Distinguishing tuberculosis from malignancy when multisystem involvement occurs: a case description

Introduction

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis, continues to pose a substantial global health challenge. Despite the significant advancements made in diagnostic methods and therapeutic interventions, TB remains a leading cause of morbidity and mortality worldwide. The disease’s diverse manifestations, especially in individuals with compromised immune systems or coinfections, can closely mimic those of malignant diseases, leading to diagnostic confusion that pose challenges even for the most experienced clinicians (1).

The lungs serve as the principal site of TB infection. However, the disease can also disseminate hematogenously, involving various organs, including the bones and lymph nodes (2). This extrapulmonary involvement complicates the clinical presentation, as it shares clinical and radiological characteristics similar to those of metastatic malignancies (2). Distinguishing between TB and malignancy is crucial, as they have fundamentally different treatment strategies, with significant implications for prognosis.

In the context of pulmonary involvement, both TB and malignant lesions can exhibit nonspecific symptoms, including cough, constitutional symptoms, and radiographic opacities (3). Similarly, skeletal TB may manifest as osteolytic lesions or periosteal reactions, which may be indistinguishable from signs of metastatic bone disease in imaging studies (4). Lymphadenopathy, a common characteristic of both conditions, further complicates the diagnostic process (5).

The distinction between TB and malignancy is not solely an academic concern, and it carries substantial implications for patient management (4). Anti-TB treatment is typically protracted and requires a specific therapeutic regimen, whereas malignancy often necessitates more aggressive interventions, including surgery, chemotherapy, or radiation therapy. Furthermore, misdiagnosing TB as malignancy, or vice versa, can result in inappropriate treatment, increased morbidity, and even mortality.

This case report describes the diagnostic challenges encountered in a 43-year-old male patient who had lymphadenopathy, bone lesions, and pulmonary nodules. The differential diagnosis included consideration of TB and malignancy, which can exhibit overlapping clinical and radiological features.

Case presentation

The patient was a 43-year-old male. In September 2021, he discovered enlarged, hard, nontender lymph nodes on the right clavicle while showering. There was no increase in local skin temperature, and he reported no fever, chills, cough, or sputum production. No treatment was given at that time. In December 2021, he experienced unexplained lower back pain, along with right chest wall pain, night sweats, and weight loss. Hydrocodone was prescribed for pain relief but provided little improvement.

The patient generally maintained good health. He was born and has lived in Beijing for an extended period. For 4 years previous to admission, he had lived in a detention center, reporting a confined, damp environment with high population density and inadequate nutrition. He denied exposure to epidemic areas, contaminated water, or toxic substances. The patient had a 30-year smoking history of about 20 cigarettes per day but had not smoked in 3 years. He also denied alcohol consumption. He had one daughter, and his children and spouse were healthy. All relatives were reported to be well, with no family history of genetic disorders or similar illnesses. HIV serology was negative, and no other causes of immunosuppression were identified.

The diagnosis and treatment process (hospitals 1–6)

The patient sought care at multiple institutions between March 2022 and May 2022 for progressive symptoms. The key diagnostic events are summarized chronologically.

Hospital 1 (Beijing Daxing District People’s Hospital) (March 8)

At hospital 1, an elevated C-reactive protein (CRP) level of 42.2 mg/L (reference <5 mg/L) was reported. Chest computed tomography (CT) suggested metastatic malignancy due to mediastinal or hilar lymphadenopathy and destructive bone lesions.

Hospital 2 (Beijing Friendship Hospital, Capital Medical University) (March 10–30)

A rib mass biopsy showed granulomatous inflammation, but there were negative findings for TB-specific stains and polymerase chain reaction (PCR).

Positron emission tomography-computed tomography (PET-CT) (March 18) revealed high fluorodeoxyglucose (FDG) uptake (maximum standardized uptake value 13.8) in lung nodules, widespread lymph nodes, and bony lesions, highly suggestive of malignancy.

A left iliac bone biopsy (March 30) was positive for M. tuberculosis nucleic acid, while a concurrent neck mass biopsy was negative.

Hospital 3 (Beijing Chest Hospital) (April 12)

The T-SPOT.TB test was positive. Pathological review of prior iliac biopsy confirmed granulomatous inflammation. The patient started his initial anti-TB treatment with isoniazid, rifampicin, ethambutol, and pyrazinamide from April 1 to April 25, 2022, but this did not relieve the pain.

