Pure Ground-Glass Opacity Neoplastic Lung Nodules: Histopathology, Imaging, and Management

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1 ardiopulmonary Imaging Review Lee et al. Imaging GGO Neoplastic Lung Nodules ardiopulmonary Imaging Review FOUS ON: Ho Yun Lee 1 Yoon-La hoi 2 Kyung Soo Lee 1 Joungho Han 2 Jae Ill Zo 3 Young Mog Shim 3 Jung Won Moon 1 Lee HY, hoi YL, Lee KS, et al. Keywords: adenocarcinoma in situ, T, ground-glass opacity (GGO) nodule, high-resolution T (HRT), lung adenocarcinoma, minimally invasive adenocarcinoma, solitary pulmonary nodule (SPN) DOI: /JR Received ugust 28, 2013; accepted after revision October 8, This study was supported by Korean Foundation for ancer Research grant no. KFR Department of Radiology, Samsung Medical enter, Sungkyunkwan University School of Medicine, 50, Ilwon-dong, Gangnam-gu, Seoul , Korea. ddress correspondence to K. S. Lee (kyungs.lee@samsung.com). 2 Department of Pathology, Samsung Medical enter, Sungkyunkwan University School of Medicine, Seoul, Korea. 3 Department of Thoracic Surgery, Samsung Medical enter, Sungkyunkwan University School of Medicine, Seoul, Korea. WE This is a web exclusive article. JR 2014; 202:W224 W X/14/2023 W224 merican Roentgen Ray Society Pure Ground-Glass Opacity Neoplastic Lung Nodules: Histopathology, Imaging, and Management OJETIVE. The purpose of this article is to discuss histologic diagnosis of pure pulmonary ground-glass opacity nodules (GGNs), high-resolution T (HRT) findings and pathologic correlation, and management. ONLUSION. When pure GGNs are greater than 15 mm in diameter with nodularity or have high pixel attenuation (> 472 HU), the nodules are more likely to be invasive adenocarcinomas. Sublobar resection with a secured safety margin and without nodal dissection is performed for HRT-suggested pure-ggn invasive adenocarcinomas and has a 100% 5-year survival rate. I n 2011, the International ssociation for the Study of Lung ancer (ISL), the merican Thoracic Society (TS), and the European Respiratory Society (ERS) proposed a new international multidisciplinary classification system for lung adenocarcinoma [1]. The new classification system, which is based on highresolution T (HRT)-pathologic correlation studies, can be used by radiologists, pulmonologists, and surgeons for predicting adenocarcinoma histopathologic subtype and patient prognosis and for planning appropriate intervention [2 6]. For example, groundglass opacity (GGO) extent within a peripheral lung nodule seen on HRT can be correlated with the extent of lepidic tumor growth on histopathology [7 9]. However, uncertainty and ambiguity remain regarding this classification, particularly on pure ground-glass opacity nodules (GGNs) in terms of histopathologic diagnosis, detailed correlation between GGNs seen on HRT and histopathologic findings, and management. This article presents the histologic definition of adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive adenocarcinoma for pure GGNs seen on HRT according to the 2011 ISL/TS/ERS classification scheme, HRT findings and T-pathologic correlation, and management methods. Histologic Invasion and Diagnosis of denocarcinoma In Situ, Minimally Invasive denocarcinoma, or Invasive denocarcinoma Histologic invasion is defined as tumor cellular arrangement in acinic or papillotubular structures or solid nests in a fibroblastic stroma, often accompanied by collagenization [10] (Fig. 1). The structural deformity of the stromal elastic fiber framework with invasion can be evaluated by the use of elastic stains [5]. However, sometimes the discrimination between fibroblastic or myofibroblastic proliferation and myofibroblastic invasion might be difficult to define histologically. Imai et al. [11] suggested that TGF- β1 is likely to be significantly stronger in patients with minimally invasive adenocarcinoma than in those with adenocarcinoma in situ, and the increased expression may be associated with minimal invasion and infiltration of the myofibroblastic stroma. The diagnosis of adenocarcinoma in situ or minimally invasive adenocarcinoma cannot be firmly established without entire histologic sampling of the tumor [1]. For accurate diagnosis of minimally invasive adenocarcinoma or invasive adenocarcinoma seen as GGNs on HRT, detailed evaluation of the extent of stromal invasion is essential. Thus, without wholetumor sampling, small invasive components (stromal invasion of 5 mm in thickness in W224 JR:202, March 2014

