Talaromyces marneffei mimics lung cancer along with mediastinal and hilar lymph node metastases: a case description

Introduction

Talaromyces marneffei (T. marneffei) is a dimorphic fungus that is endemic to Southeast Asian countries (1), and bamboo rats are its natural hosts. T. marneffei infections rarely occur in immunocompetent individuals. Owing to the difficulty in distinguishing T. marneffei infection from peripheral lung cancer when the infected area is restricted to the lungs and the formation of a pulmonary tumor is observed, T. marneffei infection is frequently misdiagnosed as peripheral lung cancer owing to radiographic similarities, as various fungal infections can radiologically mimic malignancies (2). Here, we discuss the presentation and diagnosis of T. marneffei infection in an immunocompetent male to improve physicians’ understanding of the disease.

Case description

An immunocompetent 56-year-old male smoker who had previously consumed a cooked wild bamboo rat presented with a cough that had persisted for one month and underwent enhanced computed tomography (CT) imaging (Figure 1A,1B), which revealed a pulmonary mass in the right lung (arrow). The mass exhibited irregular characteristics, including spicules, lobulation, or cavities, and certain areas exhibited ground glass density. These features implied unclear margins and a relatively invasive nature. Due to the ineffectiveness of antibacterial therapy, the mass was suspected to be a tumor. The patient was subsequently admitted to our hospital and underwent fluorine-18 fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) imaging. The scan revealed a hypermetabolic mass in the upper lobe of the right lung as well as enlargement of the clavicular area (Figure 1C, arrows). The larger segment measured approximately 7.6 cm × 7.6 cm, and the margins exhibited lobulation and delicate spicules. FDG uptake was evident, with a maximum standardized uptake value (SUVmax) of approximately 17.62. The enlargement of multiple lymph nodes was observed in the right supraclavicular region, mediastinum (stations 1R, 3R, 3A, 4R, 7, and 8), and right hilar region. Focal FDG uptake was considered to be pathological, with the largest lesion located in mediastinal station 4R, measuring approximately 2.4 cm × 1.8 cm (Figure 1D, arrows), and demonstrating a SUVmax value of 8.95. These findings suggest a high probability of malignancy and the presence of lung cancer along with mediastinal and hilar lymph node metastases. Laboratory examinations revealed a white blood cell count of 12.85×10⁹/L, an absolute neutrophil count of 10.15×10⁹/L, the absolute lymphocyte count is 1.73×10⁹/L, an absolute eosinophil count of 0.15×10⁹/L, an absolute basophil count of 0.03×10⁹/L, a procalcitonin level of 0.06 µg/L, and a hypersensitive C-reactive protein level of 152.31 mg/L. However, the levels of the tumor markers carcinoembryonic antigen, cytokeratin 19 fragment, and neuron-specific enolase were not elevated. In addition, the patient underwent two CT-guided lung nodule biopsies and one biopsy of the lymph node in the right clavicular region. Histopathological examination of the right lung biopsy revealed thickened alveolar septa, fibrous tissue proliferation, and diffuse infiltration of lymphocytes, plasma cells, and histiocytes. Additionally, histopathological analysis of the right supraclavicular lymph node biopsy confirmed that the lesions were benign. On the day of the third biopsy, the patient developed a fever, which prompted bronchoscopy and bronchoalveolar lavage. Bronchoalveolar lavage fluid (BALF) was utilized for metagenomic next-generation sequencing (mNGS) and conventional bacterial and fungal culture. The mNGS procedure was conducted by Huada Biotechnology (Guangzhou) Co., Ltd. (BGI). Specifically, DNA was extracted from the sample using the TIANMicrobe Magnetic Bead Method Pathogen DNA Extraction Kit (NG550-01), according to the manufacturer’s instructions. The sequencing library was constructed using the Illumina^® DNA Prep Kit. An Agilent 2,100 bioanalyzer was used for quality control of the DNA libraries. Quality qualified libraries were pooled, and a DNA nanoball was made and sequenced by the MGISEQ-2000 platform. The raw sequencing data were initially evaluated using FastQC. Trimmomatic was applied to filter out low-quality reads and adapter sequences. After quality trimming, the processed reads were aligned to the human reference genome (hg19) using BWA (http://bio-bwa.sourceforge.net/) to remove host-derived sequences. Low-complexity regions of the remaining nonhuman reads were then removed before the reads were aligned to the BGI microbial reference database Protein Model Database (PMDB). The PMDB database includes 10,989 bacterial species linked to human diseases (comprising 196 mycobacterial species and 159 species from Mycoplasma, Chlamydia, and Rickettsia), 1,179 fungal species, 5,050 viral species, and 282 parasitic species. Pathogen identification was based on the number of mapped reads, and the results were further integrated with clinical findings for final interpretation. The day following the submission of the sample for inspection, mNGS analysis of the lavage fluid revealed that the patient was infected with T. marneffei. Following an additional ten days of incubation, a small quantity of T. marneffei was isolated from conventional bacterial and fungal culture, thereby further confirming the clinical diagnosis. The patient was then prescribed antifungal therapy consisting of intravenous voriconazole (200 mg twice daily) and intravenous amphotericin B (AmB; 30 mg; 0.5 mg/kg body weight once daily). The patient’s fever was alleviated, and the cough steadily improved after treatment. Eleven days after treatment, a repeat CT revealed a notable reduction in the size of the lung mass (Figure 1E,1F). After approximately 40 days of treatment, the lung mass had essentially disappeared (Figure 1G,1H).

