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Flashcards in 45 Lung Cancer Deck (27)
1

Epidemiology

  • Lung cancer is one of the most common causes of cancer and is one of the most deadly. Approximately 170,000 new cases of lung cancer are diagnosed each year in the US. Lung cancer accounts for 14% of all cancer diagnoses and 25 – 30 % of all cancer deaths. It is the leading cause of cancer death in the developed world; no other form of cancer approaches the impact of carcinoma of the lung and bronchus on mortality. In several countries (Australia, France, Germany), lung cancer is the leading cause of death of any cause. Other cancers, such as those arising from the breast and prostate, are more common, but they have a better prognosis for 5-year survival than lung cancer.
  • Lung cancer was a rare tumor in the early part of the 20th century. As tobacco smoking became epidemic in the early and middle parts of the 1900’s, lung cancer rates began to climb. In 1965, 52% of men and 34% of women were smokers. By 1991, these rates had fallen to 28% and 24%, respectively.
  • Cigarette smoking appears to be holding constant at approximately 25% of the adult population in the US.
  • Gender differences in lung cancer rates follow the cigarette smoking trends. See Figure 1 below depicting lung cancer rates in men and women. In particular, note that lung cancer incidence and death rate increased for women but decreased for men since the late 1980’s. This is likely due to the increased rate with which women started smoking in the 1950’s and possibly to an increased susceptibility to the carcinogenic effects of tobacco smoke (discussed below). It is likely that as cigarette smoking decreases in prevalence in the middle-aged population, lung cancer rates will start to fall later this century (Figure 2).

2

Screening

  • In August 2013, based on the results of the National Lung Screening Trial (NLST), the United States Preventive Services Task Force (USPSTF) updated the guidelines for lung cancer screening for the 1st time since 2004. These new recommendations advocate for lung cancer screening with low dose CT scans (LDCT) for:
    • Adults 55 – 79
    • > 30 pack year smoking history
    • Smoked within past 15 years
    • Grade B = insurance companies are required to cover without co-pay or deductible (ACA)
  • The following factors should be incorporated in lung cancer screening.
    • 1) Include counseling of potential benefits & harms
    • 2) Conduct screening at similar centers to NLST – multidisciplinary coordinated care (centers of excellence)
    • 3) Incorporate quality metrics
    • 4) Screening is not a substitute for smoking cessation

3

Classification

  • Bronchogenic carcinoma is by far the most common form of lung malignancy. It is divided into two major forms:
  • Non-Small Cell Carcinoma (NSCLC) 
    • This group includes adenocarcinomas, squamous carcinomas, and large cell, undifferentiated carcinomas. This is the most frequently encountered group of lung malignancies.
  • Small Cell Lung Carcinoma 
    • This group accounts for about 20 % of lung cancers. It is sometimes referred to as oat cell carcinoma. It tends to have an aggressive course, metastasizes early, and has a poor prognosis.
    • Other lung cancers include carcinoid tumors, mucoepidermoid tumors, pulmonary lymphomas, and adenoid cystic tumors. Together, they comprise about 5% of all lung malignancies.The remaining information in this lecture pertains specifically to bronchogenic carcinomas. Other types of lung malignancy will not be discussed further

4

Relative frequencies of lung cancer

  • Non small Cell Lung Cancer: 75%
    • Adenocarcinoma: 35%
    • Squamous Cell: 30%
    • Large-Cell: 10%
  • Small Cell Lung Cancer: 20%
  • Others: 5%
    • Carcinoid
    • Lymphomas
    • Mucoepidermoid tumors
    • Adenoid cystic carcinomas
    • Sarcomas

5

Etiology:
Tobacco smoke and asbestos

  • Tobacco smoke
    • Exposure to tobacco smoke is the etiologic exposure for at least 90% of lung cancers. The exposure can be direct – through active inhalation of tobacco smoke – or indirect (so-called “second hand smoke”), the result of being in the same environment as a smoker. Figure 3 below illustrates the relative risk of certain types of exposures involving tobacco smoke and/or co-carcinogens. Recent research suggests that females may be more susceptible to the effects of tobacco smoke than males
  • Asbestos
    • Asbestos is a naturally occurring fibrous silicate that has long been used in construction trades as insulation and a fire retardant. It has two main forms: chrysotile (curvy fibers) and amphibole (straight fibers). Chrysotile is more commonly used in manufacturing, but both have carcinogenic potential. When asbestos is combined with cigarette smoke exposure, there is an exponential increase in the risk of lung cancer

