Clinical significance of a solitary ground-glass opacity (GGO) lesion of the lung detected by chest CT

1. Introduction 

Recent advances in CT screening have lead to increased focal ground-glass opacity (GGO) detection in the peripheral lung [1], [2]. GGO is a finding on high-resolution CT (HRCT) lung images, and has also been described as haziness with increased lung attenuation and preserved bronchial and vascular margins [3], [4]. These characteristics may be caused by partial filling of air spaces, interstitial thickening, partial collapse of alveoli, normal expiration or increased capillary blood volume [3]. It is known that GGO is a nonspecific finding, and the appearance of a focal area of GGO in thin-section CT images can indicate a variety of disorders, such as, inflammatory disease, pulmonary fibrosis, alveolar hemorrhage or a neoplasm [3], [5]. Recently, several studies on GGO have been published because of the possibility that it represents early lung cancer. Jang et al. reported that focal areas of GGO may indicate early stage bronchioloalveolar carcinoma (BACC)[6], and Kuriyama et al. also found that the presence of a GGO area on a HRCT image is useful for differentiating a small localized BACC from a small adenocarcinoma [7]. It has also been reported that the percentage of GGO area within a solitary nodule is related to prognosis [8], [9], [10], [11].

Current reports on GGO deal with patients that have already been diagnosed as having BACC or atypical adenomatous hyperplasia (AAH). However, the disappearance or regression of a GGO lesion during clinical follow-up is not infrequent, and this encouraged us to investigate the clinical significance of GGO detected by chest CT including HRCT.

This study was designed to further our understanding of the natural history of solitary GGO and to identify predictors of benign or malignant lesions by prospective study.

2. Patients and methods 

2.2. Methods 

GGO lesions were classified as pure GGO (pGGO) or mixed GGO (mGGO) based on the presence of a solid component within a nodule on a HRCT image at a lung window level.

GGO size was defined as maximal diameter. Lesions of <1cm were followed up by chest HRCT 3 month later, and those of ≥1cm were investigated by percutaneous needle biopsy (PCNB). Lesions that increased in size beyond 1cm or with a newly developed solid component at follow-up CT were investigated by PCNB. Standard lobectomy was performed for GGOs diagnosed as malignancies (Fig. 1). Chest CT images were obtained using an MX 8000 IDT(Philips), SOMATOM sensation 16(SIEMENS) or a Light speed (General Electric) unit. Images were obtained using a window level of—600 Hounsfield units (HU), a window width of 1500HU (lung window), and a level of 30HU and a width of 400HU (mediastinal window). Conventional CT images were obtained from the thoracic inlet to the lung base using a 5mm section thickness and a 5mm section spacing, and HRCT images were obtained at a section thickness of 1mm. Two pulmonologists and two radiologists identified GGO sizes and margins, and decided on the presence of a solid portion. Complete blood cell counts (CBCs) were performed to determine leukocyte and eosinophil counts in blood. According to the 1999 WHO classification, tissues diagnosed as lung cancer were reviewed by two pathologists. Statistical analyses were carried out using SPSS 11.0. The Student's t-test was used to compare age, GGO size, WBC count, eosinophil count and the Chi-square test was used to compare sex and GGO margins between the malignant and nonmalignant groups. Statistical significance was accepted for p<0.05.

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Fig. 1. The GGO diagnostic algorithm used in this study. Single GGO lesions sized 1–3cm by chest HRCT were examined by PCNB/VATS. Follow-up chest HRCT was performed for GGO lesions <1cm.

3. Results 

3.1. Demographic findings of patients with GGO 

One hundred and eighty-six patients with GGO were included from January 2004 to December 2005, and all patients received a follow-up evaluation or definitive treatment after first evaluation. These 186 study subjects comprised 134 men and 52 women. Mean age, mean GGO size and mean follow-up duration were 54 years, 12.7mm and 8.6 months (1–24 months), respectively (Table 1).

Table 1. Clinical and radiological findings

	Total number	186
	Mean age (years)*	54.0±11.4(29–80)
	Sex	M(134), F(52)
	F/U duration (months)*	8.6±6.5(1–24)
	GGO size (mm)*	12.7±6.2
	WBC (μL−1)*	6385±1783
	Eosinophil (μL−1)*	355±442
	Eosinophil (%)*	5.3±5.7

*Mean±S.D.