2 Imaging GGO Neoplastic Lung Nodules minimally invasive adenocarcinoma) could not be identified or the extent of the invasive component could not be quantified. In addition, tumor procurement should be performed strategically for molecular or immunohistochemical studies. The reliability of the frozen section technique for correct diagnosis of GGNs is high, with accuracy greater than 94% [12, 13]. ecause of differing interpretations for the presence or absence of invasion, the kappa values (± SD) for typical and difficult cases for the presence of invasion are 0.55 ± 0.06 and 0.08 ± 0.02, respectively, with consistent subdivision by the same pathologists into invasive and noninvasive categories. Morphologic features attributable to the discrepant interpretation of invasion judgments include the interpretation of a stromal component as tumor-related stroma with fibroblasts versus benign scarring or fibroelastosis, misinterpretation of alveolar wall inflammation as invasive disease, and interpretation of a mucinous lepidic component as invasive [14]. Stromal Invasion on Pathology Versus Solid omponent on T: onfusion in ommunication etween Microscopic and T Realms Ground-Glass Opacity Nodules on High- Resolution T HRT is characterized by two physical parameters: thin-section (1.0- to 1.5-mm section thickness) T scans and high-frequency reconstruction algorithms. HRT resolution ranges from 200 to 300 μm [15]. Lung lesions, composed of microscopic changes under T resolution capability, manifest as GGO (hazy increased opacity with the preservation of bronchial and vascular margins on HRT). The GGO lesion is caused histopathologically by partial filling of airspaces; alveolar wall (interstitial) thickening due to fluid, cells, or fibrosis; partial collapse of alveoli; increased capillary blood volume; or a combination of these, the common factor is partial replacement of lung air [16]. For imaging GGNs, thin-section scanning and thin-section (usually 1.5 mm) reconstruction or reformation should be adopted [17]. When nodules are reconstructed or reformatted with thicker section thicknesses, partial volume averaging effect occurs, which affects nodule attenuation values. In such a circumstance, nodules with some degree of soft-tissue attenuation within a GGN might be classified as pure GGNs. The GGO of adenocarcinoma in situ generally manifest as regions of slightly higher attenuation relative to the faint opacity of atypical adenomatous hyperplasia. This difference in GGN attenuation is probably due to histopathologic dissimilarity in the amount of alveolar airspace and cellular components contained within the nodule or the thickness of alveolar walls [18]. ecause the invasive component in minimally invasive adenocarcinoma ( 5 mm in its greatest dimension), defined histopathologically [1], does not contribute much to the increase in T attenuation, minimally invasive adenocarcinoma also appears as a pure GGN of greater than 10 mm in diameter. Moreover, pure GGNs of greater than 16.4 mm in diameter have been reported to represent histopathologically invasive adenocarcinoma [19]. D Fig. 1 Histologic differences among normal lung, adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive adenocarcinoma. D, Schematic drawings show histopathologic differences among normal lung (), areas of adenocarcinoma in situ (), minimally invasive adenocarcinoma (), and invasive adenocarcinoma (D). rrows in D indicate areas of lepidic tumor growth that surround stromal invasion (SI) components in and D. Stromal invasion is 5 mm or less in thickness in minimally invasive adenocarcinoma () and more than 5 mm in invasive adenocarcinoma (D). ecause alveolar spaces may not be completely replaced by solid tumors in minimally invasive adenocarcinoma and even in invasive adenocarcinoma, lesions in and D may appear as ground-glass opacity nodules. Stromal Invasion on Pathology but Nonsolid on T For pathologists, chest physicians, and radiologists to communicate effectively, conceptual differences should be recognized between microscopic and T information [17]. This may be explained