6

Etiology:
Radon and wood smoke / air pollution

  • Radon
    • Radon is a naturally occurring gaseous decay product of radium. It has carcinogenic potential and is estimated to account for 10% of lung malignancies. Uranium miners carry the greatest risk of radon exposure and thus have the greatest risk of radon exposure and thus have an increased risk of lung malignancy (see Fig. 3). The Environmental Protection Agency has established guidelines for acceptable amounts of radon in houses.increased risk of lung malignancy (see Fig. 3). The Environmental Protection Agency has established guidelines for acceptable amounts of radon in houses.greatest risk of radon exposure and thus have an increased risk of lung malignancy (see Fig. 3). The Environmental Protection Agency has established guidelines for acceptable amounts of radon in houses.increased risk of lung malignancy (see Fig. 3). The Environmental Protection Agency has established guidelines for acceptable amounts of radon in houses
  • Wood smoke / air pollution
    • Wood smoke is a risk for lung cancer in certain developing areas in the world. Air pollution contains carcinogenic substances, but the degree of risk has not been clearly established

7

Pathobiology of lung cancer

  • Lung cancer development exists on a continuum of molecular, cellular, and tissue damage leading ultimately to clinical neoplasia. Unfortunately, our understanding of the molecular pathogenesis of lung cancer is still rudimentary. It does appear that N-nitrosamines and poly-aromatic hydrocarbons (PAH) are the most carcinogenic components of cigarette smoke. PAH’s are associated with squamous cell tumors, and N-nitrosamines are associated with adenocarcinomas. Key molecular events related to smoking are responsible for transformation of bronchial epithelial cells into malignant cells. These events have become better understood in the past several years. An area of intense current interest in cancer biology is the role of driver mutations

8

Pathobiology of lung cancer:
Role of oncogenes

  • Oncogenes are components of the human genome which, when mutated, allow for the malignant transformation of a cell. Several oncogenes have been detected in NSCLC and Small-Cell Lung Cancer. The best described oncogenes in human lung cancer are c-myc, K-ras, and c-erbB2. These genetic mutations affect different aspects of the cell cycle and have been associated with effects on survival among patients with the same type of tumor but discordant for the presence of one of these mutations. Molecular-profiling studies indicate that activating mutations in the epidermal growth factor receptor (EGFR), PI3K, BRAF, and K-ras genes are generally nonoverlapping and identifiable in approximately 40% of non–small-cell lung cancers. These mutations, plus others that contribute to tumor progression ("driver" mutations), can be found in almost half of all non–small-cell lung cancers.
  • C-myc: is detected in small cell lung cancer and results in alterations in gene transcription.
  • K-ras: this group of genes codes for cytoplasmic and membrane proteins involved in cell-cell signal transduction. Point mutations at specific codons is the mechanism by which K-ras is transformed from a proto-oncogene to an oncogene.
  • C-erbB2: This oncogene encodes for a tyrosine kinase. Its main function is in regulating epithelial cell growth (EGFR)

9

Pathobiology of lung cancer:
Genes

  • Gene deletions
    • Deletion of the short arm (p) of chromosome 3 has been consistently found in bronchial epithelial cells of lung of smokers and in lung cancer cells.
  • Tumor Suppressor/Promotor Genes
    • Loss of function or mutations in the Retinoblastoma gene (Rb) or in P53 can result in loss of tumor suppressor activity and the subsequent development of lung tumors. Early experimental work suggests that replacement of abnormal P53 with a wild-type P53 in lung cancer cells can suppress tumor growth.
    • The two proto-oncogenes that are most commonly mutated in pulmonary adenocarcinomas are K-ras and EGFR. Nearly 90% of lung-cancer– specific EGFR mutations comprise a leucine-to-arginine substitution at position 858 (L858R) and deletion mutants in exon 19 that affect the conserved sequence LREA (delE746-A750). These mutations cause constitutive activation of the tyrosine kinase of the EGFR by destabilizing its autoinhibited conformation, which is normally maintained in the absence of ligand stimulation