3.2. Comparisons of the pGGO and mGGO groups in terms of clinical, radiographic and histologic characteristics 

Of the 186 patients with a solitary GGO lesion, 69 had pGGO and 117 mGGO. mGGOs were larger than pGGOs (pGGO: 10.0±5.9mm versus mGGO: 14.3±5.8mm, p<0.0001), and mGGOs were more spiculated than pGGOs (p<0.0001) (Table 2). Of the 69 pGGO cases, 10 were confirmed histologically, 26 were transient and 33 cases were unchanged at follow-up. Of the 117 mGGO cases, 29 were confirmed histologically, 57 were transient and 31 were unchanged at follow-up. The probabilities of disappearance or regression were 37.6% (26/69) for pGGO and 48.7% (57/117) for mGGO (Fig. 2). Most of the regressions and disappearances (23 of 26 pGGOs and 56 of 57 mGGOs were found at first follow-up, within 3 months. Fig. 3 showed the typical HRCT findings of malignant or transient pGGO and mGGO.

Table 2. Clinical, radiographic and histologic characteristics of pGGO and mGGO

	Characteristics	pGGO (69)	mGGO (117)	p-Value
	Male/female	50/19	84/33	0.92
	Age (years)*	54.6±11.5	53.6±11.4	0.58
	Size (mm)*	10.0±5.9	14.3±5.8	<0.0001
	WBC (μL−1)*	6140±1686	6522±1828	0.18
	Eosinophil (μL−1)*	275±358	401±479	0.07
	Smoking	30	59	0.48
	Nonsmoking	33	52
	Margin
	Smooth	46	34	<0.0001
	Lobulating	18	41
	Spiculated	5	42

*Mean±S.D.

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Fig. 2. Clinical courses of GGO in this study. Of 69 pGGO lesions, 26 lesions regressed or disappeared and 7 were pre-malignant or malignant. Of 117 mGGO lesions, 57 regressed or disappeared and 26 were malignant.

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Fig. 3. HRCT findings of pGGO and mGGO. (A) pGGO of RUL diagnosed as BACC (pT1N0M0). The figure on the right (A2) shows the PCNB procedure used for diagnosis. (B) mGGO in the left lower lobe diagnosed as adenocarcinoma with predominant BACC features (pT1N0M0). The right HRCT (B2) was taken 3 months after initial HRCT (B1). PCNB and left lower lobectomy were performed for persistent mGGO. (C) Spontaneous disappearance of mGGO after 3 months (C2) as compared with the initial HRCT (C1). This 62-year-old male patient showed high blood eosinophilia (15.0%) and had a history of eating raw cow liver. (D) Spontaneous disappearance of mGGO after 3 months (D2)(D1; initial HRCT). This patient showed normal blood eosinophilia (2.1%).

The characteristics of GGO lesions that were confirmed or regressed/disappeared spontaneously at follow-up were analyzed (total 122 patients: 36 pGGOs and 86 mGGOs). Patients still on follow-up evaluation (64 patients), were excluded from further analysis. Thirty-three cases (7 pGGO, 26 mGGO) were diagnosed as lung cancer, and in 89 cases (29 pGGO, 60 mGGO) lesions were benign or transient. The overall probability of malignancy for GGO was 33/122 (27.0%). Lung cancer was diagnosed in 7 of 36 (19.4%) histologically confirmed or transient pGGO cases (excluding the 33 patients that remained on follow-up), and in 26 of 86 (30.2%) histologically confirmed or transient mGGO cases (excluding the 31 patients that remained on follow-up). Therefore, no significant difference in cancer incidence rate was observed between the pGGO and mGGO groups (19.4% versus 30.2%, p=0.22) (Fig. 2, Table 3).

Table 3. Rate of malignancy according to GGO subtype and sex

		Malignancy	Benign/transient
	Total cases	33	89
	pGGO/mGGO	7(19.4%)/26(30.2%)*	29/60
	Male/female	17 (18.3%)**/16(55.2%)**	76/13

* p=0.22. ** p<0.0001.

Lung cancer was diagnosed in 17 of 93 (18.3%) men and in 16 of 29 (55.2%) women, and this difference in lung cancer incidence rate was significantly higher in women (Table 3).

3.3. Clinical, radiographic and histologic characteristics of pGGO cases 

Of the 36 histologically confirmed or transient pGGO cases, 7 were diagnosed as having a pre-malignant or malignant lesion (1 AAH, 5 BACC and 1 adenocarcinoma) and 29 pGGO lesions were diagnosed as benign or transient. The lung cancer incidence rate was significantly higher in females and nonsmokers (p=0.005, 0.049, respectively) (Table 4 and Fig. 2). Of 10 pGGO lesions confirmed histologically, we performed PCNB on eight. Seven were diagnosed by PCNB (four BACC, one adenocarcinoma, one pulmonary infiltrate with eosinophilia (PIE) and one focal inflammatory change). One undiagnosed case was treated by VATS-lobectomy and found to be AAH. VATS-lobectomy was performed in two cases without preceding PCNB, and one BACC and one type II pneumocyte hyperplasia were found. There were three pGGO lesions under 1cm among the 10 pGGO lesions confirmed histologically because of the appearance of a solid portion. One BACC, one AAH and one type II pneumocyte hyperplasia were found.

