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Lung Neoplasms
Zube B
Schwartzs 11
1
Introduction
• Lung cancer is the leading cancer killer in the
United States
• The overall 5-year survival for all patients with
lung cancer is 15%
• Positive survival factors are female sex, younger
age, and white race
• Most patients are diagnosed at an advanced
stage of disease, so therapy is rarely curative
2
Epidemiology
• Cigarette smoking is the primary cause of lung
cancer
– 2 lung cancer cell types, squamous cell carcinoma and
small cell carcinoma, are extraordinarily rare in the
absence of cigarette smoking
– Only 15% of lung cancers are not related to smoking, and
the majority of these are adenocarcinomas
• Over 3000 chemicals have been identified in tobacco
smoke, but the main chemical carcinogens are
polycyclic aromatic hydrocarbons
3
Cont.
• The risk of developing lung cancer escalates with the
number of cigarettes smoked, the number of years
smoked, and the use of unfiltered cigarettes
– Conversely, the risk of lung cancer declines with smoking
cessation
– However, even after smoking cessation, the risk never drops
to that of people who never smoked
• Secondhand (or passive) smoke exposure has been
shown to confer an excess risk of 25% of developing lung
cancer when a nonsmoker lives with a smoker
4
Cont.
• Preexisting lung disease (TB, COPD) confers an
increased risk of lung cancer (up to 13%)
– Related to poor clearance of inhaled carcinogens
and/or to the effects of chronic inflammation
• Exposure to a number of industrial compounds,
including asbestos, arsenic, and chromium
compounds
– Combination of asbestos exposure and cigarette
smoking together have a multiplicative effect on risk,
as opposed to an additive effect
5
Normal Lung Histology
• The tracheobronchial tree consists of approximately 23 airway
divisions to the level of the alveoli
– It includes the main bronchi, lobar bronchi, segmental bronchi, and
terminal bronchioles (i.e., the smallest airway vessels that lack
alveoli and are lined by bronchial epithelium)
• The tracheobronchial tree is normally lined by pseudostratified
ciliated columnar cells and mucous (goblet) cells except the
respiratory bronchioles which are lined by cuboidal epithelium
– The normal bronchial epithelium also contains bronchial submucosal glands,
which are mixed salivary-type glands containing mucous cells, serous cells, and
Kulchitsky cells (neuroendocrine cells)
– These can give rise to salivary gland–type tumors (previously referred to as
"bronchial gland tumors"), including mucoepidermoid carcinomas and
adenoid cystic carcinomas
6
Cont.
• The alveolar spaces have two primary cell types,
referred to as type I and II pneumocytes
– Type I pneumocytes cover 95% of the surface area of
the alveolar wall, but comprise only 40% of the total
number of alveolar epithelial cells
• These cells are not capable of regeneration because they
have no mitotic potential
– Type II pneumocytes cover only 3% of the alveolar
surface, but comprise 60% of the alveolar epithelial
cells
– In addition, clusters of neuroendocrine cells are seen
in the alveolar spaces
7
Preinvasive Lesions
• Squamous Dysplasia and Carcinoma In Situ
– Increased cell size, an increased number of cell layers,
an increased nuclear:cytoplasmic ratio, increased
mitoses, and changes in cellular polarity
• Atypical Adenomatous Hyperplasia
– Rrepresents the beginning stage of a stepwise evolution
to bronchoalveolar carcinoma and then to
adenocarcinoma
• Diffuse Idiopathic Pulmonary Neuroendocrine Cell
Hyperplasia (DIPNCH)
– Preinvasive stages of carcinoid tumors
8
Invasive or Malignant Lesions
• Lung cancer is broadly divided into 2 main groups
based primarily on light microscopic
observations:
– Non-small-cell lung carcinoma
• Squamous cell carcinoma
• Adenocarcinoma (including bronchoalveolar carcinoma)
• Large-cell carcinoma
– Neuroendocrine tumors
• Typical carcinoid
• Atypical carcinoid
• Large-cell neuroendocrine carcinoma
• Small-cell carcinoma
Although they differ
in appearance
histologically, their
clinical behavior
and treatment is
similar
9
Squamous Cell Carcinoma
• It accounts for 30 to 40% of lung cancers
• It is the cancer most frequently found in men and is highly
correlated with cigarette smoking
• It is primarily located centrally and arises in the major bronchi,
often causing the typical symptoms of centrally-located
tumors, such as hemoptysis, dyspnea, bronchial obstruction
with atelectasis, and pneumonia
– Occasionally a more peripherally-based SqCC will develop in a
tuberculosis scar or in the wall of a bronchiectatic cavity
• Central necrosis is frequent and may lead to the radiographic
findings of a cavity (possibly with an air-fluid level)
– Such cavities may become infected, with resultant abscess
formation
10
Adenocarcinoma
• Accounts for 25 to 40% of all lung cancers
• It occurs with equal frequency in males and females
• Most often a peripherally-based tumor, thus it is
frequently discovered incidentally on routine chest
radiographs
• Symptoms of chest wall invasion or malignant pleural
effusions dominate
• Histologically, adenocarcinoma is composed of glands
with or without mucin production, combined with
destruction of contiguous lung architecture
11
Bronchoalveolar Carcinoma
• A relatively unusual (5% of all lung cancers) subtype of
adenocarcinoma that has a unique growth pattern
– Rather than invading and destroying contiguous lung parenchyma,
tumor cells multiply and fill the alveolar spaces
• Because of their growth within alveoli, BAC tumor cells from
one site can aerogenously seed other parts of the same lobe or
lung, or the contralateral lung
– This growth pattern and tendency produces 3 radiographic
presentations: a single nodule, multiple nodules (in single or
multiple lobes), or a diffuse form with an appearance mimicking
that of a lobar pneumonia
• Because tumor cells fill the alveolar spaces and envelop
small airways rather than destroying them, air
bronchograms can be seen, unlike with other carcinomas
12
Large-Cell Carcinoma
• Accounts for 10 to 20% of lung cancers and may
be located centrally or peripherally
• As implied by the name, the cells are large, with
diameters of 30 to 50 micrometers
• They are often admixed with other cell types
such as squamous cells or adenocarcinoma
• It can be confused with a large-cell variant of
neuroendocrine carcinoma
– Differentiated with immunohistochemical staining
13
Neuroendocrine Neoplasms
• Recently, neuroendocrine lung tumors have
been reclassified into neuroendocrine
hyperplasia and three separate grades of
neuroendocrine carcinoma (NEC)
14
Cont.
