Pulmonary Neoplasms

What are the key learning objectives regarding pulmonary neoplasms?

Discuss the recommendations for screening for lung cancer; describe the risk factors; pathophysiology; epidemiology; clinical presentation; diagnostic testing; and treatment options for specific lung cancers.

Which specific types of lung cancer should be understood regarding risk factors; presentation; diagnosis; and treatment?

Squamous cell carcinoma; Adenocarcinoma; Adenocarcinoma in situ; and Large cell carcinoma.

What advanced topics related to lung cancer must be recognized?

Oncogene mutations and targeted gene therapy; paraneoplastic syndromes associated with bronchogenic carcinoma; histopathology; metastatic spread; and prognosis for the most common types of bronchogenic carcinoma.

Why is lung cancer considered a major health burden globally and in the US?

It is the leading cause of cancer deaths in both men and women; remains the leading cause of death for cancer in the US and the world.

What were the approximate estimates for new diagnoses and deaths from lung cancer in the US in 2022; according to the American Cancer Society (ACS)?

236;740 new diagnoses and 130;180 deaths; accounting for ~12% of new cancer diagnoses and 21% of all cancer deaths.

What is the estimated number of annual worldwide deaths due to lung cancer?

Approximately 1.8 million deaths due to lung cancer worldwide each year.

What is the median age at diagnosis for lung cancer in the US?

71 years; it is unusual under age 40 [3; 4].

What is the combined relative 5-year survival rate for lung cancer?

Between 15-25%.

What percentage of lung cancer cases are caused by cigarette smoking?

85-90% of lung cancer.

Name several environmental risk factors for lung cancer other than cigarette smoke.

Exposure to environmental tobacco smoke; radon; asbestos; diesel exhaust; ionizing radiation; metals (arsenic; chromium; nickel; iron oxide); and industrial carcinogens [4; 5].

What familial factor is recognized as a risk factor for lung cancer?

Familial predisposition is also recognized.

Which certain diseases are associated with an increased risk of lung cancer?

Pulmonary fibrosis; COPD; and sarcoidosis.

What are the specific criteria for annual lung cancer screening using a low dose CT scan (LDCT)?

Between the ages of 50-80; at least a 20 pack-year smoking history; and currently smoke or have quit within the past 15 years.

What factors must be discussed during consultation regarding lung cancer screening?

The pros vs cons and limitations; patients should generally be in good health and understand the possible need for subsequent evaluation of abnormal findings.

What is a consideration regarding annual screening and follow-up?

Cost of annual screening and follow-up.

When should annual lung cancer screening be stopped?

Once the patient has not smoked for 15 years or has a limited life expectancy.

Is screening with plain chest radiograph (CXR) recommended for lung cancer?

No; it is NOT recommended for lung cancer.

Are blood tests currently used for early detection of lung cancer?

They are currently only being used in clinical trials.

What preventative measure should be emphasized to patients who currently smoke or recently quit?

They should be educated about the importance of smoking cessation and provided with resources and supportive care to do so.

What is the most effective strategy for reducing the burden of lung cancer?

Prevention.

Into what two major categories is lung cancer divided; based on staging and treatment options?

Small cell lung cancer (SCLC) and Non-small cell lung cancer (NSCLC).

Name the common subtypes of Non-small cell lung cancer (NSCLC).

Squamous cell carcinoma; Adenocarcinoma; Adenocarcinoma in situ (formerly bronchioloalveolar cell carcinoma); and Large cell carcinoma.

How is lung cancer often diagnosed regarding symptoms?

Often asymptomatic at diagnosis and found incidentally.

What are the most common constitutional symptoms seen in patients with lung cancer?

Anorexia; weight loss; or weakness (occurs in 55-90% of patients).

What common respiratory symptom affects up to 60% of patients?

A new cough or change in a chronic cough.

What other signs might be seen clinically?

Hemoptysis; lymphadenopathy; hepatomegaly; clubbing of the fingers.

Upon what does the clinical presentation of lung cancer depend?

Type and location of primary tumor; extent of local spread and presence of metastasis or paraneoplastic syndromes.

What are paraneoplastic syndromes?

Patterns of organ dysfunction related to immune-mediated or secretory effects of neoplasms.

How frequently do paraneoplastic syndromes occur in lung cancer patients; and when can they manifest?

Occurs in 10-20% of patients with lung cancer; may precede; accompany or follow the diagnosis of lung cancer.

Which systems can paraneoplastic syndromes affect?

Nervous system; endocrine system; hematologic system; dermatologic system; etc.

Which specific paraneoplastic syndrome is classically associated with Small Cell Carcinoma (SCLC)?

