imaging of pulmonary nodules - healthcare professionals

Imaging of Pulmonary Nodules

Bradley R. Trotter, MD, DABR, DABNM

Department of Radiology

[email protected]

B R Trotter, MD Scott & White Healthcare

Imaging of Pulmonary Nodules:Overview

• Background: From Nodules to Lung Cancer

• Review of Imaging Modalities: Tools of theTrade

• Review of Imaging Features: “To benign ornot to benign, that is the question.”

• Likelihood of Malignancy: “… damned lies,and statistics”

• Recommendations: Putting it together


Background: From Nodules toLung Cancer


Background: Pulmonary Nodules

• “A round opacity, at least moderately wellmarginated, and no greater than 3 cm inmaximum diameter”

• “Round” meaning roughly circular or ovalshaped but also “spherical” in its 3-dimensional nature (not flat or plaque-like)

• Completely surrounded by lung parenchymaand not associated with adenopathy,atelectasis, or pneumonia



• May be solitary (SPN) or multiple, whichaffects likelihood of various differentialdiagnostic considerations

• When multiple, imaging features of eachnodule identified must be considered , inaddition to consideration as a whole

• Although our discussion primarily relates tosolitary (or clearly dominant) pulmonarynodules, also useful in the setting of multiple



• Very common imaging finding, particularlysince advent of helical and multidetector CT

• Studies report prevalence of one or morenodules from 8% to 69% on CT

• Vast majority are benign (95%-98% in moststudies)



• Idealistic goals of imaging:

– Definitively identify all malignant nodules, andthereby beneficially affect patient outcomes

– Definitively identify all benign nodules, andthereby avoid the morbidity and cost of invasiveprocedures or further imaging that provide notrue benefit

• Disappointingly, this remains elusive despiteextensive experience and research



• Realistic goal of imaging of pulmonarynodules:

– Determine which are benign and need no furtherevaluation

– Determine which are suspicious for malignancyand refer for definitive resolution

– For nodules that remain indeterminate:

• Determine which require biopsy

• Determine which require follow-up


Background: Lung Cancer

• Our discussion of pulmonary nodulesultimately falls within the context of lungcancer, which directly influences ourmanagement decisions regarding nodules

• A few points are worth noting for ourdiscussion …



• It is, overall, an aggressive disease:

– “More people in the United States die from lungcancer than from any other type of cancer. This istrue for both men and women.”

– In the United States in 2008:

• 208,493 diagnosed with lung cancer

• 158,592 died from lung cancer

• Although, incidence and death has more recently beendeclining following a trend of decreasing smoking



• It is a costly disease:

– Estimated impact on U. S. economy is over $300billion annually

– Management decisions should includeconsideration of cost effectiveness that is, asmuch as possible, based on proven clinicaloutcomes research



• There are known risk factors:

– Smoking:

• Accounts for 90% of lung cancers in the U. S.

• 15x to 30x more likely to develop or die from lungcancer than nonsmokers

• Risk increases with degree and duration (pack years)

• Currently estimated 94 million current or formersmokers in the U. S. at increased risk



• Other known risk factors include:– Second hand smoke

– Asbestos, radon, or uranium exposure

– Radiation therapy to the thorax, such as withlymphoma or breast cancer

– Family history of lung cancer in 1st degree relative

– Age: risk increases with age; rare under age 35

– Chronic lung diseases

– Personal history of prior lung cancer



• It is a heterogeneous disease:

– Non-small cell lung cancer (NSCLC)

• 80%-85% of lung cancer

• Squamous cell, Adenocarcinoma, Large-cell, other

• 5 year survival 50%-70% stage IA to 2% stage IV

• Can be detected at earlier stages with CT (NLST: 30%-75% stage 1A depending on type of NSCLC)

• Role of screening with CT to detect at earlier stage?

