Differentials
Non-small cell lung cancer
SIGNS / SYMPTOMS
Most signs and symptoms are similar to SCLC. Typical features include cough, hemoptysis, chest pain, dyspnea, and hoarseness (if recurrent laryngeal nerve paralysis). Weight loss, shortness of breath, and malaise are other potential presenting symptoms.
Finger clubbing and hypertrophic osteoarthropathy may be present and are more common in non-small cell lung cancer compared with SCLC.
INVESTIGATIONS
CT chest shows size, location, and extent of primary tumor; evaluates for hilar and/or mediastinal lymphadenopathy and distant metastases
Sputum cytology shows characteristic malignant cells. Specificity greater than 95%, sensitivity variable between 20% and 70%. More likely to be positive with central lesions compared with peripheral lesions.
Pathologic sampling for diagnosis may be performed via CT-guided biopsy or bronchoscopy with transbronchial biopsy (with or without endobronchial ultrasound). Endobronchial brushings, washings, and alveolar lavage may also yield informative material.
Pneumonia/bronchitis
SIGNS / SYMPTOMS
Typical symptoms include fever, cough, dyspnea, and chest pain.
Recurrent pneumonia or bronchitis in a smoker or former smoker should raise the suspicion of lung cancer.
INVESTIGATIONS
CXR is the first test performed. CT imaging can be helpful to evaluate pulmonary masses that might not be well visualized with chest x-ray.
Bronchoscopy can also be used to assess for endobronchial lesions or to biopsy suspicious pulmonary masses.
Carcinoid tumor
SIGNS / SYMPTOMS
Often asymptomatic with normal physical exam. May cause cough, dyspnea, hemoptysis, unilateral wheezing, or postobstructive pneumonia if tumor is endobronchial or compressing central bronchi.
INVESTIGATIONS
CT chest: 80% of carcinoid tumors appear as an endobronchial nodule and 20% as a parenchymal nodule, with smooth, rounded borders and highly vascularized.
Flexible bronchoscopy shows raised, pink, vascular, lobulated lesions. Endobronchial forceps biopsy is usually required for pathology to be diagnostic; bronchial brushings, sputum specimens, and lavage fluid rarely provide sufficient tissue for a conclusive diagnosis.
Metastatic cancer from a nonthoracic primary site
SIGNS / SYMPTOMS
Signs and symptoms depend on the location of the primary tumor and distant disease and may include pain, weight loss, malaise, cough, dyspnea, clubbing, or focal wheezing. Physical findings may be present depending on the location and extent of the disease.
INVESTIGATIONS
CT chest shows one or multiple nodules of variable sizes from diffuse micronodular opacities (miliary) to well-defined masses. Lesions are often irregular and in the periphery of the lower lung zones.
CT/MRI head, CT abdomen and pelvis: extrapulmonary cancers that commonly metastasize to the lung include melanoma; thyroid carcinoma; esophageal cancer; ovarian cancer; sarcomas; and adenocarcinomas of the colon, breast, kidney, and testis.
PET-fluorodeoxyglucose (FDG) scan shows increased uptake in both primary and distant sites. Certain metastatic lesions, such as renal cell carcinoma, have a lower probability of 18-FDG uptake.
CT-guided transthoracic needle aspiration (TTNA) can reveal characteristic malignant cells. Pneumothorax complicates 20% to 30% of TTNA procedures. The choice between bronchoscopy and TTNA is based on lesion size, location, risks, and local expertise.
Biopsy during flexible bronchoscopy and biopsy may show characteristic malignant cells. Bronchoscopy has a 100% yield for endobronchial lesions (which are extremely rare in metastatic deposits from other primary tumors).
Infectious granuloma
SIGNS / SYMPTOMS
History may include travel to endemic areas, pet/animal exposures, and specific leisure activities (e.g., caving).
May feature cough, dyspnea, hemoptysis, weight loss, fever, joint aches, skin lesions, and night sweats, or no symptoms. Many possible causes: Histoplasma capsulatum, Mycobacterium tuberculosis, Coccidioides immitis, Cryptococcus neoformans, Aspergillus, Pseudallescheria boydii, Fusarium spp, zygomycetes, and others.
