Role of ¹⁸F-FDG PET/CT in the diagnosis and treatment response assessment of primary pulmonary lymphoma

Introduction

Pulmonary lymphoma includes the subtypes primary pulmonary lymphoma (PPL) and secondary pulmonary lymphoma (SPL) (1). PPL is a rare disorder; it represents only 0.3–1% of all primary pulmonary malignancies and accounts for less than 1% of all cases of non-Hodgkin lymphoma (2-4). PPL is primarily defined as clonal lymphoid proliferation originating from the pulmonary parenchyma or bronchi with or without hilar lymph node involvement and without extrathoracic lymphoma at diagnosis or within the subsequent 3 months (5-7). In contrast, SPL refers to the intrapulmonary infiltration of extrapulmonary lymphoma, which is caused mainly by direct infiltration of mediastinal lymphoma or metastasis from distant lymphoma lesions to the lungs through blood or lymphatic channels, accounting for 25% to 40% of all lymphoma cases (8). Although the pathological origins of PPL and SPL differ, their imaging and clinical manifestations in the lungs and mediastinum are similar. Considering the different treatment strategies for PPL and SPL, the diagnosis of PPL requires excluding the possibility of SPL (9,10). Therefore, PPL diagnosis must first exclude the presence of extrapulmonary lesions (11).

Patients with PPL often present with nonspecific pulmonary symptoms such as cough, hemoptysis, dyspnea, and chest pain or constitutional symptoms such as fever and weight loss (12-14). The radiological findings of PPL are also nonspecific, showing single or multiple unilateral or bilateral lesions forming ground-glass opacities (GGOs), nodules, masses or mass-like consolidations, patchy shadows, and consolidations (14-16). The nonspecific imaging and clinical manifestations make the diagnosis of this disease very difficult; consequently, PPL is often misdiagnosed as pneumonia, tuberculosis, lung cancer, or SPL, which affects the clinical treatment and prognosis (17-19).

The imaging examinations related to PPL include X-ray, computed tomography (CT), and ¹⁸F-fluorodeoxyglucose positron emission tomography/CT (¹⁸F-FDG PET/CT), among which most of the previous imaging-related studies were reports on CT morphology that were limited by a small sample size and a lack of systematic research (16). As an imaging approach that combines PET and CT, PET/CT can be employed to determine the metabolic characteristics and imaging features of a PPL (20). PET/CT has been widely used in the diagnosis, differential diagnosis, staging, restaging, treatment efficacy evaluation, prognosis prediction, and follow-up of lymphoma (21-23). However, few studies have reported the clinical application of PET/CT in the diagnosis and treatment of PPL, and most of them are case reports (24,25).

Considering this background, a total of 22 PPL patients who had undergone ¹⁸F-FDG PET/CT were included in this study, and the clinical significance of various PET/CT morphological and metabolic parameters was comprehensively evaluated. In addition, further comparative analysis of imaging features before and after treatment was conducted, the results of which may contribute to a better understanding of this disease. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-922/rc).

Methods

Patients and clinicopathologic characteristics

This retrospective study included 22 patients diagnosed with PPL who were treated at The Third Affiliated Hospital of Kunming Medical University between February 2014 and September 2023. PPL was defined as clonal lymphoid proliferation originating from the pulmonary parenchyma or bronchi, with or without hilar lymph node involvement, and without extrathoracic lymphoma at diagnosis or within three months thereafter. All patients met the following eligibility criteria: (I) aged between 18 and 80 years; (II) had undergone an ¹⁸F-FDG PET/CT scan before receiving treatment; and (III) had a confirmed pathological diagnosis of lymphoma. The pathological classification of PPL was based on the revised World Health Organization Lymphoma Classification [2016]. Specific subtypes of PPL were determined using imaging, histopathological examination, immunohistochemical staining, and, where necessary, genetic testing.

Baseline data, including demographic details, clinical symptoms, B symptoms, pathological results, lactate dehydrogenase (LDH) levels, treatment modalities, and International Prognostic Index (IPI) scores, were collected from all patients prior to treatment. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Boards at The Third Affiliated Hospital of Kunming Medical University (No. KYLX2025-151) and individual consent for this retrospective analysis was waived.

