment varies widely

Neuroblastoma: - The most common malignant solid tumor of childhood (after CNS) - By definition, is malignant. Not necessarily so because of clinical behavior. - Most patients <5 years old, half <2 years old, may be congenital - Arise in the adrenal medulla, but also along the sympathetic chain ganglia (or dorsal root ganglia) anywhere from the base of the skull to the pelvis - Usually sporadic (no family history), seen with increased incidence in VRD, tuberous sclerosis, Hirschsprungs disease, others - May present with mass only or constitutional symptoms - Commonly metastatic at presentation may involve bizarre sites (orbits, skin) - 90% secrete catecholamines but HTN rare