Natural History of Pure Ground-Glass Opacity After Long-Term Follow-up of More Than 2 Years

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1 Natural History of Pure Ground-Glass Opacity After Long-Term Follow-up of More Than 2 Years Ken Kodama, MD, Masahiko Higashiyama, MD, Hideoki Yokouchi, MD, Koji Takami, MD, Keiko Kuriyama, MD, Yoko Kusunoki, MD, Tomio Nakayama, MD, and Fumio Imamura, MD Departments of Thoracic Surgery, Diagnostic Radiology, Field Research and Internal Medicine, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan Background. Pure ground-glass opacity (PGGO) is a new entity that has been clearly defined on highresolution computed tomography (CT) during the last half decade. It is important to investigate the natural history of PGGO through long-term observation for the management of this new entity. Methods. We investigated 19 patients with PGGO(s) defined on high-resolution computed tomography and retained as PGGO for more than 2 years. The PGGOs of 11 patients were detected at annual mass screening by low-radiation dose CT (low-dose CT), 7 at CT after cancer resection, and 1 incidentally on CT. After long-term observation, 10 of 19 patients underwent operation and 9 are currently being followed-up with CT. Their growth characteristics and histologic findings are reported. Results. The median period was 32 months, ranging from 24 to 124 months. The sizes of PGGOs at the time of discovery were 4 to 18 mm in largest diameter (average 8.6 mm). During, the size of PGGO showed no change in 8 patients, increased slightly (up to 5 mm) in 6 patients, and increased by more than 5 mm in 5 patients. Ten patients had limited resection (segmentectomy or wide wedge resection) with negative surgical margin by intraoperative lavage cytology of the resection margin of the lung. Of them, 5 patients had adenocarcinoma, 3 pulmonary lymphoproliferative disorder, and 1 each atypical adenomatous hyperplasia and focal fibrosis. There was no clear tendency between the degree of size change and histology. In all but 1 of 9 patients with only, the PGGOs showed either no change or only a slight increase within 5 mm in largest diameter. Conclusions. These data suggest that some PGGOs will never progress to clinical disease and would be included in the category of overdiagnosis bias. However, a prior history of lung cancer should significantly raise the index of suspicion, as 4 of 5 proven cancer cases in this small series fell into that category. Because of the difficulties of preoperative and intraoperative histodiagnosis of PGGO, minimally invasive surgery may be appropriate from the viewpoints of both diagnosis and curability. (Ann Thorac Surg 2002;73:386 93) 2002 by The Society of Thoracic Surgeons In 1997, Collins and associates [1] alphabetically listed 19 lesions showing ground-glass opacity on computed tomography (CT), including acute chest syndrome, bronchiolitis obliterans organizing pneumonia, cytomegalovirus and other pneumonias, and cancer and lymphoproliferative disorders, among many others. However, most of these show a diffuse or mixed (not solitary or pure) appearance. Solitary pure ground-glass opacity (PGGO), or solitary pure ground-glass attenuation (PGGA), shadow is a new entity that has been defined by highresolution CT (HRCT) during the last half decade. In particular, small PGGOs ( 10 mm in largest diameter) were never detected by conventional chest roentgenography or early-generation CT. To date, 49 patients with PGGO have been surgically Accepted for publication Oct 16, Address correspondence to Dr Kodama, Department of Thoracic Surgery, Osaka Medical Center For Cancer and Cardiovascular Diseases, Nakamichi, Higashinari-ku, Osaka , Japan; kdm@ma2.justnet.ne.jp. treated at our institution. Most of them were discovered at annual screening using low-radiation dose computed tomography (low-dose CT) or conventional CT during postoperative of lung cancer. After surgery for PGGO, most of them were histologically noninvasive bronchioloalveolar carcinoma (BAC) [2, 3] or atypical adenomatous hyperplasia (AAH) [4]. The most recent World Health Organization histologic typing of lung and pleural tumors has classified BAC as a noninvasive subtype of adenocarcinoma of the lung [5]. The counterpart with an invasive component was classified as adenocarcinoma with mixed subtypes. Recently, Breathnach and colleagues [6] reported the favorable 5-year survival rate in patients with stage I BAC compared with the same stage of adenocarcinoma (83% versus 63%, p 0.04). We recently reported the results of semiquantitative analysis of the GGO area in the adenocarcinoma as a useful independent prognostic indicator for deciding the operative method [7]. However, because of the short history of this new entity (PGGO), its natural 2002 by The Society of Thoracic Surgeons /02/$22.00 Published by Elsevier Science Inc PII S (01)

