Lung adenocarcinoma concurrent with pulmonary cryptococcosis: a case report and literature review

Abstract

Pulmonary cryptococcosis (PC) is a common opportunistic fungal infection caused by Cryptococcus neoformans or Cryptococcus gattii. PC primarily invades the respiratory system, followed by the central nervous system. Few clinical reports have examined the coexistence of PC and lung cancer. This study reports the case of a 54-year-old immunocompetent PC patient with lung adenocarcinoma. Chest CT revealed multiple nodules in the right lung, with the largest nodule located in the dorsal segment of the right lower lobe. 18 F‑FDG positron emission tomography-computed tomography (PET-CT) revealed elevated glucose metabolism in the dorsal segment of the right lower lobe, which suggested lung cancer. The metabolism level of the nodule in the basal segment of the right lower lobe and the anterior segment of the right upper lobe was not abnormally increased, but the possibility of a malignant tumour could not be excluded. The pulmonary nodules in the dorsal segment and the basal segment of the right lower lobe were simultaneously resected via video-assisted thoracic surgery (VATS), and the final histopathology revealed primary lung adenocarcinoma and pulmonary cryptococcal infection, respectively. After surgery, antifungal treatment was administered for 3 months. Over the 3-year follow-up, contrast-enhanced computed tomography (CT) revealed no recurrence of either disease. This case study highlights the possibility of dualism in the diagnosis of multiple pulmonary nodules on chest CT, such as the coexistence of lung cancer and PC. Surgical resection is recommended for micronodules that are not easy to diagnose via needle biopsy; in addition, early diagnosis and treatment are helpful for ensuring a good prognosis. This paper reports the clinical diagnosis and treatment of one patient with pulmonary cryptococcal infection of the right lung complicated with lung adenocarcinoma, including 3 years of follow-up, providing a reference for clinical practice.

Introduction

Cryptococcus species are important fungal pathogen bacteria that cause invasive infections. They are more common in some immunocompromised patients, including patients with HIV infection, solid organ transplantation, cancer, diabetes, and treatment with corticosteroids or immunosuppressants [1]. In recent years, the incidence of cryptococcal infection in immunocompetent hosts has increased [2]. This infection is caused mainly by Cryptococcus neoformans and Cryptococcus gattii and is most often detected in the lungs, followed by the central nervous system. A few patients may develop pulmonary cryptococcosis (PC) infection, which can spread to the nervous system [3].

Radiologically, pulmonary cryptococcal infection is nonspecific and correlated with the immune status of the host [4, 5]. Isolated cryptococcal nodules are a common radiological manifestation in immunocompetent patients [6]. Moreover, air bronchograms in nodules or masses are significantly more common in immunocompetent individuals than in immunocompromised patients, whereas cavities within nodules/masses are more likely to be seen on chest CT in immunocompromised patients, such as individuals with AIDS [7]. PC lesions are most often found in the right lung [8]. When PC is characterized by nodules or masses, its imaging manifestations are easily confused with those of lung cancer and lung metastasis [9].

The association between lung cancer and the coexistence of cryptococcal infection is currently unclear. Some authors believe that advanced cancer may cause immune deficiency and lead to cryptococcal infection [10]. To date, only nine English-language publications have reported 18 cases of PC with lung cancer [8,9,10,11,12,13,14,15,16]. Underlying immunosuppressive diseases, such as diabetes, cancer, or systemic lupus erythematosus, are present in 27.8% of patients [9, 11, 13, 15]. In general, these two types of cooccurring infections can be divided into two types: cryptococcal infections, which occur in lung cancer nodules or masses [9, 16]; and cryptococcal infections and lung cancer nodules/tumours, which are two different types of lesions [8].

The common feature of such cases is that they are radiologically unspecific and are usually detected after surgical resection or percutaneous lung biopsy. As with other early-stage lung cancers, cancerous nodules or masses are treated with aggressive surgical removal, while PC usually requires postoperative antifungal therapy. The prognosis of patients with lung cancer is related to the pathological and clinical stage, and the prognosis is usually good. This paper reports the case of a 54-year-old patient with lung adenocarcinoma combined with PC infection.

Case presentation

A 54-year-old female presented to Taihe Hospital, Shiyan, China, for routine physical examination in October 2020. The patient denied cough, sputum, haemoptysis, difficulty breathing, fever, chest pain, other respiratory-related symptoms or any other systemic discomfort. A CT scan revealed a pure ground-glass nodule with a diameter of approximately 1.4 cm in the dorsal segment of the right lower lobe, indicating a high suspicion of a tumour. Another nodule in the basal segment of the right lower lobe with a diameter of approximately 0.6 cm (Fig. 1A, D) suggested intrapulmonary metastasis. The doctor recommended hospitalization for further examination and treatment.