Table 4. Clinical, radiographic and histologic characteristics of pGGO cases

	Characteristics	pGGO (cancer)	pGGO (benign or transient)	p-Value
	Male/female	3/4	26/3	0.005
	Age (years)*	57.3±11.4	52.8±13.5	0.40
	Size (mm)*	15±8.5	11.1±6.2	0.21
	Pathology	AAH:1
		BACC:5
		Adenoca:1
	Stage	pT1N0M0:7 (including one AAH)
	WBC (μL−1)*	5473±1618	6654±1820	0.11
	Eosinophil (μL−1)*	159±89	370±391	0.1
	Smoking	2	20	0.049
	Nonsmoking	5	9
	Margin
	Smooth	3	14	0.82
	Lobulating	3	13
	Spiculated	1	2

*Mean±S.D.

3.4. Clinical, radiographic and histologic characteristics of the mGGO cases 

PCNB was performed on 23 of the 29 mGGO lesions confirmed histologically; the remaining six were diagnosed by VATS without PCNB. Of the histologically confirmed 29 mGGO cases, 26 were diagnosed as malignant and 3 as benign (1 aspergillosis, 1 tuberculosis and 1 type II pneumocyte hyperplasia). The 26 mGGO cases diagnosed as lung cancer were composed of nine BACCs, 16 adenocarcinomas and one large cell carcinoma (Fig. 2). Twenty-five cases were at pT1N0M0 and one case was at pT4N0M0 (adenocarcinoma) due to a satellite nodule within the same lobe, which was undetected by preoperative HRCT. We performed PCNB/VATS on five mGGOs of less than 1cm because of an increased solid portion, and three BACCs and two adenocarcinomas were found. Twenty-four cases underwent lobectomy, and two cases underwent wedge resection and concurrent chemoradiation because of poor pulmonary function. Of the 23 mGGO lesions investigated by PCNB, 4 diagnoses were revised postoperatively. One case was changed from BACC to adenocarcinoma and one case from adenocarcinoma to BACC. The other two cases were changed from atypical cells to adenocarcinoma. Women, an older age, and a spiculated margin were found to be significantly more frequent among malignant mGGO cases than among transient mGGO cases. However, in transient mGGO cases, blood eosinophil counts were statistically higher than in mGGO cases diagnosed as cancer. No difference in GGO size was observed between mGGO cases diagnosed as cancer and benign or transient mGGO cases (Table 5).

Table 5. Clinical, radiographic and histologic characteristics of mGGO cases

	Characteristics	mGGO (cancer)	mGGO (benign or transient)	p-Value
	Male/female	14/12	50/10	0.004
	Age (years)*	59.1±10.0	50.5±11.2	0.01
	Size (mm)*	16.8±5.9	14.2±5.6	0.06
	Pathology	BACC:9
		Adenoca:16
		Large cell ca:1
	Stage	pT1N0M0:25
		pT4N0M0:1
	WBC (μL−1)*	6152±1826	6733±1757	0.17
	Eosinophil (μL−1)*	153±117	591±574	<0.0001
	Smoking	6	37	0.001
	Nonsmoking	20	23
	Margin
	Smooth	2	21	0.001
	Lobulating	7	25
	Spiculated	17	14

*Mean±S.D.

4. Discussion 

Recent advances in CT screening have led to an increase in the detection of focal GGO in the lung that is undetectable by simple chest X-ray [1], [2], [12], and created considerable interest in the relation between GGO and lung cancer. Kakiruma et al. analyzed the progressions of eight pGGO cases diagnosed as lung cancer, and classified these during follow-up into three types: those that increased in size (increasing type, n=5), decreased in size with the appearance of a solid component (decreasing type, n=2), and those that were stable in size but increased in density (density type, n=1)[13]. Nakakima et al. suggested that patients with a localized pGGO should undergo pathologic examination, because 60% of surgically resected pGGOs were pathologically diagnosed as carcinomas [3]. However, there were disappearing lesions among these GGO lesions, and malignancy rates differed for pGGO and mGGO lesions [14]. Because of the different levels of progression shown by GGO lesions their management is difficult. To our knowledge, the difference between persistent GGO and disappearing GGO (including the distinction between pGGO and mGGO) has not been examined by prospective study. In a previous study, GGO was classified as pGGO or mGGO according to TDR (the tumor shadow disappearance rate) [9], but in the present study, we defined a GGO lesion as mGGO when it contained a solid portion in the pulmonary window level setting.