2 Ann Thorac Surg KODAMA ET AL 2002;73: NATURAL HISTORY OF PURE GROUND-GLASS OPACITY 387 history is completely unknown. Diligent long-term will be the only means to elucidate the natural history of PGGO and to determine whether surgical intervention is acceptable or unnecessary, ie, contributing to overdiagnosis bias [8 11]. The purpose of this study was to elucidate the natural history of PGGO cases which were detectable only on CT scan and were observed for more than 2 years. Patients and Methods Between January 1996 and March 2001, a total of 49 patients with PGGO underwent operation at our institution. When we defined the period as the duration from the first detection of PGGO on CT to the operation, the preoperative median period for those 49 patients was 6 months. Of those patients, 38 underwent operation within 18 months and 1 additional patient within 19 months. The remaining 10 patients with long-term preoperative of more than 2 years were enrolled in this study to clarify the natural history of PGGO. An additional 9 patients whose PGGO is now under without operation for more than two years were also added to the present study. The estimated doubling time of asymptomatic solitary pulmonary nodules is usually less than 2 years. Thus, we thought that a longer more than 2 years would be sufficient to elucidate the natural history of PGGO. Of the 19 patients with PGGO, 10 were men and 9 were women. The average age at the time of discovery of PGGO was 62 years (range 35 to 76 years). The patients underwent periodical CT, including the HRCT, throughout their clinical course or at an annual mass screening. When the size and density were unchanged on CT after 3 months, the next CT was scheduled for 6 months later. If no change was detected on the reexamination, the next CT was scheduled for 1 year later. Pure ground-glass attenuation is defined as a shadow completely occupied with a hazy increased attenuation of the lung, with preservation of the bronchial and vascular margins in the lesion on HRCT [1]. When the PGGO is too small to palpate or is located inside of the lung parenchyma without any change in visceral pleural surface, preoperative marking under CT using a 1-mL to 2-mL cocktail with indocyanine green (25 mg/3 ml) and iohexol (300 mg/ml) was done beneath the pleura just above the target lesion. Results The demographic characteristics of the 19 patients are presented in Table 1. Pure ground-glass attenuation was discovered at an annual mass screening using low-dose CT in 11 cases, at postoperative CT examination for lung cancer in 6 cases (patients 1 to 4, 9, and 12) and for renal cell carcinoma in 1 case (patient 17), and at CT taken incidentally in 1 case. In Patients 1 to 4 and 12, the PGGO was found in the contralateral lung of the operated site and, with the exception of patient 4, was confirmed by retrospective review of preoperative CT. The smaller PGGO in patient 9 was also confirmed in the operative site by retrospective review of preoperative CT. Of the patients with solitary PGGOs, the PGGO was located in the right upper lobe in 6 patients, left upper lobe in 5, left lower lobe in 2, middle lobe in 2, and right lower lobe in 2. There were 2 patients with multiple solitary PGGOs. Patient 4 had two PGGOs, both located in the left upper lobe. Patient 11 had multiple PGGOs involving all lobes. The median was 32 months (range 24 to 124 months). The sizes of PGGOs at the time of discovery were 4 to 18 mm in largest diameter (average 8.6 mm) in the 17 patients with solitary PGGO. The largest diameters in the 2 patients with multiple PGGOs (patients 4 and 11) were 15 mm and 10 mm, respectively. During, the size of PGGO increased by more than 5 mm in 5 patients (Fig 1A and B), increased slightly (up to 5 mm) in 6 patients, and showed no change in 8 patients. Percutaneous needle aspiration cytology or histology were appropriate only in 3 patients because of the small, fine biopsy target. At each periodic examination, the advantages and disadvantages of surgical treatment, were discussed, and informed consent based on the individual PGGO characteristics was obtained. As a result, 10 patients agreed to receive surgical intervention. The remaining 9 patients elected to continue further because of the following reasons: no change in size or the PGGOs were less than 10 mm in patients 13, 