Which Lung Nodules Need Follow-up?

A 65 year old man who is a lifelong smoker undergoes low dose CT scan of the chest given recent onset cough and night sweats. The scan picks up a 8 mm nodule in the right upper lobe. Thoracic lymph nodes are not enlarged and there are no other lesions. How does one follow up?

The incidentally discovered solitary lung nodule must be one of the commonest problems faced by clinicians. Further, in the USA in particular, there is insurance coverage for low dose CT scannning of current smokers or ex-smokers aged 50-75 who have quit within the last 15 years, who have at least a 30-pack year smoking history. Studies have shown that such screening reduces lung cancer related mortality by 20%.

But which nodules do you ignore and which do you follow-up?

Studies conducted in smokers show that several factors predict risk of a cancerous lung nodule. Size is probably the most important. Nodules less than 5 mm carry <1% risk of cancer. This risk rises to 50% with nodules greater than 20 mm. A lesion bigger than 30 mm is classified as a "mass" rather than as a nodule. Other factors which increase risk of a nodule being cancerous are older age, female gender, family history of lung cancer, location in the upper lobe, emphysema, a part-solid rather than pure solid or ground glass (also called sub-solid) nodule and spiculation. The likelihood of cancer decreases when the number of nodules crosses four. Other factors also influence the likelihood of cancer being present. While most patterns of calcification are thought to favour a benign nodule, eccentric calcification increases the risk that the nodule is cancerous. Popcorn calcification is characteristic of hamartomas, while central calcification is usually benign. Peri-fissural nodules are almost always benign. Nodules which have been shown to grow on successive CT scans are clearly suspicious. However, the pace of growth matters. Most cancerous nodules have a "tumour-doubling time" between 20 and 400 days. Nodules which double in less than 20 days are likely to be infective. While most nodules taking more than 400 days to double in diameter on CT are likely to be benign, this does not apply to ground glass (subsolid) or part solid nodules. These lesions, particularly the subsolid nodules can only be picked up on CT, but not on chest Xray. Subsolid or part solid nodules can represent in situ adenocarcinoma, minimally invasive adenocarcinoma, lepidic adenocarcinoma, or carcinoid, are particularly common in non-smokers, and take longer to increase in size, with a tumour doubling time of up to 800 days. While solid nodules need only be followed up for 2 years, subsolid or part solid nodules need follow-up for 3 years. There is an on-line resource, available from Brock University, Canada, based on the Pan Can study which was then validated in a British Colombian cohort, which incorporates the above factors into a risk model. http://www.uptodate.com/contents/calculator-solitary-pulmonary-nodule-malignancy-risk-brock-university-cancer-prediction-equation?source=see_link&utdPopup=true Using the calculator, subjects are classified into 3 groups in terms of the likelihood that lung cancer is present <5% 5-65% >65%

With the lowest risk group, it is only necessary to do surveillance CT scans at algorithm determined intervals. The intermediate risk group should have a PET scan to assess the likelihood of cancer (>2.5 SUV being suspicious), while the highest risk group would have a direct non-surgical or surgical biopsy.

Normally, nodules less than 5 mm need no further follow-up unless they are part-solid. Larger solid nodules less than 8mm (called sub-centimetre nodules although the threshold is 8 mm rather than 1 cm), would need follow up up to 2 or 3 years depending on whether they are solid or subsolid. Nodules larger than 8 mm would ordinarily be scanned after 3-6 months, with repeat scans in 9-12 months and 18-24 months. If the nodule has grown more than 50% between scans or by more than 20% in two dimensions, it will need a biopsy.

Any lymph node involvement would mandate a biopsy straightaway.

Just a word of caution. These guidelines were designed for smokers and have not been validated in non-smokers. The predominant cancer in non-smokers is adenocarcinoma, which tend to be peripherally located ground glass nodules. Small cell cancers are solid nodules, also peripherally located, while squamous cell cancers are usually central lesions.

Endocarditis Is Not Always Infective

A 31 year old lady presents to you with a history of recent recurrent "bruising". Although she has no active lesions at the moment and looks quite well, pictures taken on her mobile phone show a substantial dark area on the left ring finger and larger, incomplete dark circular lesions on her upper shins. The GP has checked her ANA. It's negative. Inflammatory parameters are normal. She has two healthy children.

A 71 year old man presents with transient dark lesions on his fingers. On his second visit, you are lucky enough to catch sight of some of these dark areas on the fingers. They are tender. The patient is well and apyrexial without audible murmurs. You diagnose Osler's nodes and ask for blood cultures and echo.

All perfectly reasonable. Except that it may not be enough.

The prospect of embolic lesions from the heart valves is terrifying, but not all such cases are infective endocarditis. There are other possibilities.

Young women with SLE often have Libman Sacks lesions on left sided heart valves, particularly the mitral valve. This is three times more common in those with anti-phospholipid antibodies, which can exist independently of lupus. Although subjects with SLE and Libman Sack's lesions tend to have active lupus, often associated with lupus nephritis, subjects with aPL alone may have been hitherto asymptomatic. While it is important to dip the urine for blood and protein to screen for lupus nephritis, immune glomerulonephritis in infective endocarditis can cause an active urinary sediment.

In fact, Glomerulonephritis is one of the four immune manifestations of infective endocarditis, the other three being Osler's nodes, Roth spots and a false positive Rheumtoid factor (aid memoire GORR).

Treatment would be immunosuppression and anticoagulation, although there are no RCTs that support the use of the former in Libman Sacks endocarditis.

The old man with "Osler nodes" may have cancer, with thrombotic, non infective endocarditis. Clots, present on the heart valves (again more common on the left), are thought to be due to hypercoagulability. Such patients may often have occult DVTs or pulmonary emboli. Gastric or pancreatic cancers may have associated portal or mesenteric vein thrombosis. Apart from treatment of the underlying cancer, these patients need clexane. Warfarin would be ineffective.

Cancer and infective endocarditis can co-exist due to Streptococcus bovis septicaemia. These patients often have underlying colon cancer. Others have cirrhosis.

Subjects with left atrial myxoma can present exactly like subacute bacterial endocarditis with fever, lassitude, murmurs and embolic phenomena. Echo may pick up pedunculated lesions on the mitral valve.

A final non-infective cause of cardiac emboli is eosinophilia. Regardless of the underlying cause of eosinophilia, prolonged or high eosinophil counts go through three phases- cardiac microabscesses, a flabby, poorly contractile myocardium and endomyocardial fibrosis. It is in the second stage that clots build up, often in the left ventricle, which can then embolise and cause strokes, renal or splenic infarcts, just like infective endocarditis.

Eosinophilia can also occur secondarily in subjects with cholesterol emboli, usually from the aorta. These often present in the elderly with renal impairment and livedo in the lower limbs following an invasive procedure such as cardiac catheterisation. There are reports of cholesterol emboli occurring after anticoagulation.

It is important to consider these non-infective causes of endocarditis in subjects with cardiac vegetations on echo, who are culture negative and do not have the expected response to antibiotics.