Figure 1 Chest CT and ¹⁸F-FDG PET images. (A,B) The lung window and mediastinal window of the enhanced CT image revealed a mass (arrows) in the right lung. (C) ¹⁸F-FDG PET showed a hypermetabolic mass (arrows) in the superior lobe of the right lung. The larger segment measured approximately 7.6 cm × 7.6 cm, with a SUVmax of approximately 17.62. (D) ¹⁸F-FDG PET showed the enlargement of multiple lymph nodes enlargements located in mediastinal station 4R, the larger segment measured approximately 2.4 cm × 1.8 cm, with a SUVmax of approximately 8.95. (E,F) Eleven days after treatment, the size of the lung mass decreased (arrows). (G,H) Forty days after treatment, the lung mass had basically disappeared (arrows). CT, computed tomography; ¹⁸F-FDG PET, fluorine-18 fluorodeoxyglucose positron emission tomography; SUVmax, maximum standardized uptake value.

Ethical considerations

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was provided by the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

T. marneffei has a complicated growth process during which various cell types are produced during its life cycle, including conidia, hyphae, and yeast, all of which play essential roles in its pathogenicity. Temperature is the main factor that triggers differentiation into various cell types. The optimal growth temperature of this dimorphic fungus is 28 ℃; when the temperature exceeds 32 ℃, the morphology of the cells transitions from mycelial to yeast, the growth of which is maximized at 37 to 39 ℃. At temperatures above 39 ℃, fungal development is stunted (3).

T. marneffei is generally believed to originate from the soil where rodents live, and humans become infected by inhaling conidia from the environment. Bamboo rats are considered the natural hosts of T. marneffei. Therefore, a history of travel in endemic areas and bamboo rat consumption may increase susceptibility to infection, and such information is important for T. marneffei infection diagnosis. In endemic areas, T. marneffei infections are primarily a complication of HIV infection, and mortality can reach 100% if the pathogen is left uncontrolled (4). Although rare, T. marneffei infections can occur in immunocompetent individuals (5). Owing to global travel, areas in which T. marneffei is endemic have gradually expanded from Southeast Asian countries to additional regions, such as northern China, eastern India, the Korean Peninsula, Japan, and eastern Australia (4).

After inhalation, the conidia attach to the bronchoalveolar epithelium, are phagocytosed by and proliferate in macrophages—where they transform into yeast to establish infection—and then disseminate to other internal organs through the reticuloendothelial system, especially the lungs, liver, spleen, lymph nodes, and bone marrow. The most common clinical manifestations of T. marneffei infection are fever, cough, skin lesions, hepatosplenomegaly, and lymph node enlargement (4). However, these manifestations are observed mainly in immunodeficient patients infected with T. marneffei. In immunocompetent patients, the pathological changes associated with T. marneffei infection are primarily the development of granulomatous lesions and suppurative reactions (6). T. marneffei infection, when restricted to the lungs and includes the formation of a pulmonary tumor, is difficult to distinguish from peripheral lung cancer; thus, such infections might be accidentally misdiagnosed (7).