• The primary focus when discussing imaging ofpulmonary nodules



• It is a heterogeneous disease:

– SCLC

• 15%-20% of lung cancers

• 5 year survival 20% limited-stage to <1% extensive-stage

• Unlikely detection when limited-stage due to itsaggressive nature

• Screening with CT less likely to impact outcome (NLST:86% stage III-IV)


Review of Imaging Modalities:Tools of the Trade


Review of Imaging Modalities:Pulmonary Nodules

• Chest radiograph (CXR)

• Computed Tomography (CT)

• Positron Emission Tomography (PET)

• PET-CT (no, it’s not the same thing)

• (Flouroscopy, MRI, US)


Review of Imaging Modalities:Chest Radiograph

• Low cost

• Low radiation exposure

• Low utility as primary imaging modality ofpulmonary nodules

• No utility for lung cancer screening


Review of Imaging Modalities:Chest Radiograph

• However, CXR is a common entry point intothe evaluation of pulmonary nodules whendetected incidentally

• Prevalence of nodules on CXR is about 0.2% to9% depending on population


Review of Imaging Modalities:Computed Tomography

• Tomographs (slices) eliminate the problem ofsuperimposed structures on radiographs

• Volumetric data acquisition on modern scannersallows slice reconstruction in any plane

• Highly sensitive for detection of pulmonarynodules as small as 1-2 mm

• Unfortunately limited specificity

• Can be performed with or without IV contrastenhancement



• High spatial and contrast resolution allowdetermination of important morphologicfeatures of nodules

• Thin-sections (1-3 mm slice thickness) shouldbe utilized for evaluation of nodulemorphology (IV contrast unnecessary)



• IV contrast-enhanced densitometry can beperformed to assess nodule enhancementcharacteristics

• More accurate determination of importantancillary findings: adenopathy, bronchialinvolvement, pleural involvement, etc.

• Low-dose (radiation) imaging may be used forany needed follow-up exams (or screening)


Review of Imaging Modalities:Positron Emission Tomography

• IV administration of 18F-fluorodeoxyglucose(FDG)

• Degree of tissue uptake reflects its relativemetabolic activity (glucose)

• Many malignancies demonstrate significantlygreater uptake of FDG compared with normaltissues and appear “hot” on PET images

• >90% sensitivity for nodules 1-3 cm; lowerspecificity is about 80%


Review of Imaging Modalities:PET-CT

• It’s like Reese’s Peanut Butter Cups

• It’s a PET scan with an anatomic contrastagent

• It’s a CT scan with a metabolic contrast agent

• Either way, combines benefits of bothmodalities with higher sensitivity andspecificity than for either PET or CT alone

• Reimbursement? (CMS <4 cm; confirm local)


Review of Imaging Modalities:Other

• Flouroscopy:

– Biopsy guidance

– Can be used as an inexpensive problem solving tool

• MRI has little role in imaging of pulmonarynodules but has utility in the evaluation ofthoracic malignancies

• Ultrasound has little role in imaging of pulmonarynodules although may occasionally be used forbiopsy localization


Review of Imaging Features:“To benign or not to benign,

that is the question.”


Review of Imaging Features:“To benign or not to benign …”

While there are a few imaging features thatallow for a confidant diagnosis of a benignpulmonary nodule, there are none that arediagnostic of malignancy


Review of Imaging Features:Benign

• Benign pattern of calcification

• Stability of size

• Presence of fat

• (Keep in mind the definition of a pulmonarynodule)



• Benign patterns of calcification in a smoothlymarginated nodule (or smoothly lobulated ifhamartoma):

– Diffuse (granuloma)

– Central (granuloma)

– Laminated or concentric (granuloma)

– Popcorn (hamartoma)



• Any other pattern of calcification isindeterminate

• “Caveat”: patients with history of bonemalignancy may have calcified nodules thatresemble benign granulomas



• Stability of size:– Comparison with older exams is essential in

evaluation of pulmonary nodules (retrospect?)