• Grade I NEC (classic or typical carcinoid)
– It is a low-grade NEC
– An epithelial tumor which arises primarily in the
central airways, although 20% of the time it occurs
peripherally
• It classically presents with hemoptysis, with or without
airway obstruction and pneumonia
– It occurs primarily in younger patients
15
Cont.
• Grade II NEC (atypical carcinoid)
– A group of tumors with a degree of aggressive
clinical behavior and much higher malignant
potential
– Unlike Grade I NEC, these tumors are etiologically
linked to cigarette smoking and are more likely to
be peripherally located
16
Cont.
• Grade III NEC large-cell type
– Occur primarily in heavy smokers
– These tumors tend to occur in the middle to
peripheral lung fields
17
Cont.
• Grade III NEC small-cell type (small-cell lung
carcinoma [SCLC])
– The most malignant NEC
– Accounts for 25% of all lung cancers
– These tumors are centrally located and consist of
smaller cells with a diameter of 10 to 20 m that have
little cytoplasm and very dark nuclei
– They are the leading producer of paraneoplastic
syndromes
18
Salivary Gland–Type Neoplasms
• Adenoid cystic carcinoma and mucoepidermoid
carcinoma
– Both tumors occur centrally due to their site of
origin
– Adenoid cystic carcinoma is a slow-growing tumor
that is locally and systemically invasive
• It tends to grow submucosally and infiltrate along
perineural sheaths
– Mucoepidermoid carcinoma consists of squamous
and mucous cells and is graded as low or high grade
19
Clinical Presentation
20
Cont.
21
Based on Tumor Histology
• Squamous cell and small-cell carcinomas frequently
arise in main, lobar, or first segmental bronchi, which
are collectively referred to as the central airways
• Symptoms of airway irritation or obstruction are
common
– Cough
– Hemoptysis
– Dyspnea (due to bronchial obstruction with or without
postobstructive atelectasis)
– Wheezing (due to high-grade airway obstruction)
– Pneumonia (caused by airway obstruction with secretion
retention and atelectasis)
22
Cont.
• Adenocarcinomas are often located peripherally
• For this reason, they are often discovered
incidentally as an asymptomatic peripheral
lesion on chest x-ray
• When symptoms occur, they are due to pleural
or chest wall invasion (pleuritic or chest wall
pain) or pleural seeding with malignant pleural
effusion
23
Cont.
• Bronchoalveolar carcinoma may present as a
solitary nodule, as multifocal nodules, or as a
diffuse infiltrate mimicking an infectious
pneumonia (pneumonic form)
– In the pneumonic form, severe dyspnea and
hypoxia may occur, sometimes with expectoration
of large volumes (over 1 L/d) of light-tan colored
fluid, with resultant dehydration and electrolyte
imbalance
24
Based on invasion of thoracic
structures
• Chest wall invasion
– Pleuritic pain, from noninvasive contact of the
parietal pleura with inflammatory irritation and
from direct parietal pleural invasion
– Localized chest wall pain, with deeper invasion and
involvement of the rib and/or intercostal muscles
– Radicular pain, from involvement of the intercostal
nerve(s)
25
Cont.
• Tumors (usually adenocarcinomas) originating in
the posterior apex of the chest, referred to as
superior sulcus tumors, may produce the
Pancoast syndrome
– Depending on the exact tumor location, symptoms
can include:
• Apical chest wall and/or shoulder pain (from involvement of
the first rib and chest wall)
• Horner's syndrome (unilateral enophthalmos, ptosis, miosis,
and facial anhidrosis from invasion of the stellate
sympathetic ganglion)
• Radicular arm pain (from invasion of T1, and occasionally
C8, brachial plexus nerve roots) 26
Cont.
• Phrenic nerve invasion
– Shoulder pain (referred)
– Hiccups
– Dyspnea with exertion because of diaphragm
paralysis
– Radiographically, the diagnosis is suggested by
unilateral diaphragm elevation on chest x-ray, and
can be confirmed by fluoroscopic examination of
the diaphragm with breathing and sniffing (the
"sniff" test)
27
Cont.
• RLN invasion
– Voice change, often referred to as hoarseness, but
more typically a loss of tone associated with a
breathy quality
– Coughing, particularly when drinking liquids
28
Cont.
• Superior vena cava (SVC) syndrome
– Variable degrees of swelling of the head, neck, and
arms
– Headache
– Conjunctival edema
– Most frequently occurs with small-cell carcinoma,
with bulky enlargement of involved mediastinal
lymph nodes and compression of the SVC
29
Cont.
• Pericardial invasion may lead to pericardial
effusions (benign or malignant)
– Associated with increasing levels of dyspnea
and/or arrhythmias, and with the potential to
develop pericardial tamponade
30
Cont.
• Invasion of a vertebral body
– Back pain, which is often localized and severe
• If the neural foramina are involved, radicular pain may
also be present
31
Cont.
• Invasion of esophagus
– Dysphagea
– Usually secondary to external compression by
enlarged lymph nodes involved with metastatic
disease, usually with lower lobe tumors
32
Cont.
• Invasion of the diaphragm
– Dyspnea
– Referred shoulder pain
– Pleural effusion
33
Paraneoplastic Syndromes
• The majority of such syndromes are caused by small-cell
carcinomas
• Paraneoplastic syndromes may produce symptoms even
before symptoms are produced by the primary tumor,
thereby leading to early diagnosis
• Their presence does not influence resectability or the
potential to successfully treat the tumor
• Symptoms of the syndrome often will abate with
successful treatment, and recurrence may be heralded
by recurrent paraneoplastic symptoms 34
Cont.
Endocrine
• Hypercalcemia (ectopic
parathyroid hormone)
• Cushing's syndrome
• SIADH
• Carcinoid syndrome
• Gynecomastia
• Hyperthyroidism
• Hypercalcitoninemia
• Elevated growth hormone
• Elevated prolactin, FSH, LH
• Hypoglycemia
Neurologic
• Encephalopathy
• Subacute cerebellar
degeneration
• Progressive multifocal
leukoencephalopathy
• Peripheral neuropathy
• Autonomic neuropathy
• Eaton–Lambert syndrome
• Optic neuritis
• Polymyositis
35
Cont.