14, and 17 to 19; lesions involving all lobes in patient 11; advanced age in patient 15; severe ulcerative colitis in patient 16; and poor pulmonary function in patient 12. Preoperative CT marking was used in 3 patients (patients 5, 6 and 10) in whom the PGGO was deeply seated in the lung parenchyma without any pleural changes and seemed difficult to identify during operation. Seven patients underwent wide wedge resection with a sufficient safe margin of more than 20 mm in width. Video-assisted thoracic surgery was used in 3 of 7 patients with wide wedge resection. Three patients underwent segmentectomy: patient 2 because of lesion size; patient 4, lesion number; and patient 7, lesion location. Intraoperative lavage cytology of the resection margin showed an absence of cancer cells in all 10 patients with limited resection (wide wedge resection or segmentectomy). The pathologic specimens demonstrated adenocarcinoma with mixed subtypes in 1 patient (patient 1), BAC in 4 (patients 2 to 5), lymphoproliferative disorder in 3 (patients 7 to 9), and AAH and focal fibrosis in 1 patient each (patients 6 and 10, respectively). Of note, four of five carcinomatous lesions were discovered at CT in the patients with previously resected lung cancer; these were considered as multiple primary lung cancers. The postoperative median for the 10 patients was 15 months. At present, 9 patients are alive without

3 Table 1. Patient Demographics Patient No. Age at Discovery (y) Sex No. of Lesions Means of Detection Location (lobe) Preoperative Follow-up (mo) Initial/Final Size (mm) Surgery Histology Outcome 1 57 M 1 Postoperative Left upper 124 8/25 WWR AC with MS Disease-free a 2 66 M 1 Postoperative Right lower 96 18/20 Segmentectomy BAC Disease-free 3 70 M 1 Postoperative Right upper 32 4/10 WWR BAC Disease-free 4 76 M 2 Postoperative Left upper 28 15/25 & Segmentectomy BACs Dead without recurrence?/ M 1 CT screening Middle 26 7/7 VATS WWR BAC Disease-free 6 60 F 1 Incidentally Right upper 29 6/6 VATS WWR AAH Disease-free 7 47 M 1 CT screening Right upper 39 6/10 Segmentectomy PLD Disease-free 8 35 M 1 CT screening Middle 24 11/14 WWR PLD Disease-free 9 64 F 1 Postoperative Left lower 52 10/25 WWR PLD Disease-free F 1 CT screening Right upper 37 8/8 VATS WWR Fibrosis Disease-free F Many CT screening All lobes / 10 b ND BAC or AAH c Alive with lesions F 1 Postoperative Left upper 48 18/20 ND Unknown Alive with lesion F 1 CT screening Left lower 36 6/6 ND Unknown Alive with lesion F 1 CT screening Right upper 34 5/5 ND Unknown Alive with lesion M 1 CT screening Right upper 30 10/13 ND Unknown Alive with lesion M 1 CT screening Left upper 30 8/14 ND Unknown Alive with lesion F 1 Postoperative Left lower 26 5/5 ND Unknown Alive with lesion F 1 CT screening Left upper 26 8/8 ND Unknown Alive with lesion M 1 CT screening Right lower 30 8/8 ND Unknown Alive with lesion a Involving recurrence from prior cancer. b Some of lesions have shown only a slight increase in size or density, but remained within 10 mm in diameter; c Probably. AAH atypical adenomatous hyperplasia; AC with MS adenocarcinoma with mixed subtypes; CT computed tomography; ND not done; PLD pulmonary lymphoproliferative disorder; VATS video-assisted thoracic surgery; WWR wide wedge resection. 388 KODAMA ET AL Ann Thorac Surg NATURAL HISTORY OF PURE GROUND-GLASS OPACITY 2002;73:386 93

4 Ann Thorac Surg KODAMA ET AL 2002;73: NATURAL HISTORY OF PURE GROUND-GLASS OPACITY 389 Fig 1. Computed tomogram from 57-year-old man (patient 1) with long-term of pure ground-glass opacity (PGGO) for more than 10 years. Patient had undergone operation for adenocarcinoma originating in right upper lobe 10 years previously. (A) Small PGGO in left upper lobe (arrow) was pointed out as a function of the retrospective review of conventional CT taken at that operation. (B) On 124 months later, high-resolution computed tomography shows enlargement of PGGO from 8 mm (A) to 25 mm in diameter. (C) Most of the resected specimen reveals bronchioloalveolar carcinoma (hematoxylin and eosin, 2.5). (D) Focus of invasive adenocarcinoma can also be recognized. (Hematoxylin and eosin, 66.) recurrence. Patient 4, who had two lesions of BAC, died of stomach cancer 2 years after the segmentectomy without lung cancer recurrence. Patient 1 had initially undergone operation for adenocarcinoma, with a diameter of 23 mm invading visceral pleura of the right upper lobe 124 months previously. His CT films taken before the first operation (Fig 1A) were reviewed retrospectively, and proved that his PGGO in the left upper lobe had increased during the long-term of more than 10 