Fig. 1

Chest CT. (a) Chest CT showed a 1.4-cm-diameter nodule (red arrow) in the dorsal segment of the right lower lobe, highly suspected peripheral lung cancer. (b) Chest CT scan showed the cancerous nodule in the dorsal segment of the right lower lobe after resection. (c) Chest CT revealed no recurrence of lung cancer after 3 years of follow-up. (d) Chest CT showed a 0.6 × 0.4 cm nodule in the basal segment of the right lower lobe (red arrow), which was suspected to be lung metastasis. (e) Chest CT scan showing resection of the nodule in the basal segment of the right lower lobe, which pathologically diagnosed as Cryptococcus. (f) Chest CT scan showed no recurrence evidence for the resected PC nodule in the basal segment of the right lower lobe over 3 years of follow-up

The patient had normal immune function, no travel history, no history of contact with pigeon manure or soil, no history of smoking or alcohol consumption in the past month, and no steroid or antibiotic treatment before admission. The patient denied a history of malignant tumours, diabetes, autoimmune diseases, hepatitis, or tuberculosis. At the time of admission, her vital signs were normal. There was no skin lesion, enlarged lymph node, or splenomegaly at the time of physical examination. The breath sounds in both lungs were clear, and obvious dry and wet rales were not heard in either lung. She denied a history of surgery or trauma.

Laboratory examination revealed the following parameters: white blood cells, 4.77 billion (G)/L (neutrophils: 62.3%; lymphocytes: 30%; eosinophils: 0.8%; basophils: 0.6%); red blood cells, 4.01 trillion/L; haemoglobin, 115 g/L; platelet count, 248 G/L; alanine aminotransferase, 9.3 U/L; aspartate aminotransferase, 15.4 U/L; γ-glutamyl transferase, 27.3 U/L; total bilirubin, 12.7 µmol/L; nonconjugated bilirubin, 10.6 µmol/L; conjugated bilirubin, 2.1 µmol/L; total bile acids, 2.2 µmol/L; albumin, 45.6 g/L; high-sensitivity C-reactive protein, 0.36 mg/L; and the erythrocyte sedimentation rate, 4 mm/h. The patients was negative for the tuberculosis antibody. Sputum Gram stain and bacterial culture did not reveal any microorganisms. Sputum acid-fast staining and sputum culture did not reveal acid-fast bacilli. Bronchoscopy did not reveal abnormalities. Cytology, bacteriology, and pathology of the lavage fluid were negative. 18 F‑FDG-Positron emission tomography-computed tomography (PET-CT) showed an elevated glucose metabolism in the dorsal segment of the right lower lobe, which suggested lung cancer. The metabolism level of the nodule in the basal segment of the right lower lobe and the anterior segment of the right upper lobe was not abnormally increased, but the possibility of a malignant tumour could not be excluded.

Based on the PET-CT results, we mainly considered the possibility of tumor in the dorsal tubercle of the right lower lobe, while no obvious elevated glucose metabolism was observed in the other nodules puncture was difficult. To clarify the nature of the right lower lobe nodule, a percutaneous lung puncture biopsy of the ground glass nodule in the dorsal segment of the right lower lobe was planned. However, radiologically, the nodule in the dorsal segment of the right lower lobe is close to the blood vessel, with a risk of severe bleeding, and the tumour is more likely. The nodules in the basal segment of the right lower lobe cannot be ruled out as tumours, but if the whole right lung was removed, the scope would be larger. After communication with the patient, surgical resection of the nodules of the lower right lung was performed. Moreover, combined with the PET‒CT results, mediastinal lymph node dissection is recommended for safety reasons, especially if the remaining nodules are atypical. Preoperative assessment was performed on the basis of patient wishes. The patient underwent lobectomy and mediastinal lymph node dissection via VATS to remove the nodules in the dorsal and basal segments of the right lower lobe. The gross tissue was grayish-red and soft (Fig. 2B).