in a manner similar to differences in microscopic honeycombing cyst and honeycombing cyst on HRT (diameter and wall thickness of microscopic honeycombing cyst, μm and μm, respectively, compared with those of honeycombing cyst by HRT, 3 10 mm and 1 3 mm, respectively) [17]. Similar differences may occur regarding how microscopic invasion of 5 mm or smaller on histopathology appears on HRT images. Thus, because of the limited resolution ( mm) of HRT images, stromal or myofibroblastic invasion of 5 mm or smaller in minimally invasive adenocarcinoma or even of greater than 5 mm in invasive adenocarcinoma may manifest as pure GGN on HRT [19] (Figs. 2 5). HRT diagnostic criteria for minimally invasive adenocarcinoma have not been clearly defined. The presence of solid components of greater than 5 mm in thickness within a GGN on HRT is considered a malignant criterion differentiating invasive adenocarcinoma from adenocarcinoma in situ or minimally invasive adenocarcinoma [20], even though pure GGNs on HRT may show invasive adenocarcinoma on histopathology (Figs. 2 5). Such confusion may be related to the direct application of histopathologic invasion criteria to the HRT imaging diagnosis of minimally invasive adenocarcinoma. Many investigators do not attempt to differentiate minimally in- JR:202, March 2014 W225

3 Lee et al. Fig. 2 Growing ground-glass opacity nodule proven to be adenocarcinoma in situ with surgical resection in 45-year-old woman. and, Transverse thin-section (2.5-mm section thickness) T scans obtained at level of great vessels over follow-up period of 31 months show growing nodule (from 8 to 12 mm in diameter) (arrows) in right upper lobe., Photograph of gross pathologic specimen shows yellow tan tumor nodule (arrow). D, Low-magnification (H and E, 40) photomicrograph shows tumor cells growing along preexisting alveolar walls (lepidic tumor growth) with no evidence of stromal invasion. vasive adenocarcinoma from invasive adenocarcinoma on HRT (by referring to both minimally invasive adenocarcinoma and invasive adenocarcinoma collectively as invasive adenocarcinoma ) [21]. In our experience, most GGNs containing any solid component on HRT are invasive adenocarcinomas (Fig. 6) unless the solid component is caused by alveolar collapse or thick scar tissue. Typical minimally invasive adenocarcinomas are usually seen on T as pure GGNs of greater than 10 mm in diameter without an internal solid component [19]. Travis et al. [1] suggested that all histologic subtypes other than lepidic-predominant adenocarcinoma show solid nodule on T. However, as shown in Figures 4 and 5, well-organized acinar or papillary-predominant adenocarcinomas can also be seen as pure GGNs. D Noninvasive on Pathology but Solid omponent Present on T Scar formation is a characteristic histologic feature in peripheral lung adenocarcinoma, and the degree of scar formation (collagenization in the fibrotic focus) is closely correlated with tumor growth and patient prognosis [5, 22] (Fig. 6). The scar tissue (fibrotic focus) without an invasive component within a peripheral lung adenocarcinoma in situ may occasionally present as a solid component within a GGN on HRT. Likewise, the invasive component in a minimally invasive adenocarcinoma may be present on the periphery of a fibrotic focus. Furthermore, in this particular condition, the lesion may manifest as a GGN harboring a solid component on HRT. Other conditions that may manifest as a solid component within a pure GGN include collapse of alveoli, mass of tumor cells or macrophages filling alveolar sacs, and intraalveolar hemorrhage [23]. Of course, solid nests of an invasive component in a peripheral adenocarcinoma with or without a fibrotic focus appear as a solid component within a GGN on HRT (Fig. 6). High-Resolution T Findings and eyond on Minimally Invasive denocarcinoma and Invasive denocarcinoma Physical parameters are different among three kinds of tumors adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive adenocarcinoma presenting as pure GGNs on HRT. The measurement of the mass of a nodule (or nodule mass) is known to be useful for the detection of GGN growth [24]. Nodule mass (in grams) can be calculated by multiplying nodule volume by mean nodule attenuation. Nodule mass therefore increases as