years (Fig 1B). The reason for the long-term was refusal of the operation by the patient. Eventually we received informed consent to the operation and successfully removed the PGGO of 25 mm diameter by wide wedge resection. Despite the increase in size, his lesion maintained the PGGO appearance on HRCT (Fig 1B) until operation. However, an invasive component was histologically demonstrated and diagnosed as adenocarcinoma with mixed subtypes (Fig 1C and D). Although a recurrence was recently discovered in this patient s right thorax, it is considered to be late recurrence of the first cancer on which the operation was conducted 124 months previously. A pulmonary lymphoproliferative disorder was found in 3 patients (patients 7 to 9). The disorder was subclassified as postinflammatory change with lymphoid hyperplasia in patient 7, as lymphoid interstitial pneumonia (LIP) in patient 8 (Fig 2), and as low-grade marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue in patient 9. The disorders included irregularly shaped air spaces surrounded by enlarged bronchioloalveolar septa with strong lymphocyte infiltration. Patient 11 underwent CT screening, which demonstrated numerous PGGO lesions that were 10 mm or less in diameter (Fig 3A) and involved all lobes. Because

5 390 KODAMA ET AL Ann Thorac Surg NATURAL HISTORY OF PURE GROUND-GLASS OPACITY 2002;73: Fig 2. Computed tomogram from 35-year-old man (patient 8) with lymphoid interstitial pneumonia. (A) After 24 months of, high-resolution computed tomography shows slight enlargement (from 11 mm to 14 mm) in diameter of pure ground-glass opacity in middle lobe (arrow). (B) Resected specimen showing irregularly shaped multiple air spaces. (Hematoxylin and eosin, 2.5.) (C) Higher-power microscopic finding reveals irregular alveolar wall thickening due to dense infiltrate of small lymphocytes. (Hematoxylin and eosin, 66.) 4 Comprehensive histologic examination of the entire specimen showed many lesions composed of BAC (Fig 3B) or AAH. Since the operation, many residual PGGOs in other lobes have been followed for 37 months; to date, although most of them remain stable, some of them have shown only a slight increase in size or density on CT. At our hospital, there were also 39 patients with PGGO who underwent operation after standard within 19 months. During the preoperative period, image-guided needle biopsy was performed in only 14 patients, and a true positive was confirmed in only 8 patients. Postoperative histologic results for these 39 patients indicated 34 with BAC, 4 with adenocarcinoma with mixed subtypes, and 1 with AAH. The average diameter of the lesions was 13.3 mm. Of the 4 patients with adenocarcinoma with mixed subtypes, the average diameter was 27.0 mm (range 15.0 to 45.0 mm). The postoperative median for these patients was 30 months. Except for 1 patient who died of cerebral infarction, all patients are alive at present, without recurrence. adenocarcinoma was shown by needle aspiration cytology in the largest PGGO found in right upper lobe, we performed right upper lobectomy in December Comment Randomized controlled trials of lung cancer screening using chest radiography have consistently shown an excessive number of cancer cases as well as longer survival in screened groups, but no difference in mortality between screened and control populations [12]. Henschke and colleagues [8] reported that, compared with chest radiography, low-dose CT greatly increases the likelihood of detection of small noncalcified nodules and, thus, of lung cancer at an earlier and more curable stage. On low-dose CT, noncalcified nodules were detected three times as often as on chest radiography, malignant tumors four times as often, and stage I tumors six times as often. Moreover, the malignant tumors detected on low-dose CT were substantially smaller than those detected on chest radiography, even within stage I. When noncalcified nodules are discovered on low-dose CT, we usually conduct HRCT to estimate the quality of the nodules. As a result, PGGO came to be identified as one subgroup of such noncalcified nodules, and the incidence of discovery has dramatically increased in the last half decade. A focal area of ground-glass opacity found on HRCT could be considered as an early sign of BAC [2, 3]. However, the natural history of the lesion occupied completely by ground-glass opacity (ie, PGGO)