10

Pathology

  • Bronchogenic carcinoma is divided into Small Cell Carcinoma and Non Small Cell Carcinoma. Pathologists are able to agree on the appropriate classification of an individual tumor type about 95% of the time. Pathologists have a more difficult time distinguishing different subtypes of non-small cell tumors. Mixed tumors showing elements of Small Cell and Non-Small Cell types of cellular patterns are common

11

Pathology:
Adenocarcinoma and squamous cell carcinoma

  • Adenocarcinoma
    • This form of non-small cell carcinoma tends to present as a peripheral nodule or mass (a mass = nodule > 3 cm). It has increased in frequency over the past 20 years, replacing squamous cell cancer as the most common form of lung cancer. Pathologically, look for pseudo-gland formation and intra-cytoplasmic mucin. A 2011 expert panel has revised the classification of adenocarcinoma to incorporate bronchioalveolar cell carcinoma
  • Squamous cell carcinoma
    • This common form of bronchogenic carcinoma is strongly associated with smoking. It tends to present as a bronchogenic (meaning emanating from the internal bronchial airway) tumor in the central airways. It may develop central cavities, which can be quite large at the time of presentation. Obstruction of the bronchus commonly occurs. Pathologically, the hallmark feature is keratinization. Keratin “pearls” are swirls of keratinized material with a characteristic appearance on H&E staining

12

Pathology:
Bronchioloalveolar cell carcinoma (BAC)

  • Bronchioloalveolar carcinoma (BAC) is a subtype of adenocarcinoma of the lung that is distinguished by its peripheral location, well-differentiated cytology, growth along intact alveolar septa (the so-called "lepidic" growth pattern). Of all the major forms of bronchogenic carcinoma, BAC is the form least strongly associated with cigarette smoking. BAC has 2 presentations: as a nodule/mass or as an alveolar infiltrate. A hallmark symptom of BAC is bronchorrhea, the expectoration of large amounts of clear, watery secretions. However, the future of BAC as a distinct clinical entity is unclear, as a 2011 expert panel has eliminated the term bronchioloalveolar carcinoma (BAC) and lesions that were formerly classified as BAC are now placed in one of several revised categories of adenocarcinoma

13

Pathology:
Large cell, undifferentiated carcinoma and small cell carcinoma

  • Large cell, undifferentiated carcinoma
    • This tumor type lacks more specific features that would confirm adenocarcinoma or squamous cell tumor. It tends to present as a large bulky mass with necrosis
  • Small cell carcinoma
    • These tumors are highly associated with cigarette smoking. Small cell tumors tend to present in the central chest area with early lymph node involvement. At the time of diagnosis, the hilar and mediastinal lymph nodes are frequently very enlarged. Small cell cancer tends to metastasize early. Brain, liver, and bone marrow are common sites of metastasis. Pathologically, small cell cancer consists of a pleomorphic population of small cells with hyperchromatic nuclei and dispersed chromatin

14

Diagnosis

  • The goal is to detect and diagnose cancers early and surgically remove them. Unfortunately, most patients with lung cancer (approximately 80%) are not candidates for surgery at the time of presentation.
  • Diagnostic options (from least to most invasive):
    • Sputum cytology
      • Simple to obtain; has a high false negative rate.
    • Bronchoscopy
      • Allows inspection of airways for extent of bronchial spread; can be used to biopsy many lesions. Bronchoscopy has a very high diagnostic yield when the tumor is endobronchial. Biopsy of adjacent structures, such as lymph nodes and peribronchial masses, can also be performed via transbronchial needle biopsy. Peripheral masses can be biopsied with a bronchoscope using a transbronchial forceps technique. Diagnostic yield varies with the size of the lesion, the location in the lungs, and operator experience. Bronchoscopy is safe, and the risk benefit ratio is favorable in most patients. There are several newer bronchoscopic techniques including endobronchial ultrasound (EBUS) and electronavigational bronchoscopy (ENB) that facilitate lung cancer diagnosis.
    • Image-guided Needle Biopsy
      • This technique is appropriate for peripheral nodules that might be difficult to approach with bronchoscopy. Usually done under CT scan guidance, transthoracic needle biopsies entail a small degree of risk (pneumothorax) and are usually well tolerated.
    • Surgical Biopsy
      • This is the most invasive technique but also the most definitive. Surgical biopsies can be done using an open technique or with one that uses a Video Assisted Thoracoscopic (VAT) technique. VAT entails lower post-operative morbidity and pain than the traditional thoracotomy