Skeletal
• Clubbing
• Pulmonary hypertrophic
osteoarthropathy
Cutaneous
• Hyperkeratosis
• Dermatomyositis
• Acanthosis nigricans
• Hyperpigmentation
• Erythema gyratum
repens
• Hypertrichosis
lanuginosa acquista
36
Cont.
Hematologic
• Anemia
• Leukemoid reactions
• Thrombocytosis
• Thrombocytopenia
• DIC
• Eosinophilia
• Pure red cell aplasia
• Leukoerythroblastosis
Other
• Nephrotic syndrome
• Hypouricemia
• Secretion of vasoactive
intestinal peptide with
diarrhea
• Hyperamylasemia
• Anorexia or cachexia
37
Cont.
• Hypertrophic pulmonary osteoarthropathy (HPO)
– Characterized by tenderness and swelling of the ankles, feet,
forearms, and hands
• Symptoms may be severe and debilitating
• Clubbing of the digits may occur
– It is due to periostitis of the fibula, tibia, radius, metacarpals,
and metatarsals
– Plain films of the affected areas show periosteal
inflammation and elevation
• A bone scan demonstrates intense but symmetric uptake in the
long bones
– Relief is afforded by aspirin or NSAIDs and by successful
surgical or medical eradication of the tumor
38
Cont.
• Hypercalcemia
– It occurs in up to 10% of patients with lung cancer and
is most often due to metastatic disease
– However, 15% of cases are due to secretion of ectopic
parathyroid hormone–related peptide, most often with
squamous cell carcinoma
• Diagnosis can be made by measuring elevated serum levels of
parathyroid hormone
– Symptoms include lethargy, depressed level of
consciousness, nausea, vomiting, and dehydration
– Following complete resection the calcium level will
normalize
39
Cont.
• Endocrinopathies
– Caused by the release of hormones or hormone
analogues into the systemic circulation
– Most occur with SCLCs
40
Cont.
• Cont.
– SIADH
• Occurs in 10 to 45% of patients with SCLC
• Characterized by confusion, lethargy, and possible
seizures
• Diagnosed by the presence of hyponatremia, low
serum osmolality, and high urinary sodium and
osmolality
41
Cont.
• Cont.
– Cushing's syndrome
• Due to production of ACTH-like molecule and occurs
principally in patients with SCLC
• ACTH production is autonomous and not suppressible by
dexamethasone
• Because the serum elevation of ACTH is rapid, the physical
signs of Cushing's syndrome (e.g., truncal obesity, buffalo
hump, striae) are unusual
• Dx
– Hpokalemia (<3.0 mmol/L); nonsuppressible elevated plasma cortisol
levels that lack the normal diurnal variation; elevated blood ACTH
levels
42
Cont.
• Peripheral and central neuropathies
– Among the most common in lung cancer,
particularly in SCLC and squamous cell carcinoma
– Felt to be immune mediated
– Up to 16% of patients with lung cancer have
evidence of neuromuscular disability
– In patients with neurologic or muscular symptoms,
central nervous system (CNS) metastases must be
ruled out with imaging
43
Cont.
• Lambert-Eaton syndrome
– A myasthenia-like syndrome usually seen in patients
with SCLC
– Autoimmune phenomena
– Gait abnormalities are due to proximal muscle
weakness and fatigability
– Therapy is directed at the primary tumor
– For patients with refractory symptoms, treatment is
medical
• Guanidine hydrochloride, Prednisone, Azathioprine, and
occasionally plasma exchange.
• Unlike with myasthenia gravis patients, neostigmine is usually
ineffective
44
Metastatic Symptoms
• Metastases occur most commonly in the CNS, vertebral
bodies, bones, liver, adrenal glands, lungs, and skin and
soft tissues
– At diagnosis, 10% of patients with lung cancer have CNS
metastases; another 10 to 15% will develop CNS metastases
– Bone metastases are seen in 25% of all patients with lung
cancer
• They are primarily lytic, producing localized pain
• Lung cancer is the most common cause of spinal cord compression
(Direct extension of a vertebral metastasis or foraminal invasion
from the primary tumor)
– Liver and adrenal metastases are most often an incidental
finding on CT scan
– Skin and soft tissue metastases occur in 8% of patients
dying of lung cancer, and generally present as painless
subcutaneous or intramuscular masses
45
Nonspecific Symptoms
• Lung cancer often produces a variety of
nonspecific symptoms such as:
– Anorexia
– Weight loss
– Fatigue
– Malaise
• Should raise concern about possible metastatic
disease
46
Diagnosis, Evaluation, and
Staging
47
Cont.
• Assessment encompasses three areas:
– The primary tumor
– Presence of metastatic disease
– Functional status (the patient's ability to tolerate a
pulmonary resection)
48
Assessment of the Primary Tumor
• History
– Pulmonary, nonpulmonary thoracic, and
paraneoplastic symptoms
• P/E
– Chest
– Voice
• Investigation
– Contrast CT scan
– Routine use of MRI in lung cancer patients is reserved
for those with:
• Contrast material allergies
• Suspected mediastinal, vascular, or vertebral body invasion
49
Cont.
• Tissue diagnosis
– Bronchoscopy
• Particularly useful for centrally-located tumors
• Tissue can be obtained by one of four methods:
– Brushings and washings for cytology
– Direct forceps biopsy of a visualized lesion
– FNA with a Wang needle of an externally compressing lesion without
visualized endobronchial tumor
– Transbronchial biopsy with the use of forceps guided to the lesion by
fluoroscopy
– Transthoracic needle aspiration and biopsy
• Ideally suited for peripheral lesions not easily accessible by
bronchoscopy
• Image guided (CT or Fluoroscopy) FNA or core-needle biopsy is
performed
• The primary complication is pneumothorax (in up to 50% of
patients), which is usually minor and requires no treatment
• Three biopsy results are possible: malignant, a specific benign
50
Cont.
