Pulmonary cryptococcosis coexisting with lung cancer: a Chinese multicenter retrospective study

Introduction

The genus ‘Cryptococcus’ contains opportunistic pathogens such as Cryptococcus neoformans and Cryptococcus gattii. Pulmonary cryptococcosis (PC) is caused by infection with Cryptococcus (1,2). Cryptococcus infection is usually caused in immunocompromised individuals, such as human immunodeficiency virus (HIV)-infected individuals, solid organ transplant recipients, and other patients receiving immunosuppressive therapy (3). In recent years, with increasing awareness of the disease, there have been increasing reports of individuals with normal immunity to Cryptococcus infection (4,5). Cryptococcus gatti is a pathogenic yeast of humans and other animals, which causes disease in immunocompromised or immunocompetent hosts (6). PC can present as single nodule (mass) or multiple nodules on chest computed tomography (CT), which is difficult to distinguish from lung cancer (7,8). There are few reports of PC coexisting with lung cancer, and most of them are individual case reports (9-15). This article looked at the pathological diagnostic systems of 22 tertiary hospitals and screened 46 patients with nodular PC coexisting with lung cancer, which is currently the largest number reported. This study retrospectively analyzed the imaging features of 46 cases. We hope that us reporting the characteristics of the population, laboratory tests, treatment, and prognosis can help clinical physicians to better understand this disease. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1227/rc).

Methods

Patients

We collected a total of 4,763 cases of PC confirmed by pathology from multiple tertiary hospitals from 2015 to 2024. Finally, 46 patients with nodular PC combined with lung cancer were selected from 22 tertiary hospitals (Table S1; Figure 1). The demographic data, comorbidities, clinical manifestations, laboratory findings, radiological information, treatment modalities, and outcomes were extracted from the electronic medical records of patients. The follow-up patient information was obtained on regular clinic visits, with the last follow up taking place on 31 December 2024.

Figure 1 Patient screening process diagram.

Pathological diagnosis

The pathological specimens of 36 patients were obtained through thoracoscopic lung tissue resection, 6 through percutaneous lung biopsy, and 4 cases were diagnosed through bronchoscopy biopsy or lavage fluid. For pathological diagnosis, hematoxylin and eosin (H&E) staining served as the primary method, whereas periodic acid-Schiff (PAS) staining was specifically employed for Cryptococcus identification. After review by two pathologists, the final pathological diagnosis was determined.

Radiological assessment

All patients underwent at least one thin-layer plain chest CT scan during their first visit, and the CT description and diagnosis were reviewed by two radiologists.

Laboratory testing

Laboratory studies including white blood cells (WBC), liver function, and serum creatinine (Scr) levels were conducted for all patients at their first visit. Laboratory data were analyzed using institution-specific reference ranges from the original reporting hospitals, as documented in each patient’s first medical record. A total of 7 cases tested positive for serum cryptococcal antigen (CrAg), and these specimens were obtained from blood, cerebrospinal fluid, or bronchoalveolar lavage fluid.

Statistical analysis

The data analysis was performed with the software SPSS 26.0 (IBM Corp. Armonk, NY, USA). Data normality was evaluated through the Kolmogorov-Smirnov test. Normally distributed continuous variables were expressed as mean ± standard deviation, whereas non-normally distributed data were summarized as median and interquartile range (IQR). Categorical variables were described using frequency counts and percentages. Depending on data distribution, continuous variables were compared using either the independent samples t-test or the Mann-Whitney U-test. For categorical data, the Chi-squared test was employed. A two-sided significance level of 0.05 was adopted, with P<0.05 indicating statistical significance.

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Research Ethics Committee of Beijing Shijitan Hospital, Capital Medical University (No. sjtkyll-lx-2022). All participating hospitals were informed of and agreed to the study. The committee waived the requirement for informed consent because the study was retrospective, all information was anonymous, and there was no risk to the participants.