either volume or attenuation increases. Thus, mass measurements can help detect GGN growth earlier and are more reliable than volume or diameter measurements, particularly in GGNs. ccording to one study [19], nodule mass and the presence of an air bronchogram were significantly different among GGNs of adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive adenocarcinoma. Nodule mass was significantly higher in invasive adenocarcinoma than in adenocarcinoma in situ but was not different between adenocarcinoma in situ and minimally invasive adenocarcinoma or between minimally invasive adenocarcinoma and invasive adenocarcinoma. The presence of an air bronchogram was more frequently observed in invasive adenocarcinoma than in adenocarcinoma in situ but was not different between adenocarcinoma in situ and minimally invasive adenocarcinoma or between minimally invasive adenocarcinoma and invasive adenocarcinoma. On multivariate analysis, large tumor size and high nodule mass significantly favored the diagnosis of invasive adenocarcinoma. The quantitative HRT parameter evaluation of pure GGNs enables prognostic stratification of the three kinds of early adenocarcinomas. Histogram analysis of conventional T metrics (pixel values) may help differen- W226 JR:202, March 2014

4 Imaging GGO Neoplastic Lung Nodules tiate between adenocarcinoma in situ and invasive adenocarcinoma. For differentiation between adenocarcinoma in situ and adenocarcinoma, a mean T number with a cutoff value of 472 HU was optimal, with sensitivity of 75% and specificity of 81% [18, 25]. In a different study, the mean attenuation value ( 626 ± 84.4 HU) of preinvasive or minimally invasive adenocarcinomas was significantly lower than that ( 507 ± HU) of invasive adenocarcinomas [19]. ustom-developed programs can help calculate volumetric rates of GGO, semiconsolidation, and solid parts to whole nodules even though solid parts show a punctate distribution. Pure GGN and semiconsolidative nodules show no solid parts on HRT images. Most pure GGNs are preinvasive adenocarcinomas and are often indolent tumors. y contrast, semiconsolidative nodules tend to be adenocarcinomas with pathologically invasive foci and grow in size [26]. s GGNs evolve and grow, invasive components with the structural deformity of stromal elastic fiber framework appear within a homogeneous lepidic background [5]. Thus, pixel values are expected to become inhomogeneous as invasive components increase in extent. Future investigations measuring pixel value inhomogeneity (textile analysis estimating entropy) may help differentiate among adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive adenocarcinoma, with the highest entropy seen in invasive adenocarcinoma. D Fig year-old woman with minimally invasive adenocarcinoma, which appeared as one of multiple ground-glass opacity nodules (GGNs) on T. and, Transverse thin-section (2.5-mm section thickness) T scans obtained at levels of great vessels () and aortic arch () show multiple GGNs in right upper lobe measuring 18 mm (arrow, ) proven to be minimally invasive adenocarcinoma, 14 mm (solid arrow, ) proven to be minimally invasive adenocarcinoma, 11 mm (open arrow, ) proven to be adenocarcinoma in situ, and 5 mm (arrowhead, ) proven to be atypical adenomatous hyperplasia., Low-magnification photomicrograph (H and E, 40) of pathologic specimen obtained from nodule in shows mainly lepidic growth pattern of tumor cells along alveolar walls. Note areas (arrows) of focal stromal invasion, which measured 3 mm in thickness with acinar pattern of tumor growth. D, High-magnification photomicrograph (H and E, 200) seen on arrow area in shows acinar adenocarcinoma consisting of round to oval shaped malignant glands invading fibrous stroma. What Happens on Genetic lterations in denocarcinoma In Situ, Minimally Invasive denocarcinoma, and Invasive Lung denocarcinoma? Prevalence and specificity of molecular alterations in lung adenocarcinomas, including GGNs, have been described. large study was recently published describing the prevalence of epidermal growth factor receptor (EGFR) and KRS (GTPase KRas) mutations in adenocarcinoma in situ and minimally invasive adenocarcinoma [27]. In this study, EGFR mutations were associated with a high frequency of adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic and papillary subtypes (frequency: 85.7% in adenocarcinoma in situ, 83.3% in minimally invasive adenocarcinoma, and 71.4% in lepidic- and 68.5% in papillary-predominant invasive adenocarcinoma) of lung adenocarcinoma, followed by acinar (38.4%) and micropapillary (40.1%) subtypes, whereas the mutations were uncommon in solid subtype tumors (14.3%). KRS mutations were detected in 8.3% of minimally invasive adenocarcinomas, but no mutations were observed in adenocarcinoma in situ or lepidic subtypes of invasive adenocarcinoma. In a 2013 reclassification study, Tsuta et al. [28] reported that the EGFR mutation is most prevalent in papillarypredominant adenocarcinoma (56.0%), followed by lepidic predominant adenocarcinoma (44.6%) and adenocarcinoma in situ plus minimally invasive adenocarcinoma (39.0%). KRS mutations were most prevalent in invasive mucinous adenocarcinoma (74.4%) and were positive in 4.0% of adenocarcinoma in situ plus minimally invasive adenocarcinoma. naplastic lymphoma kinase translocations were most prevalent in micropapillary predominant adenocarcinomas (15.0%), but they were not detected in adenocarcinoma in situ plus minimally invasive adenocarcinoma or lepidic predominant adenocarcinoma. Lee et al. [29] retrospectively correlated quantitative T features of resected lung adenocarcinoma with EGFR mutations in East sian patients and found that GGO volume percentage in tumors with exon 21 missense mutation is significantly higher than that in tumors with other EGFR mutation status. This can be associated with the fact that exon 21 missense mutation was significantly more frequent in lepidic-predominant adenocarcino- JR:202, March 2014 W227

5 Lee et al. mas, including adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant invasive adenocarcinoma. In a retrospective study evaluating successive changes in peripheral lung adeno- carcinomas of predominantly GGO on T and correlating with biomolecular markers, oki et al. [30] found that as the solid component increases within a pure GGN, the immunohistochemistry of the TP53 protein becomes D Fig. 4 Invasive lung adenocarcinoma in 70-year-old woman who has breast cancer., Transverse high-resolution (1.25-mm section thickness) T scan obtained at ventricular level shows 24-mm ground-glass opacity nodule (arrow) in left lower lobe., Photograph of gross pathologic specimen obtained with left lower lobectomy shows ovoid gray tan tumor nodule (arrow) in superior segment of left lower lobe., Low-magnification photomicrograph (H and E, 12) shows mainly lepidic growth pattern of tumor cells along alveolar walls. Note areas (arrows) of central invasive acinar structure measuring 6 mm in thickness. D, Photomicrograph (H and E, 40) focused on arrow area in shows acinar adenocarcinoma consisting of round to oval shaped malignant glands invading fibrous stroma. Fig. 5 Invasive lung adenocarcinoma in 51-year-old man., Transverse high-resolution (1.25-mm section thickness) T scan obtained at level of basal segmental bronchi shows 23-mm ground-glass opacity nodule in right lower lobe., Photograph of gross pathologic specimen obtained with right lower lobectomy depicts ovoid gray tan tumor nodule (arrows). lso note small central scar tissue (arrowheads) with black pigment., Low-magnification photomicrograph (H and E, 12) shows mainly lepidic growth pattern of tumor cells along alveolar walls. Note areas (arrows) of stromal invasion of acinar pattern measuring 10 mm in thickness. positive. EGFR mutations were found in both pure and mixed GGNs. The authors concluded that lung adenocarcinomas with a predominant GGO often possess EGFR mutations, and interval increase in the solid component may be related to TP53 alteration. hung et al. [31] reported that synchronous GGNs can have different EGFR or KRS mutational profiles, suggesting that those lesions arise as independent events rather than intrapulmonary spread or systemic metastasis. Histopathologic, Radiologic, and linical Importance of Minimally Invasive denocarcinoma The concept of minimally invasive adenocarcinoma proposed in the new international multidisciplinary classification system for lung adenocarcinoma renders a histologic back- W228 JR:202, March 2014