Imaging

¹⁸F-FDG PET/CT images were acquired using the Syngo platform (Siemens Healthineers, Erlangen, Germany) at the PET/CT Center of The Third Affiliated Hospital of Kunming Medical University. The ¹⁸F-FDG radiotracer was produced using a PET micro-cyclotron and a chemical synthesis system, achieving a radiochemical purity of no less than 97%. The CT parameters were standardized at 120 kV and 150 mA, with a slice thickness of 5 mm and a layer spacing of 4.25 mm (Table S1).

All 22 patients fasted for 6–8 hours, and their blood glucose levels were checked to ensure that they were below 11.1 mmol/L. Each patient received an intravenous injection of ¹⁸F-FDG (0.1–0.15 mCi/kg) after a 15-minute resting period. A PET scan was performed after 60 minutes of rest following bladder emptying and hydration. The scanning range extended from the top of the skull to the upper femur, with additional limb scans as needed. The Syngo Multimodal Workplace System (Siemens Healthineers) was used to assess whole-body structures through the region of interest (ROI) function. Two experienced PET/CT diagnostic specialists independently interpreted the images in a double-blind manner.

Imaging analysis

The morphological features of PET/CT were assessed for the presence of pulmonary nodules, masses, mass-like consolidations, consolidations, patchy shadows, and GGO. All the images were also assessed for evidence of other associated CT signs, such as air bronchograms, translobar signs, bronchiectasis, cavities, and halo signs. The involvement of the hilar or mediastinal nodes, pleura and chest wall was also assessed.

The PET/CT metabolic parameters evaluated in this study included standardized uptake value maximum (SUVmax), mean standardized uptake value (SUVmean), total lesion glycolysis (TLG), and metabolic tumor volume (MTV). PET and CT data were processed using tumor metabolism assessment software, and ROIs were delineated along the margins of the primary lesions. A fixed threshold of 41% SUVmax was used to segment the lesions automatically in the transverse, sagittal, and coronal planes (26-28). The total TLG was calculated as the sum of the TLG values from all the lesions, whereas the total MTV was the sum of the MTV values from all the lesions (26).

Ten patients underwent posttreatment ¹⁸F-FDG PET/CT scans. These patients were evaluated according to the Deauville five-point scale from the 2014 Lugano criteria and the ∆SUVmax method. The Deauville scale assigns scores based on visual interpretation of PET scans, ranging from no uptake (score of 1) to marked uptake or new lesions (score of 5). A decrease in the SUVmax between pre- and posttreatment PET scans (∆SUVmax) was calculated. Additionally, ∆TLG and ∆MTV were computed using the same methodology (29). All Δ values (ΔSUVmax, ΔMTV, ΔTLG) represent percentage changes from baseline to post-treatment, calculated as: ΔParameter (%) = [(baseline value − post-treatment value)/baseline value] × 100%.

Images of ¹⁸F-FDG PET/CT were evaluated separately by two senior or associate chief physicians of nuclear medicine. Inter-reader agreement for qualitative imaging features (e.g., lesion morphology, Deauville score) was quantified using Cohen’s kappa (κ) statistic. Kappa values were interpreted as follows: ≤0.20 (poor), 0.21–0.40 (fair), 0.41–0.60 (moderate), 0.61–0.80 (good), and 0.81–1.00 (excellent). For continuous metabolic parameters (SUVmax, MTV, TLG), intraclass correlation coefficients (ICCs) with 95% confidence intervals (CIs) were calculated. If there is a disagreement, a consensus can be reached through negotiation or decision-making by the diagnostic team of the department.