• Thoracoscopy
– It is potentially a valuable staging tool for assessing the
primary tumor's relationship to contiguous structures
• Thoracotomy
– Required in cases of:
• A deep-seated lesion that yielded an indeterminate needle
biopsy result or that could not be biopsied for technical reasons
– FNA, a Tru-Cut biopsy, or preferably an excisional biopsy is done
• Inability to determine invasion of a mediastinal structure by any
method short of palpation
– When a pneumonectomy is required, a tissue diagnosis of
cancer must be made before excision
51
Assessment of Metastatic Disease
• Distant metastases are found in about 40% of patients with
newly diagnosed lung cancer
• History
– Presence or absence of new bone pain, neurologic symptoms, and
new skin lesions
– Constitutional symptoms (e.g., anorexia, malaise, and unintentional
weight loss of greater than 5% of body weight) suggest either a
large tumor burden or the presence of metastases
• P/E
– Examination of all systems
• Laboratory studies
– LFT, Serum calcium level
• Elevation of either hepatic enzymes or serum calcium levels typically
occurs with extensive metastases
52
Cont.
• Mediastinal Lymph Nodes
– Chest CT
• Most effective noninvasive method available to assess the mediastinal and
hilar nodes for enlargement
• Any CT finding of metastatic nodal involvement (i.e., nodal diameter more
than 1 cm) must be confirmed histologically
– Up to 30% of the nodes are enlarged from noncancerous reactive causes such as
inflammation due to atelectasis or pneumonia secondary to the tumor
• A negative CT result (lymph nodes less than 1.0 cm) generally is more
accurate
– PET (more accurate than CT)
– Endoesophageal ultrasound
– Bronchoscopic FNA of paratracheal lymph nodes (Stations 4R, 7, and
4L)
– Mediastinoscopy
• It remains the standard method of tissue staging of the mediastinum
53
Cont.
• Pleural Effusion
– No pleural effusion should be assumed to be
malignant
• Cytologic proof of the presence of malignant cells is
required
• Effusion is often secondary to the atelectasis or
consolidation seen with central tumors, or it can be
reactive or secondary to cardiac dysfunction
– However, pleural effusion associated with a peripherally-based
tumor, particularly one that abuts the visceral or parietal pleural
surface, does have a higher probability of being malignant
54
Cont.
• Evaluation of distant metastasses
– Multiorgan scanning
• Brain CT or MRI
• Abdominal CT
• Bone scan
– Or PET scan
– Routine preoperative multiorgan scanning is not
recommended for patients with a negative clinical
evaluation and clinical stage I disease
• However, it is recommended for patients with regionally
advanced (clinical stage II, IIIA, and IIIB) disease
55
Assessment of Functional Status
• Two flights of stairs
• Flat surface
• Pulmonary functions
– Routinely performed when any resection greater than
a wedge resection will be performed
• FEV1
– >2L can tolerate pneumonectomy and >1 L can tolerate lobectomy
– Or percent predicted value >50%
• DLCO (carbon monoxide diffusion capacity )
• O2max (Maximal O2 consumption)
• Quantitative perfusion scan
– To estimate the functional contribution of a lobe or
whole lung
Other pertinent elements of the assessment
are current smoking status and sputum
production
Smoking should be stopped for ideally 8 wks
but atleast 2 wks before surgery
Sputum production: cause should be treated
56
Lung Cancer Staging
• Occult stage
– Microscopically identified cancer cells in lung
secretions on multiple occasions (or multiple daily
collections); no discernible primary cancer in the
lung
• Stage 0
– Carcinoma in situ
57
Cont.
• Stage IA
– Tumor surrounded by lung or visceral pleura ≤3
cm arising more than 2 cm distal to the carina (T1
N0)
• Stage IB
– Tumor surrounded by lung >3 cm, or tumor of any
size with visceral pleura involved arising more
than 2 cm distal to the carina (T2 N0)
58
Cont.
• Stage IIA
– Tumor ≤3 cm not extended to adjacent organs, with
ipsilateral peribronchial and hilar lymph node
involvement (T1 N1)
• Stage IIB
– Tumor >3 cm not extended to adjacent organs, with
ipsilateral peribronchial and hilar lymph node
involvement (T2 N1)
– Tumor invading chest wall, pleura, or pericardium but
not involving carina, nodes negative (T3 N0)
59
Cont.
• Stage IIIA
– Tumor invading chest wall, pleura, or pericardium and
nodes in hilum or ipsilateral mediastinum (T3, N1–2) or
tumor of any size invading ipsilateral mediastinal or
subcarinal nodes (T1–3, N2)
• Stage IIIB
– Direct extension to adjacent organs (esophagus, aorta,
heart, cava, diaphragm, or spine); satellite nodule in
same lobe, or any tumor associated with contralateral
mediastinal or supraclavicular lymph-node involvement
(T4 or N3)
60
Cont.
• Stage IV
– Separate nodule in different lobes or any tumor
with distant metastases (M1)
61
Treatment
62
Early-Stage Disease
• Stages I and II
• The current standard of treatment is surgical resection
– Lobectomy
– Sleeve lobectomy
– Pneumonectomy (rarely performed)
• Indicated primarily for :
– Larger central tumors involving the distal main stem bronchus when a
bronchial sleeve resection is not possible
– When resection of involved N1 lymph nodes cannot be achieved short of
pneumonectomy
• Other options (for patients unfit for surgery due to
inadequate pulmonary reserve or other medical
conditions)
– Limited surgical resection (Segmentectomy or wedge
resection) OR
– Radiotherapy
63
Locoregional Advanced Disease (stage III)
• Surgical resection as sole therapy has a limited
role in stage III disease
– Therefore, definitive treatment of stage III disease
(when surgery is not felt to be feasible at any
time) is usually a combination of chemotherapy
and radiation
• Chemo followed by radiation or given at the same time
(concurrent)
• Neoadjuvant chemo is another option
64
Metastatic disease
• The treatment of patients with stage IV
disease is chemotherapy
– Surgery has a very limited value (metastasectomy)
65
Small-Cell Lung Carcinoma
• It is not generally treated surgically
– These aggressive neoplasms have early widespread
metastases
– Patients with either early or metastatic stage are
treated primarily with chemotherapy and radiation
• Three groups of SCLC are recognized:
– Pure small-cell carcinoma (sometimes referred to as oat
cell carcinoma)
– Small-cell carcinoma with a large-cell component
– Combined (mixed) tumors
66
Metastatic Lesions to the Lung
• Features suggestive of metastatic disease are
multiplicity; smooth, round borders on CT scan
• Surgical resection has a role in properly selected
patients
– The primary tumor must already be controlled
– The patient must be able to tolerate general anesthesia,
potential single-lung ventilation, and the planned
pulmonary resection
– The metastases must be completely resectable
according to CT imaging
– There must be no evidence of extrapulmonary tumor
burden
– Alternative superior therapy must be unavailable
67
The End!
