Pulmonary cryptococcosis (PC) is a common opportunistic fungal infection caused by Cryptococcus neoformans or Cryptococcus gattii (1), which mainly invades the respiratory system, followed by the central nervous system (CNS) (2). It usually occurs in immunocompromised patients, such as patients with human immunodeficiency virus (HIV) infection, solid organ transplantation or autoimmune diseases, as well as patients who use corticosteroids and other immunosuppressants (3,4). However, the incidence of PC has recently increased rapidly in hosts with normal immune function (5,6). Different immune statuses may affect the pulmonary CT manifestations of cryptococcosis (7,8). The diagnosis of PC is challenging due to its diverse and nonspecific CT findings, which may mimic those of lung cancer, bacterial pneumonia or tuberculosis (5). Previous studies have indicated that advanced cancer may lead to immunodeficiency and cause cryptococcosis (9,10). Previous studies have reported on PC coexisting with lung carcinoma (9,11–17). Most of the reported cases presented with respiratory symptoms and a small number of them were asymptomatic. Certain cases are accompanied with other underlying diseases, such as diabetes, tumor history or systemic lupus erythematosus (11,12,14,17). In general, this coexistence relationship may be broadly divided into two types; one is that cryptococcal infection occurs in lung cancer nodules or masses (9,18); the other is that cryptococcal infection and lung cancer nodules/masses belong to two different lesions (15). It is radiologically nonspecific and is usually found by surgical excision or percutaneous lung biopsy. As with other early lung cancer, the treatment for lung cancer nodules or masses is aggressive surgical resection, while PC usually requires postoperative antifungal therapy. The prognosis of lung cancer is related to the pathological and clinical stage of lung cancer, and cryptococcal infection usually has a better prognosis. The present study reported the case of a 65-year-old patient with pulmonary adenocarcinoma complicated with PC infection.

A 65-year-old Han Chinese woman who worked as a crop farmer presented to Taihe Hospital (Shiyan, China) for a routine physical examination in August 2018. The patient had no respiratory symptoms and denied any other discomfort. Chest CT showed a 2.4×2.0-cm nodule in the anterior segment of the left superior lobe (Fig. 1A), which was highly suspected to be peripheral lung cancer. A 1.3×0.9-cm nodule was detected in the posterior basal segment of the left lower lobe (Fig. 1), which was suspected to be intrapulmonary metastasis. Hospitalization was recommended for further examination and treatment.

The patient denied any respiratory symptoms, such as cough, sputum, fever, chest pain, wheezing or weight loss. Immune function was normal, the patient had no history of travel or exposure to pigeon feces or soil, no history of smoking or alcohol consumption within the last month, and had not been extensively treated with hormones and/or antibiotics before coming to the hospital. The patient's medical history included surgery for varicose veins in the left lower extremity 30 years earlier, cataract surgery of the left eye 10 years ago and hemorrhoid surgery 2 years previously. On admission, the vital signs etc. were normal On physical examination, there were no skin lesions, lymphadenopathy or splenomegaly.

Laboratory examination indicated the following: Whole blood leukocytes, 4.82×10⁹/l [neutrophils, 68.8% (normal range, 50–70%); lymphocytes, 24.3% (normal range, 20–50%); monocytes, 5.6% (normal range, 3–10%); eosinophils, 1.5% (normal range, 0.4–8%); basophils, 0% (normal range, 0–1%)]; red blood cells, 4.37×10¹²/l (normal range, 4.3 to 5.8×10¹²/l); hemoglobin, 127 g/l (normal range, 130–175 g/l); platelets, 175×10⁹/l (normal range, 125 to 350×10⁹/l); blood glucose, 4.45 mmol/l (normal range, 3.9–6.1 mmol/l); total bilirubin, 9.8 µmol/l (normal range, 3.42–20.5 µmol/l); aspartate aminotransferase, 17 U/l (normal range, 0–40 U/l); alanine aminotransferase, 12 U/l (normal range, 0–50 U/l); lactate dehydrogenase, 99 IU/l (normal range, 100–240 IU/l); and highly sensitive C-reactive protein, 0.15 mg/l (normal range, 0–5 mg/l). A urinalysis and microscopic examination were normal. Tumor markers were as follows: Neuron-specific enolase, 10.1 ng/ml (normal range, 0–16.3 ng/ml); carcinoembryonic antigen, 1.77 µg/l (normal range, 0–5 µg/l); and ferritin, 357 ng/ml (normal range, 30–400 ng/ml), all of which were at normal levels; however, Cyfra21-1 was 3.75 µg/l higher than the upper limit of the normal level (normal range, 0–3.3 µg/l). Sputum Gram staining (19) and bacterial culture showed no microorganisms. Acid-fast staining (20) and sputum culture showed no acid-fast bacteria. Bronchofiberscopy showed no lesions in the trachea and bronchus, and bacterial, cytological and pathological examinations from the bronchoscope provided negative results.