Statistical analysis

Patient outcomes were monitored through telephone follow-ups and outpatient visits. Overall survival (OS) was defined as the time from PPL diagnosis to death or loss to follow-up. Kaplan-Meier survival curves were generated, and log-rank tests were performed for statistical comparisons. Continuous variables (SUVmax, SUVmean, MTV, TLG) were assessed for normality using Shapiro-Wilk tests. Since the data deviated from normality (P<0.05 for MTV and TLG) and subgroup sample sizes were small (MALT: n=16; non-MALT: n=6), non-parametric Mann-Whitney U tests were used for all metabolic parameter comparisons. Some categorical variables were analyzed using Fisher’s exact tests due to small expected cell counts. All the statistical analyses were conducted using IBM SPSS Statistics, version 24.

Results

Patient characteristics

A total of 22 patients were retrospectively included in the study, comprising 16 male and 6 female patients, with a median age of 56.5 years (range, 20–79 years). Among these patients, 20 (90.9%) presented respiratory symptoms, including dry cough, cough with sputum, blood-tinged sputum, chest tightness, chest pain, and difficulty breathing (Table 1). Cough with sputum was the most common symptom observed in 10 patients (45.4%). Two patients were asymptomatic, and no cases of hemoptysis were recorded. Additionally, some patients present with systemic symptoms such as fever, fatigue, night sweats, weight loss, and decreased appetite. Weight loss was the most common systemic symptom, reported in 6 patients (27.2%), whereas fever was observed in only 1 patient (4.5%). A total of 20 (90.9%) patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) score ranging from 0 to 1, and only 2 (9.1%) patients had a score of 2. Nine patients (40.9%) had a history of long-term smoking, with 2 of these patients also reporting long-term alcohol consumption. Seven patients (31.8%) had conditions associated with immunosuppression, including 1 patient with human immunodeficiency virus (HIV), 1 with rheumatoid arthritis, 2 with hepatitis B, and 3 with type II diabetes.

An erroneous diagnosis was made in 17 patients (77.3%) at the initial hospital visit, and only 5 patients (22.7%) were diagnosed with lymphoma. Thirteen patients with erroneous diagnoses had inflammatory diseases, including pneumonia (9 patients), tuberculosis (2 patients) and inflammatory granuloma (2 patients). The other patients were misdiagnosed with lung cancer (2 patients) or malignant lung lesions (2 patients).

The pathological subtypes included mucosa-associated lymphoid tissue (MALT) lymphoma, diffuse large B-cell lymphoma (DLBCL), BCLu-DLBCL/Chl (B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma), with MALT lymphoma being the most common (16/22, 72.7%), followed by DLBCL (4/22, 18.2%). Only 1 patient had elevated LDH, while 14 patients had elevated tumor markers, including carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), cancer antigen 724 (CA724), cancer antigen 153 (CA153), cancer antigen 19-9 (CA19-9), cancer antigen 242 (CA242), cytokeratin 19 fragment (CYRFA21-1), neuron-specific enolase (NSE), and squamous cell carcinoma (SCC) antigen. Except for CA125, which was elevated by 9.05 times the upper limit, the increases in other tumor markers did not exceed 3 times the normal range (Table 2). Inflammatory markers such as C-reactive protein and leukocytes were elevated in only 2 patients (9.09%). Diagnostic methods included CT-guided needle biopsy (9/22, 40.9%), bronchoscopy (6/22, 27.3%), surgery (6/22, 27.3%), and endobronchial ultrasound (1/22, 4.5%). The treatment regimens varied: 13 patients (59.1%) received chemotherapy alone; 3 patients (13.6%) underwent surgery and chemotherapy; 2 patients (9.09%) were treated with chemotherapy and radiotherapy; 2 patients (9.09%) received chemotherapy and targeted therapy; and 2 patients (9.09%) underwent combination therapy, including chemotherapy, surgery, radiotherapy, and targeted therapy.