68

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2.Lung Neoplasms.pptx

  • 2. Introduction • Lung cancer is the leading cancer killer in the United States • The overall 5-year survival for all patients with lung cancer is 15% • Positive survival factors are female sex, younger age, and white race • Most patients are diagnosed at an advanced stage of disease, so therapy is rarely curative 2
  • 3. Epidemiology • Cigarette smoking is the primary cause of lung cancer – 2 lung cancer cell types, squamous cell carcinoma and small cell carcinoma, are extraordinarily rare in the absence of cigarette smoking – Only 15% of lung cancers are not related to smoking, and the majority of these are adenocarcinomas • Over 3000 chemicals have been identified in tobacco smoke, but the main chemical carcinogens are polycyclic aromatic hydrocarbons 3
  • 4. Cont. • The risk of developing lung cancer escalates with the number of cigarettes smoked, the number of years smoked, and the use of unfiltered cigarettes – Conversely, the risk of lung cancer declines with smoking cessation – However, even after smoking cessation, the risk never drops to that of people who never smoked • Secondhand (or passive) smoke exposure has been shown to confer an excess risk of 25% of developing lung cancer when a nonsmoker lives with a smoker 4
  • 5. Cont. • Preexisting lung disease (TB, COPD) confers an increased risk of lung cancer (up to 13%) – Related to poor clearance of inhaled carcinogens and/or to the effects of chronic inflammation • Exposure to a number of industrial compounds, including asbestos, arsenic, and chromium compounds – Combination of asbestos exposure and cigarette smoking together have a multiplicative effect on risk, as opposed to an additive effect 5
  • 6. Normal Lung Histology • The tracheobronchial tree consists of approximately 23 airway divisions to the level of the alveoli – It includes the main bronchi, lobar bronchi, segmental bronchi, and terminal bronchioles (i.e., the smallest airway vessels that lack alveoli and are lined by bronchial epithelium) • The tracheobronchial tree is normally lined by pseudostratified ciliated columnar cells and mucous (goblet) cells except the respiratory bronchioles which are lined by cuboidal epithelium – The normal bronchial epithelium also contains bronchial submucosal glands, which are mixed salivary-type glands containing mucous cells, serous cells, and Kulchitsky cells (neuroendocrine cells) – These can give rise to salivary gland–type tumors (previously referred to as "bronchial gland tumors"), including mucoepidermoid carcinomas and adenoid cystic carcinomas 6
  • 7. Cont. • The alveolar spaces have two primary cell types, referred to as type I and II pneumocytes – Type I pneumocytes cover 95% of the surface area of the alveolar wall, but comprise only 40% of the total number of alveolar epithelial cells • These cells are not capable of regeneration because they have no mitotic potential – Type II pneumocytes cover only 3% of the alveolar surface, but comprise 60% of the alveolar epithelial cells – In addition, clusters of neuroendocrine cells are seen in the alveolar spaces 7
  • 8. Preinvasive Lesions • Squamous Dysplasia and Carcinoma In Situ – Increased cell size, an increased number of cell layers, an increased nuclear:cytoplasmic ratio, increased mitoses, and changes in cellular polarity • Atypical Adenomatous Hyperplasia – Rrepresents the beginning stage of a stepwise evolution to bronchoalveolar carcinoma and then to adenocarcinoma • Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNCH) – Preinvasive stages of carcinoid tumors 8
  • 9. Invasive or Malignant Lesions • Lung cancer is broadly divided into 2 main groups based primarily on light microscopic observations: – Non-small-cell lung carcinoma • Squamous cell carcinoma • Adenocarcinoma (including bronchoalveolar carcinoma) • Large-cell carcinoma – Neuroendocrine tumors • Typical carcinoid • Atypical carcinoid • Large-cell neuroendocrine carcinoma • Small-cell carcinoma Although they differ in appearance histologically, their clinical behavior and treatment is similar 9
  • 10. Squamous Cell Carcinoma • It accounts for 30 to 40% of lung cancers • It is the cancer most frequently found in men and is highly correlated with cigarette smoking • It is primarily located centrally and arises in the major bronchi, often causing the typical symptoms of centrally-located tumors, such as hemoptysis, dyspnea, bronchial obstruction with atelectasis, and pneumonia – Occasionally a more peripherally-based SqCC will develop in a tuberculosis scar or in the wall of a bronchiectatic cavity • Central necrosis is frequent and may lead to the radiographic findings of a cavity (possibly with an air-fluid level) – Such cavities may become infected, with resultant abscess formation 10
  • 11. Adenocarcinoma • Accounts for 25 to 40% of all lung cancers • It occurs with equal frequency in males and females • Most often a peripherally-based tumor, thus it is frequently discovered incidentally on routine chest radiographs • Symptoms of chest wall invasion or malignant pleural effusions dominate • Histologically, adenocarcinoma is composed of glands with or without mucin production, combined with destruction of contiguous lung architecture 11
  • 12. Bronchoalveolar Carcinoma • A relatively unusual (5% of all lung cancers) subtype of adenocarcinoma that has a unique growth pattern – Rather than invading and destroying contiguous lung parenchyma, tumor cells multiply and fill the alveolar spaces • Because of their growth within alveoli, BAC tumor cells from one site can aerogenously seed other parts of the same lobe or lung, or the contralateral lung – This growth pattern and tendency produces 3 radiographic presentations: a single nodule, multiple nodules (in single or multiple lobes), or a diffuse form with an appearance mimicking that of a lobar pneumonia • Because tumor cells fill the alveolar spaces and envelop small airways rather than destroying them, air bronchograms can be seen, unlike with other carcinomas 12
  • 13. Large-Cell Carcinoma • Accounts for 10 to 20% of lung cancers and may be located centrally or peripherally • As implied by the name, the cells are large, with diameters of 30 to 50 micrometers • They are often admixed with other cell types such as squamous cells or adenocarcinoma • It can be confused with a large-cell variant of neuroendocrine carcinoma – Differentiated with immunohistochemical staining 13