Hospitals 4 and 5 (Peking University Cancer Hospital and Beijing Shijitan Hospital) (April 29 and May 5)

Due to ongoing pain, lymph node dissections were performed. Histopathology from both institutions revealed necrotizing granulomatous inflammation, with hospital 5’s specimen showing extensive caseous necrosis, highly suggestive of TB.

Hospital 6 (Beijing Tsinghua Changgung Hospital) (May 25)

The patient was referred to the infectious disease department for further management.

Our hospital’s diagnostic and treatment process

The patient was admitted to our hospital with persistent pain requiring regular analgesics.

Physical exam

A 0.5-cm lymph node was palpable in the right supraclavicular fossa. No other enlarged superficial lymph nodes were found.

Laboratory investigations

Key results were as follows: CRP level, 10.83 mg/L (reference <5 mg/L); erythrocyte sedimentation rate (ESR), 44 mm/h (reference <15 mm/h); fibrinogen level, 4.62 g/L (reference, 2–4 g/L); T-SPOT.TB test, strong positivity; interferon gamma (IFN-γ), 599.87 pg/mL; and interleukin 2 (IL-2), 281.51 pg/mL. Tumor markers, autoantibodies, and repeat Xpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) assays were negative.

Histopathology (June 2)

An ultrasound-guided biopsy of the left iliac soft tissue mass revealed granulomatous inflammation with necrosis. The pathology report revealed proliferative fibrous tissue with significant infiltration of histiocytes, lymphocytes and plasma cells, granulomatous nodules, and necrosis, as illustrated in Figure 1A-1C. Acid-fast staining suggested positivity for bacteria (Figure 1D), supporting the diagnosis of granulomatous inflammation.

Figure 1 Histopathological and hematoxylin and eosin staining results of the puncture tissue from the left iliac bone lesion. (A-C) The proliferative fibrous tissue was infiltrated by a significant number of histiocytes, lymphocytes, and plasma cells, forming granulomatous nodules and necrosis. (D) Acid-fast staining revealed the presence of suspiciously positive bacilli (red circle). A: 20×; B, C, D: 40×.

Imaging findings

The extent of lymph node and bone involvement were detailed by ultrasound, CT, and magnetic resonance imaging (MRI) conducted at our hospital (Figures 2-4), which directly informed the decision to proceed with a targeted biopsy of the iliac lesion.

Figure 2 Ultrasonic examination results. (A-C) Ultrasound findings of iliac bone lesions from June 22, 2022. The left iliac bone showed (A) localized bone density discontinuity with (B) an irregular hypoechoic mass measuring about 4.5 cm × 5.6 cm and poorly defined borders. (C) No significant blood flow signals were observed. An ultrasound-guided biopsy was conducted on the solid lesion (the arrow indicates the puncture needle). (D,E) Ultrasound examination of supraclavicular lymph nodes from May 30, 2022. (D) An enlarged lymph node in the right supraclavicular fossa displayed signs of destruction and an indistinct structure, (E) while color Doppler imaging revealed irregular blood flow signals around it.

Figure 3 Axial skeleton imaging findings. (A-D) Enhanced MR images of the cervical spine from June 7, 2022, showed bone destruction and a soft tissue mass in the left vertebral body and C5–C7 vertebral attachments, with significant enhancement (yellow arrows). The larger mass measured about 3.4 cm × 2.6 cm and was likely the result of bone metastasis (A: T2 sagittal; B: T1 sagittal; C: T1 transverse; D: T1 coronal). (E-G) Enhanced MR images of the lumbosacral vertebrae from June 7, 2022, showed multiple enhanced nodules and masses (yellow arrows), with the largest on the right side of the L3 vertebra measuring about 4.0 cm × 5.3 cm (E: T1 sagittal; F: T1 transverse; G: T2 sagittal). (H-J) Enhanced MR images of the thoracic vertebrae from June 7, 2022, showed bone destruction and a soft tissue mass at the T7–T12 vertebrae, with (H-J, yellow arrows) significant enhancement and compression of the thoracic cord at T7. These findings suggested bone metastasis (H: T1 coronal; I: T1 transverse; J: T1 sagittal). (K-M) Enhanced CT scans of the abdomen from May 31, 2022, showed multiple bone destructions and soft tissue masses in the L1 and L3 vertebrae and the left iliac bone (yellow arrows) diagnosed as multiple bone metastases. CT, computed tomography; FAR, foot-anterior-right; MR, magnetic resonance.

