The advent of computed tomography screening for lung cancer will increase the incidence of ground-glass opacity (GGO) nodules detected and referred for diagnostic evaluation and management. GGO nodules remain a diagnostic challenge; therefore, a more systematic approach is necessary to ensure correct diagnosis and optimal management. Here we present the latest advances in the radiologic imaging and pathology of GGO nodules, demonstrating that radiologic features are increasingly predictive of the pathology of GGO nodules. We review the current guidelines from the Fleischner Society, the National Comprehensive Cancer Network, and the British Thoracic Society. In addition, we discuss the management and follow-up of GGO nodules in the light of experience from screening trials. Minimally invasive tissue biopsies and the marking of GGO nodules for surgery are new and rapidly developing fields that will yield improvements in both diagnosis and treatment. The standard-of-care surgical treatment of early lung cancer is still minimally invasive lobectomy with systematic lymph node dissection. However, recent research has shown that some GGO lesions may be treated with sublobar resections; these findings may expand the surgical treatment options available in the future.
Localization, Marking, and Surgical Management of GGO Nodules
Suspicious GGO nodules may have to be surgically removed via video-assisted thoracoscopic surgery (VATS) for diagnostic or therapeutic reasons. However, GGO nodules are often difficult to locate due to their size and morphology. The preferred surgical procedure is VATS in combination with a marking of the GGO nodule. Most of the evidence regarding markers is derived from studies of peripherally located solid nodules smaller than 15 mm. It is generally assumed that the techniques used in the latter setting will also be effective in cases of GGO nodules. The marking consists of CT-guided injection of 0.2 mL of methylene blue at the periphery of the nodule in combination with a small amount of dye at the subpleural region at the level of the nodule to serve as guidance for the surgeon. In a recent prospective randomized trial, CT-guided percutaneous placement of microcoil markers in combination with fluoroscopic-guided VATS resection was significantly better than procedures in which nodule localization was via finger palpation only in small (mean nodule diameter, 12 mm) solid and subsolid nodules (93% vs 48%; P < .01). Other techniques available are intraoperative ultrasonography, hook wire placement, injection of lipiodol, and injection of radioisotope. Centrally located GGO lesions are more difficult to resect and may in rare cases require a diagnostic lobectomy, even though this should be the diagnostic approach of last resort.
The current guidelines recommend lobectomy with systematic lymph node dissection as the minimal resection in cases of stage I/II invasive carcinoma. In recent years, improvements in CT scanning resolution, combined with increased use of CT screening, has led to the increased detection of GGO lesions that represent noninvasive or MIA types of lung cancer with a favorable prognosis.[8,56] In a CT screening context, the indication for surgery should always be carefully considered, and the decision should be made by a multidisciplinary board. This is a necessary precaution in order to avoid resection of nonmalignant lesions, which if left alone might have regressed/disappeared and could in principle represent instances of the overdiagnosis of lung cancer. However, when a malignant diagnosis has been made, surgery is the primary curative treatment option. In some cases, sublobar resection may offer the same long-term survival as lobectomy, and without an increase in the likelihood of local recurrence.[58,59] In the past, sublobar resection has primarily been reserved for operable but high-risk patients in whom the optimal surgical approach must be modified. However, in recent years, especially in Japan, considerable research has gone into the evaluation of sublobar resections in non–high-risk patients. The potential benefits of sublobar resection would be to spare healthy lung tissue, making for better respiratory capacity, and to allow for the possibility of future surgical treatment in the event of a new primary lung cancer.
It is possible to use radiologic criteria to identify an early noninvasive adenocarcinoma—eg, when the GGO nodule size is less than 2 cm and the C/T ratio is below 0.25 (cT1a), or when the C/T ratio is below 0.5 in a GGO nodule less than 3 cm in size (cTa-b). In these patients, wide wedge resection is being compared with segmentectomy in an ongoing prospective, randomized trial conducted by the Japan Clinical Oncology Group (Table). For radiologically invasive lung tumors (cTaN0M0) 2 cm or less in diameter and a C/T ratio greater than 0.5, lobectomy vs segmentectomy is being investigated in another randomized trial conducted by the Japan Clinical Oncology Group (Table). In the United States, the Cancer and Leukemia Group B 140503 trial (ClinicalTrials.gov identifier: NCT00499330) is comparing lobectomy vs wedge resection or segmentectomy. With more extensive use of CT screening, it is expected that more GGO lesions will be detected, and hence the indications for sublobar resection will need to be considered more often. However, it is important that the oncologic benefit of the surgical procedure be monitored by conducting adequate follow-up and registering results, to make possible the systematic evaluation of the procedures used. Segmentectomy is oncologically superior to a wedge resection, since it provides wider resection margins and a lower local recurrence rate. If a wedge resection is performed, it should be done with a resection margin greater than 2 cm, or greater than the maximal tumor diameter.[63,64]
GGO nodules remain a diagnostic challenge, and therefore a more systematic approach is necessary to ensure an optimal workup. Persisting GGO nodules larger than 5 mm should be followed for at least 4 years. PET/CT has limited value in the diagnostic workup of GGO nodules. Growth of more than 2 mm in maximal diameter is considered significant. Development of a solid component in a pure GGO nodule, or growth of a pre-existing solid component in a part-solid GGO nodule, is predictive of invasive malignancy. In such cases, invasive techniques such as CT-guided biopsy or nodule removal by VATS should be considered. The current standard of care for surgical treatment of early lung cancer (cT1a-bN0M0) is still VATS lobectomy. Recent research has shown that some GGO lesions with low C/T ratios may be treated by sublobar resection. However, final recommendations with regard to this must await the results of ongoing randomized trials in the United States and Japan.
Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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