To obtain a definitive diagnosis, a CT-guided percutaneous lung biopsy was performed on a nodule of radiologically high suspicion of lung cancer in the anterior segment of the left upper lobe, which was pathologically confirmed to be adenocarcinoma. To evaluate the stage of lung cancer and select appropriate treatment, a CT-guided percutaneous lung biopsy was performed on the nodule in the posterior basal segment of the left inferior lobe 1 week later, which was confirmed by histopathology as PC infection. Histologically, hematoxylin & eosin staining (21) revealed granulomatous inflammation and yeast-form fungi in multinucleated cells, and cryptococcus was identified by periodic acid Schiff (PAS), Gomori methenamine silver (GMS) and mucicarmine (MC) staining (Fig. 2A-D, respectively). The above staining procedures were performed according to standard protocols. Two weeks later, the patient underwent thoracoscopic resection of the left lung cancer. Macroscopic examination revealed that the excised 14×9.5×3.5-cm upper left lobe included a 3.1×2.5×2-cm mass with gray and grayish black sections, solid, medium in texture, and indistinct from the surrounding boundary (Fig. 3). The mass was adjacent to the pleura and did not involve the bronchus. Histologically, the tumor cells were moderately to poorly differentiated adenocarcinoma of the acinar and micropapillary type (Fig. 4A-D), and no cryptococcal infection was observed. No metastatic cancer was found in the lymph nodes (0/11), the bronchial incisive margin was negative and the pathological TNM stage was T2aN0Mx. In addition, the patient received fluconazole (Pfizer Inc.) 200 mg/day antifungal therapy for 6 months. Within five years after the resection, the patient was admitted to the respiratory department of our hospital regularly for further follow-up (every 6 months for the first 2 years and once a year for the last 3 years), and the latest follow-up was in August 2023. The patient was in good condition and contrast-enhanced CT showed no recurrence of either disease (Fig. 1B, C, E and F).