Nonspecific skin findings may be seen in atypical mycobacteria and cryptococcosis. Lymphadenopathy may be present with active disease.
INVESTIGATIONS
CT-guided transthoracic needle aspiration (TTNA) can be used for diagnostic sampling. Pneumothorax complicates 20% to 30% of TTNA procedures. The choice between bronchoscopy and TTNA is based on lesion size, location, risks, and local expertise.
CT chest typically shows lesions <2 cm diameter and round with smooth borders. Old granulomatous disease may feature central, laminated, or diffuse calcification patterns. Mediastinal lymphadenopathy without calcifications is sometimes present. Nodules from angioinvasive fungi (e.g., Aspergillus, Pseudallescheria boydii, Fusarium species, and zygomycetes) may demonstrate the "halo sign" (ground-glass opacity surrounding the nodule). Occasionally, calcifications can be seen in the spleen or liver.
Fungal serologies: positive during active infection. The exact role of fungal serologies in assessing lung nodules is unclear. However, they provide valuable evidence of exposure to histoplasmosis, cryptococcosis, aspergillosis, coccidioidomycosis, and mucormycosis.
Flexible bronchoscopy and biopsy can sometimes provide samples for identification and culture and sensitivity of the organism.
PET: usually negative (<2.5 standardized uptake values). May be positive in active infectious processes.
Sarcoidosis
SIGNS / SYMPTOMS
Cough, dyspnea, fatigue, weight loss, fever, night sweats, rash, eye pain, photophobia, blurred vision, and red eye. Pulmonary exam is usually unrevealing. Can affect any organ, so physical findings depend on specific organs affected. Skin lesions including maculopapular eruptions, subcutaneous nodular lesions, and red-purple skin lesions.
INVESTIGATIONS
CT chest: mediastinal adenopathy often present with sarcoid. Sarcoid nodules have predilection for upper zones, though can be located throughout the lung.
Flexible bronchoscopy and biopsy can demonstrate presence of noncaseating granulomas. The identification of granulomas on tissue obtained by bronchoscopy should be performed by a pathologist and stained for infectious agents before assuming a noninfectious cause.
CT-guided transthoracic needle aspiration (TTNA) can provide access to material from some lesions inaccessible to flexible bronchoscopy. The identification of granulomas on tissue obtained by TTNA should be performed by a pathologist and stained for infectious agents before assuming a noninfectious cause.
Laboratory markers: ACE elevation may be seen in sarcoidosis but is nonspecific.
Rheumatoid arthritis
SIGNS / SYMPTOMS
Arthralgias, pain, skin nodules, pleural effusions, pleuritis, joint pain, and deformity.
INVESTIGATIONS
CT chest typically shows lung nodule 3 mm to 7 cm, predominantly in peripheral upper and mid-lung zones. May show cavitation.
Flexible bronchoscopy and biopsy shows rheumatoid necrobiotic nodule. The identification of granulomas on tissue obtained should be performed by a pathologist and stained for infectious agents before assuming a noninfectious cause. Necrobiotic nodules demonstrate a central zone of eosinophilic fibrinoid necrosis surrounded by palisading fibroblasts, the nodule often centered on necrotic inflamed blood vessels.
Laboratory markers: patients with lung nodules due to rheumatoid arthritis frequently have high levels of rheumatoid factor, although seronegative cases have been reported.
Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis)
SIGNS / SYMPTOMS
Cough, chest pain, dyspnea, hemoptysis, rhinorrhea, epistaxis, ear/sinus pain, hoarseness, fever, fatigue, anorexia, weight loss, palpable purpura, painful ulcers, uveitis, upper airway inflammation, and sinus pain.
INVESTIGATIONS
CT chest shows solitary or multiple lung nodules. Airways are frequently affected.
Flexible bronchoscopy or CT-guided transthoracic needle aspiration (TTNA) may show necrotizing granulomatous inflammation. The identification of granulomas on tissue obtained by bronchoscopy or TTNA should be performed by a pathologist and stained for infectious agents before assuming a noninfectious cause.
Laboratory markers: anti-neutrophil cytoplasmic antibody (ANCA). ANCA testing results depend on the extent and severity of the disease. Generalized granulomatosis with polyangiitis demonstrates >90% C-ANCA or PR-3 positivity. Limited granulomatosis with polyangiitis demonstrates 60% ANCA positivity.
