Pulmonary cryptococcosis (PC) is an invasive fungal disease caused mainly by Cryptococcus (C.) neoformans or C. gattii. It may be present in immunocompetent or immunocompromised patients. The radiographic features of PC vary, and the most common computed tomography manifestation is the presence of solitary or multiple pulmonary nodules or masses distributed in the outer zone of the lung field. The appearance of nodular or mass-like PC on computed tomography scans resembles that of primary or metastatic lung cancers, and differential diagnosis is sometimes difficult. The coexistence of PC and malignant tumors is rarely observed.

This paper reports three cases of PC combined with lung adenocarcinoma diagnosed by video-assisted thoracic surgery lung biopsy, which were successfully managed by early diagnosis and treatment.

The present case report might serve as a reminder not to neglect PC coexisting with adenocarcinoma. Early diagnosis and treatment lead to a better prognosis.

Pulmonary cryptococcosis (PC) is a fungal infection that results from the inhalation of spores from Cryptococcus neoformans[1]. The infection usually occurs in immuno-compromised patients, especially in those with T-lymphocytopenia[2]. The multiple nodular shadows that manifest, particularly in the peripheral lung, can sometimes be confused with malignant tumors and metastatic cancer based on nonspecific symptoms and radiological findings. Many case reports have focused on the misdiagnosis of PC as a malignant tumor[3]. This study aimed to describe three cases of multiple nodules with imaging findings, which were eventually diagnosed by thoracoscopy as PC coexisting with lung adenocarcinoma. After treatment, they all had a better prognosis. The coexistence of PC and malignant tumor was presented only in a few reports[4-9], and it is often easily misdiagnosed. Delayed treatment of malignant tumor results in a higher pathologic stage and poorer prognosis.

There was no evidence of recurrence at 2 years postoperatively and after fluconazole treatment in these three cases.

PC coexisting with pulmonary carcinoma is rare, with only one case each reported in Japan, China, South Korea, and other countries in East Asia[4-9]. The aforementioned three cases had multiple lung nodules, and the patients were ultimately diagnosed with PC coexisting with adenocarcinoma by lung tissue biopsy. The cases highlighted the possibility of duality in the diagnosis of multiple pulmonary nodules based on the CT examination. They point to the possibility of the coexistence of PC and adenocarcinoma and indicate that the pathological results of one lesion cannot represent the characteristics of all lesions. In such cases, close follow-up and biopsy of multiple lesions may be required.

The clinical symptoms of the aforementioned cases were nonspecific, including mainly cough and sputum; cases might also be asymptomatic. The results of routine blood tests and tumor marker CEA for these cases were normal. Serum cryptococcal antigen detection tests by latex agglutination were performed in one case, with negative results. The PC nodules in these cases were located in the field of the lung, adjacent to or involving the pleura; single or multiple nodules with a diameter of less than 1 cm were predominant. The CT findings of lung cancer consisted of a solitary nodule shadow accompanied by a variety of CT tumor-like signs, such as lobulation signs, burr signs, pleura depression signs, and focal ground-glass opacity. In one case (case 3), lung cancer and cryptococcus nodules were located in the same lung lobe. In the remaining two cases, the lung cryptococcosis nodules and lung cancer nodules were not on the same side of the lung lobe. Nodular or mass-type PC is easily misdiagnosed as lung cancer or metastatic cancer. Notably, the differences in imaging findings between the two diseases may help in identification: PC nodules predominantly occur adjacently to the pleura, have different shapes and sizes, and are limited to a single lung lobe; pulmonary metastatic tumors that usually present with variable in sizes and shapes with smooth edges frequently occur in the lower lungs. In most reported cases, the pathological type of lung cancer was pulmonary adenocarcinoma, which was similar to that in patients in this study. Cryptococcus may prefer residing in the peripheral lung, and therefore it is difficult to obtain a definitive diagnosis for multiple pulmonary nodules in the peripheral lung on chest CT. Attention should be paid to the characteristics of the nodule, and thoracoscopic surgery should be performed in time so that patients can be diagnosed and treated as early as possible. A definite diagnosis for the patients in this study took less time. The nodules with different etiology have characteristic imaging manifestations, and pathology is the key to diagnosis.

Cryptococcal infections affect a variety of hosts, including those who have severely compromised immune systems and those who have “normal” immune systems. However, they are occasionally found in immunocompetent hosts and are more likely to occur in immunosuppressed patients, such as those undergoing organ transplant or long-term glucocorticoid therapy and those with hematological malignancies, diabetes, and liver cirrhosis, among others. In China, PC is the third most common pulmonary fungal infection; most patients with PC in China have no underlying disease[10]. The patients in the present study denied any history of contact with birds or polluted environment and had not traveled recently. When and where these patients became infected with spores was not known. Harada et al[4] suggested that the coexistence of the two lesions was coincidental. However, Robinson et al[7] proposed that lung cancer caused immunosuppression and secondary cryptococcal infection. The relationship between lung cancer and PC should be further explored.

The present study provided many interesting insights into the differential diagnosis of multiple pulmonary nodules. Resection of the lesion should be performed under medically permissive conditions to obtain a definitive diagnosis for pulmonary nodules suspected as malignancy.