Figure 4 Enhanced chest CT scan on May 31, 2022. The imaging showed enlarged lymph node shadows in the right pulmonary hilum and mediastinum, the largest measuring about 23 mm. (A,B) The enhanced scan indicated uneven enhancement of these structures (yellow arrows). (C) An 11 mm × 10 mm nodular shadow was present in the dorsal segment of the left lower lobe, along with several smaller nodules (yellow arrow). (D) A 5-mm nodular shadow was also noted in the outer basal segment of the left lower lobe (yellow arrow). The CT report suggested that the left lower lobe nodule could be malignant, and the enlarged lymph nodes were likely metastatic. CT, computed tomography.

Case analysis

The confluence of histological evidence (granulomas and caseous necrosis), a strongly positive IFN-γ release assay and multisystem involvement confirmed disseminated TB. The initial poor treatment response was noted but attributed to factors other than misdiagnosis.

Treatment

The patient declined further biopsy. He was diagnosed with concurrent hepatitis B and began on treatment with entecavir. A modified anti-TB regimen (isoniazid, linezolid, rifampicin, and pyrazinamide) was initiated on June 13, 2022, alongside supportive care. His pain improved, and he was discharged to continue treatment.

Follow-up and prognosis

After discharge, the patient’s symptoms significantly resolved. Follow-up imaging (Figure 5) objectively demonstrated the significant resolution of lesions following anti-TB therapy, confirming treatment efficacy. Furthermore, the normalization of inflammatory markers (ESR, IFN-γ, and IL-2) plotted over time (Figure 6) indicated a serological correlation with the patient’s clinical recovery.

Figure 5 Imaging results after more than 1 year of antituberculosis treatment. (A-D) Chest CT scans from November 18, 2023. (C) The nodular opacity in the dorsal segment of the left lower lobe, noted on May 31, 2022, was not clearly visible in the examination (yellow box). (D) The small, round nodule in the external basal segment remained unchanged (yellow circle). (A,B) Multiple lymph nodes in the right hilum and mediastinum appeared to have reduced in size since the previous assessment, with the largest measuring about 9 mm in short diameter (yellow box). (E,F) MRI of the thoracic vertebrae from August 28, 2023, showed multiple lesions at the T8, T11, and T12 vertebrae, with a surrounding soft tissue mass that had decreased in size since previous assessments. Bone destruction in the thoracic vertebrae had also diminished compared to earlier evaluations (E: T2 sagittal section; F: T1 sagittal section). CT, computed tomography; MRI, magnetic resonance imaging.

Figure 6 Graph of ESR and IFN-γ (T-N) and IL-2 levels. There were temporal variations in (A) ESR, (B) IFN-γ, and (C) IL-2 levels among patients from May 26, 2022, to August 11, 2023. After standardized antituberculosis treatment, the biomarkers gradually returned to baseline levels. ESR, erythrocyte sedimentation rate; IFN-γ, interferon gamma; IL-2, interleukin 2.

TB was confirmed in the patient.

All procedures in this study were performed in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from 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

This case report describes a 43-year-old male patient exhibiting multisystem involvement, highlighting the diagnostic challenges associated with differentiating between TB and malignant lesions (6). The clinical presentation of the patient, characterized by lymphadenopathy, bone lesions, and pulmonary nodules, illustrates the overlapping features that may contribute to initial diagnostic ambiguity. This case is particularly instructive because it demonstrates that even when imaging findings (such as high FDG uptake on PET-CT) strongly suggest malignancy, TB must remain a primary consideration in the differential diagnosis, especially in regions where TB is endemic. Systemic TB remains a significant public health challenge, and the global research community has made substantial progress in elucidating its clinical manifestations and enhancing the diagnostic methodologies (7).

Imaging modalities, particularly CT and MRI, were pivotal in the initial assessment. CT scans provided detailed views of bone destruction, lymph node enlargement, and potential metastatic spread, while MRI offered insights into soft tissue involvement and the extent of marrow infiltration (8). The distinct patterns of FDG uptake on PET-CT further assisted in characterizing the lesions as malignant or inflammatory, highlighting the indispensable role of imaging in the diagnostic process (9). However, this case underscores the limitation of relying solely on imaging characteristics, as the radiographic features of TB can be indistinguishable from those of metastatic malignancy.

Laboratory tests can play a crucial role in distinguishing TB from malignancy (10). Elevated inflammatory markers such as CRP and ESR are nonspecific but indicative of an active process (11). If the T-SPOT.TB test is positive, mycobacterial infection is suggested (12). However, in our case, the absence of acid-fast bacilli in sputum smears and the negative X-pert MTB/RIF assay added to the diagnostic ambiguity. Tumor markers were within normal limits, which did not support a malignant etiology. This pattern of laboratory findings—positive immunologic evidence of TB exposure but negative microbiologic confirmation—is characteristic of paucibacillary extrapulmonary TB and reinforces the need for histologic confirmation.