6 Ann Thorac Surg KODAMA ET AL 2002;73: NATURAL HISTORY OF PURE GROUND-GLASS OPACITY 391 Fig 3. Computed tomogram from 65-year-old-woman (patient 11) with multiple pure ground-glass opacities (PGGOs). (A) Multiple small PGGOs were found in all lobes of lung. Computed tomographic slice reveals three PGGOs (arrows) in the right upper lobe. The lobe, including the maximal PGGO (10 mm in diameter), was removed. (B) Comprehensive histologic examination of resected specimens demonstrated existence of many smaller lesions revealing bronchioloalveolar carcinoma or atypical adenomatous hyperplasia. (Hematoxylin and eosin, 66.) During 37 months of postoperative, only a slight increase in size or density was recognized in some residual PGGOs scattered in all lobes. has remained unknown. The present study was conducted to elucidate the natural history and the histologic characteristics of PGGOs observed for more than 2 years. From our experience, if the PGGO is due to acute inflammation or bleeding, it usually disappears during the initial 3-month period. When the PGGO shows an increase in size or density at 3 to 6 months of, we usually recommend that the patient undergo diagnostic intervention or thoracotomy to completely remove the lesion, as a choice of management. Transthoracic biopsy guided by CT has offered an alternative to open surgical biopsy for preoperative diagnosis. Although rare, tumor dissemination after CT-guided biopsy is a potential risk [13]. Use of this diagnostic modality should be considered on an individual basis in light of the operative risk as well as the potential for curative resection [13]. On the other hand, when PGGO remained the same size and density for 3 months or more, periodic using CT should be an option, based on considerations of lesion size at discovery and patient factors such as age, cardiopulmonary function, or coexistence of other diseases. As 4 of 5 patients (patients 1 to 4) with proven cancers in this study had a prior history of lung cancer, postoperative PGGO in lung cancer patients should be closely monitored. In 1997, we reported the feasibility of segmentectomy as an intentional limited resection for selected patients with small lung cancers [14]. Because patient enrollment was completed in September 1996, only one BAC with PGGO was included in that cohort for analysis. The incidence of the discovery of PGGOs has dramatically increased since Because of a lack of clinical data regarding this new entity, we are advancing a prospective study on the feasibility of limited resection such as wide wedge resection or segmentectomy in combination with preoperative CT marking and intraoperative lavage cytology of the resection margin [15]. Given the high success rate (only one error among 41 procedures to date), we believe that our marking method is a more reliable as well as a less expensive method for detecting nonvisible and nonpalpable intrapulmonary lesions. Of course, we always confirm the complete removal of the target lesions by postoperative CT. It is often difficult to perform intraoperative histodiagnosis by using frozen sections. The PGGO is too small and soft; thus it is extremely difficult to accurately choose a suitable site for freezing. We therefore believe that the lavage cytology is preferable here. If a positive finding is obtained on lavage cytology, we prefer standard lobectomy to limited resection. We believe that this treatment modality will decrease the risk of local recurrence at the resection margin of the lung. Elective thoracotomy of smaller stage I lung cancers is less costly than treatment of later-stage lung cancers, most of which require a combination of radiotherapy and chemotherapy and may necessitate thoracotomy [8]. As a step toward the goal of therapy for patients with PGGO, it is important to elucidate the natural history of PGGO, especially to avoid overdiagnosis bias. Thus, management of PGGO (which never include early-stage aggressive cancers such as small cell carcinoma or undifferentiated carcinoma) should be different from management of small, peripheral, noncalcified solitary nodules showing soft-tissue density on CT. In conclusion, when the size of PGGO remains stable or increases only slightly over the long term, a variety of histologic entities, from BAC to benign lesions such as lymphoproliferative disorder or focal fibrosis, should be considered. A prior history of lung cancer should significantly raise the index of suspicion, as four of five proven cancers in this small series fell into that category. However, because of the difficulties of preoperative or even intraoperative histodiagnosis of small PGGO, wide wedge resection or segmentectomy in combination with intraoperative lavage cytology of the resection margin of the lung should be recommended as a safe and minimally invasive method in the treatment of PGGO.