Imaging characteristics of ¹⁸F-FDG PET/CT

Based on previous research, the PET/CT findings were classified into six major CT signs: single or multiple nodules (Figure 1), mass (Figure 2), mass-like consolidation (Figure 3), consolidation (Figure 4), patchy shadow (Figure 5), and GGO (Figure 6). Excellent agreement was observed for major CT signs classification (κ=0.86, 95% CI: 0.75–0.97) and Deauville scoring (κ=0.82, 95% CI: 0.70–0.94). Patients presented with one or more of these signs simultaneously, with consolidation being the most common manifestation (50%), followed by nodules (45.4%), patchy shadows (40.9%), masses (27.2%), mass-like consolidations (9.1%), and GGOs (9.1%) (Table 3). According to the imaging findings, patients were categorized into five patterns: node type, mass type, mass-like consolidation or consolidation type, patchy type, and mixed type. Two or more CT signs of lesions present in the same patient were divided into the mixed type (Figure 4), which was the most prevalent, observed in 9 patients (40.9%), followed by the node type (6/22, 27.3%), consolidation or mass-like consolidation type (5/22, 22.7%), mass type (1/22, 4.5%), and patchy type (1/22, 4.5%). Notably, none of the patients exhibited GGOs alone; GGOs were always accompanied by other lesion types.

Figure 1 Multiple nodules in the left lung. ¹⁸F-FDG PET/CT scan of a 59-year-old woman with DLBCL. The MIP of the PET scan before treatment (A) shows multiple hypermetabolic lesions in the left lung with an SUVmax of 9.9. Axial PET/CT images (C,E,G) before treatment revealed nodules in various locations in the left lung, including involvement of the pleura and chest wall at the upper lingual segment. After treatment, MIP PET (B) revealed the absence of abnormal hypermetabolic lesions in the left lung. Axial posttreatment PET/CT images (D,F,H) confirmed the disappearance of FDG-avid lesions, with a Deauville score of 1. ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; CT, computed tomography; DLBCL, diffuse large B-cell lymphoma; MIP, maximum intensity projection; PET, positron emission tomography; SUVmax, maximum standardized uptake value.

Figure 2 Mass with a cavity in the left lung. ¹⁸F-FDG PET/CT scan of a 49-year-old man with MALT lymphoma. ¹⁸F-FDG PET (A), CT (B), and fused PET/CT (C,D) images show a mass with cavities (red arrow) and abnormal FDG uptake with an SUVmax of 8.09. The lesion crosses the oblique fissure of the pleura (green arrow). Lobectomy revealed the mass to be primary MALT lymphoma. ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; CT, computed tomography; MALT, mucosa-associated lymphoid tissue; PET, positron emission tomography; SUVmax, maximum standardized uptake value.

Figure 3 Mass-like consolidation in the left upper lobe. ¹⁸F-FDG PET/CT scan of a 41-year-old man with MALT lymphoma. CT (A,C) and PET/CT (B,D) revealed two mass-like consolidations with halo signs at the edges and air bronchograms (black arrow in lung window and white arrow in mediastinal window) within the larger lesion. Air bronchograms sign is less pronounced in small lesion and only visible on the mediastinal window (white arrow head). These lesions presented high FDG uptake, with an SUVmax of 13.9. Postoperative pathology confirmed the diagnosis of primary MALT lymphoma. ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; CT, computed tomography; MALT, mucosa-associated lymphoid tissue; PET, positron emission tomography; SUVmax, maximum standardized uptake value.

Figure 4 Pulmonary consolidation with air bronchogram signs. ¹⁸F-FDG PET/CT scan of a 51-year-old woman with MALT lymphoma. CT (A,C) and PET/CT (B,D) show a large consolidation in the right lung, extending across the lobes. There is avid FDG uptake within the lesion. Air bronchogram signs are visible (black and white arrows). A CT-guided needle biopsy confirmed the diagnosis of primary MALT lymphoma. ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; CT, computed tomography; MALT, mucosa-associated lymphoid tissue; PET, positron emission tomography.

Figure 5 Patchy shadow in the left lower lobe. ¹⁸F-FDG PET/CT scan of a 49-year-old man with MALT lymphoma. CT (A,C) and PET/CT (B,D) revealed an abnormally hypermetabolic patchy shadow in the left lower lobe, with an SUVmax of 6.1. The lesion demonstrates heterogeneous density with both solid and nonsolid components. ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; CT, computed tomography; MALT, mucosa-associated lymphoid tissue; PET, positron emission tomography; SUVmax, maximum standardized uptake value.