Results

Demographic information

The 46 patients we selected came from 11 different provinces and 22 different hospitals. These 46 patients (25 males and 21 females) ranged from 23 to 81 years of age (median: 54 years; mean ± SD: 54.74±13.01 years). There is one case with a history of contact with brown eucalyptus trees. A total of 20 patients had pre-existing medical conditions, including diabetes mellitus type 2, coronary atherosclerotic heart disease, hepatitis B, and postoperative lung cancer.

Clinical manifestations

In this retrospective cohort, the most common presenting symptoms included cough (15/46 cases, 32.6%), sputum production (8/46, 17.4%), and fever (3/46, 6.5%), whereas hemoptysis (1/46, 2.2%) and chest pain (2/46, 4.3%) were less frequent. Notably, these nonspecific clinical manifestations overlap substantially with other pulmonary infections, and a significant proportion of cases may remain asymptomatic.

Pathological analysis revealed that adenocarcinoma predominated (41/46 cases, 89.1%), with rare occurrences of squamous cell carcinoma (1/46, 2.2%) and poorly differentiated carcinoma (1/46, 2.2%) (Table 1).

Imaging characteristics

The imaging of PC coexisting with lung cancer in this article can be divided into four types—type I: solitary nodule (n=6), type II: ground-glass nodules + solid nodules (n=14), type III: multiple nodules (≥2) (n=18), and type IV: new nodules after lung cancer surgery (n=8). The above four classifications were presented in the form of pattern diagrams (Figure 2).

Figure 2 The 4 observed possible imaging forms of nodular pulmonary cryptococcosis combined with lung cancer. Type I: solitary nodule; type II: ground-glass nodules + solid nodules; type III: multiple nodules (≥2); type IV: new nodules after lung cancer surgery.

This article presents the imaging of 4 cases (patients A, B, C, D) of nodular PC combined with lung cancer. An additional 3 cases (patients E, F, G) of PC combined with lung cancer were also listed for imaging and pathological comparison. Patients A and B mainly presented with multiple nodules (type III), whereas patients C and D mainly presented with ground-glass nodules and solid nodules (type II) (Figure 3). This type of imaging presentation is usually considered as lung cancer with pulmonary metastasis before surgical resection. The imaging of patient E presented as a solitary mass, and the pathological report after wedge resection of the lung lobe showed lung adenocarcinoma with cryptococcal infection (Figure 4). The imaging features of patients F and G were ground-glass nodules and solid nodules. Preoperatively, it was believed that the solid nodule was a malignant lesion. Pathological examination after lobectomy suggested that the solid nodule was infected with Cryptococcus, and the ground-glass nodule was an early adenocarcinoma (Figures 5,6).

Figure 3 Imaging of pulmonary cryptococcosis coexisting with lung cancer [type III: (A,B) and type II: (C,D)]. (A1) is adenocarcinoma in the upper lobe of the right lung, and (A2) is a cryptococcal nodule in the lower lobe of the right lung. (B1) is adenocarcinoma in the upper lobe of the right lung, and (B2) is a cryptococcal nodule in the middle lobe of the right lung. (C1) is adenocarcinoma in the upper lobe of the left lung, and (C2) is a cryptococcal nodule in the lower lobe of the left lung. (D1) is adenocarcinoma in the upper lobe of the right lung, and (D2) is a cryptococcal nodule in the lower lobe of the left lung. The red boxes highlight the lesion sites (C1,D1).

Figure 4 Patient E’s imaging is a solitary mass (type I), and the pathological result is adenocarcinoma (hematoxylin and eosin staining) with cryptococcal infection (periodic acid-Schiff). The red arrows identify characteristic Cryptococcus forms.

Figure 5 Patient F’s (type II) imaging ground-glass nodules correspond to adenocarcinoma pathology (hematoxylin and eosin staining), whereas solid nodules correspond to cryptococcal infection pathology (periodic acid-Schiff). The red arrows identify characteristic Cryptococcus forms.

