Malignancy

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  Bronchogenic carcinoma: accounts for approximately 35% of SPNs.

  
  
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  The majority of bronchogenic carcinomas in the United States are non–small lung cancer (NSCLC).

  
  
  
  
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    Adenocarcinomas (including bronchoalveolar cell): most common of the NSCLC, presents as peripheral mass in 49% to 80% of cases.

    
    
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    Squamous cell carcinomas: now second most common of the NSCLCs, presents as a peripheral mass in 43% to 55% of cases.

    
    
    
    
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      Decrease prevalence of squamous cell carcinoma, traditionally presenting as a central tumor, relative to adenocarcinoma, is postulated to be due to the decrease in nicotine and tar levels in cigarettes, which promotes a pattern of deeper inhalation resulting in increased exposure of peripheral lung tissue to smoke and a consequent increase in peripheral origin of lung cancer.

    
    
    
    
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    Large cell carcinoma: a rare cause of an SPN

    
    
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    Small cell carcinoma: accounts for less than 5% of SPNs

    
    
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    Proteonomics, the study of protein expression, and genomics will probably dictate future treatment, de-emphasizing the importance of cell type.

  
  
  
  
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  Metastases: accounts for approximately 23% of SPNs.

  
  
  
  
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    An SPN in patients with lymphoma or leukemia is almost always a primary bronchogenic carcinoma.

    
    
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    An SPN in patients with carcinomas of the head and neck, squamous cell carcinoma, carcinoma of the bladder, breast, cervix, bile ducts, esophagus, ovary, prostate, or stomach is more likely to be a primary bronchogenic carcinoma than metastasis.

    
    
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    An SPN in patients with carcinoma of the salivary glands, adrenals, colon, kidney, thyroid, thymus, or uterus has an equal probability or being a primary bronchogenic carcinoma and a metastasis.

    
    
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    An SPN in patients with melanoma, sarcoma, or testicular cancer is more likely to be a solitary metastasis than primary bronchogenic carcinoma.

    
    
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    Colorectal carcinoma accounts for 30% to 40% of all solitary metastatic SPNs to the lung and is the most likely source of a solitary metastatic nodule.

    
    
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    An SPN in the absence of a known primary is unlikely to be a metastasis, and a persistent diagnostic workup for an extra-thoracic primary is not cost effective.

  
  
  
  
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  Other malignancies

  
  
  
  
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    Carcinoid, adenosquamous carcinoma, sarcomatoid carcinoma, and salivary gland tumors

  
  

Benign causes

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  Infectious granuloma: about 80% of benign SPNs

  
  
  
  
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    Histoplasmosis, tuberculosis, are coccidioidomycosis are the etiology of the most commonly resected SPNs

    
    
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    The prevalence of coccidioidomycosis or histoplasmosis as the cause of a SPN may be extremely high in a local endemic area.

  
  
  
  
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  Hamartoma: about 10% of benign SPNs

  
  
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  Vascular:

  
  
  
  
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    Arteriovenous malformation (AVM)

    
    
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    Pulmonary artery aneurysm

  
  

Other:

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  Rheumatoid nodule

  
  
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  Wegener’s granulomatosis

  
  
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  Rounded atelectasis

  
  
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  Organizing pneumonia

  
  
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  Pulmonary infarct

  
  
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  Sarcoidosis

  
  
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  Amyloidosis

  
  
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  Bronchial atresia

Frequently asymptomatic

Cough, fever, hemoptysis

Cigarette smoking is the overwhelming risk factor for developing a malignant SPN.

Several clinical models have been developed to estimate the probability of malignancy in an SPN.

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  In the most recently developed model

  
  
  
  
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    Current or former cigarette use, older age, increase in nodule diameter are associated with higher risk of malignant SPNs

    
    
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    Increase in the number of years since quitting smoking is associated with lower likelihood of malignant SPN

    
    
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    Recently diagnosed lung cancer or a history of recent extrathoracic malignancy were not independent predictors of malignancy

    
    
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    In contrast to the Mayo Clinic model, this model found that upper lobe SPNs were not more likely to be malignant

  
  
  
  
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  A history of an extrathoracic malignancy at least 5 years before the time of SPN detection has been reported as an additional predictor of a malignant SPN in the Mayo Clinic model.

  
  
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  An additional risk factor is a history of lung cancer in first-degree relatives.

Evidence for a specific lung cancer susceptible gene has been reported.

