Neoplasms of The Lung
Neoplasms of The Lung
Neoplasms of The Lung
Lung cancer is largely a disease of modern man and was considered quite rare before 1900.
Leading cause of cancer-related death in North America and Europe, killing more than three
times as many men as prostate cancer and nearly twice as many women as breast cancer.
Tobacco consumption is the primary cause of lung cancer.
While tobacco smoking remains the primary cause of lung cancer worldwide, more than 60% of
new lung cancers occur in never smokers (smoked <100 cigarettes per lifetime).
Moreover, 1 in 5 women and 1 in 12 men diagnosed with lung cancer have never smoked.
Epidemiology
Lung cancer is the most common cause of cancer death among American men and women.
Lung cancer is rare below age 40, with rates increasing until age 80, after which the rate tapers
off.
The projected lifetime probability of developing lung cancer is estimated to be approximately
8% among males and approximately 6% among females.
Risk Factors
Cigarette smokers have a tenfold or greater increase in risk.
A deep sequencing study suggested that one genetic mutation is induced for every 15 cigarettes
smoked.
The size of the risk reduction increases with the length of time the person has quit smoking.
Cigarette smoking increases the risk of all the major lung cancer cell types.
Environmental tobacco smoke (ETS) or secondhand smoke is also an established cause of lung
cancer.
With a 20–30% increase in lung cancer observed among never smokers married for many years
to smokers.
Other risk factors including occupational exposures to asbestos, arsenic, bischloromethyl ether,
hexavalent chromium, mustard gas, nickel, and polycyclic aromatic hydrocarbons.
The risk of lung cancer appears higher among individuals with low fruit and vegetable intake
during adulthood.
Ionizing radiation is also an established lung carcinogen.
Prior lung diseases such as chronic bronchitis, emphysema, and tuberculosis have been linked to
increased risks of lung cancer as well.
Smoking Cessation
Stopping tobacco use before middle age avoids more than 90% of the lung cancer risk
attributable to tobacco.
Smoking cessation can even be beneficial in individuals with an established diagnosis of lung
cancer, as it is associated with improved survival, fewer side effects from therapy, and an overall
improvement in quality of life.
Physicians need to understand the essential elements of smoking cessation therapy.
The individual must want to stop smoking and must be willing to work hard to achieve the goal
of smoking abstinence.
Inherited Predisposition to Lung Cancer
First-degree relatives of lung cancer probands have a two- to threefold excess risk of lung cancer
and other cancers, many of which are not smoking-related.
Individuals with inherited mutations in RB (patients with retinoblastoma living to adulthood) and
p53 genes may develop lung cancer.
Pathology
Lung cancer is used for tumors arising from the respiratory epithelium (bronchi, bronchioles, and
alveoli).
World Health Organization classification, epithelial lung cancers consist of four major cell types:
small cell lung cancer (SCLC) and the so-called non-small cell lung cancer (NSCLC) histologies
including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.
These four histologies account for approximately 90% of all epithelial lung cancers.
The remainder include undifferentiated carcinomas, carcinoids, bronchial gland tumors
(including adenoid cystic carcinomas and mucoepidermoid tumors), and rarer tumor types.
Tumors may occur as single or mixed-type histology.
The histologies associated with heavy tobacco use are squamous and small cell carcinomas.
Squamous carcinoma was the most commonly diagnosed form of NSCLC.
Adenocarcinoma has replaced squamous cell carcinoma as the most.
In lifetime never smokers adenocarcinoma tends to predominate.
Among women and young adults (<60 years), adenocarcinoma tends also to be the most
common form of lung cancer.
Small cell carcinoma is a poorly differentiated neuroendocrine tumor that tends to occur as a
central mass with endobronchial growth and is strongly associated with smoking.
There is often widespread cellular necrosis.
May produce specific peptide hormones such as adrenocorticotrophic hormone (ACTH),
arginine vasopressin (AVP), atrial natriuretic factor (ANF), and gastrin-releasing peptide (GRP).
Squamous cell carcinomas tend to occur centrally and are classically associated with a history of
smoking.
Adenocarcinomas often occur in more peripheral lung locations and may be associated with a
history of smoking.
