A Case

1. A Case • Mr. G • 61 y/o male transferred from OSH for weakness, HA • Had abnormal imaging discovered at OSH • Sx’s present for ~3-4 months • What else do you want to know?

2. Case continued • HA’s occur 3-4 times/day, lasting 10-15 minutes with a black spot in the center of his R eye visual field • Was seen 2 months earlier in UCC, evaluated by neuro who recommended MRI, scheduled 11 days from now

3. Case continued • Notes LUE weakness, intermittently dropping objects • Intermittent LLE weakness and increased sense of smell • Remainder of ROS unremarkable except for some mild increased SOB • Next?

4. Case continued • PMH – migraines, depression, DLD • Social – handyman, former factory worker, remote EtOH (16 years ago), 1.5-2 ppd with 80 pack year hx • Medications – combivent, metoprolol, simvastatin, ASA, omeprazole, naproxen • After history comes…

5. Case continued • Physical exam • 97.2 – 88 – 20 – 138/82 – 95% RA • GEN: Alert, intermittent confusion • HEENT: NC/AT, PERRLA, EOMI, MMM • RESP: CTAB, occ wheeze • CVS: RRR No g/m/r • ABD: Soft. NT/ND +BS • EXT:Warm, well-perfused. No c/c/e

6. Case continued • NEURO:Grossly non-focal with good motor strength bilaterally in upper and lower extremities. Sensation intact. Noted to have transient weakness/instability on ambulation by nursing staff. • Now what?

7. Case continued • Work-up includes: • Labs Na K Cl CO2 BUN Cr Glu Ca 137 4.6 105 23 21 0.83 146 9.9 TP Alb TB AP AST ALT 7.6 4.4 0.6 100 18 17 WBC Hgb Hct Plt 7.4 16.8 47.7 246

8. Case continued • Imaging as follows: • CT head - at least two mass lesions in the right cerebral hemisphere resulting in extensive right cerebral edema and leftward subfalcine shift and ventricular effacement. There is sulcal effacement as well. No uncal herniation is identified. There is no associated hemorrhage." Also noted mass lesion posterior in the left parietal lobe w/ ass’d edema

9. Case continued • MRI - Multiple supratentorial metastatic lesions with the largest lesion in the right parietal lobe with mass-effect and midline shift of 1 cm. Focal area of chronic ischemic change/gliosis in the right cerebellar hemisphere

10. Case continued • Next step? • Treat the acute process • Steroids: Decadron 6mg Q6h • SSI • Neuro following So what about that CXR?

11. Case continued • CXR - Right hilar soft tissue fullness, recommend CT chest as well as chronic appearing coarse interstitial densities in the lungs are likely reflecting sequela from smoking and/or emphysema • CT Chest - Subcarinal and right hilar adenopathy with maximal diameter of 2.3 cm associated with several right lung nodules • CT Abd/pelv – unremarkable

12. Case continued • A diagnostic test was performed • Bronch showed: • Negative endobronchial bx • BAL negative for malignant cells • Subcarinal LN bx: non-small cell lung ca

13. Case continued • Pt discharged after acute process resolved and was seen by H/O in f/u – completed course of radiation therapy to brain and initiated on Tarceva • T1N1M1 = stage IV • Despite therapy had progression of disease so was initiated on carbo/taxol therapy • Repeat MRI showed worsening cerebral edema

14. Case continued • Three months later pt admitted for worsening fatigue/weakness • Hospice services initiated and patient passed away 9 days later

15. Lung Cancer Matthew Knoch Senior Talk May 20th and 22nd, 2009 University Hospitals Case Medical Center and VA, Cleveland OH

16. Objectives • Identify background knowledge of lung cancer rates and incidence, including etiology and causal factors • Learn the different types of lung malignancies and understand their diagnosis, staging and prognosis • Understand the basic treatment options

17. Background Information • Most common type of cancer in industrialized nations – leading cause of mortality from cancer • Accounts for 13% of all new cancer diagnoses and 30% of cancer deaths in men and 7% of deaths among both sexes however incidence in women is increasing greatly • Remains the most frequent fatal malignancy, ~91K male and ~71K female deaths/year

18. Background Information (Cont) • Annual deaths have increased from 18,000 in 1950 to 158,000 in 1997 in US and roughly 900,000 deaths worldwide with >50% of those in developed countries • Death rate has also increased 3-fold from 19.9 to 74 per 100,000 in men and 7-fold 4.5 to 31 per 100,000 in women during same time period • Spectrum of disease – more deaths than the next 3 most common cancers combined (colon/rectum, breast and prostate) – 114,690 cases/90,810 deaths in men and 182,460 cases/71,030 deaths in women in 2008

19. Background Information (Cont) • Accounts for 13% of all malignancies in both sexes • Most often occurs between ages 40-70, peaks in the 50-60 age range

20. So what causes lung cancer? Probably multifactorial (genetics?) Not the Only cause (90% of cases)…but also based upon: 1. Amount of daily smoking 2. Tendency to inhale 3. Duration of smoking 4. Age of initiation of smoking? Increases risk by about 10-20 fold over non-smokers in retrospective studies compared with control subjects, shown by landmark epidemiologic studies in the 1950’s in US/Britain

21. It doesn’t stop there • Cancers of the lip, tongue, oropharynx, throat, bladder and kidney cancer are all implicated in smoking So what helps? • Smoking cessation 10 years out returns risk level to that of nonsmokers (dose response relationship exists)

22. Why are cigarettes so bad and how do they cause cancer? • Over 1200 chemical substances (50 identifiable carcinogens) found in the smoke of cigarettes including: • Initiators such as PAH • Promoters such as phenol derivatives • Radioactive elements: polonium-210, carbon-14, potassium-40 • Others: arsenic, nickel, molds, additives

