Differentials
Small cell lung cancer
SIGNS / SYMPTOMS
Typical features include cough, hemoptysis, chest pain, dyspnea, and hoarseness (if recurrent laryngeal nerve paralysis). Frequently ill-looking, short of breath, with signs of recent weight loss.
Finger clubbing and hypertrophic osteoarthropathy may be present but is less common in small cell lung cancer compared with NSCLC.
Usually wheezing from underlying COPD or bronchial obstruction, rales due to postobstructive pneumonia or atelectasis, or diminished breath sounds from bronchial obstruction are present unless early disease.
Facial and upper extremity swelling, distended neck veins, and dilated collateral vessels may indicate compression of the superior vena cava.
Features related to distant metastases (e.g., bone pain and/or pathologic fractures from bony metastases; confusion, personality change, seizures, weakness, focal neurologic deficits, nausea and vomiting, and headaches from brain metastases).
INVESTIGATIONS
CT chest often shows massive lymphadenopathy and direct mediastinal invasion, common features of small cell lung cancer.
Sputum cytology is a noninvasive and relatively simple diagnostic method with high specificity but low sensitivity, and the cost may outweigh the usefulness in terms of patient management.
Flexible bronchoscopy plus biopsy provides pathologic confirmation of diagnosis. Endobronchial masses can be biopsied with forceps. Endobronchial brushings, washings, and alveolar lavage increase the diagnostic yield. Transbronchial needle aspiration biopsy of accessible parenchymal lesions and mediastinal lymph nodes is now possible. Detection of small peripheral lesions (<2 cm) is improved by use of endobronchial ultrasound.
Metastatic cancer
SIGNS / SYMPTOMS
Symptoms will relate to the site of the primary tumor and there may be general symptoms of pain, weight loss, malaise, cough, dyspnea, clubbing, and focal wheezing. Physical findings may or may not be present depending on nature and stage of tumor.
INVESTIGATIONS
CT chest shows one or multiple nodules of variable sizes, from diffuse micronodular shadows (miliary) to well-defined masses. Often irregular and often in the periphery of the lower lung zones.
Sputum cytology may reveal characteristic malignant cells. Yield is higher with large endobronchial lesions or large masses.
CT/MRI head, 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 testicle.
PET-FDG scan shows increased uptake in nodules and at primary site. In metastatic disease, PET scan aids in the identification of the primary site and allows for appropriate staging whenever malignancy is confirmed. Certain metastatic lesions have a lower probability of 18-fluorodeoxyglucose (FDG) uptake, such as renal cell carcinoma.
Flexible bronchoscopy and biopsy shows characteristic malignant cells. Bronchoscopy has a 100% yield for endobronchial lesions.
CT-guided transthoracic needle aspiration (TTNA) can reveal characteristic malignant cells in some lesions inaccessible to flexible bronchoscopy. Pneumothorax complicates 20% to 30% of procedures. The choice between bronchoscopy and TTNA is based on lesion size, location, risks, and local expertise.
Pneumonia/bronchitis
SIGNS / SYMPTOMS
Clinical and radiologic features of bronchitis or pneumonia should improve with appropriate treatment.
Recurrent pneumonia or bronchitis in a smoker or former smoker should raise the suspicion of lung cancer.
INVESTIGATIONS
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 biopsy suspicious pulmonary masses.
Organizing pneumonia (cryoptogenic organizing pneumonia or bronchiolitis obliterans organizing pneumonia)
SIGNS / SYMPTOMS
Normally presents as an influenza-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 crepitations. 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.
Actinomycosis
SIGNS / SYMPTOMS
Initially nonproductive cough, and later, fever and features of sepsis; hemoptysis and chest wall pain due to direct involvement
INVESTIGATIONS
CT may show cancer-like appearances as this infection crosses tissue planes. Culture of tissue or secretions reveals gram-positive cocci identified as Actinomyces spp.
Nocardiosis
SIGNS / SYMPTOMS
Initially nonproductive cough, and later, fever and features of sepsis; hemoptysis and chest wall pain due to direct involvement; nocardiosis confined to immunocompromised host
INVESTIGATIONS
CT may show cancer-like appearances as this infection crosses tissue planes. Culture of tissue or secretions reveals gram-positive cocci identified as Nocardia.
Pulmonary tuberculosis
SIGNS / SYMPTOMS
Cough longer than 2 to 3 weeks, discolored or bloody sputum, night sweats and 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., M kansasii and M avium), may be positive for AFB stain.