  • 14. Neuroendocrine Neoplasms • Recently, neuroendocrine lung tumors have been reclassified into neuroendocrine hyperplasia and three separate grades of neuroendocrine carcinoma (NEC) 14
  • 15. Cont. • Grade I NEC (classic or typical carcinoid) – It is a low-grade NEC – An epithelial tumor which arises primarily in the central airways, although 20% of the time it occurs peripherally • It classically presents with hemoptysis, with or without airway obstruction and pneumonia – It occurs primarily in younger patients 15
  • 16. Cont. • Grade II NEC (atypical carcinoid) – A group of tumors with a degree of aggressive clinical behavior and much higher malignant potential – Unlike Grade I NEC, these tumors are etiologically linked to cigarette smoking and are more likely to be peripherally located 16
  • 17. Cont. • Grade III NEC large-cell type – Occur primarily in heavy smokers – These tumors tend to occur in the middle to peripheral lung fields 17
  • 18. Cont. • Grade III NEC small-cell type (small-cell lung carcinoma [SCLC]) – The most malignant NEC – Accounts for 25% of all lung cancers – These tumors are centrally located and consist of smaller cells with a diameter of 10 to 20 m that have little cytoplasm and very dark nuclei – They are the leading producer of paraneoplastic syndromes 18
  • 19. Salivary Gland–Type Neoplasms • Adenoid cystic carcinoma and mucoepidermoid carcinoma – Both tumors occur centrally due to their site of origin – Adenoid cystic carcinoma is a slow-growing tumor that is locally and systemically invasive • It tends to grow submucosally and infiltrate along perineural sheaths – Mucoepidermoid carcinoma consists of squamous and mucous cells and is graded as low or high grade 19
  • 22. Based on Tumor Histology • Squamous cell and small-cell carcinomas frequently arise in main, lobar, or first segmental bronchi, which are collectively referred to as the central airways • Symptoms of airway irritation or obstruction are common – Cough – Hemoptysis – Dyspnea (due to bronchial obstruction with or without postobstructive atelectasis) – Wheezing (due to high-grade airway obstruction) – Pneumonia (caused by airway obstruction with secretion retention and atelectasis) 22
  • 23. Cont. • Adenocarcinomas are often located peripherally • For this reason, they are often discovered incidentally as an asymptomatic peripheral lesion on chest x-ray • When symptoms occur, they are due to pleural or chest wall invasion (pleuritic or chest wall pain) or pleural seeding with malignant pleural effusion 23
  • 24. Cont. • Bronchoalveolar carcinoma may present as a solitary nodule, as multifocal nodules, or as a diffuse infiltrate mimicking an infectious pneumonia (pneumonic form) – In the pneumonic form, severe dyspnea and hypoxia may occur, sometimes with expectoration of large volumes (over 1 L/d) of light-tan colored fluid, with resultant dehydration and electrolyte imbalance 24
  • 25. Based on invasion of thoracic structures • Chest wall invasion – Pleuritic pain, from noninvasive contact of the parietal pleura with inflammatory irritation and from direct parietal pleural invasion – Localized chest wall pain, with deeper invasion and involvement of the rib and/or intercostal muscles – Radicular pain, from involvement of the intercostal nerve(s) 25
  • 26. Cont. • Tumors (usually adenocarcinomas) originating in the posterior apex of the chest, referred to as superior sulcus tumors, may produce the Pancoast syndrome – Depending on the exact tumor location, symptoms can include: • Apical chest wall and/or shoulder pain (from involvement of the first rib and chest wall) • Horner's syndrome (unilateral enophthalmos, ptosis, miosis, and facial anhidrosis from invasion of the stellate sympathetic ganglion) • Radicular arm pain (from invasion of T1, and occasionally C8, brachial plexus nerve roots) 26
  • 27. Cont. • Phrenic nerve invasion – Shoulder pain (referred) – Hiccups – Dyspnea with exertion because of diaphragm paralysis – Radiographically, the diagnosis is suggested by unilateral diaphragm elevation on chest x-ray, and can be confirmed by fluoroscopic examination of the diaphragm with breathing and sniffing (the "sniff" test) 27
  • 28. Cont. • RLN invasion – Voice change, often referred to as hoarseness, but more typically a loss of tone associated with a breathy quality – Coughing, particularly when drinking liquids 28
  • 29. Cont. • Superior vena cava (SVC) syndrome – Variable degrees of swelling of the head, neck, and arms – Headache – Conjunctival edema – Most frequently occurs with small-cell carcinoma, with bulky enlargement of involved mediastinal lymph nodes and compression of the SVC 29
  • 30. Cont. • Pericardial invasion may lead to pericardial effusions (benign or malignant) – Associated with increasing levels of dyspnea and/or arrhythmias, and with the potential to develop pericardial tamponade 30
  • 31. Cont. • Invasion of a vertebral body – Back pain, which is often localized and severe • If the neural foramina are involved, radicular pain may also be present 31
  • 32. Cont. • Invasion of esophagus – Dysphagea – Usually secondary to external compression by enlarged lymph nodes involved with metastatic disease, usually with lower lobe tumors 32
  • 33. Cont. • Invasion of the diaphragm – Dyspnea – Referred shoulder pain – Pleural effusion 33
  • 34. Paraneoplastic Syndromes • The majority of such syndromes are caused by small-cell carcinomas • Paraneoplastic syndromes may produce symptoms even before symptoms are produced by the primary tumor, thereby leading to early diagnosis • Their presence does not influence resectability or the potential to successfully treat the tumor • Symptoms of the syndrome often will abate with successful treatment, and recurrence may be heralded by recurrent paraneoplastic symptoms 34
  • 35. Cont. Endocrine • Hypercalcemia (ectopic parathyroid hormone) • Cushing's syndrome • SIADH • Carcinoid syndrome • Gynecomastia • Hyperthyroidism • Hypercalcitoninemia • Elevated growth hormone • Elevated prolactin, FSH, LH • Hypoglycemia Neurologic • Encephalopathy • Subacute cerebellar degeneration • Progressive multifocal leukoencephalopathy • Peripheral neuropathy • Autonomic neuropathy • Eaton–Lambert syndrome • Optic neuritis • Polymyositis 35