However, adenocarcinomas are the most common type of lung cancer occurring in never
smokers.
Histologically, the tissue may contain the presence of glands, papillary structure,
bronchioloalveolar pattern, cellular mucin, or solid pattern if poorly differentiated.
Bronchioloalveolar carcinoma (BAC) is a subtype of adenocarcinoma that grows along the
alveoli without invasion and can present radiographically as a single mass, as a diffuse
multinodular lesion, as a fluffy infiltrate, and on screening CT scans as a "ground-glass" opacity
(GGO).
Large cell carcinomas tend to occur peripherally and are defined as poorly differentiated
carcinomas of the lung composed of larger malignant cells without evidence of squamous,
glandular differentiation, or features of small cell carcinoma by light microscopy.
Historically, for treatment and prognostication purposes, the major distinction has been between
SCLC and NSCLC, as these tumors have quite different natural histories and therapeutic
approaches.
Immunohistochemistry
The diagnosis of lung cancer most often rests on the morphologic or cytologic features correlated
with clinical and radiographic findings.
Immunohistochemistry may be used to verify neuroendocrine differentiation within a tumor,
with markers such as neuron-specific enolase (NSE), CD56 or neural cell adhesion molecule
(NCAM), synaptophysin, chromogranin, and Leu7.
Immunohistochemistry is also helpful in differentiating primary from metastatic
adenocarcinomas.
Thyroid transcription factor 1 (TTF-1), identified in tumors of thyroid and pulmonary origin, is
positive in more than 70% of pulmonary adenocarcinomas and is a reliable indicator of primary
lung cancer, provided a thyroid primary has been excluded.
Cytokeratins 7 and 20 used in combination can help narrow the differential diagnosis;
nonsquamous NSCLC, SCLC, and mesothelioma may stain positive for CK7 and negative for
CK20, while squamous cell lung cancer will be both CK7 and CK20 negative.
Molecular Pathogenesis
The exact cell of origin for lung cancers is not known.
Whether one cell of origin leads to all histologic forms of lung cancer is unclear.
However, at least for lung adenocarcinoma, type II epithelial cells (or alveolar epithelial cells)
have the capacity to give rise to tumors.
For SCLC, cells of neuroendocrine origin have been implicated as precursors.
The stem cell concept may explain the failure of standard medical therapies to eradicate lung
cancers, even when there is a clinical complete response.
Disease recurs because therapies do not eliminate the stem cell component, which may be more
resistant to chemotherapy.
Early Detection and Screening
The clinical outcome for lung cancer is related to the stage at diagnosis.
Accordingly, it is presumed that early detection of occult tumors will lead to improved survival.
Early detection is a process that involves screening tests, surveillance, diagnosis, and early
treatment.
By contrast, screening is defined as a systematic testing of asymptomatic individuals for
preclinical disease.
In order for a screening program to be successful, the burden of disease within the population
must be high, effective treatment must be available that can reduce mortality rate, and the test
must be accessible, cost-effective, and both sensitive and specific.
No impact on lung cancer–specific mortality rate using screening chest radiographs with or
without sputum cytology in high-risk patients (age >50 years or history of smoking).
Clinical Manifestations
More than half of all patients diagnosed with lung cancer present with advanced disease at the
time of diagnosis.
The majority of patients present with signs, symptoms, or laboratory abnormalities that can be
attributed to the primary lesion, local tumor growth, invasion or obstruction of adjacent
structures, growth at distant metastatic sites, or a paraneoplastic syndrome.
The prototypical lung cancer patient is a current or former smoker of either sex, usually in the
seventh decade of life.
A history of chronic cough with or without hemoptysis in a current or former smoker with COPD
aged 40 years or older should prompt a thorough investigation for lung cancer even in the face of
a normal chest x-ray.
A persistent pneumonia without constitutional symptoms and unresponsive to repeated courses
of antibiotics also should prompt an evaluation for the underlying cause.
In addition, lung cancer can spread transbronchially, producing tumor growth along multiple
alveolar surfaces with impairment of gas exchange, respiratory insufficiency, dyspnea,
hypoxemia, and sputum production.
Constitutional symptoms may include anorexia, weight loss, weakness, fever, and night sweats.