Fig. 2

Macroscopic examination revealed that the resected 9.5 × 7 × 2 -cm dorsal segment of the right lower lobe included a 1.5 × 1.2 × 0.5-cm nodule with gray-and-black sections, solid, and not clear from the surrounding boundary. The nodule was 0.5 cm away from the pleura and did not involve the bronchus, the rest of the lung tissue was grayish red and soft (A). Macroscopically, the resected 12 × 9.6 × 3-cm basal segment of the right lower lobe included a 0.6 × 0.5 × 0.5-cm nodule with gray-black, solid and medium in texture, the boundary with the surroundings was unclear, the nodules were 0.3 cm away from the pleura and did not involve the bronchus. The rest of the lung tissue was grayish-red and soft (B)

Histopathology revealed that the nodule in the dorsal segment of the right lower lobe was invasive adenocarcinoma. The tumour cells presented with acinar cells (Fig. 3A-D), and no cryptococcal infection was observed. No cancer metastasis was observed in the lymph nodes, with a pathological TNM stage of T1aN0Mx, but the patient refused further molecular detection to assist with treatment. Histopathologically, the nodule in the basal segment of the right lower lobe suggested granulomatous inflammation, and yeast-like fungus could be observed in the multinucleated giant cells. Cryptococcus was identified by periodic acid Schiff (PAS), Gomori methenamine silver (GMS) and mucicarmine (MC) staining (Fig. 4A-D, respectively). The above staining procedures were performed according to standard protocols.

Fig. 3

Histopathological findings of the resected nodule in the basal segment of the right lower lobe. (a) Granulomatous with multinucleated giant cells could be observed, which contained many yeasts (H&E staining, ×200). (b) The yeasts were positive for PAS staining (red arrow, ×200). (c) The yeasts were positively stained by Gomori methenamine silver (yellow arrow, ×200). (d) mucicarmine‑positive organisms (red arrow, ×200)

Fig. 4

Histopathological examination of the resected nodule in the dorsal segmental of right lower lobe. (a) The tumor cells showed obvious atypia, dense arrangement, deep staining of nuclei, different sizes of nuclei, abundant cytoplasm (H&E staining, ×100). Immunohistochemical staining showed positive results for (b) Ki-67 (×100), (c) Napsin A (×100), and (d) TTF-1 (×100)

After surgery, the patient received fluconazole (Pfizer) at 200 mg/day orally for 3 months. During the 3 years after surgery, the patient was regularly followed up in our hospital (every 6 months in the first year and once a year in the next 2 years), and the latest follow-up was in September 2023. The patient was in good condition, no significant changes were observed in the nodule in the anterior segment of the right upper lobe and contrast-enhanced CT revealed no recurrence of either disease (Fig. 1B, C, E, F).

Discussion

In the present case, a definite histopathological diagnosis of PC complicated with lung adenocarcinoma was confirmed through VATS. The patient had no immune deficiency and no history of exposure to pigeons or soil. In the end, the diseased pulmonary nodule was resected via VATS, and antifungal treatment was administered after the surgery. During the 3-year follow-up, there was no recurrence of either disease.

Cryptococcosis is caused mainly by Cryptococcus neoformans, which is common in China. This pathogen, which is usually found in pigeon droppings and soil, mainly invades the lungs and central nervous system [6]. According to previous reports, PC predominantly occurs in immunodeficient populations, such as HIV-positive hosts [17]. Cryptococcal infection has been observed in an increasing number of immunocompetent patients in recent years. According to a retrospective study in China, immunocompetent patients account for approximately 60% of PC cases [18]. As shown in this case, the patient had no underlying disease and was immunocompetent.