Figure 6 Patient G’s (type II) imaging ground-glass nodules correspond to adenocarcinoma pathology (hematoxylin and eosin staining), whereas solid nodules correspond to cryptococcal infection pathology (periodic acid-Schiff). The red arrows identify characteristic Cryptococcus forms.

There were 6 cases of solitary nodules (13%), distributed subpleurally. There were 14 cases of ground-glass nodules + solid nodules (30.4%), all distributed unilaterally, of which 9 cases were distributed subpleurally. The distribution of multiple nodules (≥2) on lung CT is relatively random, be it unilateral or bilateral. There were 18 cases of multiple nodules (≥2) (39.1%), with 10 cases (55.6%) distributed unilaterally, and 8 cases (44.4%) distributed bilaterally, including 8 cases (44.4%) distributed subpleurally. There were 8 cases (17.4%) of new nodules after lung cancer surgery, all distributed unilaterally, and 4 cases distributed subpleurally (Table 2).

Lobulation sign and bronchovascular bundle sign were the most common (n=17, 40.0%), followed by burr (n=16, 34.8%) and halo sign (n=14, 30.4%). Other symptoms included vacuolar sign (n=12, 26.1%), bronchograms (n=5, 10.9%) pleural indentation (n=13, 28.3%), pleural thickening (n=10, 21.7%), pleural effusion (n=3, 6.5%), and mediastinal lymph node enlargement (n=5, 10.9%) (Table 3).

The first type is solitary nodule (n=6). All 6 cases of solitary nodular type were diagnosed by lobectomy pathology, and 1 case was also confirmed to have positive CrAg testing. There were 3 cases who did not use antifungal drugs after surgery, and 6 cases had good follow-up prognosis. The second type is ground-glass nodules + solid nodules (n=14). There were 14 cases of ground-glass nodules and solid nodules diagnosed through wedge resection of lung lobes. Antifungal treatment was administered after surgery in 3 cases, whereas 8 cases did not receive antifungal treatment. The prognosis was good. The third type is multiple nodules (≥2) (n=18). A total of 12 cases of multiple nodular type were diagnosed by wedge resection of lung lobes, 2 cases were diagnosed by lung biopsy, 5 cases were confirmed by positive CrAg testing, 10 cases were treated with antifungal therapy, 5 cases were not treated with antifungal therapy, 1 case had unknown cause of death, and 17 cases had a good prognosis. The fourth type is new nodules after lung cancer surgery (n=8). There were 3 cases of newly developed nodules after surgery confirmed through wedge resection of lung lobes, 5 cases were diagnosed through lung biopsy, 7 cases were treated with antifungal therapy, and 1 case was not treated with antifungal therapy. The prognosis was good (Table 4).

Laboratory testing

Patients were divided into two groups based on the presence or absence of underlying diseases. There were no significant differences in WBC count, platelets, neutrophils, lymphocytes, transaminase, and Scr levels between the two groups (Table 5).

Discussion

There are few reports of PC coexisting with lung cancer, and most of them are individual case reports (16,17). A retrospective study reported on 2,908 patients clinically diagnosed with lung malignant tumors, of which 37 (1.3%) were ultimately diagnosed with infections through pathology, with fungal infections being the most common (n=17; 46%) (18). The most common imaging manifestation of these misdiagnosed cases was solitary pulmonary nodules (18). Our retrospective study screened 46 cases of nodular PC coexisting with lung cancer from 4,765 cases, with an incidence rate of approximately 0.96%. In actual clinical practice, it may be more prone to misdiagnosis. Pulmonary nodules are the most common radiological feature, but these are not specific to PC (19). Nodular PC presents similar imaging features to lung cancer, and positron emission tomography (PET)/CT cannot distinguish it well (1,20). All cases of lung cancer in this article were diagnosed through pathology, and postoperative detection of PC coexisting with lung cancer. Moreover, pulmonary nodules were mistakenly identified as lung cancer before surgery. This article collected 46 patients with nodular PC complicated with lung cancer, which should be the largest number of cases among the currently available literature. We divided PC coexisting with lung cancer into four categories on imaging—type I: solitary nodule, type II: ground-glass nodules + solid nodules, type III: multiple nodules (≥2), and type IV: new nodules after lung cancer surgery. The type I and type II nodules are mostly distributed subpleurally, so when we suspect the possibility of PC, percutaneous lung biopsy may be necessary. Solitary mass/nodule (type I), ground-glass nodule + solid nodule (type II), and multiple nodules have been reported in previous cases (type III), reminding us to make careful judgments and develop correct treatment plans (21,22). Postoperative new nodules do not necessarily indicate metastasis, and there is also a possibility of PC. A case report of newly developed nodules misdiagnosed as metastatic tumors after lung malignant tumor surgery, and pathological findings during thoracoscopy revealed PC (23). Studies have also attempted to use a deep learning local-global model for distinguishing nodular PC from lung cancer (24). Identifying different types of imaging characteristics can be of great benefit; not all multiple nodules in the lungs are lung cancer metastases.