6 Imaging GGO Neoplastic Lung Nodules bone on how a lung adenocarcinoma evolves from adenocarcinoma in situ to minimally invasive adenocarcinoma or eventually to invasive lung adenocarcinoma. The minimally invasive adenocarcinoma is histopathologically defined as 5 mm or less in the greatest dimension in any one focus; histologic subtypes other than a lepidic pattern (thus, acinar, papillary, micropapillary, or solid); if multiple microinvasive areas are found in one tumor, the size of the largest invasive area should be measured in the largest dimension; it should be 5 mm or less in size, but the size of invasion is not the summation of all such foci if more than one occurs; and finally, if the tumor has lymphatic, blood vessel, or pleural invasion or it contains tumor necrosis, the minimally invasive adenocarcinoma diagnosis should be discarded [1]. Fig. 6 Invasive adenocarcinoma manifesting as part-solid nodule containing central scar tissue and invasive component of acinar pattern in 53-year-old man., Transverse thin-section (2.5-mm section thickness) T scan obtained at level of carina shows 25-mm ground-glass opacity nodule (arrows) containing central solid component (arrowhead) within it., Low-magnification photomicrograph (H and E, 40) shows central fibrotic scar (solid arrows) containing invasive acinar components (open arrows) within peripheral portion of scar tissue that is surrounded by lepidic tumor growth (arrowheads). Whole tumor consists of 50% lepidic tumor growth pattern, 30% central fibrotic scar, and 20% acinar pattern. Fig. 7 Slow but steady evolution of pure groundglass opacity nodule over follow-up period of 9 years in 64-year-old man., Transverse T scan (5.0-mm section thickness) obtained at level of proximal bronchus intermedius in June 2004 shows 4.3-mm ground-glass opacity nodule (arrow) in right upper lobe., Follow-up T scan (1.0-mm section thickness) obtained in pril 2008 shows enlarged nodule (arrow) measuring 8.3 mm in diameter., nother follow-up T scan (2.5-mm section thickness) obtained in ugust 2011 shows more enlarged nodule (arrow) measuring 12.5 mm in diameter. D, Recent follow-up study (2.5-mm section thickness) obtained in ugust 2013 shows more enlarged nodule (arrow) measuring18.0 mm in diameter with some internal solid component (arrowhead). Tumor was resected and proven to be lepidic- and acinarpredominant adenocarcinoma. D JR:202, March 2014 W229

7 Lee et al. However, in imaging and clinical perspectives, minimally invasive adenocarcinoma is not much different from adenocarcinoma in situ in terms of morphologic features of a pure GGN. It may show somewhat larger size and higher attenuation than adenocarcinoma in situ [19]. In addition, we cannot make a histologic diagnosis of minimally invasive adenocarcinoma until the complete resection of a pure GGN is executed. The GGN of minimally invasive adenocarcinoma may be followed until the nodule reaches 15 mm in diameter. Therefore, radiologic and clinical differentiation of minimally invasive adenocarcinoma from adenocarcinoma in situ may not be as important as histopathologic differentiation. Furthermore, patients with minimally invasive adenocarcinoma have 100% or near-100% 5-year disease-free survival as do those with adenocarcinoma in situ when the lesions are completely resected [4, 5, 32, 33]. Management Surgical Resection There has been no unified consensus on surgical resection indications for pure GGNs. ecause tumors of greater than 10 mm (e.g., minimally invasive adenocarcinoma) in diameter tend to have an invasive component and evolve into invasive adenocarcinoma eventually [34, Stable < 5 mm iennial T hange in size or density or appearance of solid component 35], pure GGNs of greater than 16.4 mm in diameter represent histopathologically invasive adenocarcinoma [19], tumorous pure GGNs show perfect 5-year survival after complete surgical removal [2 5], and confirmatory histopathologic diagnosis cannot be made until complete resection and detailed pathologic analysis are performed [19], pure GGNs of greater than 15 mm in diameter may be resected (oral communication, Kusumoto M, National ancer enter Hospital, Tokyo, Japan). In addition, at our institution, pure GGNs of less than 10 mm in diameter are usually followed until they reach 15 mm in diameter. Nodule localization