Clinically, cryptococcal infections usually present with nonspecific symptoms, such as cough, expectoration, chest pain, shortness of breath, and haemoptysis, or the individual may even be asymptomatic [19]. Therefore, pulmonary nodules are usually detected during routine physical examination in asymptomatic patients with normal immune function. However, the limitations of chest X-ray in physical examination, it is easy to miss the small lesions. Therefore, chest CT is generally recommended for patients. In addition, radiologically, the CT findings, such as nodules or masses, consolidation, halo signs, ground-glass opacity, and cavities, are nonspecific in PC patients with normal immune function. Nodules and masses are the most common radiological findings and are usually single or multiple [20]. However, for immunocompromised patients, cavities within the nodules and masses are more likely to be visible by imaging, which is particularly common in AIDS patients. PC nodules are mostly distributed in the subpleural lung and are located in a single lung lobe [9]. However, in this case, scattered nodules were observed in multiple lung lobes, which is unusual compared with previous cases and this pattern made it easier to misdiagnose pulmonary metastases during the diagnostic process. The chest CT findings of lung metastases are mostly oval, single or multiple nodules with well-defined edges, which are difficult to distinguish. PET-CT did not reveal elevated glucose metabolism in the remaining nodules. However, according to previous reports in the literature, pulmonary nodules less than 8 mm in size tend to have low or no 18FDG uptake due to partial volume effects, whereas lesions > 8 mm in size have a high negative predictive value (NPV) for excluding malignancy. Therefore, the results of PET‒CT cannot provide good evidence for the exclusion of metastatic tumours [21]. Currently, the commonly used methods for diagnosing PC are the serum cryptococcal antigen (CrAg) test and histopathological examination. Serum CrAg has high sensitivity and specificity for identifying cryptococcal central nervous system infections. However, CrAg tests for PCs characterized by solitary nodules usually present false-negative results, whereas positive results are more common in invasive or disseminated PCs, which may be due to a low fungal load or the presence of capsule-defective strains of Cryptococcus [22]. In addition, CrAg-positive serum is usually maintained for several months in cured PC patients; thus, CrAg cannot be considered an optimal means to evaluate patient prognosis and treatment efficacy [22, 23]. Histopathologically, haematoxylin-eosin (H&E), periodic acid Schiff (PAS), Gomori methenamine silver (GMS) and mucicarmine (MC) staining were combined to identify PCs [9].

Cases of PC complicated with lung cancer are rare, and the relationship between the two diseases is unclear. Harada et al. [14] suggested that lung cancer occurred before PC, but owing to the particularity of their case, the granulomatous inflammation with coagulative necrosis caused by Cryptococcus was located in the area of papillary adenocarcinoma, and the papillary adenocarcinoma exhibited fibrotic changes in the central region, which typically represents old lesions. Robinson et al. [10] suggested that lung cancer may lead to immunosuppression, which increases the susceptibility to Cryptococcus infection. Li and Huang et al. concluded that PC occurs after lung cancer [9, 13]. However, it is notable that in the abovementioned cases, cancerous nodules and cryptococcal nodules coexisted within the same lesion. However, considering the diversity of pulmonary nodules caused by cryptococcal infection, as observed in the present case, there were multiple nodules in the right lung. We speculated it is also possible that PC infection precedes lung cancer; that is, pulmonary cryptococcal infection can lead to the occurrence of lung cancer. Similar to the coexistence of tuberculosis and lung cancer [24], chronic inflammation of the lungs caused by tuberculosis may lead to the genogenic activity of bronchial epithelial DNA. Alternatively, Mycobacterium tuberculosis DNA may integrate into bronchial epithelial cells to induce tumour transformation [25]. There is currently no relevant evidence for this hypothesis; the coexistence of these two lesions may be a simple coincidence, and further research is needed to clarify the correlation between them.

A comprehensive search of the PubMed, Google Scholar, and Web of Science databases revealed only 18 reported cases of lung cancer combined with PC, as shown in Table 1. Among these patients, 13 were immunocompetent, and five patients had underlying disease or immunosuppression, including diabetes, hypertension, gastric cancer, viral hepatitis, systemic lupus erythematosus, and a history of steroid use. Our patient had normal immune function and no history of underlying disease. However, among 18 previously reported cases, seven patients were asymptomatic; the remaining 11 patients had respiratory symptoms, including cough, sputum, dyspnoea, blood in the sputum and even chest pain. These cases were radiographically dominated by pulmonary nodules. In addition, seven patients presented with lung cancer and PC limited to the same lesions. However, in the present case, multiple nodules were present in the right lung. According to previous case reports, the histological types of cancerous nodules differ among patients. Among these patients, 13 had adenocarcinoma, 3 had squamous cell carcinoma, and 2 had alveolar cell carcinoma. In our case, the lung cancer nodule was an adenocarcinoma. Almost all patients were treated with surgery combined with antifungal therapy. As shown in Table 1, these patients were followed up for 10 months to 5 years, with three cases of cancer recurrence and one case of death. The patient in our case was followed up for 3 years after surgery, and there was no recurrence of either disease.

Table 1 Clinical data of previously reported cases of PC complicated with lung cancer

In conclusion, cases of PC complicated with lung cancer are rarely reported. Therefore, when radiology suggests multiple nodules, in addition to considering the possibility of primary malignant nodules or intrapulmonary metastasis, we cannot ignore the possibility of cryptococcal nodules. Aggressive surgical removal is recommended for suspected malignant pulmonary nodules combined with other nodules whose nature is not clear.