– 2 years of stability widely accepted as consistentwith benign etiology and standard of care

– 2 years based on studies of volume doubling-timeof benign and malignant lesions:

• 30-480 days typical of malignant nodules

• Median about 160-180 days for malignant nodules

• However, reported range is actually quite broad



• CT 2004 • CT 2012



• Stability of size:

– Caveat: non-solid (ground-glass opacity) nodulesthat are malignant are more likely to havesignificantly longer doubling times and should befollowed longer (3+ years)

– Measurement accuracy is critical

– For “spherical” structures, diameter increase ofonly 26% is a doubling of volume: Equates tomere 1 mm diameter increase for a 4mm nodule!




– Especially for smaller nodules, visual comparisonhas been shown inaccurate, and physicalmeasurement should be performed

– Measurement most accurate on soft-copy imageswith electronic calipers

– Any enlargement compared with baselinemeasurement considered suspicious and shouldprompt further evaluation




– Automated volumetric analysis software haspromise to allow for more precise determinationof nodule growth

– Caution: cancers may occasionally demonstratetemporary decrease of overall size—a single studydemonstrating decrease of size may not beadequate to confirm a benign etiology



• Presence of fat:– Within a smooth or smoothly lobulated SPN

essentially diagnostic of hamartoma

– Present in approximately 60%

• Caution: be certain the lesion contains fat asartifact from volume averaging may mimic

• “Caveat”: metastases from liposarcoma andrenal cell carcinoma may occasionally containfat


Review of Imaging Features:Probably Benign

• Other probably benign imaging findings:

– FDG PET standardized uptake value (SUV)<2.5

– Clustered nodules

– Very small size (<4 mm <<1%)

– Concave margins

• Follow-up CT imaging


Review of Imaging Features:Mimics

• Additional benign pulmonary imaging findingsmay mimic a nodule (experience…or cojones):– Arteriovenous malformation—feeding and

draining vessels

– Mucocele—tubular branching mucus filled dilatedbronchi

– Rounded atelectasis—comet tail appearance andassociated with pleural thickening

– Flat lesions—scarring that may be appreciatedwith multiplanar imaging



• Rounded atelectasis • Flat lesion/scar



• Mucocele • Mucocele


Review of Imaging Features:Suspicious for Malignancy

• Larger size: as size approaches 3 cm,likelihood of malignancy approaches 90%

• Spiculated margin: approximately 90%predictive value for cancer

• Lobulated margin more suspicious thansmooth



• Non-solid attenuation or ground-glass opacity(GGO) in part or entirety:

– 34%-43% of GGO nodules cancer

– 40%-50% of partial-solid nodules <1.5 cm cancerand increases further with increasing size

• Cavitation with thick walls:

– 84%-95% cancer if wall thickness >16 mm

– 95% benign when wall thickness <4 mm



• Air containing: air bronchograms, airbronchiolograms, and air filled cystic spacesoccur more commonly in malignant thanbenign nodules

• Upper lobe location: 70% of cancers in upperlobes; also 1.5x more likely in right lung

• These findings prompt further evaluation…


Review of Imaging Features:Further Evaluation

• FDG PET-CT

– Usable for nodules >8-10 mm diameter

– Because volume averaging from motion canartificially decrease apparent FDG activity, may beless useful for nodules located near diaphragm orheart, especially if small



• FDG PET-CT

– Much more reliable for solid than GGO nodules:

• >90% sensitivity for cancer in solid nodules (withexception of carcinoid tumor—probably 50%)

• Probably <50% sensitive for purely GGO cancers such asadenocarcinoma in situ (formerly BAC)

– Result determined by degree of activity in nodulerelative to other body structures:

• Subjective visual evaluation

• Quantitative evaluation (SUV 2.5)



• Solid nodule • GGO nodule



• FDG PET-CT

– Excellent test when used appropriately butprobably a tendency for overutilization

– Questions to consider:

• Is it uncertain whether to simply watch and wait or toproceed with biopsy/resection? If yes then…

• Will the PET result determine whether or not toproceed with biopsy/resection? If yes then…

• Proceed with PET imaging



• FDG PET-CT

– Most useful and cost effective when:

• Low to moderate (5%-60%) pre-test probability ofmalignancy

• Clinical risk assessment and nodule morphologiccharacteristics are discordant

• Indeterminate nodule in a high risk patient

– May be useful in other situations but can be anunnecessary and added expense—be judicious



• FDG PET-CT

– If very low (<5%) likelihood of malignancy, PET isnot needed to justify observation (watch and wait)with follow-up CTs

– If high (>60%) likelihood of malignancy, PET is notneeded to justify biopsy/resection

– Important: All PET negative nodules should beobserved with follow-up CTs to confirm stabilityfor at least 2 years: If grow, biopsy



• Contrast Enhanced CT Densitometry:

– Usable for nodules at least 10 mm diameterwithout cavitation or central necrosis

– Compare baseline unenhanced attenuation withpeak contrast-enhanced attenuation

– <15 Hounsfield units (HU) enhancement isessentially diagnostic of benign etiology (99%)

– >15 HU is nonspecific

– “Ask your doctor if this test is right for you…”


Likelihood of Malignancy:“…damned lies, and statistics”


Likelihood of Malignancy

• Determining the statistical probability ofmalignancy for a given nodule is essential toproper management, including decisionsregarding imaging studies

– Qualitatively by an experienced clinician—there isprobably a tendency to overestimate theprobability of malignancy in low risk patients

– Quantitatively with mathematical model


Likelihood of Malignancy:Logistic Regression Model

• Mayo clinic study using multiple logisticregression analysis identified 6 independentpredictors, 3 clinical and 3 imaging related:

– Age, smoking, and history of prior extrathoraciccancer more than 5 years earlier

– Nodule diameter, spiculated margin, and upperlobe location



• Probability of Malignancy = eˣ/(1+eˣ)

– Where x = -6.872 + (0.0391 x Years of age)

+ (0.1274 x Diameter in mm)

+ 0.7917 if smoker

+ 1.3388 if prior extrathoracic cancer >5 years ago

+ 1.0407 if spiculated margin

+ 0.7838 if upper lobe



• 40 year old, nonsmoker, no prior malignancy,with a 5 mm smoothly marginated nodule in alower lobe: Probability of malignancy = 0.9%

• 65 year old, smoker, no prior malignancy, witha 15 mm spiculated nodule in an upper lobe:Probability of malignancy = 55%

• 70 year old, smoker, no prior malignancy, witha 25 mm spiculated nodule in an upper lobe:Probability of malignancy = 87%


Likelihood of Malignancy:Bayesian Analysis

• Uses validated likelihood ratios for variousindependent clinical and imaging variables toestimate the probability of malignancy

• Based on Bayes Theorem:

New odds = Prior odds x Likelihood Ratio

• Likelihood ratios >1 increase the probability ofmalignancy while ratios <1 lower it



• Clinical variables increasing probability:

– Age >50 years

– Smoking history ≥30 pack years

– Hemoptysis

– History of prior malignancy



• Imaging variables increasing probability:

– Diameter >2.0 cm

– Upper or middle lobe location

– Spiculated margin

– Thick walled cavitation

– Absence of calcification

– FDG PET SUV >2.5

– CT densitometry enhancement >15 HU


Likelihood of Malignancy:“SPN Calculator”

• An easily accessible and useable “SPNCalculator” with both the Bayesian analysisand logistic regression models can be foundon the web at

www.chestx-ray.com/SPN/SPNProb.html

• Extremely cool so check it out


Recommendations:Putting It Together


Recommendations:

• Clinical management of an imaging finding

• Distill the clinical and imaging variables andformulate a plan of action that is broadlyapplicable and adheres to the standard of care


Recommendations:

• First things first:– Comparison with old imaging studies cannot be

overemphasized! (Turn on the retrospectoscope)• May obviate need for any further expensive and

potentially harmful evaluation. Team effort of clinician,radiologist, and patient.