Figure 6 Ground-glass opacities in the right middle lobe. ¹⁸F-FDG PET/CT scan of a 49-year-old man with MALT lymphoma. PET (A), CT (B), and PET/CT (C,D) revealed ground-glass opacities (circles) in the middle lobe of the right lung, with mild FDG uptake and an SUVmax of 2.4. Postoperative pathology identified the lesion as primary MALT lymphoma. ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; CT, computed tomography; MALT, mucosa-associated lymphoid tissue; PET, positron emission tomography; SUVmax, maximum standardized uptake value.

Additionally, 16 patients (72.7%) had associated CT signs, including air bronchograms (12/22, 54.5%) (Figures 3,4), translobar signs (11/22, 50.0%) (Figure 2), bronchiectasis (9/22, 40.9%), cavities (6/22, 27.3%) (Figure 2), and halo signs (2/22, 9.1%). Significant differences in major CT patterns and associated CT signs between MALT lymphoma patients and non-MALT lymphoma patients were not observed (Table S2).

¹⁸F-FDG metabolic features of PPLs

Lesions in the lungs varied in distribution, appearing as single, multiple, or diffuse lesions (involving all five lobes). Most patients (14/22, 63.6%) had nonsingle lesions. The measurable lesion diameters ranged from 0.9 to 13.5 cm, excluding diffuse lesions. Metabolic parameters showed high consistency: ICC for SUVmax was 0.98 (95% CI: 0.96–0.99), MTV 0.95 (95% CI: 0.91–0.98), and TLG 0.94 (95% CI: 0.89–0.97). The SUVmax values ranged from 0.76 to 54.99. The average SUVmax of all patients was 9.91, with a range of 0.76 to 54.99. The average SUVmax for DLBCL patients was 21.08, with a range of 4.66 to 54.99, whereas the average SUVmax for MALT lymphoma patients was 6.16, with a range of 0.76 to 13.96. Significant differences were found in the SUVmax across the MALT lymphoma patients and non-MALT lymphoma patients (P=0.01) (Table S2). DLBCL patients had the highest median SUVmax, SUVmean, and TLG values, whereas MALT lymphoma patients had the highest MTV. The SUVmean ranged from 0.5 to 27.89, with DLBCL patients having a mean of 10.01 and MALT lymphoma patients having a mean of 3.49. The SUVmean also significantly differed across the MALT and non-MALT types (0.039) (Table S2). The SUVmax and SUVmean values for MALT lymphoma patients were markedly lower than those for DLBCL patients. MTV and TLG showed considerable variability due to the differing sizes and distributions of lesions. The MTV ranged from 0.65 to 1,864.07 cm³, and the TLG ranged from 0.325 to 10,307.31 g (Table 4).

Five patients presented with mediastinal or hilar lymph node involvement, eight had signs of pleural thickening, and five had pleural effusion. Using the Ann Arbor staging criteria (30), 13 patients (59.1%) were classified as stage IE, 5 (22.7%) as stage IIE, 1 (4.5%) as stage IIEW (involving the chest wall muscles), and 3 patients (13.6%) as stage IV (with diffuse lesions in both lungs and involvement of five lobes).

PET/CT evaluation for response assessment

Ten of the 22 patients underwent posttreatment PET/CT evaluation. Among these patients, 5 received chemotherapy alone, 2 underwent surgery and chemotherapy, 1 received chemotherapy and targeted therapy, 1 was treated with radiotherapy and chemotherapy combined with targeted therapy, and 1 received surgery and targeted therapy. Four patients were evaluated at the midpoint of treatment using the Deauville five-point scale, where 1 patient was PET negative (1–3 points) and 3 were PET positive (4–5 points, as shown in Figure 5). The results of the ∆SUVmax method, with a threshold of 71% (31), were consistent with those of the Deauville scale assessment. Similarly, the ∆MTV and ∆TLG results aligned with the ∆SUVmax in 3 patients. Notably, a patient with a Deauville scale of 5 presented an 85% reduction in MTV and a 96% reduction in TLG.