Other risk factors are history of pulmonary fibrosis due to collagen vascular disease, adult respiratory distress syndrome, or radiation, previous exposure to asbestos, uranium and radon.

Malignant SPN in usual institial pneumonia develops in periphery of lower lobe in area of fibrosis.

Lung cancer is uncommon in people younger than age 40 and rare in people younger than age 35.

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  Exceptions are patients with human immunodeficiency virus who have increased risk for developing lung cancer and may develop it at an earlier age.

Plain chest radiograph

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  Nineteen percent of SPNs were missed owing to factors such as small size, partial obscuration by superimposing structures, failure to compare current with prior radiographs, use of a faulty search pattern, poor viewing conditions, and poor technical quality of images.

  
  
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  An SPN is seldom detected on chest radiography until it is 9 mm in diameter.

  
  
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  Approximately 90% of newly discovered SPNs are visible in retrospect on prior chest radiographs.

  
  
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  Benign features

  
  
  
  
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    Size: 90% of SPNs smaller than 2 cm are benign.

    
    
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    Location: Benign SPNs distributed equally throughout lungs and location cannot be used as an independent predictor of benignity or malignancy.

    
    
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    Calcification: Benign patterns of calcifications are laminated (concentric), uniform, central nidus, and popcorn.

    
    
    
    
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      The first three types are associated with granulomatous disease.

      
      
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      Popcorn calcification is seen in one-third of hamartomas.

      
      
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      Calcification patterns are more easily demonstrated on CT than chest radiographs.

      
      
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      About 45% of benign SPNs demonstrate no calcification.

    
    

  
  

Margin characteristics

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  A smooth rounded margin is associated with benign diagnosis.

  
  
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  Twenty to thiry-four percent of SPNs with a smooth rounded margin are malignant. Most SPNs are metastatic.

Growth Rate

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  Benign SPNs have doubling time of less than 1 month or more than 16 months.

  
  
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  An increase of SPN diameter by 26% is equivalent to doubling of SPN volume.

  
  
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  Stability of nodule size over 2 years is no longer considered adequate for diagnosis of benignity, especially with small SPNs.

Other

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  Unequivocal evidence on previous examinations that the nodule is the end stage of a previous benign process such as infarction or previous granulomatous infection

  
  
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  Cavitary wall thickness cannot be used to accurately differentiate between benign and malignant SPNs because of considerable overlap. Commonly quoted data is as follows: wall thickness less than 4 mm is generally benign; greater than 16 mm is generally malignant, and a 4- to 16-mm wall thickness is indeterminate.

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  Malignant features

  
  
  
  
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    Size: SPNs approaching 3 cm are more likely to be malignant.

    
    
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    Location

    
    
    
    
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      Lung cancer is 1.5 times more common in the right lung than the left lung.

      
      
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      Seventy percent of lung cancers occur in the upper lobes, but this was not confirmed in one recent series.

    
    
    
    
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    Calcification

    
    
    
    
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      An eccentric calcification may represent a malignant lesion with dystrophic calcification or a malignant SPN that has engulfed a benign SPN.

      
      
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      Carcinoids, metastatic osteosarcomas, and chondrosarcomas may have dense foci of calcification or be entirely calcified and simulate a benign SPN.

      
      
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      Mucin-secreting tumors such as colon or ovarian cancers may have stippled or psammomatous calcification and may also simulate a benign SPN.

    
    
    
    
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    Margin characteristics: spiculated on plain film

    
    
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    Growth rate

    
    
    
    
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      Doubling time for most malignant SPNs is between 30 and 400 days

      
      
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      Fast-growing metastases and lymphoma can have a shorter doubling time.

    
    
    
    
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    Other: 84% to 95% of cavitary SPNs with irregular-walled cavities thicker than 16 mm tend to be malignant.

  
  

Often used to confirm that the nodule seen on chest radiograph is indeed solitary and within the lung parenchyma. Imaging is also useful for further characterization.

Size:

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  Highly accurate at determining nodule size and doubling time.

  
  
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  A 6-m nodule incidentally discovered on computed tomography (CT) scan is up to 30 times more likely to be benign than malignant

Density:

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  Calcification: better than plain radiograph at detecting and characterizing calcification

  
  
  
  
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    SPN with density above 200 Houndsfield units (HUs) can be considered benign if no other malignant features are present.

  
  
  
  
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  Fat: can exclude malignancy in most instances by detecting fat density.

