The present study demonstrates that pars-solid GGN and pure GGN can have a different evolution during a 3-year follow-up. In patients with a history of cancer (or at high risk of lung malignancy), the presence of a pure or pars-solid GGN can be linked with new cancer or metastasis in a small percentage of cases (3/68 = 4,4%). However, if the pars-solid is present, FDG PET/CT is useful to identify the presence of lung malignancy with a sensitivity of 100%, while in case of pure GGN or small pars-solid GGN, CT imaging remains the preferred imaging modality.
During their follow-up period, cancer patients may develop numerous pulmonary abnormalities, from progression of disease with the appearance of lung metastases or a secondary lung neoplasm, to potential for disease and/or chemotherapy related immunosuppression. Chemotherapeutic drugs can also be pneumotoxic and cause lung parenchymal lesions. In a patient with known or suspected neoplasia, the diagnostic work-up for the appearance of one or more solid nodules on CT is well-defined since these have been proven to be metastases in 73% of cases (Seo et al., 2001). In contrast, the underlying cause of GGNs or part-solid GGNs is unclear. In the present study, we assessed the clinical significance of GGNs and part-solid GGNs in 68 oncology subjects during their observational period. All patients underwent serial CT scans for the characterization of nodules for a period of 3 years.
We found that only three patients showed a slow increase in the size of both ground-glass and solid components. Therefore, although the development of GGNs and part-solid GGNs in our case series is relatively rare (prevalence of 0,6%), a better interpretation of these findings is nevertheless important for clinical management. A few reports have described metastases with GGNs or part-solid GGNs components (Park et al., 2008; Attinà et al., 2013; Yanagitani et al., 2009). For example, Park and colleagues (Park et al., 2008) reported that the majority of part-solid GGNs were primary lung malignancies (67.8% adenocarcinoma and bronchiolo-alveolar carcinoma). These authors further showed that malignant lesions more likely had a larger ratio of solid to ground-glass component when compared to benign lesions (atypical adenomatous hyperplasia or AAH, focal fibrosis, and chronic granulomatous inflammation). In the recent report by Attina et al. (Attinà et al., 2013), the evolution of subsolid pulmonary nodules in cancer patients, seven out of 146 nodules were histologically confirmed as metastasis from extrapulmonary primary malignancy and five out of 146 confirmed as primary lung malignancy. Yanagitani et al. (Yanagitani et al., 2009) reported that ground glass metastases are uncommon findings in patients with previously diagnosed lung cancer and are difficult to distinguish from a second multifocal lung cancer. In their work, the authors reported that most of the GGNs in patients with pulmonary malignancy did not demonstrate any changes during follow-up and were histologically confirmed to be AAH. In contrast with Park’s series, in ours the progressive transformation of a GGN (9 mm) in a solid nodule (12 mm) with a surgical diagnosis of primary lung adenocarcinoma was present in only one patient. Moreover, we present some data also in contrast with Attinà et al. (Attinà et al., 2013), with a similar number of nodules tested (130 vs. 146) but with a different number of primary tumors. This difference can be due to the fact that most patients in our series (53/68, 78%) did not develop new lesions or changes in the original lesions. GGNs and part-solid GGNs remained unchanged both in the solid part (when present) and in the ground glass, for a median CT follow up of 18 months. This stability of the lesions would favor the non-metastatic hypothesis, even in the presence of metastasis in other organs. The lack of histological or biopsy information did not allow us to ascertain the origin of the nodules.