7 392 KODAMA ET AL Ann Thorac Surg NATURAL HISTORY OF PURE GROUND-GLASS OPACITY 2002;73: This study was partially funded by a Grant-in-Aid for Cancer Research (13 9) from the Ministry of Health, Labour and Welfare, Japan. References 1. Collins J, Stern EJ. Ground-glass opacity at CT: the ABCs. Am J Roentgenol 1997;169: Jang HJ, Lee KS, Kwon OJ, Rhee CH, Shim YM, Han J. Bronchioloalveolar carcinoma: focal area of ground-glass attenuation at thin-section CT as an early sign. Radiology 1996;199: Kuriyama K, Seto M, Kasugai T, et al. Ground-glass opacity on thin-section CT. Value in differentiating subtype of adenocarcinoma of the lung. Am J Roentgenol 1999;173: Kushihashi T, Munechika H, Ri K, et al. Bronchioloalveolar adenoma of the lung: CT-pathologic correlation. Radiology 1994;193: Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E. Histological typing of lung and pleural tumours, In: Sobin LH, ed. 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The pure ground glass opacity (PGGO) is a wispy, diagnostically frustrating pulmonary infiltrate which is being detected with increasing frequency as the size of the pixels necessary for computerized tomographic resolution decreases. Presently, the management of the PGGO is more controversial than the management of the mixed GGO whose solid component is invariably found to have an adenocarcinoma/bronchoalveolar element. The unknown natural history of the PGGO is addressed in a subset of 19 PGGOs from their institutional total of 49, which makes this series one of the largest, if not the largest, in the literature. The uniqueness of having a population of GGOs which have been followed for more than two years without intervention, of which 10 are eventually resected, allows the investigators to comment not only on the natural history, but on the evolving surgical philosophy and techniques for localization and resection. The actual indications for resection remain vague and growth of a PGGO does not seem to be a failsafe for neoplasm since only 4 of 7 growing PGGOs were malignant, and 1 of the 3 non-growing lesions proved to be bronchoalveolar cancer. Neither initial size nor degree of growth correlated with pathologic diagnosis, but the take-home mes- sage is that PGGOs in patients with a previous history of lung cancer (n 5) have a high rate of malignancy (n 4). The authors have stressed that intraoperative localization can be problematic and the use of preoperative, percutaneous marking with indocyanine green may help. It is encouraging that complete resections could be accomplished with a wedge or segmentectomy, but the long-term repercussions of this conservative approach on survival or recurrence remain anecdotal at this time. The article should stimulate thoracic surgeons to think about how their practices will be impacted by ongoing, research-oriented screening programs and how these lesions should be handled in a consistent manner. That s just the rub...there is no consistent manner to handle these lesions. The dilemma begs for an international consortium of dedicated lung cancer screening clinical researchers, such as the International Early Lung Cancer Action Project, to form a retrospective and prospective registry of PGGOs in order answer basic radiographic, cytologic, pathologic and therapeutic questions. Thoracic surgeons should develop a strategic plan of collaboration with the large lung cancer screening consortia that will lead to trials which may justify less than lobectomy solutions for these patients. Moreover, the first order of business may be a randomized trial of surgical intervention versus continued surveillance in order to sort out 2002 by The Society of Thoracic Surgeons /02/$22.00 Published by Elsevier Science Inc PII S (01)