Syndrome of inappropriate antidiuretic hormone (SIADH).

Which cancer type is most commonly associated with neoplastic syndromes?

SCLC most commonly associated with neoplastic syndromes.

Which specific paraneoplastic syndrome is classically associated with Squamous Cell Carcinoma?

Hypercalcemia.

What are other common paraneoplastic syndromes associated with lung cancer?

Increased ACTH production; anemia; hypercoagulability; peripheral neuropathy; and the Lambert-Eaton myasthenic syndrome.

Why is recognizing paraneoplastic syndromes important?

Treatment of the primary tumor may improve or resolve symptoms even if the cancer is not curable.

How is the definitive diagnosis of lung cancer established?

Through examination of a tissue or cytology specimen.

Describe the utility of sputum cytology in lung cancer diagnosis.

It is highly specific but insensitive; the yield is highest with lesions in central airways.

Name procedures used to establish a definitive diagnosis.

Bronchoscopy; examination of pleural fluid and biopsy are also used.

What is a risk associated with CT-guided biopsy of peripheral nodules?

It has a high yield but can put the patient at risk for pneumothorax.

What procedure can diagnose lung cancer in patients with malignant pleural effusions?

Thoracentesis.

What procedure is used to sample palpable supraclavicular or cervical lymph nodes?

Fine-needle aspiration (FNA).

What other diagnostic procedures may be used if less invasive techniques fail?

Mediastinoscopy; video-assisted thoracoscopic surgery (VATS) and thoracotomy.

What are the capabilities of bronchoscopy in diagnosing lung cancer?

Visualization of the major airways; cytology brushing of visible lesions or lavage of lung segments with cytologic evaluation of specimens; biopsy of other hard to access areas.

Upon what does the diagnostic yield of bronchoscopy depend?

Size and location of lesions.

What newer technique improves the ability to identify early endobronchial lesions?

Use of fluorescence bronchoscopy.

What technique allows approach to small peripheral nodules via bronchoscopy?

Electromagnetic navigational bronchoscopy.

What combination of imaging modalities is important for identifying metastases?

Combination of PET and CT.

What conditions can cause false-positive PET scans in lung cancer workup?

Sarcoidosis; tuberculosis or fungal infections.

When is MRI of the brain required in lung cancer diagnosis?

In all patients with SCLC and in patients with NSCLC with at least stage II disease or poorly differentiated histology.

Why are PET scans inadequate for evaluating brain metastases (METS)?

Due to normal physiologic FDG uptake in the brain.

What percentage of lung cancer cases does SCLC represent; and what is its typical location and presentation?

Represents ~13% of cases; is of bronchial origin; typically begins centrally and infiltrates submucosally to cause narrowing of the bronchus without a discrete luminal mass.

Describe the aggressiveness and metastatic tendency of SCLC upon presentation.

Aggressive cancers that often involve regional or distant metastasis on presentation; often metastasizes to regional lymph nodes.

Into what two traditional categories is SCLC divided?

Limited disease (30% of cases) and Extensive disease (70% of cases).

Define Limited SCLC disease.

Tumor is limited to unilateral hemithorax.

Define Extensive SCLC disease.

Tumor extends beyond the hemithorax.

What staging system is used for SCLC?

Staged according to TNM staging system.

What is crucial during history and PE for SCLC?

To exclude obvious metastatic disease and to determine patient’s performance status.

What basic laboratory tests should all SCLC patients have checked during the initial workup?

CBC; electrolytes; calcium; creatinine; liver function tests and albumin.

What is the usual treatment for SCLC; given that it is rarely amenable to surgery?

Combination chemotherapy.

Is surgery ever an option for SCLC?

Yes; in patients with very early; limited stage disease; however these patients still get chemo.

What two common chemotherapeutic agents are used for SCLC; and what is the typical outcome?

Cisplatin and etoposide; they have strong response rates however remission is usually short-lived and the disease often recurs.

What recent addition improves survival modestly in extensive-stage SCLC?

Addition of immunotherapy along with chemo.

For patients with limited SCLC; what treatment is given concurrently with chemotherapy to improve survival?

Radiation.

What is the long-term prognosis for SCLC patients; even with treatment?

Patients rarely live >5 years after diagnosis even with treatment.

Why is prophylactic radiation considered for SCLC patients?

SCLC has a high rate of brain METS.

In which SCLC patients is prophylactic radiation considered?

In patients with limited-stage disease OR extensive-stage who have responded well to chemo.

How does Non-small cell lung cancer (NSCLC) compare to SCLC in terms of growth and treatment amenability?

NSCLC is slower growing and more amenable to surgery compared to SCLC.

What percentage of cases does Squamous Cell Carcinoma represent; and what are its classic location and presentation?