As reported in literature, the probability of malignancy is variable with regard to the densitometric features of the lesions (part-solid GGNs: 63%; GGNs:18%; solid PNs: 7%) (Leef & Klein, 2002). Guidelines for the management of GGNs and part-solid GGNs in patients without a previous diagnosis of cancer have been proposed and recently reviewed by Godoy and Naidich (Godoy & Naidich, 2009). In contrast with solid nodules guidelines, those for GGNs and part-solid GGNs do not distinguish patients at high risk from those at low risk for a pulmonary tumour. This is due to a: a) high incidence of adenocarcinomas (that frequently appear as GGNs or part-solid GGNs) in young nonsmokers; b) 2-year follow up not being long enough to characterize these lesions as benign or malignant, as they ought to be followed for at least 3 years. It should be noted that PET/CT does not have a role in the management of this kind of lesions since, as reported by many authors (Kim et al., 2012a; Chiu et al., 2012), adenocarcinomas of the lung show low FDG uptake and have low probability of nodal or distant metastasis (Kim et al., 2012b). In the present report, we found a significant uptake of FDG in only three patients with part-solid lesions that showed progressive changes at CT scans. FDG PET/CT cannot replace diagnostic CT in the definition of GGN due to: 1) the resolution power of a diagnostic CT is higher (5 mm vs 2 mm, respectively for PET/CT and diagnostic CT); 2) breathing during the scans (free breathing during PET/CT and deep-inspiration breath-hold during diagnostic CT) and 3) cost savings. For this latter point, based on the Italian tariffs, the costs of a thoracic diagnostic CT is significantly lower than a whole-body FDG PET/CT (77,67€ for CT without contrast enhancement-ce or 124,11€ with ce vs. 1.094,00 € for PET/CT, based on the Italian Healthcare System). However, PET/CT remains useful to characterize the pars-solid of the GGN, particularly in patients at high risk of metastases (i.e. patients with a history of cancer).
Conversely from GGNs, part-solid GGNs likely represent invasive malignancies with a high “a priori” probability and should receive a follow up CT at 3 months. If in this period, part-solid GGN has not disappeared or decreased in dimensions, it should be surgically resected after a FDG PET/CT examination. Controls that are too close in time are thus not indicated, and this is consistent with our findings, since nodules followed up at 1 month did not show any variation.
The actual guidelines for GGNs and part-solid GGNs (Naidich et al., 2013) are not be reproducible in subjects with other known neoplasms, even if the nodule characteristics are similar both in oncology and non-oncology subjects. From our analysis it emerged that the presence of stable and single or multiple GGNs in 46/53 patients (87%) during the follow-up of 48 months was indicative of a benign lesion, not an evolving one (such as AAH or small areas of fibrosis-AIS).
In many cases, oncology patients are immunodepressed due both to the neoplasm and to the specific therapy and therefore, they have a higher probability of infection. This latter condition can be masked by the general clinical conditions of the patient, particularly during pharmaceutical administration. In oncology subjects, among many of the pathogens that are correlated with opportunistic infections of the lung, some can determine parenchymal alterations such as GGNs or part-solid GGNs. In our series, GGNs rapidly disappeared (~2 months) in eight patients without any treatment. These lesions were correlated with small inflammatory processes, both non-specific or in relation to organizing pneumonia.
Moreover, many drugs can determine pulmonary toxicity, with the appearance in 10% of patients undergoing chemotherapy (Hurria et al., 2011). Bleomycine, cyclophosphamide, carmustine, busulfan and methotrexate are more frequently correlated with pulmonary toxicity, but more recent experimental drugs for oncology patients can cause similar alterations (Cooper Jr et al., 1986; Erasmus et al., 2002). Early diagnosis is important for the progressive worsening of the clinical condition, if the pharmacological agent is not withdrawn. In the present report, potentially pneumotoxic drugs (sorafenib, sunitinib, taxolo, cisplatino) were employed in nine enrolled patients. In four of these patients, CT examinations showed the appearance of multiple GGNs during therapy that disappeared after a median period of 3.5 months without any specific treatment.
Therefore in our series, all disappearing nodules during follow-up resulted pure ground glass at CT scan. Conversely, all increased nodules were part-solid GGNs. The radiological characteristics of lung nodules can be useful for oncologists in guiding the correct therapeutic choice during the follow-up of their patients.
Limitations of the present report are associated with the lack of bioptic or surgical confirmation in each case where pure and part-solid GGs did not demonstrate significant variations during follow-up. Moreover, being a retrospective study, follow-up periods were not homogeneous. Finally, the number of cases is limited, although it is not so different from other similar work that was conceived in a similar clinical-radiological setting. Lastly, we reconstructed CT images by using 2.0 and 2.5 mm in slice thickness. Although the current recommendations by Naidich et al. (Naidich et al., 2013) reported that to establish lesions as true GGNs, a thin CT section of 1 mm is preferable, whenever possible, other previous reports, such as Park et al. (Park et al., 2008), have demonstrated that a thickness between 1 and 5 mm can be considered. Moreover, the present study was conceived in an oncology setting where patients are frequently sent to multiple diagnostic examinations.