Thoracic Imaging 2003 - Society of Thoracic Radiology

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