At the end of treatment, 10 patients underwent PET/CT imaging. Using the Deauville five-point scale, 4 patients were PET-negative, and 6 were PET-positive. When the ∆SUVmax was evaluated, the same results were observed in 7 patients. Two patients who were PET-negative according to the Deauville five-point scale were classified as PET-positive via the ∆SUVmax; one of these patients had an SUVmax of 68%, close to the negative threshold, and showed significant reductions in MTV (93%) and TLG (98%). Another patient with a Deauville scale of 5 had a 75% reduction in the SUVmax but exhibited a significant increase in the MTV (−160%) and only a slight decrease in the TLG (16%) (Table 5).

Notably, two patients exhibited paradoxical metabolic responses. One was patient 4 (MALT lymphoma), post-treatment SUVmax increased by 11% (ΔSUVmax =−11%) despite reductions in MTV (−30%) and TLG (−11%), suggesting inflammatory changes or heterogeneous treatment effect. Another was patient 21 (DLBCL): MTV surged by 157% (ΔMTV =−157%) with new lesions, indicating disease progression despite partial SUVmax reduction (75%). This patient succumbed to disease within 12 months.

Survival analysis

Survival data were collected through telephone and outpatient follow-ups for 21 of the 22 patients, resulting in a dropout rate of 4.5%. The median follow-up time was 48.7 months. As of June 1, 2024, only 2 patients (Patient 7 and Patient 19) had died. The estimated average OS was 105.3 months, with no median OS determined.

Discussion

As a clonal lymphoproliferative disease, PPL is a rare form of primary malignant lung tumor (32). In this study, we retrospectively analyzed 22 patients with PPL and assessed their clinical and pathological characteristics, PET/CT imaging findings, metabolic features, and prognoses. To our knowledge, this study represents the largest to date focused on the application of ¹⁸F-FDG PET/CT in PPL. Consistent with previous research, MALT lymphoma and DLBCL were the predominant subtypes in our cohort (14). Specifically, 20 of the 22 patients in this study had MALT lymphoma or DLBCL.

Previous studies have reported a greater incidence of PPL in men than in women, which is supported by our findings, where the male-to-female ratio was 2.7:1 (14,33). Some conflicting reports suggest similar sex distributions, likely due to the relatively small sample sizes used in studies on this rare disease (34). Additionally, PPL primarily affects middle-aged and elderly patients, as demonstrates by the fact that only two patients in our study were younger than 40 years at diagnosis (35).

Previous studies have shown that PPL may be related to immune diseases and a long-term smoking history, but the rate is variable (24,36,37). In our study, 2 (9.1%) patients had immune diseases, including rheumatoid arthritis and HIV, and this rate was included in previous studies. Nine (40.9%) patients had a long-term smoking history ranging from 10 to 30 years, which was lower than that reported in previous studies (68%) (24,36).

The clinical symptoms of PPL are typically nonspecific, and patients often present with respiratory or constitutional symptoms. In contrast to previous studies indicating that approximately one-third of PPL patients are asymptomatic (38), 20 (90.9%) of the 22 patients in this study presented respiratory symptoms. Cough was the most common presenting symptom, with a rate of 45.4%, with only one patient (4.5%) experiencing fever. A study in which pneumonic-type primary pulmonary lymphoma was differentiated from pneumonia by Li et al. reported a fever rate of 52.3%; this low incidence of fever can help differentiate PPL from infectious pulmonary conditions (18).

