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(Chest. 2002;121:1464-1467.)
© 2002 American College of Chest Physicians

Focal Ground-Glass Opacity Detected by Low-Dose Helical CT*

Masao Nakata, MD; Hideyuki Saeki, MD; Ichiro Takata, MD; Yoshihiko Segawa, MD; Hiroshi Mogami, MD; Koichi Mandai, MD and Kenji Eguchi, MD

* From the Departments of Surgery (Drs. Nakata and Saeki), Internal Medicine (Drs. Takata, Segawa, and Eguchi), Radiology (Dr. Mogami), and Pathology (Dr. Mandai), National Shikoku Cancer Center Hospital, Ehime, Japan.

Correspondence to: Masao Nakata, MD, National Shikoku Cancer Center Hospital, Horinouchi 13, Matsuyama, Ehime, 790-0007, Japan; e-mail: mnakata{at}shikoku-cc.go.jp


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objective: Focal ground-glass opacity (GGO) has been detected increasingly by low-dose helical CT. Although focal GGO suggests in situ neoplastic lesion in the peripheral lung, it remains controversial how to manage these lesions. The purpose of this study was to evaluate the pathologic and radiologic characteristics of focal GGO in order to develop a standard of treatment for these lesions.

Patients: Forty-three patients with persistent focal GGO <= 2 cm in size from January 1998 to September 2000 were studied. Thoracoscopic lung biopsy was performed consecutively for persistent focal GGO following a several-month observation period (mean, 3.7 months).

Results: The histologic diagnoses were bronchioloalveolar carcinoma (BAC) in 23 patients, adenocarcinoma with mixed subtypes in 11 patients, and atypical adenomatous hyperplasia (AAH) in 9 patients. None of 34 carcinoma patients had lymph node involvement. All of 17 lesions >= 1 cm in size were malignant. GGO with solid components on high-resolution CT were highly associated with adenocarcinoma (malignant rate, 93.3%).

Conclusions: Persistent focal GGO after observation for several months was a finding of early adenocarcinoma or its precursor. Especially, lesions >= 1 cm in size or GGO with solid component were significant signs of malignancy. We concluded lung biopsy should be attempted for persistent focal GGO.

Key Words: atypical adenomatous hyperplasia • bronchioloalveolar carcinoma • ground-glass opacity • helical CT


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
With recent advances in CT screening, an increase in the detection of faint nodules in the peripheral lung has been noted.1 2 3 Focal ground-glass opacity (GGO) is one of those prevalent findings detected by low-dose helical CT. Focal GGO suggests in situ neoplastic lesion in the peripheral lung.4 However, because GGO is a nonspecific finding that may be caused by various disorders, including inflammatory disease, fibrosis, and neoplastic disease,5 whether lung biopsy should be considered has remained controversial. The purpose of this study was to evaluate the pathologic and radiologic characteristics of focal GGO in order to develop a standard of treatment.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients in whom small GGO was detected at initial CT scan were re-evaluated with a high-resolution CT at a 3-month interval. From January 1998 to September 2000, 46 patients were identified as having persistent focal GGO <= 2 cm in diameter. Three patients refused surgical intervention and continued scheduled follow-up CT. Therefore, a total of 43 patients received the prospective thoracoscopic surgery (15 male and 28 female patients; age range, 27 to 81 years; average, 59.4 years) after a several-month observation period (range, 1 to 24 months). Of the 43 patients, GGO was detected on helical CT screening for lung cancer in 16 patients. In the remaining 27 patients, GGO was unexpectedly identified on the CT scan for other reasons.

GGO was defined as hazy increased attenuation of the lung without obscuration of the underlying vascular markings.6 CT scanning was performed on a Somatom Plus 4 (Siemens Medical Systems; Erlangen, Germany) [helical scan with 2-mm-thick sections at one breath hold]. Sixteen to thirty-two slices with 1-mm interslice spacing were used. After reconstruction with an edge-enhancing algorithm, the images were photographed using a window level of 500 Hounsfield units (HU), a window width of 1,500 HU (lung windows), and a level of 0 HU and a width of 400 HU (mediastinal windows).

All lesions were resected after a several-month observation period. Thoracoscopic wedge lung biopsy was performed as a diagnostic procedure. When the lesion was diagnosed as carcinoma by the intraoperative microscopic examination of a frozen-section specimen, lobectomy followed except for patients with poor pulmonary reserve. The entire resected lesion was fixed in formalin and embedded in paraffin. Several 3-µm sections around the maximum diameter of the tumor were stained with hematoxylin and eosin and examined by light microscopy. According to the revised World Health Organization histologic classification, bronchioloalveolar carcinoma (BAC) was defined as a tumor exhibiting pure bronchioloalveolar growth pattern with an increase in thickness of alveolar septa and no evidence of stromal, vascular, or pleural invasion (Fig 1 ). Adenocarcinoma with a prominent bronchioloalveolar pattern that had an invasive component was classified as adenocarcinoma with mixed predominant BAC. Atypical adenomatous hyperplasia (AAH) was defined as lesion in which the involved alveoli and respiratory bronchioles are lined by monotonous, slightly atypical cuboidal to low columnar epithelial cells with dense nuclear chromatin, inconspicuous nucleoli, and scant cytoplasm (Fig 2 ).



