Ann Thorac Surg 2006;81:1194-1197
© 2006 The Society of Thoracic Surgeons
Original article: General thoracic
Pathologic and Biological Assessment of Lung Tumors Showing Ground-Glass Opacity
Yasuhiko Ohta, MD
a
,
*
,
Yosuke Shimizu, MD
a
,
Takeshi Kobayashi, MD
a
,
Osamu Matsui, MD
b
,
Hiroshi Minato, MD
c
,
Isao Matsumoto, MD
a
,
Go Watanabe, MD
a
a Department of General and Cardiothoracic Surgery, Kanazawa University School of Medicine, Kanazawa, Japan
b Department of Radiology, Kanazawa University School of Medicine, Kanazawa, Japan
c Department of Pathology, Kanazawa University School of Medicine, Kanazawa, Japan
Accepted for publication October 31, 2005.
* Address correspondence to Dr Ohta, Department of General and Cardiothoracic Surgery, Kanazawa University School of Medicine, Kanazawa, 920-8641 Japan (Email: yohta{at}med.kanazawa-u.ac.jp).
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Abstract
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BACKGROUND: We evaluated the pathologic and biological aspects of lung tumors 3.0 cm or less in diameter with the appearance of ground-glass opacity (GGO).
METHODS: Of 988 patients with non-small cell lung cancer who underwent operations at our institute between January 1994 and December 2004, 87 resected lung tumor specimens that showed GGO appearance on helical computed tomography were obtained from 81 patients. Forty-four lesions were pure GGO with no solid component in the tumor and 43 lesions were mixed GGO consisting of areas of attenuation with a solid component. Together with histological features, MIB1 and nm23 expression within tumors were examined immunohistochemically.
RESULTS: The mean tumor size in the pure GGO group was significantly smaller than that in the mixed GGO group. The composition of pathologic subtypes and biological characteristics were clearly different between the two groups. Although atypical adenomatous hyperplasia and localized bronchioloalveolar cell carcinoma of Noguchi's A and B were the predominant pathologic subtypes and nm23 negativity was rare in the pure GGO group, a high score for expression of MIB1 was often found in pure GGO tumors even though the tumors were less than 10 mm in diameter.
CONCLUSIONS: If the tumor is 2 cm or less in diameter, the ability of invasion and metastasis seems to be low in pure GGO tumors. However, the proliferation ability of these tumors suggests the necessity of a careful follow-up schedule if the tumor is greater than 5 mm in diameter. For mixed GGO tumors, surgical resection instead of observation is justified.
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Introduction
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With the advent of radiology (ie, helical computed tomography [CT]) mass-screening systems, our thoracic surgeons have often encountered tiny or small lung nodules with the appearance of ground-glass opacity (GGO). Interestingly some recent investigators have begun to address the possibility of lung parenchymal sublobar limited resection for this specific subgroup of small lung cancers with GGO appearance [1–7]. Although operative procedures are generally dependent on size, number, and location of the lesions, limited resection procedures such as the wedge resection are a well-recognized form of operative procedure for small-sized pure GGO. The basis of this surgical tactic is the observation that noninvasive localized bronchioloalveolar carcinoma (LBAC) and atypical adenomatous hyperplasia (AAH) are the dominant pathologic types in tumors with pure GGO appearance, and the risk of regional nodal metastasis is very low [8, 9]. On the other hand, in the management of pure GGO, the timing of the operation is also controversial. In the management of small-sized pure GGO, although some authors advocate a positive stance for video-assisted thoracic surgery biopsy, others recommend a careful follow-up schedule in Japan. Here, although surgery remains the main form of treatment for localized nonsmall cell lung cancer, indications for surgical treatment for pure GGO remain obscure. To address this issue more information is required, including determination of the biological aspects of this specific subgroup of lung tumors. The present study was performed to evaluate both pathologic and biological aspects of small lung tumors with GGO appearance.