  • 36. Cont. Skeletal • Clubbing • Pulmonary hypertrophic osteoarthropathy Cutaneous • Hyperkeratosis • Dermatomyositis • Acanthosis nigricans • Hyperpigmentation • Erythema gyratum repens • Hypertrichosis lanuginosa acquista 36
  • 37. Cont. Hematologic • Anemia • Leukemoid reactions • Thrombocytosis • Thrombocytopenia • DIC • Eosinophilia • Pure red cell aplasia • Leukoerythroblastosis Other • Nephrotic syndrome • Hypouricemia • Secretion of vasoactive intestinal peptide with diarrhea • Hyperamylasemia • Anorexia or cachexia 37
  • 38. Cont. • Hypertrophic pulmonary osteoarthropathy (HPO) – Characterized by tenderness and swelling of the ankles, feet, forearms, and hands • Symptoms may be severe and debilitating • Clubbing of the digits may occur – It is due to periostitis of the fibula, tibia, radius, metacarpals, and metatarsals – Plain films of the affected areas show periosteal inflammation and elevation • A bone scan demonstrates intense but symmetric uptake in the long bones – Relief is afforded by aspirin or NSAIDs and by successful surgical or medical eradication of the tumor 38
  • 39. Cont. • Hypercalcemia – It occurs in up to 10% of patients with lung cancer and is most often due to metastatic disease – However, 15% of cases are due to secretion of ectopic parathyroid hormone–related peptide, most often with squamous cell carcinoma • Diagnosis can be made by measuring elevated serum levels of parathyroid hormone – Symptoms include lethargy, depressed level of consciousness, nausea, vomiting, and dehydration – Following complete resection the calcium level will normalize 39
  • 40. Cont. • Endocrinopathies – Caused by the release of hormones or hormone analogues into the systemic circulation – Most occur with SCLCs 40
  • 41. Cont. • Cont. – SIADH • Occurs in 10 to 45% of patients with SCLC • Characterized by confusion, lethargy, and possible seizures • Diagnosed by the presence of hyponatremia, low serum osmolality, and high urinary sodium and osmolality 41
  • 42. Cont. • Cont. – Cushing's syndrome • Due to production of ACTH-like molecule and occurs principally in patients with SCLC • ACTH production is autonomous and not suppressible by dexamethasone • Because the serum elevation of ACTH is rapid, the physical signs of Cushing's syndrome (e.g., truncal obesity, buffalo hump, striae) are unusual • Dx – Hpokalemia (<3.0 mmol/L); nonsuppressible elevated plasma cortisol levels that lack the normal diurnal variation; elevated blood ACTH levels 42
  • 43. Cont. • Peripheral and central neuropathies – Among the most common in lung cancer, particularly in SCLC and squamous cell carcinoma – Felt to be immune mediated – Up to 16% of patients with lung cancer have evidence of neuromuscular disability – In patients with neurologic or muscular symptoms, central nervous system (CNS) metastases must be ruled out with imaging 43
  • 44. Cont. • Lambert-Eaton syndrome – A myasthenia-like syndrome usually seen in patients with SCLC – Autoimmune phenomena – Gait abnormalities are due to proximal muscle weakness and fatigability – Therapy is directed at the primary tumor – For patients with refractory symptoms, treatment is medical • Guanidine hydrochloride, Prednisone, Azathioprine, and occasionally plasma exchange. • Unlike with myasthenia gravis patients, neostigmine is usually ineffective 44
  • 45. Metastatic Symptoms • Metastases occur most commonly in the CNS, vertebral bodies, bones, liver, adrenal glands, lungs, and skin and soft tissues – At diagnosis, 10% of patients with lung cancer have CNS metastases; another 10 to 15% will develop CNS metastases – Bone metastases are seen in 25% of all patients with lung cancer • They are primarily lytic, producing localized pain • Lung cancer is the most common cause of spinal cord compression (Direct extension of a vertebral metastasis or foraminal invasion from the primary tumor) – Liver and adrenal metastases are most often an incidental finding on CT scan – Skin and soft tissue metastases occur in 8% of patients dying of lung cancer, and generally present as painless subcutaneous or intramuscular masses 45
  • 46. Nonspecific Symptoms • Lung cancer often produces a variety of nonspecific symptoms such as: – Anorexia – Weight loss – Fatigue – Malaise • Should raise concern about possible metastatic disease 46
  • 48. Cont. • Assessment encompasses three areas: – The primary tumor – Presence of metastatic disease – Functional status (the patient's ability to tolerate a pulmonary resection) 48
  • 49. Assessment of the Primary Tumor • History – Pulmonary, nonpulmonary thoracic, and paraneoplastic symptoms • P/E – Chest – Voice • Investigation – Contrast CT scan – Routine use of MRI in lung cancer patients is reserved for those with: • Contrast material allergies • Suspected mediastinal, vascular, or vertebral body invasion 49
  • 50. Cont. • Tissue diagnosis – Bronchoscopy • Particularly useful for centrally-located tumors • Tissue can be obtained by one of four methods: – Brushings and washings for cytology – Direct forceps biopsy of a visualized lesion – FNA with a Wang needle of an externally compressing lesion without visualized endobronchial tumor – Transbronchial biopsy with the use of forceps guided to the lesion by fluoroscopy – Transthoracic needle aspiration and biopsy • Ideally suited for peripheral lesions not easily accessible by bronchoscopy • Image guided (CT or Fluoroscopy) FNA or core-needle biopsy is performed • The primary complication is pneumothorax (in up to 50% of patients), which is usually minor and requires no treatment • Three biopsy results are possible: malignant, a specific benign 50
  • 51. Cont. • Thoracoscopy – It is potentially a valuable staging tool for assessing the primary tumor's relationship to contiguous structures • Thoracotomy – Required in cases of: • A deep-seated lesion that yielded an indeterminate needle biopsy result or that could not be biopsied for technical reasons – FNA, a Tru-Cut biopsy, or preferably an excisional biopsy is done • Inability to determine invasion of a mediastinal structure by any method short of palpation – When a pneumonectomy is required, a tissue diagnosis of cancer must be made before excision 51