Hamartoma
SIGNS / SYMPTOMS
Usually asymptomatic with no physical findings. About 1% to 20% of lesions are endobronchial and can cause dyspnea, wheezing, or recurrent infections, secondary to airway obstruction.
INVESTIGATIONS
CT chest shows well-demarcated peripheral nodule, with an average diameter of 1.5 cm and a heterogeneous appearance due to its content of mesenchymal tissue content. Fat attenuation is common, with or without calcification. "Popcorn" calcifications can occur in 20% of cases. Imaging findings are classic and considered diagnostic.
CT-guided transthoracic needle aspiration may be used for diagnostic sampling.
Arteriovenous malformation (AVM)
SIGNS / SYMPTOMS
Dyspnea is uncommon. May cause hemoptysis, pulmonary bruit, arteriovenous communications, or hemorrhagic telangiectasia in the skin, mucous membranes, and other organs. Cyanosis and finger clubbing may be present. Neurologic symptoms from cerebral aneurysms, cerebral emboli.
INVESTIGATIONS
CT chest shows round or oval nodule(s) ranging from 1 cm to several centimeters in diameter. Feeding artery and draining vein often identified. Most common in lower lobes. Multiple lesions in 30% of cases.
Pulmonary angiography confirms presence and location of AVMs, identifies feeding arterial and venous structures. In cases of significant hemoptysis, pulmonary angiogram is combined with bronchial artery embolization.
Arterial blood gas analysis may show decreased pO₂ and decreased oxygen saturation when arterial to venous flow is severe. In cases of severe systemic AVMs, chronic hypoxemia may cause polycythemia.
Amyloidosis
SIGNS / SYMPTOMS
Weight loss, paresthesias, dyspnea, and fatigue are the most common symptoms associated with amyloidosis and are common to all systemic forms.
Weight loss of >9 kg is common. Small vessel involvement can cause jaw or limb claudication, and rarely angina. Amyloid purpura is present in about 1 in 6 patients, typically periorbital. Eyelid petechiae are common. Hepatomegaly >5 cm below the right costal margin is seen in 10% of patients and splenomegaly is usually of modest degree.
INVESTIGATIONS
CT chest shows lung involvement characterized by focal pulmonary nodules, tracheobronchial lesions, or diffuse alveolar deposits.
Serum immunofixation shows presence of monoclonal protein; seen in 60% of patients with immunoglobulin light chain amyloidosis (AL).
Urine immunofixation shows presence of monoclonal protein; seen in 80% of patients with amyloidosis.
Immunoglobulin free light chain assay shows abnormal kappa to lambda ratio. This relatively new test has extremely high sensitivity, over 90%, for diagnosing amyloidosis.
Bronchiolitis obliterans organizing pneumonia
SIGNS / SYMPTOMS
Normally presents as a flu-like illness followed by a second illness lasting 1 to 4 months, with low-grade fever, nonproductive cough, malaise, dyspnea, and weight loss. Sometimes features pleuritic chest pain and hemoptysis.
In most patients, auscultation reveals fine, dry lung crackles. Finger clubbing is unusual.
INVESTIGATIONS
CT chest is preferable to plain chest x-ray as it gives a better assessment of the disease pattern and distribution, and potential sites for biopsy. Typical features include: patchy "ground-glass" opacities in a subpleural and/or peribronchovascular distribution; thickening of bronchial walls and cylindrical dilation; 3 to 5 mm diameter centrilobular nodules or other ill-defined nodules; mediastinal lymphadenopathy, pleural effusions.
Pulmonary function tests typically show a restrictive pattern.
Bronchoalveolar lavage (BAL) shows a mixed cell pattern, with an increase in lymphocytes, neutrophils, eosinophils, mast cells, foamy macrophages, and occasional plasma cells. CD4+/CD8+ cell ratio is decreased. Also, the ratio of lymphocytes to CD8+ cells is significantly increased.
Transbronchial lung biopsy, in combination with BAL, can be a useful approach, prior to possible open biopsy.
Open lung biopsy is often required for definitive diagnosis.