of the target GGN under T guidance may be needed, particularly when GGNs are 2 cm or more away from the pleural surface or the fissure. The establishment of a stable location of a hookwire during and after T-guided localization with sufficient wire depth is important because the distance between the hookwire tip and pleural surface is the major significant factor for successful T-guided nodule localization [36]. Securing a safe resection margin of 10 mm or more from the tumor or a margin-to-tumor ratio of 1 or higher is recommended [1, 12, 13, 37]. There have been debates on surgical resection methods for GGNs [12, 38, 39]. recent trend is video-assisted thoracoscopic surgery Persistent Pure Ground-Glass Opacity Nodule Stable 5 10 mm nnual T hange in size or density or appearance of solid component with sublobar resection rather than formal lobectomy for pure GGNs of adenocarcinoma in situ, minimally invasive adenocarcinoma, or even invasive adenocarcinoma when they are 20 mm or less in diameter [12, 39 42]. No nodal dissection or lobe-specific nodal dissection (limited dissection to the primary nodal regions draining the involved lobe) is executed in this condition. large GGN of greater than 15 mm in diameter or high attenuation value (e.g., > 472 HU) within the tumor may have the histopathology of invasive adenocarcinoma rather than adenocarcinoma in situ or minimally invasive adenocarcinoma. Even in this situation (for example, a large GGN of invasive adenocarcinoma reaching 20 mm in diameter), systematic nodal dissection is usually not planned because regional nodal metastasis is generally not detected in any patient with this condition [2, 43, 44]. The indication of such limited surgical approaches (sublobar resection and no nodal or lobespecific nodal dissection) can be expanded and applied to larger pure GGNs up to 30 mm in diameter [45]. On the other hand, without the secured surgical margin of safety (resection margin of 10 mm or more from the tumor or margin-to-tumor ratio of 1 or higher), cut-end recurrence might occur during long-term follow-up with HRT [46]. Stable >10 mm T in 3 6 mos hange in size or density or appearance of solid component iennial T nnual T T in 3 6 mos Surgical excision Fig. 8 Flowchart shows follow-up scheme and guideline for pure ground-glass opacity nodules detected incidentally or at lung cancer screening. For biennial and annual T, nodules increase or occasionally decrease in size but with an increase in internal attenuation (density). For T in 3 6 months, change in size is usually up to 15 mm in diameter. Dashed lines indicate continuation of T surveillance using unenhanced, thin-section, and low-dose techniques until life expectancy. W230 JR:202, March 2014

8 Imaging GGO Neoplastic Lung Nodules Follow-Up ssessment urrently, no optimum follow-up intervals for persistent pure GGNs have been reported. Pure GGNs are reported to have a volumedoubling time of greater than 400 days in 50 90% and greater than 800 days in 20 50% of patients [13, 47, 48]. ecause malignant pure GGNs have longer volume-doubling time compared with that of malignant solid or part-solid nodules [47, 49], follow-up studies at 12-month intervals are recommended. t our institution, a single pure GGN of 10 mm or less in diameter is repeatedly evaluated using HRT at 12-month intervals until it reaches 15 mm in diameter. The appearance of a solid portion within a pure GGO area indicates a malignant tumor with a high potential of locoregional lymph node or distant organ metastasis [34, 50], heralding the necessity of surgical resection. Lung cancer screening detected pure GGNs of 10 mm or less show slow growth but have a higher likelihood of steady growth than solid subcentimeter nodules [51] (Fig. 7). Therefore, follow-up is recommended until age 70 years or more for pure GGNs of 10 mm or less in diameter. These recommendations may be similar among various guidelines [52, 53]. urrently, follow-up intervals (e.g., annual or biennial) are not definite. ecause small GGNs less than 5 mm in diameter (the corresponding histologic diagnosis of atypical adenomatous hyperplasia) have longer volume-doubling time (859 ± days) than adenocarcinoma in situ (421 ± days) or invasive adenocarcinoma (202 ± 84.3 days), such nodules are followed