  • 52. Assessment of Metastatic Disease • Distant metastases are found in about 40% of patients with newly diagnosed lung cancer • History – Presence or absence of new bone pain, neurologic symptoms, and new skin lesions – Constitutional symptoms (e.g., anorexia, malaise, and unintentional weight loss of greater than 5% of body weight) suggest either a large tumor burden or the presence of metastases • P/E – Examination of all systems • Laboratory studies – LFT, Serum calcium level • Elevation of either hepatic enzymes or serum calcium levels typically occurs with extensive metastases 52
  • 53. Cont. • Mediastinal Lymph Nodes – Chest CT • Most effective noninvasive method available to assess the mediastinal and hilar nodes for enlargement • Any CT finding of metastatic nodal involvement (i.e., nodal diameter more than 1 cm) must be confirmed histologically – Up to 30% of the nodes are enlarged from noncancerous reactive causes such as inflammation due to atelectasis or pneumonia secondary to the tumor • A negative CT result (lymph nodes less than 1.0 cm) generally is more accurate – PET (more accurate than CT) – Endoesophageal ultrasound – Bronchoscopic FNA of paratracheal lymph nodes (Stations 4R, 7, and 4L) – Mediastinoscopy • It remains the standard method of tissue staging of the mediastinum 53
  • 54. Cont. • Pleural Effusion – No pleural effusion should be assumed to be malignant • Cytologic proof of the presence of malignant cells is required • Effusion is often secondary to the atelectasis or consolidation seen with central tumors, or it can be reactive or secondary to cardiac dysfunction – However, pleural effusion associated with a peripherally-based tumor, particularly one that abuts the visceral or parietal pleural surface, does have a higher probability of being malignant 54
  • 55. Cont. • Evaluation of distant metastasses – Multiorgan scanning • Brain CT or MRI • Abdominal CT • Bone scan – Or PET scan – Routine preoperative multiorgan scanning is not recommended for patients with a negative clinical evaluation and clinical stage I disease • However, it is recommended for patients with regionally advanced (clinical stage II, IIIA, and IIIB) disease 55
  • 56. Assessment of Functional Status • Two flights of stairs • Flat surface • Pulmonary functions – Routinely performed when any resection greater than a wedge resection will be performed • FEV1 – >2L can tolerate pneumonectomy and >1 L can tolerate lobectomy – Or percent predicted value >50% • DLCO (carbon monoxide diffusion capacity ) • O2max (Maximal O2 consumption) • Quantitative perfusion scan – To estimate the functional contribution of a lobe or whole lung Other pertinent elements of the assessment are current smoking status and sputum production Smoking should be stopped for ideally 8 wks but atleast 2 wks before surgery Sputum production: cause should be treated 56
  • 57. Lung Cancer Staging • Occult stage – Microscopically identified cancer cells in lung secretions on multiple occasions (or multiple daily collections); no discernible primary cancer in the lung • Stage 0 – Carcinoma in situ 57
  • 58. Cont. • Stage IA – Tumor surrounded by lung or visceral pleura ≤3 cm arising more than 2 cm distal to the carina (T1 N0) • Stage IB – Tumor surrounded by lung >3 cm, or tumor of any size with visceral pleura involved arising more than 2 cm distal to the carina (T2 N0) 58
  • 59. Cont. • Stage IIA – Tumor ≤3 cm not extended to adjacent organs, with ipsilateral peribronchial and hilar lymph node involvement (T1 N1) • Stage IIB – Tumor >3 cm not extended to adjacent organs, with ipsilateral peribronchial and hilar lymph node involvement (T2 N1) – Tumor invading chest wall, pleura, or pericardium but not involving carina, nodes negative (T3 N0) 59
  • 60. Cont. • Stage IIIA – Tumor invading chest wall, pleura, or pericardium and nodes in hilum or ipsilateral mediastinum (T3, N1–2) or tumor of any size invading ipsilateral mediastinal or subcarinal nodes (T1–3, N2) • Stage IIIB – Direct extension to adjacent organs (esophagus, aorta, heart, cava, diaphragm, or spine); satellite nodule in same lobe, or any tumor associated with contralateral mediastinal or supraclavicular lymph-node involvement (T4 or N3) 60
  • 61. Cont. • Stage IV – Separate nodule in different lobes or any tumor with distant metastases (M1) 61
  • 63. Early-Stage Disease • Stages I and II • The current standard of treatment is surgical resection – Lobectomy – Sleeve lobectomy – Pneumonectomy (rarely performed) • Indicated primarily for : – Larger central tumors involving the distal main stem bronchus when a bronchial sleeve resection is not possible – When resection of involved N1 lymph nodes cannot be achieved short of pneumonectomy • Other options (for patients unfit for surgery due to inadequate pulmonary reserve or other medical conditions) – Limited surgical resection (Segmentectomy or wedge resection) OR – Radiotherapy 63
  • 64. Locoregional Advanced Disease (stage III) • Surgical resection as sole therapy has a limited role in stage III disease – Therefore, definitive treatment of stage III disease (when surgery is not felt to be feasible at any time) is usually a combination of chemotherapy and radiation • Chemo followed by radiation or given at the same time (concurrent) • Neoadjuvant chemo is another option 64
  • 65. Metastatic disease • The treatment of patients with stage IV disease is chemotherapy – Surgery has a very limited value (metastasectomy) 65
  • 66. Small-Cell Lung Carcinoma • It is not generally treated surgically – These aggressive neoplasms have early widespread metastases – Patients with either early or metastatic stage are treated primarily with chemotherapy and radiation • Three groups of SCLC are recognized: – Pure small-cell carcinoma (sometimes referred to as oat cell carcinoma) – Small-cell carcinoma with a large-cell component – Combined (mixed) tumors 66
  • 67. Metastatic Lesions to the Lung • Features suggestive of metastatic disease are multiplicity; smooth, round borders on CT scan • Surgical resection has a role in properly selected patients – The primary tumor must already be controlled – The patient must be able to tolerate general anesthesia, potential single-lung ventilation, and the planned pulmonary resection – The metastases must be completely resectable according to CT imaging – There must be no evidence of extrapulmonary tumor burden – Alternative superior therapy must be unavailable 67