Apart from the brevity of symptom duration, these parameters fail to clearly distinguish SCLC
from NSCLC or even from neoplasms metastatic to lungs.
Patients with bone metastases may present with pain, pathologic fractures, or cord compression.
Those with liver metastases may present with hepatomegaly, right upper quadrant pain, anorexia,
and weight loss. Liver dysfunction or biliary obstructions are rare.
Paraneoplastic syndromes are common in patients with lung cancer, especially those with SCLC,
and may be the presenting finding or the first sign of recurrence.
Often the paraneoplastic syndrome may be relieved with successful treatment of the tumor.
Systemic symptoms of anorexia, cachexia, weight loss (seen in 30% of patients), fever, and
suppressed immunity are paraneoplastic syndromes of unknown etiology or at least not well
defined.
Weight loss greater than 10% of total body weight is considered a bad prognostic sign.
Endocrine syndromes are seen in 12% of patients; hypercalcemia resulting from ectopic
production of parathyroid hormone (PTH), or more commonly, PTH-related peptide, is the most
common life-threatening metabolic complication of malignancy, primarily occurring with
squamous cell carcinomas of the lung.
Clinical symptoms include nausea, vomiting, abdominal pain, constipation, polyuria, thirst, and
altered mental status.
Skeletal–connective tissue syndromes include clubbing in 30% of cases (usually NSCLCs) and
hypertrophic primary osteoarthropathy in 1–10% of cases (usually adenocarcinomas).
Patients may develop periostitis, causing pain, tenderness, and swelling over the affected bones
and a positive bone scan.
Diagnosing Lung Cancer
Tissue sampling is required to confirm a diagnosis in all patients with suspected lung cancer.
Tumor tissue may be obtained via minimally invasive techniques such as bronchial or
transbronchial biopsy during fiberoptic bronchoscopy, by fine-needle aspiration (FNA) or
percutaneous biopsy using image guidance, or via endobronchial ultrasound (EBUS)-guided
biopsy.
The diagnostic yield of any biopsy depends on several factors, including location (accessibility)
of the tumor, tumor size, tumor type, and technical aspects of the diagnostic procedure including
the experience level of the bronchoscopist and pathologist.
Diagnostic accuracy for SCLC versus NSCLC for most specimens is excellent, with lesser
accuracy for subtypes of NSCLC.
Bronchoscopic specimens include bronchial brush, bronchial wash, bronchioloalveolar lavage,
and transbronchial FNA.
Overall sensitivity for combined use of bronchoscopic methods is approximately 80%, and
together with tissue biopsy, the yield increases to 85–90%.
Sputum cytology is inexpensive and noninvasive but has a lower yield than other specimen types
due to poor preservation of the cells and more variability in acquiring a good-quality specimen.
The yield for sputum cytology is highest for larger and centrally located tumors such as
squamous cell carcinoma and small cell carcinoma histology.
The specificity for sputum cytology averages close to 100%, although sensitivity is generally less
than 70%.
Staging Lung Cancer
Lung cancer staging consists of two parts:
first, a determination of the location of the tumor and possible metastatic sites (anatomic
staging), and second, an assessment of a patient's ability to withstand various antitumor
treatments (physiologic staging).
All patients with lung cancer should have a complete history and physical examination, with
evaluation of all other medical problems, determination of performance status, and history of
weight loss.
Staging with regard to a patient's potential for surgical resection is principally applicable to
NSCLC.
The best predictor of metastatic disease remains a careful history and physical examination.
If signs, symptoms, or findings from physical examination suggest the presence of malignancy,
then sequential imaging starting with the most appropriate study should be performed.
If the findings from the clinical evaluation are negative, then imaging studies beyond CT-PET
are unnecessary and the search for metastatic disease is complete.
There are limited data on the use of CT-PET in the staging of patients with SCLC.
Current staging recommendations include a CT scan of the chest and abdomen (because of the
high frequency of hepatic and adrenal involvement), MRI of the brain (positive in 10% of
asymptomatic patients), and radionuclide (bone) scan if symptoms or signs suggest disease
involvement in these areas.
Bone marrow biopsies and aspirations are rarely performed given the low incidence of isolated
bone marrow metastases.