Pulmonary tuberculosis
SIGNS / SYMPTOMS
Cough longer than 2 to 3 weeks, discolored or bloody sputum, night sweats, weight loss, loss of appetite, pleuritic chest pain.
INVESTIGATIONS
Chest x-ray: primary disease commonly presents as middle and lower lung zone infiltrates. Ipsilateral adenopathy, atelectasis from airway compression, and pleural effusion can be seen. Reactivation-type (post-primary) pulmonary tuberculosis usually involves apical and/or posterior segment of right upper lobe, apicoposterior segment of left upper lobe, or superior segment of either lower lobe, with or without cavitation. As disease progresses it spreads to other segments/lobes.
Sputum smear: positive for acid-fast bacilli (AFB). Sputum may be spontaneously expectorated or induced, and at least 3 specimens should be collected (minimum 8 hours apart, including an early morning specimen, which is the best way to detect Mycobacterium tuberculosis). Organisms other than M tuberculosis, especially nontuberculous mycobacteria (e.g., Mycobacterium kansasii and Mycobacterium avium), may be positive for AFB stain.
Nucleic acid amplification tests (NAAT): positive forM tuberculosis. DNA or RNA amplification tests for rapid diagnosis. May be used on sputum or any sterile body fluid. Several commercial tests are available. Results available in less than 8 hours in the laboratory. Useful in smear-positive disease to confirm that observed mycobacteria are M tuberculosis (95% sensitivity, 99% specificity) and in smear-negative disease for rapid diagnosis (50% sensitivity, 95% specificity). In suspected smear-negative cases, a moderate to high pretest probability should guide the decision to use NAAT.
Germ cell tumor
SIGNS / SYMPTOMS
Occur mostly in men ages 20 to 40 years. About one third of patients are asymptomatic. Symptoms are related to the size of the lesion. May cause chest pain, breathing problems, cough, fever, headache, and fatigue.
INVESTIGATIONS
CT chest: germ cell tumors account for about 10% to 15% of mediastinal tumors in adults and 25% of such tumors in children. Frequently located in anterior mediastinum. CT can determine if mass is cystic or solid and whether it contains calcium or fat. Contrast enhancement provides information concerning vascularization of the mass and relationship to adjacent structures. Seminomas appear as large, well-marginated, homogeneous, anterior mediastinal mass with soft-tissue opacity or attenuation that shows minimal contrast enhancement.
Serum tumor marker tests: alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (beta-hCG), lactate dehydrogenase (LDH). beta-hCG levels are elevated in 7% to 18% of patients. AFP levels are usually normal.
Non-Hodgkin lymphoma
SIGNS / SYMPTOMS
Aggressive non-Hodgkin lymphoma (NHL) may present with fever, drenching night sweats, malaise, weight loss, cough, shortness of breath, abdominal discomfort, headache, change in mental status, dizziness, ataxia, pleural effusion, lymphadenopathy, pallor, purpura, jaundice, hepatomegaly, splenomegaly, skin nodules, and abnormal neurologic exam. Low-grade NHL patients often minimally symptomatic or asymptomatic.
INVESTIGATIONS
CT chest: frequently anterior mediastinum. Can determine if mass is cystic or solid and whether it contains calcium or fat. Contrast enhancement provides information concerning vascularization of the mass and relationship to adjacent structures.
CBC with differential: shows thrombocytopenia, pancytopenia.
Blood smear: shows nucleated red blood cells, giant platelets.
Lymph node biopsy with immunohistochemistry: shows characteristic cells. Preferably obtain excisional or core biopsy to provide information on lymph node architecture.
Mediastinoscopy: used to sample mediastinal nodes.
Hodgkin lymphoma
SIGNS / SYMPTOMS
Predominantly a disease of young adults. Most patients present with a several-month history of persistent adenopathy, most commonly of the cervical chain.
INVESTIGATIONS
Plain chest x-ray: typically shows mediastinal mass/large mediastinal adenopathy.
PET scan: involved sites appear fluorodeoxyglucose (FDG)-avid (bright) with PET imaging. Sensitivity reported to be 93% and specificity 87%.
Lymph node biopsy with immunohistochemistry: the Hodgkin cell can be a characteristic Reed-Sternberg cell, or one of its variants, such as the lacunar cell in the nodular sclerosis subtype; in nodular lymphocyte-predominant Hodgkin lymphoma, the characteristic cell is the lymphocytic and histiocytic (L&H) cell, also referred to as a popcorn cell.