Cryptococcosis is a fatal fungal infection mainly caused by Cryptococcus neoformans or Cryptococcus gattii (1). Cryptococcosis caused by Cryptococcus neoformans is common in China (22). At present, PC is the third most common pulmonary fungal infection in China and previous studies have shown that the majority of cryptococcosis cases in China were reported in HIV-uninfected patients (particularly immunocompetent hosts) (22,23). The case of the present study was a patient with normal immune function, without any history of illness of the immune system, underlying diseases such as diabetes or use of immunosuppressants or glucocorticoids. PC can be confirmed by histopathology or tissue culture (24). In the present case, the histopathologic diagnosis of PC was obtained through biopsy, surgery and special staining, such as PAS, GMS and MC. Of course, in addition to invasive diagnostic methods, there are noninvasive methods for PC, such as blood culture and Cryptococcus antigen (CrAg) (25). However, culture often yields negative results in immunocompetent hosts (26); occasionally, histopathologically confirmed cases are culture-negative (27). The CrAg test is a sensitive and specific test for the diagnosis of cryptococcosis in immunocompromised patients (28). However, the sensitivity is lower in patients with isolated PC. In the present case, the nodule in the anterior segment of the left upper lobe was highly suspected to be lung cancer on radiology, and the nodule in the posterior basal segment of the left lower lobe was suspected to be pulmonary metastasis. Therefore, initially, the possibility of cryptococcus was not considered in advance, and thus, no non-invasive tests, such as cryptococcal antigen testing, were performed before percutaneous lung biopsy. PC symptoms are nonspecific, presenting with cough, sputum, fever, dyspnea, pleuritic chest pain, hemoptysis and malaise (3,29), which are indistinguishable from other causes of pneumonia (30). However, a subset of patients are asymptomatic and the condition is usually detected incidentally during chest radiological examination (23,31). The patient of the present study had no clinical symptoms, even with lung cancer of the upper lobe of the left lung. Different immune statuses may affect the CT imaging features of patients with PC (32). Based on previous literature and clinical experience, pulmonary nodules/masses, either solitary or multiple, were the most common CT findings in PC, which usually occurs in the peripheral lung, adjacent to or involving the pleura (29,32,33). As reported in previous studies, when PC consists of solitary or multiple nodules, these nodules may be confused with lung cancer on chest CT and it is often difficult to distinguish PC from lung carcinoma (5,16). Igai et al (34) tried to distinguish PC from lung cancer by fluorodeoxyglucose positron emission tomography (FDG-PET); however, their results showed that FDG-PET has difficulty distinguishing PC from malignancies. In the patient of the present study, the confirmed posterior basal pleural nodule of the left lower lobe was consistent with this CT feature and the final diagnosis was cryptococcal infection. In the present case, multiple nodules were found in the left lung and based on chest CT, it was highly suspected that the nodules in the anterior segment of the left upper lobe were peripheral lung cancer, while the other subpleural nodules in the posterior basal segment of the left lower lobe were intrapulmonary metastases, which were later confirmed by biopsy and surgery as adenocarcinoma and PC infection, respectively. These imaging features of the present case were consistent with those reported in the literature above. Huang et al (12) suggested that cryptococcosis lesions coexisted with lung cancer and resembled primary or metastatic tumors. Harada et al (16) indicated that, since most patients were in an immunocompetent state, the coexistence of cryptococcosis and carcinoma was coincidental. However, Robinson et al (9) thought that lung malignancy may have resulted in a degree of immune suppression, predisposing the patient to infection with cryptococcus. This issue is currently controversial and further studies are needed to clarify the possible relationship between lung cancer and cryptococcal infection. It may be speculated that there is another possibility that pulmonary cryptococcal infection can lead to the occurrence of lung cancer. Similarly, The coexistence of pulmonary tuberculosis and lung cancer is not an uncommon clinical observation (35), it has been proposed that chronic inflammation in the lungs due to tuberculosis may cause clastogenic activity in the DNA of bronchial epithelium. Another possibility is lateral gene transfer; since Mycobacterium tuberculosis is an intracellular organism, bacterial DNA may integrate into bronchial epithelial cells to induce neoplastic transformation (36). In addition, for cases co-existing in the same nodule or mass, latent cryptococcus infection may have a long-term chronic inflammatory stimulation, and there is vast preclinical and clinical evidence suggesting that strong and chronic inflammatory responses promote cancer development and progression through different mechanisms (37,38). The option that PC may cause lung cancer has not been reported, but it is worthy of further research. Histopathology is still the most important diagnostic method for PC and it is often necessary to combine special staining to obtain a definitive diagnosis. It has been reported that the detection rates of C. neoformans by PAS, GMS, MC and Alcian blue staining were 100, 100, 87 and 67%, respectively (39).

A comprehensive search of the PubMed, Google Scholar and Web of Science databases was conducted and only 17 cases of PC coexisting with pulmonary carcinoma have been reported in the English language worldwide, which were from Japan, China, South Korea and Australia (9,11–17). The clinical characteristics of PC coexisting with pulmonary carcinoma in the previous literature are summarized in Table I. The patient of the present case study was asymptomatic; among the 17 patients reported in the literature, 6 were asymptomatic. Furthermore, 12 patients were immunocompetent and 5 patients had immunosuppressive and underlying diseases, including diabetes mellitus, a history of gastric cancer and thyroid adenoma resection, systemic lupus erythematosus, chronic viral hepatitis B and a history of hormone use. Compared with previous reports, the unique feature of the present case was the relatively small size of the lung cancer and PC nodule, which were 2.4×2.0 and 1.3×0.9 cm, respectively. The patient of the present study had no underlying diseases and was immunocompetent. Of the 17 patients reported in the literature, 7 were diagnosed with coexisting cryptococcosis and carcinoma within the same lobe; however, in the present case, the carcinoma nodule and cryptococcal nodule were not in the same lobe. As reported in the literature, the histological types of cancer in most cases were adenocarcinoma (13 cases), 2 cases were squamous cell carcinoma and 2 cases were alveolar cell carcinoma. The histological type of cancer in the case of the present study was adenocarcinoma. In terms of treatment, almost the same treatment method was adopted in the present case and the previous literature, namely surgical excision plus antifungal therapy. According to previous results, most of the patients had a good prognosis and the patient of the present case study was followed for 5 years with no recurrence of either disease.

The present case study reminds us of the possibility of dualism in the diagnosis of multiple pulmonary nodules based on CT examination, such as the coexistence of lung carcinoma and PC. If medical conditions permit, lesion resection should be performed to treat suspected malignant lung nodules, including cryptococcal nodules that do not respond to antifungal therapy.