The cases of all patients with the diagnosis of lung cancer as a result of CT screening for lung cancer in the I-ELCAP collaboration between 1993 and 2009 were reviewed to identify cancers abutting a cystic airspace of any size. Of these, 595 were identified as result of baseline screening and 111 as a result of repeat screening after a previous negative screening result according to the I-ELCAP protocol [13]. Consent was obtained from all participants according to the institutional review board–approved, HIPAA-compliant protocol at each of the collaborating medical centers. Contiguous axial CT images were acquired with a low-dose technique from the lung apices to the lung bases without the use of IV contrast material. The slice thickness for each study was 1.25, 2.5, or 5 mm, the thinner sections predominating in the recent years of data collection.

The case of each patient with a lung cancer abutting a cystic airspace was reviewed. The largest transaxial diameter of the cystic airspace was determined to the nearest millimeter on the CT image showing the largest cross section of the airspace. Similarly, the largest transaxial diameter of the cancerous nodule was determined by averaging the measured maximum length and width on the CT image showing the largest cross section of the nodule. All cancers were classified as to nodule consistency on the CT scan closest to when the diagnosis of lung cancer was made by an experienced chest radiologist at the coordinating center [14]. Circumferential thickening of the cystic airspace was calculated in degrees, 0° representing no focal thickening and 360° representing thickening of the entire wall of the airspace. This determination was made on the CT scan obtained immediately before resection in all cases and also on the baseline CT scan for the cancers diagnosed on annual repeat rounds. Circumferential thickening was estimated by viewing the cyst as a clock face on which every hour represented 30° (e.g., thickening at the 2 o’clock position would be assigned 60°). The CT images of the lungs were also assessed as to the presence or absence of emphysema in any lobe and, in particular, the lobe containing the lung cancer. The median size of the cysts and tumors was calculated. The chi-square test was used to compare percentages.

The cases of 26 patients (13 men, 13 women; median age, 64 years; range, 52–78 years) with lung cancer abutting or in the wall of a cystic airspace were identified (Tables 1 and 2). Of the 26 lung cancers, 20 manifested as solid nodules and six as subsolid nodules. The diagnosis was adenocarcinoma in 23 cases, squamous cell carcinoma in one case, non–small cell carcinoma in one case, and atypical carcinoid tumor in one case.

In the cases of 13 of the 26 patients, the lung cancer diagnosis was a result of annual repeat screenings after a previous negative screening result (Table 1). In all but one case, the cystic airspace was visible at all previous CT screenings, including initial CT at baseline, but thickening of the wall and the subsequent emergence of a nodule became apparent 12–118 months (median, 35 months) after the initial CT at baseline. The median diameter of the cystic airspace at initial baseline CT was 13 mm (range, 4–58 mm), and it was 16 mm (range, 4–40 mm) before the diagnosis of lung cancer. The overall size decreased in five cases, remained the same in two, and increased in six. The median thickness of the wall at initial baseline CT was 1 mm (range, 1–2 mm), and it increased markedly in all 13 patients to a median of 8 mm (range, 4–16 mm) before diagnosis. In all, once focal wall thickening was identified, it progressed until a nodule emerged that was ultimately diagnosed as lung cancer (Figs. 1A, 1B, 1C, 2A, 2B, 3A, 3B, 3C, 4A, 4B, 4C, and 4D). Initially when the cyst was seen, 10 of the 13 had no wall thickening. By the time the tumor was diagnosed, however, all had thickening, which varied from 60° to 360° (median, 90°) circumferential involvement of the wall of the cyst. The nodule when it emerged was solid in 11 patients and part solid in two. Emphysema was present in 11 of the 13 patients (85%), both in the same lobe and elsewhere in the lung.

Thirteen of the 26 patients had lung cancer diagnosed as a result of identification of a nodule on the first, baseline CT scan (Table 2). The median diameter of the cystic airspace was 10 mm (range, 5–25 mm), and the median wall thickness was 4 mm (range, 1–14 mm) (Figs. 5A, 5B, and 5C). The circumferential thickening of the cystic airspace before resection varied from 60° to 360° (median, 240°). The nodule was solid in nine patients, part solid in one patient, and nonsolid in three patients. In eight of the 13 patients (62%), emphysema was identified at CT as being present in the same lobe as the cancer and elsewhere in the lung.

The frequency with which the lung cancer abutted or was in the wall of a cystic airspace was significantly higher in annual rounds than in the baseline round (13/111 [12%] vs 13/595 [2%], p < 0.0001). The median circumferential wall thickening was less for those identified in annual rounds (90° vs 240°) but did not reach significance (p = 0.07).

Of the 26 patients, 25 underwent resection, and for 20 the histologic slides were available for review. In five cases, slides showed the tumor but not the cystic airspace and its wall. In the other 15 cases, the cystic airspace had the following features: In seven cases the airspace was markedly enlarged, had variably present remnants of destroyed alveolar septa, and was lined by observable pneumocytes, consistent with a bulla (Figs. 5A, 5B, and 5C). In five cases, a fibrous wall was infiltrated by tumor, lacked an epithelial lining, and did not have any features that suggested an origin from a bronchiectatic airway (Figs. 1A, 1B, and 1C). In the other three cases, the cystic airspace was subpleural, and its wall was lined by low cuboidal mesothelial cells consistent with a pleural bleb (Figs. 4A, 4B, 4C, and 4D).