Thymoma/thymic carcinoma
SIGNS / SYMPTOMS
Approximately 30% of patients with thymoma are asymptomatic at the time of diagnosis. May also present with cough, chest pain, signs of upper airway congestion, superior vena cava syndrome, dysphagia, or hoarseness. May have features of paraneoplastic syndromes associated with thymoma including myasthenia gravis, polymyositis, lupus erythematosus, rheumatoid arthritis, thyroiditis, and Sjogren syndrome. About 30% of patients have symptoms suggestive of myasthenia gravis (e.g., ptosis, double vision).
INVESTIGATIONS
Plain chest x-ray: in 50% of the patients, thymomas are detected by chance with plain-film chest radiography.
CT chest: 90% occur in anterior mediastinum. CT is usually accurate in predicting tumor size; location; and invasion into vessels, the pericardium, and the lung. However, it cannot accurately predict invasion or resectability.
PET scan: may be of value in determining malignancy and extramediastinal involvement.
Preoperative biopsy: indicated if there are atypical features or if imaging suggests invasive tumor and patient is under consideration for induction therapy.
Bronchogenic cyst
SIGNS / SYMPTOMS
Usually diagnosed in infancy and childhood, although 50% are diagnosed after 15 years of age. Approximately 50% of patients are asymptomatic. In adults, chest pain (often pleuritic) and dysphagia (due to esophageal compression) are the most common symptoms. May also feature recurrent cough and chest infection/pneumonia, superior vena cava syndrome, tracheal compression, and pneumothorax.
INVESTIGATIONS
2-view chest radiography: typically shows a sharply demarcated spherical mass of variable size, most commonly located in the middle mediastinum around the carina. Can appear as a solid tumor or show air-fluid level if the cyst is infected or contains secretions.
CT chest: frequently middle mediastinum, typically at the level of the mediastinum. Cysts are thin-walled with smooth borders and may contain secretions, blood, or pus. Calcifications may also be seen.
MRI: frequently middle mediastinum, typically at the level of the mediastinum. T2-weighted images show a homogeneous mass of moderate-to-bright intensity. On T1-weighted images, lesions may vary in intensity depending on protein content of the cyst.
Tracheal tumors
SIGNS / SYMPTOMS
Common symptoms include dyspnea, cough, hemoptysis, wheeze, and stridor. Less commonly, hoarseness and dysphagia may be present.
INVESTIGATIONS
Plain chest radiographs are generally insensitive for detection of tracheal tumors. Clues that may indicate the presence of a tracheal tumor include abnormal calcification, tracheal narrowing, and postobstructive pneumonia or atelectasis.
Helical CT enables accurate calculation of tumor volumes and can help differentiate mucosal lesions from submucosal lesions.
MRI can be useful in assessing extension into surrounding tissue and vascular anatomy.
Bronchoscopy allows direct visualization, opportunity for biopsy, and potential for laser treatment.
Thyroid mass
SIGNS / SYMPTOMS
Symptoms and signs depend on size of mass. May be visible/palpable as a lump on the anterior aspect of the neck. May present with dysphagia, hoarseness, difficulty breathing, and pain in neck or throat. May also be signs and symptoms of hyper- or hypothyroidism depending on the nature of the mass.
INVESTIGATIONS
Laboratory testing should include thyroid function panel, with thyroid-stimulating hormone, free T4, free T3.
I-123 thyroid scan is ordered for patients with overt or subclinical hyperthyroidism. A hyperfunctioning (hot) nodule is almost always benign. Most nodules are hypofunctioning (cold). Most of these are benign, but malignant nodules are also cold.
Ultrasound and Doppler can be used to define dimensions of thyroid nodules and solid/cystic component(s). Features suspicious of malignancy include microcalcifications, a more tall-than-wide shape, hypervascularity, marked hypoechogenicity, or irregular margins. It can also guide fine needle aspiration, which can reveal malignant cells or cyst fluid.
CT neck can evaluate cervical lymph nodes in cases of medullary thyroid cancer, and extension of the scan into the chest can help evaluate a retrosternal thyroid mass.
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