Thoracic Imaging 2003 - Society of Thoracic Radiology
Thoracic Imaging 2003 - Society of Thoracic Radiology
Thoracic Imaging 2003 - Society of Thoracic Radiology
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Assessing Growth <strong>of</strong> Indeterminate Nodules<br />
Helen T. Winer-Muram, M.D.<br />
Indiana University<br />
Why measure growth?<br />
Indeterminate lung nodules have been considered to be<br />
benign if they 1) have a “benign” pattern <strong>of</strong> calcification or 2)<br />
do not grow over a period <strong>of</strong> two years. Controversy has arisen,<br />
however, about these indicators. Gurney had four radiologists<br />
review radiographic features <strong>of</strong> 44 malignant nodules and<br />
showed that 5% had a “benign” pattern <strong>of</strong> growth. Yankelevitz<br />
et al. have used data from early studies <strong>of</strong> radiographic nodule<br />
growth to calculate that the predictive value <strong>of</strong> no growth is<br />
only 65%.<br />
Measurement <strong>of</strong> nodule growth rates <strong>of</strong>fer a way to separate<br />
benign from malignant nodules. Chest radiographic data have<br />
shown that most malignant nodules double in volume in<br />
between 20 and 400 days. Nodules that grow more quickly are<br />
more likely to be infectious, while those that grow more slowly<br />
are likely to be benign nodules (e.g., hamartomas, granulomas)<br />
(Nathan).<br />
Moreover, the advent <strong>of</strong> lung cancer screening makes the<br />
determination <strong>of</strong> nodule growth rates even more important.<br />
Screening may preferentially detect slow-growing nodules that<br />
may not be lethal. Patients with fast-growing nodules may not<br />
be curable even if the nodules are detected when they are small.<br />
In addition, the rate <strong>of</strong> growth <strong>of</strong> the lung cancer might be correlated<br />
with disease-specific mortality.<br />
How do tumors grow?<br />
For growth rates to be used for clinical decision making, it is<br />
best that the tumor growth is linear. This fact has been suggested<br />
by past radiological studies. From chest radiography (41<br />
cases) it has been shown that tumors have a linear increase in<br />
volume over time (Garland, 1963). Once the growth levels <strong>of</strong>f,<br />
(upper horizontal asymptote) there is a lethal burden <strong>of</strong> tumor<br />
and the patient is near death. That is generally at about 40 doubling<br />
times.<br />
As radiologists view nodules, we get the misconception that<br />
tumors grow faster as they enlarge. The same percent growth <strong>of</strong> a<br />
large diameter is more noticable than that <strong>of</strong> a smaller diameter.<br />
Why “watch” a nodule and not immediately get tissue?<br />
Many CT-detected indeterminate nodules are too small (< 1<br />
cm diameter) for fine needle aspiration biopsy, and some larger<br />
nodules are in anatomic locations that make biopsy difficult. In<br />
areas endemic for fungal disease, we cannot biopsy all <strong>of</strong> the<br />
indeterminate nodules that are discovered with CT. Lung cancer<br />
screening programs in the Midwest have shown that 50% <strong>of</strong><br />
patients have indeterminate nodules, most <strong>of</strong> which are benign<br />
at biopsy. Currently 20% to 40% <strong>of</strong> all resected nodules are<br />
benign. Swenson et al. have proposed including an enhanced<br />
CT study to aid in discriminating benign from malignant nodules;<br />
nodule enhancement <strong>of</strong> < 20 HU with CT (4 scans at 1<br />
minute intervals after contrast injection) has a negative predictive<br />
value <strong>of</strong> 98%.<br />
To use nodule growth rate as a way to distinguish between<br />
benign and malignant lesions, it must demonstrated that a clinically<br />
acceptable delay between initial and followup CT scans is<br />
usually sufficient to show growth. “Watchful waiting” even for<br />
one month is controversial, even though no one has shown that<br />
such a delay would have deleterious effects. In addition, measurements<br />
to assess for growth must be reproducible. Several<br />
studies using different methods have been reported.<br />
Radiography studies – diameter method<br />
(For spherical tumors a 25% increase in diameter ~ a 100%<br />
increase in volume.)<br />
Usada et al measured the doubling times (DTs) <strong>of</strong> lung cancer<br />
nodules in 174 patients. The DTs ranged from 30 to 1077<br />
days; 7% <strong>of</strong> patients had DTs > 500 days. In that study the DT<br />
was an independent predictor <strong>of</strong> mortality. In a retrospective<br />
review <strong>of</strong> 300 cases, the DTs for adenocarcinoma s were 185<br />
days, squamous cell carcinomas were 90 days, and small cell<br />
carcinomas were 65 days (Friberg). Aoki et al. described DTs<br />
vary that ranged from 42 to 1486 days in 27 cases <strong>of</strong> bronchioloalveolar<br />
cell carcinomas.<br />
Hopper found the interobserver variability to be < 15%, with<br />
a minimal detectable change <strong>of</strong> 3 to 5 mm (Hopper).<br />
CT studies – diameter method<br />
Yankelevitz et al. (1999) have calculated that the minimal<br />
measurable change in diameter is 0.3 mm or one pixel Even a<br />
nodule <strong>of</strong> 1 cm diameter with a 180 day DT will have measurable<br />
change in diameter if the interval between CT scans is at<br />
least 28 days.<br />
In a screening study, Hasegawa et al. measured 82 cancers<br />
(most adenocarcinoma) and found 27 had DTs > 450 days<br />
(33%) and 12 had DTs > 730 days (15%). They pointed out<br />
that use <strong>of</strong> a screening population may lead to a bias toward<br />
slow-growing tumors<br />
Harris measured phantoms using different window/level settings.<br />
Measurements were highly accurate with lung window<br />
settings and inaccurate with s<strong>of</strong>t tissue settings. This is evidence<br />
that serial measurements should be done with the same window/level<br />
settings.<br />
CT studies – maximum cross sectional area method<br />
Yankelevitz measured the maximal cross-sectional areas <strong>of</strong> 9<br />
malignant nodules. All had diameters < 10 mm and all had projected<br />
change in area <strong>of</strong> > 18 % in 30 days. The DTs were all <<br />
124 days. (range 53-124 days, median 75 days)<br />
For repeated area measurements <strong>of</strong> small tumors, Staron<br />
found the intraobserver coefficient <strong>of</strong> variation to be only 4-7%<br />
for an object <strong>of</strong> cross-sectional area <strong>of</strong> 705 mm 2 , a typical size<br />
for a stage I lung tumor.<br />
CT studies – volume method<br />
An exciting new development is that <strong>of</strong> volumetric measurement<br />
<strong>of</strong> nodules. Because volume varies with the cube <strong>of</strong> the<br />
diameter, for a given time period the percent change in volume<br />
is greater than the percent change in the diameter. If volume and<br />
diameter measurements are equally precise, volume changes<br />
should be detectable earlier than diameter changes. As cross-<br />
221<br />
WEDNESDAY