15

Staging:
Primary tumor (T)

  • TX Primary tumor cannot be assessed; tumor proven by sputum cytology but not seen on imaging or bronchoscopy.
  • TO No evidence of primary tumor
  • Tis Carcinoma in situ
  • T1 Tumor < 3 cm in greatest dimension, surrounded by lung or visceral pleura; not involving main bronchus
  • T1a Tumor < 2 cm in diameter
  • T1b Tumor > 2 cm but < 3 cm in diameter
  • T2 Tumor with any of the following features of size or extent
    • (a) > 3 cm but < 7 cm in greatest dimension;
    • (b) involves main bronchus, > 2 cm distal to the carina;
    • (c) invades the visceral pleura;
    • (d) Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but not involving entire lung
  • T2a Tumor > 3 cm but < 5 cm
  • T2b Tumor > 5 cm but < 7 cm
  • T3 Tumor > 7 cm or that directly invades any of the following: chest wall (incl. superior sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; or tumor in main bronchus < 2 cm distal to the carina but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung. Separate tumor nodules in the same lung.
  • T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; or tumor with a malignant pleural or pericardial effusion; or with satellite tumor nodules within the ipsilateral primary-tumor lobe of the lung

16

Staging:
Regional lymph nodes (N) and distant metastasis (M)

  • Regional lymph nodes (N)
    • NX Regional lymph nodes cannot be assessed
    • N0 No regional lymph node metastasis
    • N1 Metastasis to ipsilateral peribronchial and/or ipsilateral hilar nodes, and intrapulmonary nodes involved by direct extension of the primary tumor.
    • N2 Metastasis to ipsilateral mediastinal and/or subcarinal lymph nodes
    • N3 Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph nodes
  • Distant metastasis (M)
    • MX Presence of distant metastasis cannot be assessed
    • M0 No distant metastasis
    • M1 Distant metastasis present
    • M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural or pericardial effusion

17

Staging:
Stage grouping and staging of small cell lung cancer

  • Stage: TNM subset
    • 0 Carcinoma in situ
    • IA T1a-T1b N0M0
    • IB T2a N0M0
    • IIA T1a-T2a N1M0, T2b N0M0
    • IIB T2b N1M0, T3 N0M0
    • IIIA T1a-T3 N2M0, T3 N1M0, T4 N0-N1M0
    • IIIB T4 N2 M0, Any T; N3; M0
    • IV Any T; Any N; M1a or M1b
  • Staging of small cell lung cancer
    • This tumor cell type can be staged using the TNM classification but historically has been staged using the Veterans Administration staging system of Limited vs. Extensive disease. Limited disease is tumor confined within one hemithorax. Extensive disease is defined as any disease outside one hemithorax or pleural involvement (even if ipsilateral)

18

Staging:
Lung cancer in women

  • The age-adjusted lung cancer incidence continues to be higher in men than women. However, the magnitude of this difference is also decreasing, which reflects the fact that the female incidence rate is stabilizing while the male incidence rate continues to decrease. A notable exception to these trends exists among never smokers. In this population, the age-adjusted incidence rate of lung cancer is higher for women (14.4 to 20.8 per 100,000 person-years) than men (4.8 to 13.7 per 100,000 person-years) according to a pooled analysis of six prospective cohort studies. Furthermore, in the U. S., approximately 15 % of lung cancer in women arises in never smokers compared to only 8 percent for men. It is not known whether the magnitude of the association between cigarette smoking and lung cancer is different for women than for men. Other risk factors for lung cancer in women include radiation therapy (especially chest radiation for breast cancer) and hormonal factors, likely including estrogen. It is also likely that endocrine factors either accelerate the transition of a preneoplastic lesion to an overt malignancy or promote tumor growth once a malignancy is evident