Pathogenic culture is the gold standard for the diagnosis of T. marneffei infection but has the disadvantage of delaying the administration of antifungal treatment due to long culture cycles or inadequacies in positive culture rates. mNGS has been developed and implemented in clinical medicine to quickly provide physicians with relatively accurate diagnoses. The advantages of mNGS in fungal diagnosis have been systematically validated through multiple clinical studies. Compared with traditional fungal culture, mNGS has a substantially increased detection rate for fungal pathogens. For lung tissue biopsy specimens, mNGS demonstrates a sensitivity of 57.1%, significantly higher than that of traditional fungal culture. The specificity of mNGS is 61.5%, slightly lower than that of culture, and mNGS still provides reliable discriminatory performance, particularly in cases involving mixed infections or for samples with low pathogen burden (8). In addition, this technology allows for the direct detection of pathogen DNA and RNA in a wide range of clinical specimens—such as blood, lung tissue, and cerebrospinal fluid, but clinical assessment is needed to determine the significance of organisms detected by mNGS, especially for cases not confirmed with conventional testing (9). In patients given antibiotics, the sensitivity of mNGS remains at 52.5%, whereas that of culture-based methods decreases to 34.2% (10). In terms of detection timeliness, mNGS provides results within approximately 24 hours for blood or tissue samples and up to 48 hours in some cases, which is significantly faster than the 3 to 7 days required for traditional culture methods, thereby enabling timely support for clinical decision-making (11). In addition, unlike for PCR detection, physicians do not need to consider alternative suspected pathogens prior to performing mNGS, further promoting the highly efficient achievement of diagnosis (12). Few cases of rapid and accurate diagnosis of fungal infection by mNGS in clinical practice have been reported, and this case provides new support for exploring the potential value of mNGS in this field.

AmB is the first-line antifungal medicine for severe T. marneffei infection, followed by treatment with azoles such as itraconazole and voriconazole for weeks to months (13). However, most patients are still at risk of relapse after several months or years despite receiving antifungal therapy (6). Therefore, long-term oral azole consolidation therapy as well as secondary prophylaxis are routinely needed to prevent recurrence, and the potential of the development of resistance in T. marneffei should be considered.

The radiological presentation of a mass-like consolidation with lymphadenopathy necessitates a broad differential diagnosis. Beyond malignancy, infectious and inflammatory processes such as community-acquired pneumonia, eosinophilic pneumonia (EP), and organizing pneumonia (OP) must be considered. Bacterial pneumonia often responds to antibiotics, which was not the case here. EP classically presents peripheral, migratory opacities and is frequently associated with eosinophilia in the blood or BALF, features absent in our patient (14). OP can appear as a focal mass but is often steroid-responsive (15). The definitive diagnosis in this case was established by the microbiological evidence from BALF (mNGS and culture confirming the presence of T. marneffei), which highlights the critical role of advanced diagnostic techniques in resolving such clinical dilemmas when presentation is atypical.

Despite the successful resolution of pulmonary lesions after 40 days of antifungal therapy, this study lacked long-term follow-up data, a limitation that may obscure subclinical inflammatory activity persisting after fungal infection resolution. Consequently, the long-term recurrence risk or potential sequelae post-cure could not be assessed. The diagnostic challenge in distinguishing T. marneffei granulomas from lung cancer via ¹⁸F-FDG PET highlights the need for advanced image analysis tools. Recent studies have demonstrated that machine learning (ML)-based texture analysis of PET/CT images can quantify metabolic heterogeneity beyond standard SUVmax values (16). ML algorithms extract subvisual texture features from hypermetabolic lesions to predict the probability of malignancy. In addition, a recent study demonstrated that in patients with mediastinal lymphadenopathy on CT caused by small cell lung cancer (SCLC) metastasis or sarcoidosis (17), some texture features can be examined to discriminate between these diseases. The integration of such technology could reduce misdiagnosis rates in patients for whom PET/CT initially suggested malignancy. Future research should validate ML-driven PET/CT interpretations for endemic fungal infections.

Conclusions

In endemic areas, T. marneffei infection can be considered a differential diagnosis for lung cancer when hypermetabolic pulmonary lesions are present upon ¹⁸F-FDG PET imaging, especially for patients who have previously consumed bamboo rats. This case provides important clinical insight: fungal infection should be considered even when imaging strongly suggests malignancy, particularly for patients with a history of zoonotic exposure. While imaging has limitations, mNGS analysis of BALF can be used as a rapid method for the diagnosis of T. marneffei infection and as an important supplement to laboratory and imaging tests.

Acknowledgments

None.

Footnote

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-146/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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was provided by the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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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