Pulmonary cryptococcosis misdiagnosed as lung cancer in a man with normal immune function: A case report.

Pulmonary cryptococcosis is an opportunistic infection of cryptococcus both in immunocompetent and immunocompromised patients, who suffered from HIV infection, organ transplantation, diabetes mellitus, corticosteroid or immunosuppressive therapy, and malignancy. Pulmonary cryptococcosis is the commonest location of non-central nervous system cryptococcosis and usually presents with nonspecific symptoms. It often shows shadows on the lung, which makes it difficult to distinguish it from lung cancer. Here we report a case of a 52-year-old man with pulmonary cryptococcosis, who was misdiagnosed as lung cancer. Clinicians need to consider the possibility of pulmonary cryptococcosis and the importance of lung biopsy when treating a patient with a normal immune function that has isolated pulmonary nodules. This case also indirectly illustrates the importance of percutaneous lung biopsy in patients with isolated pulmonary nodules.

Introduction

Pulmonary cryptococcosis is commonly seen in immunocompromised patients. Immunocompromised conditions such as HIV infection, organ transplantation, diabetes mellitus, corticosteroid or immunosuppressive therapy, and malignancy are all conditions closely linked with pulmonary cryptococcosis [1,2]. But it has become an emerging disease in immunocompetent patients in recent years. A 20‐year clinical retrospective analysis from China revealed that 60% of pulmonary cryptococcosis cases were diagnosed as immunocompetent non-HIV patients [3]. Pulmonary cryptococcosis could manifest to isolate nodule or multiple nodules in the lung. Pulmonary cryptococcosis has often been initially misdiagnosed as lung cancer as some nodules also were positive about F-fluorodeoxyglucose positron emission tomography [4]. The article reported a case of isolated pulmonary cryptococcosis that was misdiagnosed as lung cancer during the Corona Virus Disease 2019 (COVID-19) pandemic.

Case report

A 52-year-old male patient came to the hospital due to cough accompanied by cough yellow phlegm, without fearless of cold, shivering, and high fever, which had lasted for one month in February 2020. The patient worked as a government official and had a history of smoking for over 30 years. A chest CT examination revealed that an 18mm irregular nodule in diameter distributed in subpleural of right lower lung and some enlarged lymph nodes in the mediastinum, the larger one was about 16 mm in diameter (Fig. 1). The radiologists suggested that both peripheral lung cancer and chronic infection can't be excluded, and a biopsy was necessary. The patient was admitted to the hospital for further examination. The results of tumor markers of lung were as follows: carcinoembryonic antigen 1.67 ng/ml (0-5.00 ng/ml), progastrin releasing peptide 56.16 pg/ml (0-68.3 pg/ml), neuron-specific enolase 13.10 ng/ml (0-15.2 ng/ml), squamous cell carcinoma antigen 1.53 ng/ml (0-1.5 ng/ml) and CYFRA21-1 3.61 ng/ml (0-3.3 ng/ml). The results of three times Mycobacterium tuberculosis cultures were negative, and tuberculosis didn't consider. The male accepted several antibacterial drugs, such as levofloxacin (500 mg ivgtt QD) and piperacillin (2 g ivgtt Q12 hours) for 14 days. After 14 days of anti-inflammatory treatment, an enhanced CT detection was performed, which showed that the lesion has no obvious change. Re-examination of serum concentrations of the lung tumor markers showed that squamous cell carcinoma antigen 2.81 ng/ml (0-1.5 ng/ml) and CYFRA21-1 3.73 ng/ml (0-3.3 ng/ml) increased more highly. A detection of 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG PET/CT) was performed, and the result of 18F-FDG PET/CT revealed that higher FDG uptake, which gave a high suspicion of lung cancer (Fig. 2). A percutaneous lung biopsy was recommended, but the suggestion was be refused. Meanwhile a thoracoscopic surgery was performed. Pathologically, several spherical fungi from the necrotic substance of the tumor were confirmed positive by HE staining and periodic acid-Schiff (Fig. 3). Finally, the patient was diagnosed with isolated pulmonary cryptococcosis and received antifungal therapy with itraconazole (200 mg po BID). Up to now, the lesion has not recurred, but the quality of his life has been affected more or less according to the patient description.

Fig. 1

Images of CT, an isolate shadow showed in lower lobe of right lung. (A) and (B) axial image non-enhanced CT of pulmonary window and mediastinal window, respectively; (C) axial image of enhanced CT; (D) the coronal MPR image. The white arrows showed the lesion.

Fig. 2

A 52-y-old man with pulmonary cryptococcosis. Axial fused PET/CT(A), MIP image(B), showed intense FDG uptake in lower lobe of right lung. The circle shows the lesion in picture A.

Fig. 3

Pathological tissue images. (A) Thoracoscopic partial lung resection of the lower lobe of the right lung revealed that the lesion was a white solid (black arrows showed). (B) Hematoxylin and eosin staining showed that the nodule was composed of necrotic substance and histiocytes, with lymphocyte infiltration (20X). (C, D) A number of spherical fungi in the necrotic substance of the nodule were confirmed positive by periodic acid-Schiff (20X).