19

Treatment:
Non-small cell carcinoma

  • At initial presentation, only about 20% of patients will have resectable disease. Surgical resection is always the treatment of choice, if possible.
  • Stages I A/B and II A/B
    • Lobectomy is the surgical treatment of choice in the management of tumor confined to one lobe of the lung. Lesser resections such as wedge resection or segmentectomy are associated with a higher rate of local recurrence. Patient factors and co-morbidities often dictate the extent of resection that can be performed (see below).
  • Stage IIIA
    • The optimal treatment for stage IIIA remains unclear. Small clinical trials have suggested that surgery + chemotherapy is superior to surgery alone, especially in selected patients with single N2 lymph node metastasis.
  • Stage IIIB
    • Surgery is not indicated for Stage IIIB disease, and the standard treatment is thoracic radiation + chemotherapy.
  • Stage IV
    • The focus of therapy is on palliation. Recent studies show that chemotherapy results in better survival rates than the best supportive care. Patients who respond to therapy gain an additional 3-9 months of life compared to non-responders. Chemotherapy has become the standard of care for patients with stage IV lung cancer and acceptable performance status

20

Treatment:
Non-small cell carcinoma:
Resectability and operability

  • Resectability of a given tumor is dependent on the stage of the tumor at the time of presentation. As stated earlier, the majority of lung tumors are unresectable at the time of diagnosis. This is because most lung tumors are detected when they are at stage IIIB or stage IV.
  • Operability is the concept that there are many factors that must be considered when deciding whether to perform surgery on a patient with lung cancer. Operability takes into account the patient’s overall health, pulmonary function, and other co-existent conditions, especially cardiovascular disease. Unfortunately, not all patients who have a resectable tumor are operable. Preoperative evaluations seek to balance the operative and post-operative risks with the potential benefits of surgical resection

21

Treatment:
Non-small cell carcinoma:
Medical therapy

  • This includes any non-operative therapy. For patients with inoperable or unresectable disease, radiation and chemotherapy have become the mainstays of therapy. Recent clinical trials have demonstrated improved survival in patients with unresectable disease who have received a combination of radiation therapy and chemotherapy. The North American Cooperative Group trial found 6% survival after 7 years of follow-up in the group of patients with unresectable stage III tumors who were treated with radiation therapy compared to 16% survival among patient treated with a combination of radiation + chemotherapy.
  • Stage IV lung cancer patients similarly appear to have longer survival if treated with palliative chemotherapy. One study found a survival of about 10% at 1 year in patients with stage IV disease who received palliative chemotherapy compared to a matched group receiving non-chemotherapy palliative care. Newer targeted therapies, such as EGFR receptor antagonists are also now available for treatment of selected non-small cell cancers that express the EGFR mutation. Regardless of whether chemotherapy is given, optimizing functional status and maintaining quality of life should be the chief goals of physicians treating patients with this stage of disease

22

Treatment:
Personalized medicine and lung cancer treatment

  • Mutation analysis of tumor cells, particularly using the rapidly evolving field of whole genome sequencing, has opened the door to personalized treatment approaches for lung cancer. Figure 5 shows the results of the Lung Cancer Mutation Consortium analysis of adenocarcinomas. These results assume increasing importance as small molecules that block driver mutations are developed (ie., EGFR antagonists). Thus, an individual patient’s tumor can be tested for specific mutations for which targeted drugs exist, personalizing therapy

23

Treatment:
Small cell carcinoma

  • Therapy for small cell lung cancer is medical as opposed to surgical in the large majority of cases. Standard therapy for limited stage disease consists of chemotherapy plus thoracic radiation. Extensive stage disease is treated with chemotherapy alone. Commonly used chemotherapy regimens are Etoposide with either Cisplatin or Carboplatin. Unfortunately, although approximately 50% of patients with limited stage disease treated with this approach develop a complete remission, the rate of relapse is about 70% at two years. The prognosis is worse for patients with extensive stage disease: 20-30% of patients obtain a complete remission of disease but relapse is virtually inevitable within one year

24

Paraneoplastic syndromes:
General and musculoskeletal disorders

  • General
    • These disorders are distant effects from tumors. They are not related to local obstruction, compression, or metastatic effects. Other tumors, such as ovarian or adrenal cancers, may cause paraneoplastic syndromes, but lung cancer is the most common cause of these conditions. Paraneoplastic syndromes occur in about 15% of lung cancer cases. Common sites and syndromes are described below:
  • Musculoskeletal Disorders
    • The predominant syndromes are digital clubbing and Hypertrophic Pulmonary Osteoarthropathy (HPO). Clubbing is not specific to lung cancer and may be seen in other conditions such as bronchiectasis and congenital heart disease. It is characterized by loss of the angle between the finger nail bed and the cuticle. Fingertips are rounded and bulbous. HPO is a painful arthropathy of the knees, ankles and wrists. A proliferative periostitis of long bones such as the femur is seen on radiographs. Its exact cause is unknown