23. More on Dose Response • The Cancer Prevention Study II (CPSII) followed >1,000,000 smokers for 6 years and found that: • 1 ppd = 22x the risk of dying from lung cancer • 2 ppd = 45x the risk of dying from lung cancer

24. Also helpful, kind of: • At least in the US: public health interventions, litigation and education have contributed to a decline in smoking and therefore lung cancer rates, however this is not the case in developing nations across the globe • Roughly 20-25% of the American population continues to smoke

25. Cigarette Consumption, per capita in adults

26. More good news… • Experiments have been unsuccessful in causing lung cancer in laboratory animals through prolonged exposure to smoke • On the other hand, bronchioloalveolar cancers have been demonstrated but these are not seen very often in human smokers

27. Other Risk Factors • Industrial – radiation exposure, asbestos, workers exposed to nickel/chromate/coal/ mustard gas/arsenic/berylium/iron/gold/ haloether and newspaper industry workers (9-15%) • Air pollution – both indoor and outdoor (1-2%), radon (10%), difficult to determine though • Second hand smoke: nonsmoking women married to smokers had a 1.2x risk of developing cancer – possible hormonal/metabolism effects, even higher if >2 ppd (roughly 3000 case/year) • Combined risk factors approach 100%

28. Molecular Genetics • So what does the cumulative effect of all of these risk factors mean? • It is thought that by the time a tumor in the lung has developed that anywhere from 10 to 20 genetic mutations have occurred before a tumor develops • These include c-myc, K-ras and p53

29. Other factors implicated • Scarring – researchers have noted cancer formation in the region of prior lung scarring • These include areas of old infarct, metallic foreign bodies, wounds and granulomatous infections • Most of these cancers are histiologically adenocarcinomas

30. Types Of Lung Cancer • Squamous cell – 25-40%, epidermoid derived • Adenocarcinoma – 25-40%, bronchial, acinar, papillary, solid, broncioalveolar • Small cell – 20-25%, oat, intermediate cell • Large cell – 10-15%, undifferentiated, giant or clear cell • Combined – squamous and adenocarcinoma

31. So what about gender? • Since the 1950’s, a >500% lung cancer mortality has been identified in women • Partially due to increasing number of women smokers, but it has also been observed that dose for dose women have increased susceptibility to carcinogen exposure than men

32. Good News • The most important risk factors implicated in lung cancer are modifiable, e.g. stop smoking

33. Mechanism of cancer formation • Begins as in situ cytologic atypia that multiplies into tumor formation • May progress into the lumen, spread to adjacent areas of carina or mediastinum with nodal involvement, pleural invasion • Intraparenchymal mass formation • Rapid growth may cause local obstruction, hemorrhage or necrosis depending on rate of growth and location

34. What lung cancer likes • Adrenals - ~50% of cancers • Liver – 30-50% • Brain – 20% • Bone – 20%

35. Adenocarcinoma • Includes bronchial-derived and bronchioloalveolar, 80% contain mucin • Incidence greatly increased in the past 20 years • Most common form in women, probably in men too; being seen more in smokers • Cause for the increase? Perhaps related to addition of filters and deeper inhalation

36. Squamous Cell Ca • More often found in men, usually associated with long smoking history • Centrally located lesions and spread locally • Later metasteses

37. Small Cell Ca • Oat cell’s given small histologic appearance • High neuroendocrine activity: • PTH-like peptides • Neuron-specific enolase • Strongly associated with Tob exposure • Centrally located

38. Large Cell Ca • Likely represent squamous cell and adenocarcinomas that are undifferentiated

39. Complications of Lung Ca • Obstruction – emphysema vs. atelectasis • PNA – abscess formation • SVC syndrome • Pericarditis • Pleuritis • Neuroendocrine abnormalities • Hypercoagulable states

40. Diagnosis • Start with H&P • Illicit good history, especially social including exposure risks • Cough, hemoptysis, weight loss, chest pain, SOB • Physical exam

41. Diagnosis • CXR – identifies nodules usually >1cm • CT Chest – more definitive view of lung parenchyma and adjacent lymph nodes • PET scan – helpful in staging to determine degree of metastases • MRI/CT brain – useful in looking at CNS involvement

42. Differential • Other than cancer: • TB • PE • MI • Other lung pathology: PTX • Simple PNA’s • Sarcoid

43. Symptoms of Lung Ca • PNA • Effusions • Hoarseness/dysphagia • SOB, diaphragm paralysis, chest pain, rib involvement • SVC Syndrome • Horner’s Syndrome – Pancoast tumors • Pericarditis/tamponade

44. Paraneoplastic syndromes • SIADH – small cell • ACTH-producing tumors – small cell • PTH/PTH-rp – squamous cell • Calcitonin • Gonadotropin • Serotonin • Lambert-Eaton syndrome – small cell

45. Work-up • If cancer is the answer, tissue is the issue • i.e. bronch vs. VATS vs. CT-guided bx or peripheral bx

46. Staging - TNM • Tumor size: • T1 < or = to 3cm • T2 > 3cm • T3 = local extension (parietal pleura, chest wall or within 2cm of carina) • T4 = spread to great vessels, trachea, mediastinum, esophagus or malignant effusion (nonresectable)

47. Staging - TNM • Lymph Node • N0 = no involvement • N1 = hilar nodes • N2 = mediastinal nodes • N3 = contralateral nodes or ipsilateral supraclavicular (nonresectable)

48. Staging - TNM • Metastases • M0 = none • M1 = presence (nonresectable)

49. Staging Continued • Stage IA - T1 N0 M0 • Stage IB - T2 N0 M0 (T > 3cm)

50. Staging Continued • Stage IIA - T1 N1 M0 • Stage IIB - T2 N1 M0 T3 N0 M0