Consistent with previous reports, the misdiagnosis rates were high at initial diagnosis in our study, as only 5 patients were accurately diagnosed with lymphoma, leading to a misdiagnosis rate of 77.3%. PPL, often misdiagnosed as pneumonia, lung cancer, tuberculosis, or pneumonia, was the most common type, accounting for 46% to 76% of the misdiagnosed types, whereas the rate was 47% in our study (12,39). Misdiagnosis can lead to inappropriate treatment and increased medical expenses. Interestingly, inflammatory markers are elevated in only 2 patients (9.09%), and the patients were diagnosed with lung cancer and malignant lung lesions at the first clinic visit. Notably, none of the patients misdiagnosed with inflammatory diseases presented elevated inflammatory markers and fever. Previous studies revealed that patients with pneumonia had a greater prevalence of fever, leucocytosis and elevated C-reactive protein levels than those with PPL (18,40). Intense FDG uptake helps reduce misdiagnosis rates, especially for non-MALT lymphoma; the average SUVmax is 19.8, and the SUVmax is obviously lower in pneumonia (18,41,42). These features help differentiate PPL from inflammatory diseases. Multiple serological tumor markers are elevated irregularly, and most tumor markers are expressed at low levels, which differs from lung cancer findings (43). Unlike other types of lymphoma (44), most PPL cases do not result in elevated LDH levels.

Imaging characteristics play a crucial role in diagnosing PPLs. In this study, patients presented various CT signs, including nodules, masses, mass-like consolidations, consolidations, patchy shadows, and GGOs, which is consistent with previous reports (16). The most common CT pattern was the mixed type, where patients presented with multiple CT signs, reinforcing the notion that PPLs often present with heterogeneous imaging findings (Figure 7). Notably, air bronchogram signs were present in more than half of the patients (Figures 3,4), which contrasts with typical lung cancer imaging patterns and can aid in differentiating PPLs from other pulmonary malignancies (39).

Figure 7 Whole-body ¹⁸F-FDG PET/CT scan of a 46-year-old man with primary MALT lymphoma divided into the mixed type. MIP PET (A) and axial PET/CT images (B-E) show multiple lesions of various sizes and shapes diffusely distributed in both lungs. The lesions included nodules (white arrowheads), masses (red long arrow), mass-like consolidations (black short arrows), consolidations (black long arrows), and patchy shadows (red arrowheads), each with varying FDG uptake. ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; CT, computed tomography; MALT, mucosa-associated lymphoid tissue; MIP, maximum intensity projection; PET, positron emission tomography.

PET/CT offers several advantages over CT in lymphoma staging, particularly for subtypes with high FDG uptake. This technology can detect metabolic changes before anatomical abnormalities become apparent, improving diagnostic accuracy and staging (45). This is particularly important in distinguishing primary pulmonary lymphoma from secondary pulmonary involvement of extranodal lymphomas. In our study, DLBCL patients had higher SUVmax values than MALT lymphoma patients, aligning with previous findings (46). Interestingly, MALT lymphoma patients had the highest MTV, suggesting that different pathological subtypes of PPL have distinct PET/CT features that may warrant further investigation. This metabolic divergence likely reflects distinct tumor biology. DLBCL, as an aggressive lymphoma, demonstrates high glycolytic flux driven by upregulated GLUT-1 transporters and hexokinase-II activity, resulting in intense per-unit FDG uptake (high SUVmax) (47). In contrast, MALT lymphoma—characterized by indolent growth—often contains abundant desmoplastic stroma, inflammatory infiltrates, and extracellular matrix (37). These non-neoplastic components dilute metabolic activity per volume unit (lower SUVmean) while contributing to volumetric expansion (higher MTV).