25

Paraneoplastic syndromes:
Metabolic disorders

  • Hypercalcemia
    • This is a common metabolic paraneoplastic syndrome. Its most common cause is secretion of a parathyroid-like substance that stimulates bone turnover. This substance is called Parathyroid Hormone Related Peptide (PTHrP). It is most commonly seen in squamous cell cancers. PTHrP increases calcium reabsorbtion and wastes sodium through the kidney.
  • Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
    • This paraneoplastic syndrome is seen in small cell lung cancers and in several non-neoplastic diseases. Small cell cancer is its most common cause. SIADH is manifested by low serum osmolality in the setting of inappropriately concentrated urine. In SIADH, there is excess water reabsorbtion through the distal collecting duct of the nephron, which results in increased urine osmolality and decreased serum [Na].
  • Cushing’s syndrome
    • This is associated with small cell cancers, although other tumor types may cause it (especially lung carcinoids). Ectopic production of ACTH is the cause of the typical physical findings associated with the disease: moon facies, hypertension, abdominal striae, diabetes mellitus, and muscle weakness

26

Paraneoplastic syndromes:
Neurologic disorders

  • A variety of neurologic syndromes are associated with small cell carcinoma. These include neuropathies, limbic encephalitis, and Lambert-Eaton Syndrome.
  • Various peripheral and cranial nerve neuropathic syndromes have been described. These syndromes have been associated with several specific antibodies against components of nerves: Anti Neuronal Antibody 1 and 2 have been described and characterized.
  • Limbic encephalitis is characterized by decreased cognitive ability and easy confusion. This may mimic early-onset dementia.
  • Lambert-Eaton Syndrome is a syndrome of proximal muscle weakness and hyporeflexia. It is seen in about 3% of all small cell lung cancer patients. This disorder is most strongly associated with small cell cancer, although it may be seen in other disorders. It is caused by a partial blockage of release of acetylcholine from the neuromuscular junction (NMJ) by antibodies directed against Ca channels in the NMJ. Remission of the tumor or decrease in disease burden usually results in decreased symptoms associated with Lambert -Eaton Syndrome

27

Paraneoplastic syndromes associated with lung cancer

  • Systemic
    • Anorexia, cachexia, weight loss*
    • Fever
    • Orthostatic hypotension
    • Nonbacterial thrombotic endocarditis
    • Dermatomyositis/polymyositis
    • Systemic lupus erythematosus
  • Cutaneous
    • Acquired hypertrichosis lanuginosa
    • Acrokeratosis (Bazex's syndrome)
    • Clubbing*
    • Dermatomyositis
    • Erythema gyratum repens
    • Exfoliative dermatitis
    • Hypertrophic pulmonary osteoarthropathy
    • Superficial thrombophlebitis*
    • Tripe palms
    • Acanthosis nigricans
    • Acquired ichthyosis
    • Acquired palmoplantar keratoderma
    • Erythema annulare centrifugum
    • Florid cutaneous papillomatosis
    • Pemphigus vulgaris
    • Pityriasis rotunda
    • Pruritus
    • Sign of Leser-Trelat
  • Endocrine/metabolic
    • Cushing's syndrome
    • Hypercalcemia*
    • Hyponatremia*
    • Hyperglycemia
    • Hypertension
    • Acromegaly
    • Hyperthyroidism
    • Hypercalcitoninemia
    • Gynecomastia
    • Galactorrhea
    • Carcinoid syndrome
    • Hypoglycemia
    • Hypophosphatemia
    • Lactic acidosis
    • Hypouricemia
    • Hyperamylasemia
  • Hematologic
    • Anemia*
    • Polycythemia
    • Hypercoagulability
    • Thrombocytopenic purpura
    • Dysproteinemia (including amyloidosis)
    • Leukocytosis/Leukoerythroblastic reaction
    • Eosinophilia
    • Sweet's syndrome
    • Vasculitis
  • Renal
    • Glomerulopathies
    • Tubulointerstitial disorders
  • Neurologic
    • Peripheral neuropathy*
    • Lambert-Eaton myasthenic syndrome*
    • Necrotizing myelopathy
    • Cerebral encephalopathy
    • Visual loss
    • Visceral neuropathy

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