Confirmation of metastatic disease, ipsilateral or contralateral lung nodules, or metastases
beyond the mediastinum may be achieved by the same modalities recommended above for
patients with NSCLC.
If a patient has signs or symptoms of spinal cord compression (pain, weakness, paralysis, urinary
retention), a spinal CT or MRI scan and examination of the cerebrospinal fluid cytology should
be performed.
The Staging System for Non-Small Cell Lung Cancer
The TNM International Staging System provides useful prognostic information and is used to
stage all patients with NSCLC.
Staging system within the T classification; T1 tumors are divided into tumors 2 cm in size, as
these patients were found to have a better prognosis compared to tumors >2 cm but 3 cm.
T2 tumors are divided into those that are >3 cm but 5 cm and those that are >5 cm but 7 cm.
T3 tumors are >7 cm.
T4 tumors include those that have additional nodules in the same lobe or tumors that have a
malignant pleural effusion.
M1a, malignant pleural or pericardial effusion, pleural nodules or nodules in the contralateral
lung, or M1b distant metastasis (e.g., bone, liver, adrenal, or brain metastasis).
Sixth and Seventh Edition TNM Staging Systems for Non-Small Cell Lung Cancer
Sixth Edition Seventh Edition
Tumor (T)
T1
Tumor 3 cm diameter without invasion Tumor 2 cm diameter, surrounded by lung or
more proximal than lobar bronchus visceral pleura, without invasion more proximal than
lobar bronchus
T1a
Tumor 2 cm in diameter
T1b
Tumor >2 cm but 3 cm in diameter
T2 Tumor >3 cm diameter OR tumor of any size
with any of the following: Tumor >3 cm but 7 cm with any of the
following:
Visceral pleural invasion
Atelectasis of less than entire lung Involves main bronchus, 2 cm distal to carina
Physiologic Staging
Patients with an FEV1 (forced expiratory volume in 1 s) of greater than 2 L or greater than 80%
of predicted can tolerate a pneumonectomy, and those with an FEV1 greater than 1.5 L have
adequate reserve for a lobectomy.
In patients with borderline lung function but a resectable tumor, cardiopulmonary exercise
testing could be performed as part of the physiologic evaluation.
The approach to a patient with a solitary pulmonary nodule is based on an estimate of the
probability of cancer, determined according to the patient's smoking history, age, and
characteristics on imaging.
Clinical characteristics (age, cigarette smoking status, and prior cancer diagnosis) and three
radiologic characteristics (nodule diameter, spiculation, and upper lobe location) were
independent predictors of malignancy.
At present, only two radiographic criteria are thought to predict the benign nature of a solitary
pulmonary nodule: lack of growth over a period >2 years and certain characteristic patterns of
calcification.
Calcification alone, however, does not exclude malignancy; a dense central nidus, multiple
punctate foci, and "bull's-eye" (granuloma) and "popcorn ball" (hamartoma) calcifications are
highly suggestive of a benign lesion.
Pneumonectomy is reserved for patients with very central tumors and should only be performed
in patients with excellent pulmonary reserve.
The 5-year survival rates are 60–80% for patients with stage I NSCLC and 40–50% for patients
with stage II NSCLC.
Patients should have a complete mediastinal node dissection.
All patients with resected NSCLC are at high risk of recurrence or developing a second primary
lung cancer.
Thus, it is reasonable to follow these patients with regular imaging.
CT scans of the chest with contrast every 6 months for the first 2 years after surgery, followed by
yearly CT scans of the chest without contrast thereafter.
Chemotherapy palliates symptoms, improves the quality of life, and improves survival in patients
with stage IV NSCLC, particularly in patients with good performance status.
Longer duration of chemotherapy has been associated with increased toxicities and impaired
quality of life.
Therefore, prolonged therapy (beyond four to six cycles) with platinum-based regimens is not
recommended in patients with advanced NSCLC.
Nonsquamous NSCLC had an improved survival when treated with cisplatin while patients with
squamous carcinoma had an improved survival when treated with cisplatin and gemcitabine.
Hamartomas
They are more common in men than in women and have a peak incidence in the 60s.
Solitary nodules.
They have a pathognomonic "popcorn" pattern of calcification in some cases.
Miesso(MD)