DISCUSSION
This study demonstrates the high sensitivity of ICG imaging, with which
tumors < 1 mm in diameter could be detected, although a
considerable number of false-positive results were obtained.
Histological examination of several ICG-positive tumor-negative
specimens revealed thrombi, hemorrhage, and hemosiderin pigmentation,
implying disturbances of the microenvironmental pulmonary bloodstream.
These histological findings suggest that ICG is detected not only when
it is absorbed by tumor cells, but also when it remains in the pulmonary
tissue because the bloodstream is disturbed. This hypothesis is
reasonable insofar as ICG is used for fundus angiography and
lymphangiography during various
operations13,14,16–18. Because ICG may be distributed
unevenly when the lesions are very small, it is difficult to distinguish
whether the tumors themselves are detected with ICG imaging or if it is
the surrounding tissues that are affected by the disturbance of the
bloodstream associated with the tumor.
The histological subtype of all true-positive specimens was the
embryonal type, and no mesenchymal component was detected. Therefore,
the applicability of ICG imaging to lesions composed of a predominantly
mesenchymal component, which are occasionally observed after
chemotherapy, has not yet been clarified.
In this study, 8 of the 250 ICG-positive lesions were not palpable
during surgery, and viable tumor nodules were identified in these
specimens on histological examination. These lesions may not be
detectable without ICG imaging. All these lesions were small, and ICG
imaging might not detect the tumors themselves, but it might usefully
detect circulatory disturbances in the surrounding tissues.
Consequently, ICG imaging is also useful in detecting these small
lesions, which are often <1 mm in diameter.
Twenty specimens were ICG negative but contained palpable nodules, and
viable tumors were confirmed on histological examination. Of these 20
specimens, 19 were taken from the same patient. The specimens from this
patient were initially ICG positive, but reverted to ICG negative, so
the character of the tumors was considered to have changed. These tumors
might have become refractory to the uptake of ICG, or might have
discharged ICG very rapidly. The remaining specimen might not have taken
up ICG, probably in response to a circulatory disturbance. Small
nonpalpable lesions that failed to take up ICG for some reason could not
be detected during surgery.
The microscopic examination of a considerable number of ICG-positive
tumor-negative (false-positive) specimens also revealed nonspecific
histological changes, such as fibrosis. To identify a false-positive
specimen during surgery is considered difficult. To achieve thorough
metastasectomy with shorter surgeries and fewer operations, further
optimization of the dose of ICG and the timing of its administration may
be essential. To minimize the resected lung volume, a wedge-shape
resection with a minimal margin performed with open thoracotomy may be
more efficient than linear-stapler thoracoscopic
surgery.10
Although the sensitivity of ICG imaging is high, several false-negative
(ICG-negative tumor-positive) specimens are confirmed, suggesting that
some metastatic tumors cannot be detected with ICG imaging. Recognizing
the limitations of metastasectomy with ICG imaging is also necessary.
Palpation during operation and preoperative imaging studies may still be
mandatory for the detection of metastatic lesions, even in the era of
ICG imaging.