The differentiation between TB and malignancy relies on a combination of clinical, radiological, and laboratory data (13). Although imaging provides morphological clues and laboratory tests offer supportive evidence, a definitive diagnosis relies on histopathological examination (13). In our case, the identification of M. tuberculosis nucleic acid in the iliac bone biopsy, along with the presence of granulomatous inflammation and necrosis in the lymph node biopsy, corresponded with established diagnostic criteria for TB. This case emphasizes that in challenging diagnostic scenarios, obtaining adequate tissue samples from affected sites is critical, and repeated biopsies may be necessary when initial results are inconclusive but clinical suspicion remains high.

The recommended treatment for systemic TB typically involves a four-drug regimen consisting of isoniazid, rifampicin, pyrazinamide, and ethambutol for the initial 2 months, followed by isoniazid and rifampicin for an additional 4 months (14). This standard regimen is endorsed by the World Health Organization and is effective for treating drug-susceptible TB (14). For drug-resistant TB, treatment may include additional drugs such as streptomycin or linezolid, depending on the specific resistance profile of the TB strain (15).

In this case, the initial poor response to anti-TB treatment sustained the diagnostic uncertainty but ultimately did not preclude the correct diagnosis. The lack of initial symptomatic improvement following the initial regimen (isoniazid, rifampicin, ethambutol, and pyrazinamide) was a significant diagnostic challenge. The subsequent marked response to the modified regimen (isoniazid, linezolid, rifampicin, and pyrazinamide) allowed for a reevaluation of the initial treatment failure. Although the patient’s eventual recovery suggests that extensive drug resistance was unlikely, the possibility of a mono- or poly-drug resistant strain that was subsequently covered by the addition of linezolid cannot be entirely ruled out, especially in the absence of drug susceptibility testing. Other potential reasons for the initial failure could include a paradoxical reaction (immune reconstitution inflammatory syndrome), which can cause transient clinical worsening, or suboptimal drug bioavailability. This sequence highlights that an initial poor response to treatment in a patient with strong pathological evidence of TB should prompt a comprehensive reassessment, including consideration of drug resistance, and should result in a premature abandonment of the TB diagnosis.

This case provides several important insights that advance clinical practice in the management of complex diagnostic scenarios. First, it reinforces the critical importance of maintaining a high index of suspicion for TB even when the overt features strongly suggest malignancy. Second, it demonstrates the necessity of a systematic diagnostic approach that prioritizes histopathological confirmation over imaging findings alone. Third, the case illustrates that initial treatment response should not override strong pathological evidence in the formulation of diagnostic decisions. These lessons are particularly valuable in resource-limited settings where advanced diagnostic modalities may be unavailable, emphasizing the enduring value of thorough clinical evaluation and targeted biopsy. By documenting this challenging diagnostic journey, we provide a framework for clinicians facing similar dilemmas, potentially reducing diagnostic delays and inappropriate treatments in comparable cases.

This case supports the use of a generalizable diagnostic strategy for multisystem involvement: After initial imaging, priority should be given to obtaining tissue for histopathology. In resource-limited settings, targeted biopsy with basic staining (e.g., acid fast) and molecular tests (e.g., TB staining and PCR) should be prioritized over advanced imaging such as PET-CT, ensuring cost-effective diagnosis while maintaining accuracy.

In conclusion, this case illustrates the complexities associated with the diagnosis and management of patients exhibiting multisystem involvement of TB and the potential for overlap with malignant lesions. It underscores the necessity of maintaining a high index of suspicion, employing a systematic approach to both diagnosis and treatment, and recognizing the essential role of multidisciplinary collaboration in attaining optimal patient outcomes. Furthermore, the case supports the need for continued research aimed at enhancing diagnostic tools and treatment strategies, particularly in relation to atypical presentations of TB.

Conclusions

This case underscores the critical importance of considering TB in the differential diagnosis of patients with multisystem involvement, even when imaging features strongly suggest malignancy. The key recommendations for clinicians include (I) maintaining a high index of suspicion for TB in atypical presentations; (II) prioritizing histopathological confirmation through biopsy as the diagnostic cornerstone; and (III) employing a multidisciplinary approach to navigate complex diagnostic scenarios. These steps are essential to avoiding misdiagnosis and ensuring appropriate management.

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-2025-1442/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 Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from 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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