PC presenting as nodules or masses is a common respiratory manifestation in immunocompetent patients. The main clinical symptoms are cough (22.3%), fever (23%), and chest pain (10.4%) (25). The main symptoms of PC coexisting with lung cancer in our study were cough (32.6%), sputum (17.4%), and fever (6.5%). We found no significant difference in clinical manifestations when PC coexisted with lung cancer; moreover, most patients had no symptoms. In this study, it was found that the blood routine, liver function, and Scr of patients with nodular PC combined with lung cancer were generally within the normal range. There was no statistically significant difference in laboratory test results, regardless of whether there was underlying disease.

In our retrospective cases, the diagnosis of nodular PC was mostly based on pathology, and there were also some cases with positive CrAg testing, with a positivity rate of about 15.5% (7/46). Adenocarcinoma of the lung accounted for the highest proportion, with only one case of squamous cell carcinoma. Some reports suggest that this is due to the fact that adenocarcinoma of the lung is mostly distributed in the periphery (22). The correlation between pulmonary cryptococcal infection and pathological types has not been reported in the literature. There were 2 cases complicated with cryptococcal meningitis (2/46). After surgical resection, some nodules were not treated with postoperative antifungal therapy, but the prognosis was good after a 1-year follow-up and no infection recurrence was observed.

This article has the following limitations: firstly, the study was retrospective and multicenter study, which may have resulted in bias during data collection and differences in laboratory values. Secondly, during the follow-up of this article, there may have been inconsistent data collection when querying the records of revisits. Thirdly, due to some missing data, this article did not provide detailed explanations on the treatment after diagnosis.

Conclusions

PC coexisting with lung cancer is relatively rare in clinical practice. This article reviews the clinical characteristics of 46 patients with nodular PC coexisting with lung cancer. Classifying the imaging manifestations of the disease into four categories allows us to gain a clearer understanding of the possible imaging manifestations of the disease.

Acknowledgments

Thanks to the research team from the Department of Respiratory and Critical Care Medicine at Beijing Shijitan Hospital. We appreciate Professor Hu Hongling and Professor Qin Lin for their help with data collection. Thanks also to all colleagues who provided data support.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1227/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1227/dss

Funding: This work was supported by National Key Research and Development Program of China (No. 2024YFC2309600); National Natural Science Foundation of China (No. 82370005); Beijing Hospitals Authority “Sailing” Program (No. ZLRK202513); Beijing Hospitals Authority “Peak” Talent Training Program (No. DFL20240703) and Excellent Talents Program of Capital Medical University (No. A2310); Industry-University-Research Innovation Fund for Chinese Universities (No. 2022IT241); the Postdoctoral Innovation Talents Support Program (No. BX20240234); National Natural Science Foundation of China (No. 82260023); and Natural Science Foundation of Guangxi Province (No. 2022GXNSFAA035646).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1227/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Research Ethics Committee of Beijing Shijitan Hospital, Capital Medical University (No. sjtkyll-lx-2022) and individual consent for this retrospective analysis was waived. All participating hospitals were informed and agreed the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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