The Mantoux test and Interferon Gamma Release Assay (IGRA) can be used as supportive evidence for tuberculosis (either active or latent). Nucleic acid amplification tests (NAAT) positive for M 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 mycobacterium 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.
Sarcoidosis
SIGNS / SYMPTOMS
Cough, dyspnea, fatigue, weight loss, fever, night sweats, rash, eye pain, photophobia, blurred vision, red eye. Pulmonary examination 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: adenopathy often present with sarcoid. Sarcoid nodules have predilection for upper zones, though can be located throughout the lung.
Flexible bronchoscopy and biopsy reveals 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 although sometimes useful in monitoring activity of the disease.
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. 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 with active disease.
INVESTIGATIONS
CT chest typically shows lesions <2 cm diameter with round, smooth borders. May have central, laminated, or diffuse calcification patterns if lesions are old. Sometimes mediastinal lymphadenopathy with or without lymph node calcifications. Angioinvasive fungi (e.g., Aspergillus, Pseudallescheria boydii, Fusarium spp. and zygomycetes) can be seen as nodules with "halo sign" or ground-glass opacity surrounding a 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 provide samples for identification and culture and sensitivity of organism.
CT-guided transthoracic needle aspiration (TTNA) can provide biopsy from some lesions inaccessible to flexible bronchoscopy. Pneumothorax complicates 20% to 30% of procedures. The choice between bronchoscopy and TTNA is based on lesion size, location, risks, and local expertise.
PET-FDG scan: usually negative (<2.5 standardized uptake values). May be falsely positive in active infectious processes.
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 claudication, calf and limb claudication, and rarely angina. Amyloid purpura is present in around 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.
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 midlung zones. May show cavitation.[99]
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 present as a central zone of eosinophilic fibrinoid necrosis surrounded by palisading fibroblasts, the nodule often being 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 shows presence of necrotizing granulomatous inflammation. The identification of granulomas on tissue obtained by bronchoscopy or transthoracic needle aspiration (TTNA) should be performed by a pathologist and stained for infectious agents before assuming a noninfectious cause.
CT-guided TTNA can provide access to some lesions inaccessible to flexible bronchoscopy.
Laboratory markers: antineutrophil cytoplasmic antibody (ANCA) detected. ANCA testing results depends on the extent and severity of the disease. Generalized granulomatosis with polyangiitis has >90% C-ANCA or PR-3 positive. Limited granulomatosis with polyangiitis has 60% ANCA positive.
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.
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.
Carcinoid tumor
SIGNS / SYMPTOMS
Often asymptomatic with normal physical examination. May cause cough, dyspnea, hemoptysis, unilateral wheezing, or postobstructive pneumonia if tumor is endobronchial.
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, pinkish, vascular, lobulated lesions. Presence of malignant cells is diagnostic. Endobronchial forceps biopsy is usually required; bronchial brushings, sputum specimens, and lavage fluid rarely provide sufficient tissue for a conclusive diagnosis.
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 lump on anterior aspect of 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 thyroxine, free triiodothyronine.
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.
Hamartoma
SIGNS / SYMPTOMS
Usually asymptomatic with no physical findings. About 1% to 20% of lesions can be endobronchial and can cause dyspnea, wheezing, or recurrent infections, secondary to airway obstruction.
INVESTIGATIONS
CT chest shows well-demarcated peripheral nodule, average diameter of 1.5 cm with heterogeneous appearance due to its content of mesenchymal tissue. Fat attenuation is common, with or without calcification. "Popcorn" calcifications can occur in 20% of cases. Imaging findings classic enough to be considered diagnostic.
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. Neurologic symptoms from cerebral aneurysms, cerebral emboli.
INVESTIGATIONS
CT chest shows round or oval nodule(s) with feeding artery and draining vein often identified. Most common in lower lobes. Multiple lesions in 30% of cases. Usually round or oval, ranging in size from 1 cm to several cm in diameter.
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 AV flow is severe. In cases of severe systemic AVMs, the chronic hypoxemia may cause polycythemia.
Bronchogenic cyst
SIGNS / SYMPTOMS
Usually diagnosed in infancy and childhood, although 50% 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 cyst is infected or contains secretions.
CT chest: frequently middle mediastinum, typically at 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 level of the mediastinum. On T2-weighted images, shows as a homogeneous mass of moderate to bright intensity. On T1-weighted images, lesions may vary in their intensity depending on protein content of the cyst.
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 airways 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. Around 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 may be of value in determining malignancy and extramediastinal involvement.
Preoperative biopsy is indicated if there are atypical features or imaging suggests invasive tumor and patient is under consideration for induction therapy.
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 and 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.
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