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Patients and Methods
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Between January 1994 and December 2004, a total of 988 patients with nonsmall cell lung cancer underwent operations at Kanazawa University Hospital. Among these cases, 87 resected lung tumor specimens measuring 3.0 cm or less in diameter that showed GGO appearance were obtained from 81 patients (33 men and 47 women; mean age, 63.6 ± 1.4; range, 36 to 86 years). Ground-glass opacity appearance, which showed a diffuse increase in attenuation without obscuring the underlying vascular markings, was reviewed on helical CT by two to three independent observers including a radiologist who are diagnostic experts in chest radiology. Pure GGO was defined as a homogeneous GGO with no solid components, and mixed GGO was defined as a GGO consisting of areas of attenuation with a solid component. Forty-four lesions obtained from 39 patients were pure GGO and 43 lesions from 42 patients were mixed GGO. For pure GGO we performed thoracoscopic wedge resection after computed tomographic-guided marking if the tumors were not diminished after several months of follow-up. For mixed GGO, we performed a video-assisted thoracic surgery biopsy by wedge resection instead of follow-up by CT. Generally, the final operative procedures for lung parenchymal resection were determined by the location of the tumor and intraoperative frozen section diagnosis. For patients with definite diagnosis of LBAC of Noguchi's type A/B [10] or AAH 1.0 cm or less in diameter, we completed the operation by wedge resection with a clear surgical margin of more than 1 cm. For patients with invasive carcinoma or uncertain intraoperative pathologic diagnosis with regard to Noguchi's classification, we performed standard resection (ie, lobectomy plus systemic lymphadenectomy). If the area of pure GGA was 1.0 to 2.0 cm in diameter and the location was definitely restricted to the left upper lobe or S6 segment, we generally performed segmentectomy instead of standard lobectomy. We performed lobectomy in patients with pure GGO measuring more than 2.0 cm in diameter. Written informed consent was obtained from all of patients included in the present study.
Immunohistochemical Assessment of nm23 and MIB1
In this study, we performed immunohistochemical assessment of proliferative activity using the monoclonal antibody MIB1, which detects the proliferation-associated antigen Ki-67. In addition to this marker of proliferative activity, we also explored the metastatic ability by assessment of nm23 expression. We selected this metastasis-associated marker because we previously confirmed its association with nodal micrometastasis in nonsmall cell lung cancer patients in the early stages of disease [11].
The primary antibodies used in the present study were an anti-nm23 monoclonal antibody (Dako Corporation, Carpinteria, CA) diluted 50-fold and an anti-MIB1 monoclonal antibody (Dako) diluted 50-fold. After reviewing the hematoxylin and eosin-stained slides of the tumor specimens, we selected blocks of the edge of the tumor area. Paraffin-embedded tumor tissues were cut into sections 4 µm thick, deparaffinized, and immunohistochemical staining was performed using the labeled streptavidin-biotin method, as previously described [11].
For assessment of nm23 protein expression, tumors were considered positive if all the epithelial cells in the lesion showed cytoplasmic staining. If any of the epithelial cells were unstained, they were considered negative [12]. Evaluation of MIB1 staining was carried out within areas with a high degree of cellularity [13, 14]. After all fields of the sections were scanned at low (x40) and high (x400) power, we selected the three most strongly stained areas and color photographs were taken in high power fields. More than 1,000 tumor cells were counted on the photographs, and proliferative activity was scored as the percentage of MIB1-positive tumor cells [13, 14].
Statistics
Associations between variables were analyzed with the 
2 test. The Mann-Whitney U test for differences in mean values was used for comparison of nominal data. Mean values are shown ± the standard error.
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Results
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The basic clinicopathological background characteristics are shown in Table 1. There were no significant differences in gender, age, or tumor location (right vs left, upper lobe vs lower lobe) between pure GGO and mixed GGO groups (Table 1). The mean tumor size in the pure GGO group was significantly smaller than that in the mixed GGO group (9.2 ± 0.5 mm vs 15.5 ± 0.8 mm; P < 0.0001). In the pure GGO group, 5 patients with GGO more than 10 mm in diameter selected initial operation, and 39 patients underwent follow-up work before operation. Of 40 lesions in these patients, 6 lesions increased in size in the mean period of 8.3 ± 3.0 months (range, 2 to 22 months), and the remaining 33 lesions showed no change in size in the mean period of 7.2 ± 1.5 months (range, 2 to 45 months). The operative procedures used for pure GGO tumors were wedge resection in 30 cases, segmentectomy in 2 cases, and lobectomy in 6 cases, whereas those for mixed GGO tumors were wedge resection in 8 cases, segmentectomy in 2 cases, and lobectomy in 32 cases. Pathologic subtypes of the tumors of 2.0 cm or less in diameter with pure GGO appearance were AAH in 7 cases, LBAC of Noguchi's type A in 25 cases, LBAC of Nuguchi's type B in 9 cases, and invasive adenocarcinoma of greater than Noguchi's type C in 2 cases. The pathologic type of one pure GGO measuring 2.2 cm in diameter was LBAC. Tumors with mixed GGO appearance were AAH in 0 cases, LBAC of type A in 5 cases, type B in 12 cases, and invasive adenocarcinoma in 26 cases. The composition of pathologic subtypes was clearly different between the two groups.