Represents ~23% of cases; arises from the bronchial epithelium; often presents as intraluminal mass; usually centrally located and can present with hemoptysis.

Which diagnostic method is more likely to diagnose Squamous Cell Carcinoma?

More likely to be diagnosed with sputum cytology.

Describe the prevalence and presentation of Adenocarcinoma.

Represents ~50% of cases; arises from mucous glands or from any epithelial cell within or distal to the terminal bronchioles; usually present as peripheral nodules or masses.

In which patient groups is Adenocarcinoma the most common type?

Smokers; women and non-smokers.

Is Adenocarcinoma easily detected early via sputum examination?

No; it is typically metastatic to distant organs and is NOT amenable to early detection through sputum examination.

What was Adenocarcinoma in situ formerly known as; and what is its prognosis?

Formerly known as bronchioloalveolar cell carcinoma; considered a subtype of adenocarcinoma and is low grade; gives the best prognosis [20; 21].

Is Adenocarcinoma in situ common?

Rare.

How does Adenocarcinoma in situ spread?

Spread along preexisting alveolar structures without evidence of invasion.

Describe the prevalence and cellular characteristics of Large Cell Carcinoma.

Represents ~1.3% of cases; heterogenous group of undifferentiated cancers that share large cells and do not fit into other categories.

Describe the aggressiveness and location of Large Cell Carcinoma.

Typically aggressive and have rapid doubling times; metastasis can occur early; present as central or peripheral masses.

What is seen on cytology for Large Cell Carcinoma?

Cytology shows large cells.

What offers the best chance for cure in NSCLC?

Surgical resection.

Name clinical features that preclude complete surgical resection in NSCLC.

Extrathoracic metastases; malignant pleural effusion; tumor involving the heart; pericardium; great vessels; esophagus; recurrent laryngeal or phrenic nerves; trachea; main carina; or contralateral mediastinal lymph nodes.

What surgical approaches are used for early-stage NSCLC cancers?

Lobectomy and sublobar resection.

When is radiation therapy considered following surgical resection?

For margin-positive disease or pathologic mediastinal lymph node involvement.

How are Stage I and Stage II NSCLC patients primarily treated?

With surgical resection when possible.

If a Stage I/II NSCLC patient is not a candidate for surgery; what treatment can they receive?

Stereotactic body radiotherapy which delivers relatively large dose of radiation to a small; well-defined target.

When is neoadjuvant or adjuvant therapy recommended in NSCLC?

Stage II and select cases of stage IB.

How are Stage IIIA and IIIB patients generally treated?

With concurrent chemotherapy and radiation therapy followed by immunotherapy.

What is the treatment strategy for Stage IV NSCLC patients?

Systemic therapy (targeted therapy; chemotherapy and/or immunotherapy) or symptom-based palliative therapy; or both.

Why is there an increased risk of perioperative complications and long-term pulmonary insufficiency in NSCLC patients undergoing lung resection?

Because many patients have moderate to severe chronic lung disease.

What essential test is required for all patients considered for NSCLC surgery?

Spirometry.

What are the therapy options for Stage IIIB and Stage IV NSCLC?

Targeted therapy; cytotoxic chemotherapy and immunotherapy.

How is the approach to advanced NSCLC therapy individualized?

Based on molecular profiling and PD-L1 testing.

What does molecular profiling analyze?

A tumor’s genetic makeup to identify specific mutations and/or biomarkers.

What is the purpose of PD-L1 testing?

Helps determine is a patient might benefit from immunotherapy; specifically immune-checkpoint inhibitors.

Do most lung cancer cases have key driver mutations?

Only a minority of lung cancer cases have these mutations.

Give examples of key driver mutations in lung cancer that may guide targeted therapy.

EGFR; ALK; BRAF; ROS1; NTRK; MET; RET and KRAS pathogenic variants.

Describe the typical patient profile and histology associated with EGFR mutations.

Usually found in non-smokers or light smokers; women; and persons with non-squamous histology (mostly adenocarcinomas).

What is the first-line treatment for EGFR mutation positive NSCLC?

EGFR tyrosine kinase inhibitor (osimertinib) over platinum-based chemo; response rates up to 70%.

Describe the typical patient profile and histology associated with ALK mutations.

Usually found in younger population with adenocarcinoma histology and in non-smokers/lighter smokers.

What are the first-line treatments for ALK mutation positive NSCLC?

ALK tyrosine kinase inhibitors (alectinib; brigatinib or lorlatinib); response rates range from 74% to 83%.

What is the patient profile and histology associated with ROS1 rearrangement mutations?

Usually adenocarcinomas found among nonsmokers or light smokers.