Men predominated (72%) in this study, which may have been associated with a higher lung cancer screening rate among men, because GGO cases were almost asymptomatic and were detected by routine screening by low dose chest CT.

In the present study, we analyzed 122 GGO cases (36 pGGO, 86 mGGO) that were histologically confirmed or in whom lesions disappeared, and we excluded 64 cases that were being followed up. The malignancy rate for mGGO (30.2%) appeared higher than that of pGGO (19.4%), but this was without significance, which may have been due to the small number of pGGO cases analyzed. In the present study, malignancy rates for the GGO types were lower than those reported previously [14], [16], which was caused by our inclusion of cases with a transient GGO lesion. When only histologically confirmed cases were included, the malignancy rates of pGGO and mGGO were 70 and 89.6%, respectively, which are similar to the 71.4 and 89.6% reported by Nakata et al. [14]. The higher malignancy rate of female GGO lesions could be explained by the fact that most GGO lesions diagnosed as cancer were BACC or adenocarcinoma in previous studies [9], [13], [14], and because a large proportion of female lung cancer cases were due to adenocarcinoma [17]. In the present study, 32 of the 33 GGO cases diagnosed as having cancer were of stage pT1N0M0 and one was of stage pT4N0M0 due to a satellite nodule in the same lobe. These findings concur with those of previous studies, which found that almost all GGO lesions diagnosed as cancer were at stage I [8], [15], [18]. In one previous study, extrathoracic metastases were identified in 13% of patients at the time of diagnosis and in 11% of patients at 1-year follow-up examinations, even in those with stage pT1, but no extrathoracic metastasis was observed [19]. This may have been because more patients with a solid nodule were included in this previous study than in the present study. Although it was reported recently that small sized pGGOs are good candidates for limited resection [15], [18], [20], [21], [22], lobectomy was performed in all cases diagnosed as cancer in the present study, which is in-line with the recommendations of the Lung Cancer Study Group report of 1995 [23]. In pGGO cases diagnosed as cancer, the proportion of women and nonsmokers was significantly larger than among transient pGGO cases, but no association was observed between pGGO and size or age.

Our main interest when we undertook this study was to investigate the clinical progression of GGO (Fig. 2, Fig. 3), and to identify those factors that predict benignity or malignancy, because a significant portion of GGO lesions (26/69 pGGO and 57/117 mGGO) disappeared or regressed during follow-up. Furthermore, most of these events (23/26 pGGO and 56/57 mGGO) were detected at first follow-up HRCTs performed within 3 months of initial HRCTs.

Blood eosinophil counts in transient mGGO cases were significantly greater than in mGGO cases diagnosed as cancer. This finding suggests that a pulmonary infiltrate with eosinophilia might be the cause of transient GGO, especially of transient mGGO. PIE may appear as a solid infiltrate with surrounding GGO (also described as a halo). Even though in most cases PIE appeared as a multiple infiltrate, in some it could have presented as a single lesion. Therefore, blood eosinophil count is expected to be a useful predictor of lesion benignity or malignancy in mGGO.

This study has several limitations. First, the follow-up duration of our study was shorter than that of other studies. Therefore, a large number of cases (64 of the 186) remain on follow-up due to a short observation period (the natural history of BACC requires at least a 2–3 year follow-up). Nevertheless, we believe that our findings will be found useful by other clinicians managing GGO because most GGO regressions or disappearances were found at first follow-ups. However, there is a possibility of an increased risk of cancer associated with GGO lesions after long-term follow-up. The second limitation is that a high proportion of Korean people consume raw meat, liver and fish, which might be related to a high incidence of transient single GGO as a manifestation of PIE. The third is that all enrolled patients were Koreans, and it is well known that adenocarcinoma, especially bronchioloalveolar cell carcinoma, in Asians differs from that in Caucasians. Therefore, racial and epidemiologic factors should be considered when interpreting our findings.

5. Conclusions 

A female gender and a mGGO with a spiculated border were identified as risk factors of GGO lesion malignancy. A significant proportion of GGO lesions were transient or regressed after only 3 months of follow-up. It was found that a high blood eosinophil count, especially in mGGO patients, strongly suggests a benign nature. We recommend that short-term follow-up by chest HRCT rather than by invasive diagnostic workups be adopted for mGGO lesions in the presence of eosinophilia regardless of lesion size.

Conflict of interest statement 

All authors declare that we do not have any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within 3 years of beginning the work submitted that could inappropriately influence our work.