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  		Figure 1.. Photomicrograph of BAC showing a tumor exhibiting pure bronchioloalveolar growth pattern with an increased thickness of alveolar septa (hematoxylin-eosin, original x 25).

 


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  		Figure 2.. Photomicrograph of AAH showing the proliferation of epithelial cells in a lepidic fashion with slightly thickened alveolar walls (hematoxylin-eosin, original x 25).

 

   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The mean interval from first detection of focal GGO to pulmonary resection was 3.7 months (range, 1 to 24 months). In the case of one 64-year-old woman, the size of GGO had increased during the observation period over 24 months. The remaining 42 lesions had not changed in size or density during the observation period. The histologic diagnoses were BAC in 23 patients, adenocarcinoma with mixed predominant BAC in 11 patients, and AAH in 9 patients. None of the 34 carcinoma patients had lymph node involvement. No patients have had any evidence of tumor recurrence to date, with a maximum follow-up of 32 months.

The clinical characteristics of patients are shown in Table 1 . The patients with adenocarcinoma were significantly older than those with AAH or BAC. Significant differences in lesion diameter were also noted. The diameters of adenocarcinoma were > 1.5 cm in two patients, 1.0 to 1.5 cm in five patients, and < 1.0 cm in four patients. The diameters of BAC were > 1.5 cm in 3 patients, 1.0 to 1.5 cm in 7 patients, and < 1.0 cm in 13 patients. The smallest diameter of BAC was 0.5 cm. However, all lesions of AAH were < 1 cm. The malignant rate of GGO >= 1 cm in diameter was 100% (17 of 17 lesions), whereas it was 65.4% (17 of 26 lesions) for GGO < 1 cm.


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  		Table 1.. Patient Characteristics*

 
In terms of radiologic characteristics, two types of GGO were identified for differentiation. GGO, which consisted of homogeneous translucent density, could be described as pure GGO (Fig 3 ). Another type could be described as mixed GGO, consisting of heterogeneous attenuation with a solid component (Fig 4 ). Of the twenty-eight patients who presented pure GGO, 8 patients were identified with AAH, 17 patients had BAC, and 3 patients had adenocarcinoma. Fifteen cases showed mixed GGO that were identified as AAH in one patient, BAC in six patients, and adenocarcinoma in eight patients (Table 2 ). The malignant rates were 93.3% (14 of 15 lesions) for mixed GGO and 71.4% (20 of 28 lesions) for pure GGO. Mixed GGO included a significantly high rate of adenocarcinoma (8 of 15 lesions; 53.3%). Microscopically, solid components in GGO were proved to be fibrosis or structural collapse of alveoli with fibroblastic proliferation.



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  		Figure 3.. Pure GGO. A thin-section CT showing a homogeneous focal translucent GGO. Histologic diagnosis was AAH (8 mm in size).

 


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  		Figure 4.. Mixed GGO. A thin-section CT showing a heterogeneous attenuation with solid components. Histologic diagnosis was BAC (16 mm in size).

 

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  		Table 2.. Radiologic Characteristics for Differentiation*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Since the introduction of low-dose helical CT into the lung cancer screening, small nodules in the periphery have become identifiable that could not previously be detected with conventional radiography. Several studies1 2 3 have demonstrated the increased incidence of small peripheral lung cancer by means of low-dose helical CT screening. However, as CT screening has resulted in an increasing number of indeterminate small nodules, another concern is the need of the appropriate treatment for these nodules. Focal GGO is one such indeterminate lesion.

GGO is a finding on high-resolution CT that is defined as hazy increased attenuation of the lung with preservation of bronchial and vascular margins.6 It is caused by the combined effects of diminished intra-alveolar air and increased cellular density, with alveolar cuboidal cell hyperplasia, thickening of alveolar septa, and partial filling of the terminal air spaces.4 Because GGO is a nonspecific finding, several differential diagnoses must be considered, including inflammatory diseases, focal fibrosis, AAH, and adenocarcinoma.5 The approach to the diagnosis is often difficult because of the small size of the lesion. In our study, small GGO detected at initial CT scan was re-evaluated with a high-resolution CT at a 3-month interval without immediate biopsy. Observation for several months might help in the differential diagnosis because an inflammatory lesion may resolve spontaneously or with treatment with antibiotics. However, it remains controversial whether lung biopsy should be considered for the persistent focal GGO.

Since 1998, thoracoscopic lung biopsy was prospectively performed for the persistent focal GGO after several months of observation. The pathologic diagnoses, which were BAC in 23 patients, adenocarcinoma with mixed bronchioloalveolar subtype in 11 patients, and AAH in 9 patients, were shown to be neoplastic lesions. The malignant rate was as high as 79.1% (34 of 43 lesions), whereas none of 34 carcinoma patients had lymph node involvement. These results suggest that persistent focal GGO is a significant sign of early stage of adenocarcinoma.