• In general, clearly growing nodules should move totissue diagnosis if not contraindicated

– If suspected infectious etiology, further diagnosticintervention, therapy, and short-term follow-upimaging best initial management


Recommendations:

• Breaks down into two categories:

– Management of small nodules ≤8-10 mm

– Management of larger nodules >8-10 mm


Small Nodules ≤8-10 mm


Recommendations:Small Nodules ≤8-10 mm

• Fleischner Society guidelines for managementof small nodules have been widely adopted

• Apply to:

– Incidentally detected nodules on CT

– Patients 35 years of age and older

• Do not apply to:

– Patient with known or suspected malignancy

– Patient with unexplained fever



MacMahon H, et al. Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the FleischnerSociety. Radiology 2005; 237: 395-400


• A few key rationales for FSG:

– Differing follow-up times for low and high riskcategories because malignant nodules generallygrow faster in smokers

– Even in smokers, <1% of nodules <4 mm willbecome lethal cancers, but this increases to 10%-20% for size about 8 mm



• A few points regarding Fleischner SocietyGuidelines (FSG):

– Are about managing nodules ≤8 mm and not meant to define management of larger nodules—FSG clearly indicate flexibility in this category

– Note that FSG do not distinguish between singleand multiple nodules

– Diameter is average of length and width

– Remember longer follow-up of GGO nodules



• Other groups:

– Patients <35 years:

• In general, follow-up CT imaging should be avoided

• Consider a 6-12 month follow-up CT if have knownmalignancy

– Patients with known or suspected malignancy falloutside of the FSG (not part of the “high risk”group) and should be managed according to thespecific clinical situation and/or protocol



• Additional considerations:

– For nodules detected incidentally on non-thoraxCT and lungs not completely evaluated, considerobtaining dedicated CT thorax to assess for anyother nodules (no consensus)

– CT image reconstruction should be contiguousslices with thickness ≤3 mm, or potentially losing important morphologic information

– Consider limited coverage on follow-up CTs


Larger Nodules >8-10 mm


Recommendations:Larger Nodules >8-10 mm

• Morphologic characterization with thin-section CT is the key imaging step:

– Diagnostic benign features?

– If not, detailed accounting of morphology

• Determining probability of malignancy is thekey clinical step

– Accounting of relevant clinical history

– Estimate or calculate probability



• More diagnostic options become feasible withlarger nodules:

– Advanced imaging with FDG PET or contrastenhanced CT densitometry

– Percutaneous needle biopsy or bronchoscopy

• Many management algorithms in theliterature—most are very similar

• Best integrate clinical and imaging variables


A management algorithm for patients with SPNs >8 mm and <30 mm in diameter.

Adapted from: Evaluation of patients with pulmonary nodules: when is it lung cancer?, ACCP evidence-based clinical practice guidelines (2nd ed.). Chest 2007; 132: 108S-130S


• “Ask your doctor if this test is right for you…”

• Details of application depend on availablelocal resources, expertise, and the wishes ofthe fully informed patient


Thank you for your attention


Resources

• cdc.gov• Chestx-ray.com• Gould MK, et al. Evaluation of patients with pulmonary nodules: when is it

lung cancer?, ACCP evidence-based clinical practice guidelines (2nd ed.). Chest2007; 132: 108S-130S

• MacMahon H, et al. Guidelines for management of small pulmonary nodulesdetected on CT scans: a statement from the Fleischner Society. Radiology2005; 237: 395-400

• NLST Research Team. Reduced lung cancer mortality with low-dose computedtomographic screening. N Engl J Med 2011; 365: 395-409

• Winer-Muram HT. The solitary pulmonary nodule. Radiology 2006; 239: 34-49

• Nicholas E, et al. Evaluation of the solitary pulmonary nodule: A practicalapproach. Applied Radiology 2010. Vol 40, No 12: 6-15

• Swenson SJ, et al. The probability of malignancy in solitary pulmonarynodules: application to small radiologically indeterminate nodules. ArchIntern Med 1997; 157: 849-855


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