  
  
  
  
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    Fat within an SPN is very specific for hamartoma, and 50% of hamartomas demonstrate focal fat attenuation on high-resolution CT (HRCT).

    
    
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    Lipoma is a very rare cause of benign fat-containing SPNs.

    
    
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    Metastatic liposarcoma and clear cell renal carcinoma are rare causes of malignant fat-containing SPNs.

  
  
  
  
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  Pure ground-glass SPN is more likely to be malignant than a solid or partly solid SPN.

Air bronchograms seen in 30% of malignant and 10% of benign SPNs.

Enhancement pattern

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  An SPN larger than 5 mm that fail to enhance by more than 15 HU is likely to be benign (negative predictive value greater than 95%).

  
  
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  Tuberculous granulomas show peripheral ring enhancement or curvilinear central enhancement.

Magnetic resonance imaging is currently not widely used for evaluation of SPNs due to its higher cost and lack of definitive diagnostic advantage relative to CT.

SPN is a major indication for F-fluoro-deoxyglucose (FDG) PET imaging. FDG uptake by a nodule is proportional to the metabolic activity of the nodule.

PDG-PET is less accurate for pulmonary nodules smaller than 1 cm because of the spatial resolution of current PET scanners.

FDG-PET can be falsely negative in cases of bronchioloalveolar cell carcinoma, carcinoid, and renal cell metastasis.

Inflammatory and granulomatous changes, such as those seen in fungal infection, pneumonia, and sarcoidosis, can give a false-positive result.

Visual or qualitative evaluation by comparing the activity of the SPN relative to the mediastinum may be sufficient for diagnosis. Quantitative analysis with standard uptake value (SUV) may not be necessary in most cases. Initially, a lung mass with an SUV greater than 2.5 was thought to be cancer and an SUV smaller than 2.5 was thought to suggest that the lung mass was benign. That is no longer thought to be true. There is no cut points to diagnose cancer in a lung mass. (See chapter 2 on radionuclide imaging for more details.)

PET/CT has better sensitivity (97%), specificity (85%), and accuracy (93%) in characterizing a nodule as malignant or benign than either CT or PET alone.

More invasive procedures are undertaken when imaging fails to exclude malignancy.

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  Transthoracic needle biopsy

  
  
  
  
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    Can sometimes be performed with fluoroscopy or ultrasound guidance, but currently, CT guidance is most commonly used

    
    
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    Recent study demonstrates a diagnostic accuracy of 77%, pneumothorax rate of 28%, and chest tube insertion rate of 2.5% for lesions smaller than 20 mm in diameter.

    
    
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    Diagnostic accuracy is significantly better for larger (>10 mm) lesions.

    
    
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    The accuracy is improved to 97% with the use of multiplanar reconstruction image.

    
    
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    The yield for a specific benign diagnosis is improved with core needle biopsy and by having an on-site pathologist to assess the adequacy of biopsy samples at the time of the procedure.

  
  
  
  
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  Bronchoscopy

  
  
  
  
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    More useful in lesions that are large, central, or have endobronchial component.

    
    
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    However, fiberoptic bronchoscopy has not been shown to be beneficial in most patients with an SPN because diagnostic yield with lesions that are small in size or peripheral in location, is poor. Newer techniques such as navigational bronchoscopy have excellent yields (see chapter 4 on diagnostic bronchoscopy).

  
  
  
  
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  Video-assisted thoracic surgery (VATS)

  
  
  
  
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    Useful for small indeterminate peripheral pulmonary nodules that are difficult to biopsy or have negative biopsy by transthoracic needle aspiration or bronchoscopy.

    
    
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    Preferred over open biopsy due to less pain, shorter hospital stays, and faster recovery.

    
    
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    Performed under general anesthesia using single lung ventilation via a double-lumen endotracheal tube

    
    
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    A recent study demonstrated a 100% success rate in obtaining a tissue diagnosis. Asymptomatic pneumothorax was observed in one case and minor intrapulmonary hemorrhage in 2 cases out of a total of 57 cases.

    
    
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    Preoperative CT-guided localization of the pulmonary nodule with hookwire or microcoil is safe, time-saving, and helpful in preventing the need to convert to thoracotomy.

  
  
  
  
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  Open-lung biopsy or excision

  
  
  
  
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    Overall morbidity is 3% to 7%.

    
    
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    For smaller and more central lesions difficult to biopsy by VATS.