The differentiation of carcinoma from AAH was difficult. It should be noted that both AAH and BAC have a high incidence among women and nonsmokers. One helpful insight is the lesion size, for the mean diameter of carcinoma was significantly larger than that of AAH. Specifically, it should be noted that all lesions >= 1 cm were carcinoma without exception. A significant difference was also noted in age, which could be explained by the hypothesis of sequential development of small AAH to adenocarcinoma. The radiologic characteristic of carcinoma is heterogeneity of GGO. GGO with solid component (mixed GGO) was malignant in 14 of 15 patients, which was an extremely high rate. Some reports7 8 have already suggested the importance of these findings. We have shown microscopically that these solid components consist of fibrosis or structural collapse of alveoli, which is often seen in adenocarcinoma.

Our current results indicate that persistent GGO with solid component or GGO >= 1 cm in size should be considered as malignant, and should be treated with lung biopsy. However, findings of pure GGO < 1 cm in size were in 12 cases of malignancy, 10 cases of BAC, and 2 cases of adenocarcinoma, which were not distinguishable from AAH. Studies have demonstrated that AAH cells have some biological properties similar to those of adenocarcinoma, such as aneuploidy,9 p53 nuclear accumulation,10 and K-ras codon 12 mutation,11 which suggested that AAH might be a precursor of adenocarcinoma of the peripheral lung. Therefore, we believe thoracoscopic lung biopsy would be advisable even for such a minute GGO.

In conclusion, persistent GGO after several months of observation was an indicator of early adenocarcinoma or its precursor. GGO of >= 1 cm in size or solid component within GGO were especially informative signs of malignancy. Future research should be directed toward the natural history or prognosis of GGO lesions because, in 34 cases of carcinoma in our study, there was no increase in lesion size except for 1 case. Aoki et al12 reported that 83% of BAC detected as focal GGO on high-resolution CT had had a tumor doubling time of > 1 year. It should be studied how long and how often we should follow up these lesions. Additionally, further studies should be encouraged to determine if limited resection would be the adequate treatment for these early adenocarcinoma detected as GGO.


   Footnotes
 
Abbreviations: AAH = atypical adenomatous hyperplasia; BAC = bronchioloalveolar carcinoma; GGO = ground-glass opacity; HU = Hounsfield units

This study was supported in part by Grant for Scientific Research Expenses for Health and Welfare Programs and the Foundation for the Promotion of Cancer Research, and by Second Term Comprehensive 10-year Strategy for Cancer Control.

Received for publication January 23, 2001. Accepted for publication September 17, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Kaneko, M, Eguchi, K, Ohmatsu, H, et al (1996) Peripheral lung cancer: screening and detection with low-dose spiral CT versus radiography. Radiology 201,798-802[Abstract/Free Full Text]
  2. Sone, S, Takashima, S, Li, F, et al (1998) Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 351,1242-1245[CrossRef][ISI][Medline]
  3. Henschke, CI, McCauley, DI, Yankelevitz, DF, et al (1999) Early lung cancer action project: overall design and findings from baseline screening. Lancet 354,99-105[CrossRef][ISI][Medline]
  4. Kushihashi, T, Munechika, H, Ri, K, et al (1994) Bronchioloalveolar adenoma of the lung: CT-pathologic correlation. Radiology 193,789-793[Abstract/Free Full Text]
  5. Collins, J, Stern, EJ (1997) Ground-glass opacity at CT: the ABCs. AJR Am J Roentgenol 169,355-367[Free Full Text]
  6. Austin, JH, Muller, NL, Friedman, PJ, et al (1996) Glossary of terms for CT of the lung: recommendations of the Nomenclature Committee of the Fleischner Society. Radiology 200,327-331[Free Full Text]
  7. Kuhlman, JE, Fishman, EK, Kuhajda, FP, et al (1988) Solitary bronchioloalveolar carcinoma: CT criteria. Radiology 167,379-382[Abstract/Free Full Text]
  8. Jang, HJ, Lee, KS, Kwon, OJ, et al (1996) Bronchioloalveolar carcinoma: focal area of ground-glass attenuation at thin-section CT as an early sign. Radiology 199,485-488[Abstract/Free Full Text]
  9. Yokozaki, M, Kodama, T, Yokose, T, et al (1996) Differentiation of atypical adenomatous hyperplasia and adenocarcinoma of the lung by use of DNA ploidy and morphometric analysis. Mod Pathol 9,1156-1164[ISI][Medline]
  10. Pueblitz, S, Hieger, LR (1997) Expression of p53 and CEA in atypical adenomatous hyperplasia of the lung [letter]. Am J Surg Pathol 21,867-868[CrossRef][ISI][Medline]
  11. Kitamura, H, Kameda, Y, Ito, T, et al (1999) Atypical adenomatous hyperplasia of the lung: implications for the pathogenesis of peripheral lung adenocarcinoma. Am J Clin Pathol 111,610-622[ISI][Medline]
  12. Aoki, T, Nakata, H, Watanabe, H, et al (2000) Evolution of peripheral lung adenocarcinomas: CT findings correlated with histology and tumor doubling time. AJR Am J Roentgenol 174,1743-1763



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