The higher proportion of cancers detected with annual as opposed to baseline scans probably reflects that these cancers are aggressive, as previously found for squamous and small cell carcinomas [15]. The lesser amount of circumferential wall thickening of the cyst wall observed in cancers detected on annual compared with those detected on baseline scans (90° vs 240°) probably reflects that the former are found earlier.

A comparison of the baseline and annual scans provides insight into cancer progression. In all of the annual cancers, the wall of the airspace was initially uniformly thin, approximately 1 mm, and over time, the wall became thicker, with increased circumferential involvement, and the nodule then emerged 12–118 months (median, 35 months) after the initial CT scan at baseline. In all, the cystic airspace was clearly present before the lung cancer itself became apparent at CT. This does not mean, however, that the cystic airspace preceded the development of the lung cancer, because a tumor might not be visible on CT images but already present and have led to formation of a cyst. Possible mechanisms that have been proposed include check-valve obstruction at the terminal bronchiolar level by an inflammatory or neoplastic process that leads to formation of the cystic airspace [8]. We did, however, find one patient (Figs. 4A, 4B, 4C, and 4D) with a cystic airspace visible at baseline that remained unchanged and only 6 years later was a nodule identified (Table 1, patient: 2).

The pathologic findings in all specimens correlated well with the radiographic findings of a large dominant cystic airspace associated with carcinoma. In cases with associated emphysema, the cancer abutted a dominant discrete cystic airspace. Although the pathologic findings reflected the radiologic findings, the histologic features of the cystic lesions were variable. Such differences are not unexpected and were described in the surgical literature as early as 1925 [16]. In spite of the somewhat variable histologic features of the cystic lesions, the radiographic findings all showed a similar progression of events, which is important for clinical follow-up and patient care, as was reported by others [9]. In all cases found at annual repeat screening, CT scans showed the initial cystic airspace had a thin wall (median diameter, 1.0 mm) that subsequently became thicker; eventually the nodule emerged and the diagnosis of lung cancer was made.

We did not identify histologic features that suggested the patient had preexisting congenital cystic lung disease, such as congenital pulmonary airway malformation (formerly called congenital adenomatoid malformation), which has been associated with the development of carcinoma [1, 17, 18]. Nor were the histologic findings suggestive of other cystic lung diseases, such as sequestration, bronchogenic or enteric duplication cysts, lymphangioleiomyomatosis, or Langerhans cell histiocytosis. To our knowledge, none of the patients were known to have Birt-Hogg-Dubé syndrome [19]. None had bronchiectasis. The findings also did not suggest the presence of a preexisting cavity secondary to granulomatous disease, nor did the histologic findings suggest that the cystic space was due to necrosis and cavitation in the tumor itself.

The features of cystic airspaces are of interest because in the older literature, it was postulated that carcinomas arising in congenital cysts were preceded by atypical epithelial proliferation of the lining of these cysts, which may progress to invasive squamous cell carcinoma, as described by Womack and Graham in a report of five cases [1]. In contrast, in more recent reports of carcinoma occurring in association with congenital pulmonary airway malformation type 1, the most common type, the tumors have been mucinous adenocarcinoma, which is postulated to arise from clusters of mucinous cells in the walls of this type of congenital pulmonary airway malformation [2, 7, 20]. Neither of these scenarios is applicable to the carcinomas in our series, which contained predominately adenocarcinomas of the nonmucinous type. Other studies of carcinomas arising in association with cysts have also reported this predominance of adenocarcinoma [2, 6, 21, 22]; squamous cell and small cell carcinomas have also been reported, although less frequently [4, 6, 8, 9, 19].

A higher frequency of lung cancer in individuals with congenital cystic emphysema was reported by Korol in 1953 [2]. He and others [1, 4, 5] proposed that such cysts may interfere with ventilation and lung clearance and thus facilitate deposition of carcinogens, causing the inner lining of the cyst to become more susceptible to metaplastic transformation. The hypothesis that malignancy in cystic lesions is due to ventilation, clearance, and deposition of carcinogens may be applicable to our case series. The lack of metaplastic epithelial lining in many of the cysts in our series, however, indicates that this finding may not necessarily be a required component for development of malignancy.

Emphysema was present in 19 of our 26 patients (73%). Stoloff et al. [5] and Lee et al. [23] reported a higher frequency of lung cancer in individuals with chronic obstructive pulmonary disease and emphysema. Evidence suggests that emphysema is an independent risk factor for lung cancer because it increases the likelihood of lung cancer fourfold to five-fold and may be a contributing factor to the development of malignancy [24].

A limitation of our study was that we did not document the presence of these cystic airspaces in participants who did not have a diagnosis of lung cancer, so we cannot estimate the overall frequency with which these cysts are associated with cancer.

In summary, radiologists interpreting chest CT scans of patients at risk of lung cancer should pay careful attention to the walls of discrete airspaces because progressive wall thickening over time may represent lung cancer.

D. F. Yankelevitz is a named inventor on a number of patents and patent applications relating to the evaluation of diseases of the chest, including measurement of nodules. Some of these, which are owned by Cornell Research Foundation (CRF), are nonexclusively licensed to General Electric. As an inventor of these patents, Dr. Yankelevitz is entitled to a share of any compensation that CRF may receive from its commercialization of these patents.