biennially. GGNs of 5 10 mm in diameter may be followed annually, and nodules of greater than 10 mm in diameter may be evaluated at 3- or 6-month intervals [54] (Fig. 8). Multiple Neoplastic Pure Ground-Glass Opacity Nodules pproximately 20 30% of patients with a predominant pure GGN who undergo surgical resection of the GGN have additional smaller GGNs in the same lobe or in a different lobe or lung [19] (Fig. 3). Histopathologic diagnosis of each GGN depends on its size or nodule mass as was the case in a single pure GGN [19, 55, 56]. Management of multiple pure GGNs of adenocarcinoma in situ, minimally invasive adenocarcinoma, or invasive adenocarcinoma has been the subject of debate. Multiple limited resection procedures may be performed if patients have double or triple GGNs and reserved pulmonary function after surgical resection. However, when patients have five or more GGNs scattered in both lungs with multilobar involvement, other options should be considered. When multiple malignant GGNs are localized deeply in one lobe or when one or more predominant nodules are localized in one lobe, lobectomy may be performed. On the other hand, when the GGNs of even size are scattered in multiple lobes or peripherally in one lobe, multiple-site wedge resections may be executed. hemotherapy has been suggested as an alternative therapeutic option, particularly when pulmonary functional reserve after multiple surgical resection precludes such procedures or technically multiple resection is implausible (multiple GGNs scattered deeply in both lungs) [55, 57]. Patients with multiple pure GGNs of minimally invasive adenocarcinoma or invasive adenocarcinoma show good prognosis [55, 58]. Even in patients with remaining GGNs because all nodules could not be resected due to bilateral lung or multilobar involvement of the GGNs, the remaining nodules do not show change in their size on follow-up T studies. Therefore, even for multiple GGNs of minimally invasive adenocarcinoma or invasive adenocarcinoma, limited resection or followup without specific treatment after surgical diagnosis of the lesions may be an appropriate management method [55]. However, longterm follow-up data have not been published for multiple pure GGNs of minimally invasive adenocarcinoma or invasive adenocarcinoma. onclusion The persistent presence of pure GGNs in the lungs on HRT leads to making a diagnosis of a neoplastic condition that has an excellent prognosis. pproximately 80% of persistent pulmonary GGNs represent histopathologically preinvasive (atypical adenomatous hyperplasia and adenocarcinoma in situ), minimally invasive adenocarcinoma, or invasive lung adenocarcinoma. The nodules show slow growth over time, with volumedoubling time of more than 400 days. s the nodule size, volume, and mass of GGNs increase physically, there appear histopathologically multifocal areas of an invasive component within a background of predominantly lepidic growth pattern. Thus, invasive components of minimally invasive adenocarcinoma or invasive adenocarcinoma may appear histopathologically when nodules are still in a pure GGO state before the appearance of a solid component on HRT. When GGNs are 15 mm or more in diameter with a high nodule mass or high attenuation (mean attenuation, > 472 HU) or harbor a solid component within them, the nodules have more likelihood of being invasive adenocarcinomas. When the GGNs are small, the nodules are usually preinvasive (atypical adenomatous hyperplasia and adenocarcinoma in situ) or minimally invasive adenocarcinoma and follow-up T is recommended until they reach 15 mm in diameter or until the patient with the nodule is 70 years old or more. The follow-up interval may be annual or biennial. Surgical resection is indicated when the GGNs are 15 mm (presumed cutoff point between minimally invasive adenocarcinoma and invasive adenocarcinoma) or more in diameter. The surgical approach is wide wedge resection or segmentectomy (sublobar resection) with secured resection margin of greater than 10 mm or a margin-to-tumor ratio of 1 or higher. Lymph node dissection is not usually performed. Such a surgical approach (sublobar resection without lymph node dissection) may be applicable to pure GGNs of 20 mm or less. 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