Discussion

As is known to us all, pulmonary cryptococcosis is an important opportunistic invasive mycosis in immunocompromised patients, especially those suffering from such as HIV infection, organ transplantation, diabetes mellitus, corticosteroid, or immunosuppressive therapy, and malignancy [5]. In Europe and the United States about 80% of cryptococcosis cases are associated with HIV/AIDS [6]. Nonetheless, most patients with cryptococcosis are not infected with HIV in China [7]. The incidence of cryptococcosis in China is on the rise, and the fungal persistence and frequent disease relapse of cryptococcosis is the main clinical problem in the past years. Several studies suggested that the incidence of cryptococcosis in immunocompetent patients increased [8]. In this case, the patient was immunocompetent without HIV infection or malignancy tumors. During the Corona Virus Disease 2019 outbreak, all Chinese responded to the government's call for segregation at home and did not get together, thus they often lacked exercise. Thus, the authors inferred that the main reason why the male had pulmonary cryptococcosis was the decrease of immunity and gave the chance of cryptococcus infection. A study reported that a major mental health burden of the public was heavy during the COVID-19 outbreak in China, and young people or healthcare workers were at a high risk of displaying psychological issues [9]. Psychological factors may play a certain role in the process of the patient's illness, the patient works as a government official, he needs to consider not only the safety of the people but also his family. Which may give him much pressure.

The most common means of cryptococcus causing infection in humans is via inhalation. The central nervous system and the lung are the two organs that comprise the main sites of cryptococcus infection [9], [10]11]. Some rare sites infection also exists, for instance, skin, joint, muscle, liver, kidney [12]. Pulmonary cryptococcosis is the most common non-central nervous system infection in those aren't infected with HIV [13]. Pulmonary cryptococcosis usually presents with nonspecific symptoms such as cough, dyspnea, chest pain, and fever both in adults and children. The nonspecific symptoms of this disease are likely to cause delays in diagnosis and proper treatment resulting in further dissemination of cryptococcus infection, even misdiagnosis [14]. The radiological appearance of pulmonary cryptococcosis may mimic other clinical conditions such as other pulmonary infections caused by bacteria, mycobacteria, parasites, or viruses, malignancy [15]. It is difficult to distinguish cryptococcosis from cancer by computed tomography (CT). 18F-FDG PET/CT has gradually become a popular imaging modality for the differential diagnosis, staging, restaging, response evaluation, and follow-up of cancer. A study revealed that about 88% of patients, lung lesions showed high FDG uptake, thus mimicking a possible malignant condition [4]. In the present case, the patient presented a pulmonary nodule with elevated lung cancer markers and high uptake of 18F-FDG, which were difficult to distinguish from lung cancer. Furthermore, after two weeks of anti-inflammatory treatment, the CT scan showed no obvious changes of the lesion (Fig. 4) and the serum concentrations of the lung tumor markers were more highly, especially the squamous cell carcinoma antigen and CYFRA21-1. Thus, the patient was misdiagnosed with lung cancer and underwent surgical treatment. Fortunately, the patient recovered well.

Fig. 4

The comparison of CT before and after anti-inflammatory treatment, and the isolate shadow showed no obvious changes of lesion in lower lobe of right lung. (A) axial image non-enhanced CT before anti-inflammatory treatment; (B) axial image of enhanced CT after two-week anti-inflammatory treatment. The white arrows showed the lesion.

The purpose of the treatment of pulmonary cryptococcosis is not only to control the symptoms and signs of the lung itself, but the most important is to prevent the spread of cryptococcal meningitis [14]. Blood culture, serum cryptococcal antigen test, and a lumbar puncture for CSF examination including measurement of the CSF opening pressure are routinely recommended, with additional investigations depending on the clinical presentation [16]. Due to the absence of prospective, randomized controlled trials or prospective cohort studies of patient outcomes, the definitive treatment recommendations of cryptococcosis are hampered. The treatment guidelines are based on retrospective case series, expert opinions [17].

The present case reminded us that shadow of the lung was a common sign in clinical work, which can attribute to many reasons, such as infections caused by bacteria, mycobacteria, parasites, fungus or viruses, malignancy, and so on. It deserves high attention and a high index of suspicion is necessary for infection of fungus. If it is difficult to identify the shadow in lung, the percutaneous lung biopsy should be performed. Both doctors and patients need to pay more attention to percutaneous lung biopsy. It suggested that clinicians should be alert to cryptococcal infection during the diagnosis of similar diseases, especially for the people with low immunity and other risk factors. Clinicians should try to determine the treatment plan after comprehensive evaluation for patients to avoid blind surgical treatment, which increases the risk of operation and patients' pain.

Ethics statement

Ethics approval was not required for this study.

Patient consent

The patient of this case approved the publication of his information.