With respect to the two biological markers, nm23 staining was found in the epithelial component and was mainly cytoplasmic in tumor cells, whereas MIB1 protein showed nuclear staining. There were significant differences in both nm23 and MIB1 expression between the pure GGA group and the mixed GGA group (Table 2). That is, nm23 expression was greater, and MIB1 expression score was lower in tumors with pure GGO appearance as compared with tumors with mixed GGO appearance. The pathologic distribution and biological characteristics of tumors 2.0 cm or less in diameter with pure GGO appearance are summarized in Table 3. Although AAH and noninvasive LBAC were predominant pathologic types of pure GGO tumors, invasive adenocarcinoma of Noguchi's C type was found in only 2 lesions (4.5%) among 44 pure GGO tumors. There were no significant differences in nm23 or MIB1 expression between pure GGO tumors 10 mm or less in diameter and those that were 10 to 20 mm in diameter. Among these three pathologic and biological factors (ie, invasive adenocarcinoma, nm23 negativity, and high MIB1 score), none of the tumors had multiple factors simultaneously if the tumor size was 1.0 cm or less in diameter.
At less than the median follow-up period after a surgery of 18 months (range, 2 to 127 months), 2 patients died of diseases other than lung cancer and 1 patient in the mixed GGO group who underwent partial resections for multiple lesions had bone metastasis develop 18 months after the operation. The pathologic type of this patient with recurrent disease was Noguchi's type C adenocarcinoma (10 mm in diameter). This type C lesion showed negativity for nm23 and an MIB1 expression rate of 10%.
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Comment
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Although clinical roentgenographic data on the natural history of small lung tumors with pure GGO appearance are sparse, a previous study showed that lung cancer nodules with pure GGO appearance do not only increase in size or density, but also decrease in size with the appearance of a solid component [15]. Therefore, although an increase in size or density, or both, suggests the absolute necessity of surgical removal, a decrease in size does not exclude the requirement of surgery. In our series, excluding 5 patients with initial operation, 34 patients with 39 pure GGO lesions went through observation with a mean follow-up period of 7 months. Six lesions increased in size, 33 lesions showed no change in size or density, and no lesions were found to have decreased or diminished in size. With respect to the operative indications in this study, as described in the Patients and Methods section, we performed video-assisted thoracic surgery for mixed GGO. Cases of pure GGO (2 cm or less in diameter) were observed for several months to exclude inflammatory changes. As the result of pathologic examination of resected specimens, 87 lesions with GGO appearance were all found to be tumors.
Pathologically, the Noguchi's classification has prevailed in Japan as a useful indicator of postoperative outcomes that would serve as a pathologic basis for the selection of patients who would benefit from limited surgery. Interestingly, several cases of noninvasive LBAC of so-called Noguchi's A and B types revealed pure GGO appearance. In our series, consistent with previous studies, a large number of pure GGO tumors were included in Noguchi's A or B adenocarcinoma or AAH, despite the tumor size. As lung cancers of Noguchi's type A and B are free from nodal metastasis, including micrometastasis [16], this observation seems to support the validity of limited operation for pure GGO (measuring 2.0 cm or less in diameter).
In this study, we further assessed the expression of two biological markers by immunohistochemical analysis: (1) MIB1 is a marker of tumor proliferation, and (2) nm23 is a putative anti-metastatic gene representing a metastasis-associated marker. Previously we confirmed that nm23 expression in early-stage nonsmall cell lung cancers is inversely correlated with nodal micrometastasis. In the present study, using these two novel markers that mirror biological aspects of the tumors, we found significant differences in their expression between pure and mixed GGO groups. These findings support the hypothesis that mixed GGO tumors represent relatively high-grade malignancy with faster growth and greater metastatic ability in comparison with pure GGO tumors. These results also compare well with the observation that the mean tumor size in the mixed GGO group was significantly greater than that in the pure GGO group. In pure GGO tumors, a low MIB1 expression score and negativity of nm23 expression were found regardless of the size of the tumors. If we look at the critical diameter of pure GGO tumor less than that at which any factors among (1) pathologically invasive type (Noguchi's C 
), (2) high score of MIB1 expression (> 5%), and (3) negativity of nm23 expression were not identified, pure GGO less than 5 mm in diameter satisfied the criteria (data not shown). Although further studies in larger numbers of clinical cases should be performed, we concluded that pure GGO 5 mm or less in diameter does not require treatment and observation over a long period of time by CT is the best option. Based on our observation that several pure GGO tumors showed high MIB1 scores even though pathologic examination revealed noninvasive Noguchi's A/B type, we concluded that a careful follow-up schedule would be needed for tumors in this category measuring more than 5 mm in diameter.
In conclusion, based on the pathologic features and expression of nm23, the invasive and metastatic potential seems to be low in pure GGO tumors. In addition, this tendency was retained irrespective of tumor size in tumors less than 2 cm in diameter. On the other hand, the tumor proliferative ability assessed by MIB1 expression seems to not be necessarily low, and careful observation is needed in cases in which the tumor is more than 5 mm in diameter. However, surgical resection is justified instead of observation for mixed GGO tumors.
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References
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Abstract
Introduction