In addition to its ability to diagnose and stage, PET/CT is valuable for assessing treatment efficacy and prognosis in lymphoma patients (48). However, research assessing treatment efficacy by PET/CT in PPL is extremely rare; prior to this, the value of ¹⁸F-FDG PET/CT for assessing treatment efficacy was not clearly understood. Previous studies in other extranodal lymphomas, including our research, have shown that PET/CT is crucial in evaluating the response to treatment in lymphomas such as primary bone lymphoma (29). Pretreatment metabolic parameters provide insight into tumor burden, whereas changes in these parameters during and after treatment reflect the treatment response (29). Ten patients underwent posttreatment PET/CT imaging in our study, and we evaluated their responses using both the Deauville five-point scale and ∆SUVmax methods. The response to treatment is variable; some patients achieved a complete response at the end of treatment (Figure 1), and 40% of patients achieved a partial response. Our data reveal both synergy and divergence between the Deauville scale and Δ-metrics (ΔSUVmax/MTV/TLG) in evaluating PPL response, driven by three key factors. First, biological heterogeneity: while the Deauville scale captures peak metabolic activity (critical for identifying resistant clones), Δ-metrics measure bulk tumor changes. Second, treatment-induced artifacts: radiotherapy or chemotherapy may trigger inflammation (elevating SUVmax, lowering Δ-values), falsely inflating Deauville scores. Third, PPL-specific limitations: persistent air bronchograms artifactually raise background FDG uptake, inflating Deauville scores—whereas ΔMTV/ΔTLG better quantify true tumor burden changes. To address these, we propose an integrative approach: during interim assessment, a ΔSUVmax >70% predicts chemosensitivity even with a Deauville score of 4; at end-of-treatment, Deauville scores 1–3 should take precedence over Δ-metrics to avoid under-treatment. Besides, our data reveal metabolic-anatomic dissociations in PPL treatment response. The paradoxical SUVmax increase in Patient 4 (Figure 8) may reflect targeted therapy induced inflammation or necrotic debris uptake. Conversely, Patient 21’s MTV surge despite SUVmax decline highlights aggressive subclonal expansion masked by partial necrosis—a pattern prognostic of poor survival in DLBCL.

Figure 8 Whole-body ¹⁸F-FDG PET/CT scan of a 45-year-old man with primary MALT lymphoma before treatment and after treatment. Pretreatment PET/CT scan (A-C) shows large areas of consolidation in the upper right lobe and both lobes of the left lung, with translobar distribution and an SUVmax of 4.8. After four cycles of chemotherapy, the PET/CT scans (D-F) revealed similar lesion areas but with increased FDG uptake (SUVmax 7.6) and a Deauville score of 5. ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; CT, computed tomography; MALT, mucosa-associated lymphoid tissue; PET, positron emission tomography; SUVmax, maximum standardized uptake value.

One of the challenges in assessing PPL treatment efficacy by CT is the persistence of radiographic abnormalities, such as bronchiectasis and residual shadows, even after treatment (16). PET/CT offers an advantage in this regard, as it can detect changes in FDG uptake that reflect tumor activity, even when anatomical changes are minimal (16). In this study, we observed changes in FDG uptake in some patients after treatment, even though the size and distribution of the lesions remained unchanged (Figure 8). However, we could not use these methods to predict long-term outcomes because of the small sample size and limited follow-up duration. Although some patients remain PET positive after treatment, their survival during follow-up suggests that although PPL is relatively resistant to treatment, it still has a favorable prognosis (49).

PPL has a relatively indolent tumor biology and generally has a favorable prognosis (1). MALT lymphoma, in particular, has an excellent prognosis, with a reported 5-year survival rate as high as 78.9% (49). The dissociation between treatment sensitivity and survival in PPL—particularly MALT lymphoma—reflects its slow-growing biology. Patients often achieve clinical stability with partial metabolic responses, whereas complete remission is uncommon. Persistent radiographic abnormalities (e.g., air bronchograms) and low-level FDG uptake may represent fibrosis or chronic inflammation rather than active disease, explaining the favorable long-term outcomes despite ‘insensitive’ treatment metrics. In our study, after a median follow-up period of 48.7 months, only two patients died. However, treatment strategies for MALT lymphoma remain controversial (1). While surgery and radiotherapy are sometimes recommended for localized disease, chemotherapy is typically preferred for diffuse cases. Some studies suggest that observation may be appropriate for early-stage MALT lymphoma, as neither surgery nor chemotherapy has improved OS in these patients (49).

This study has several limitations. As this was a retrospective single-center study, the results require validation through multicenter prospective research. Additionally, the excellent prognosis of patients with PPL, with only two deaths during the follow-up period, limits our ability to assess the prognostic value of metabolic parameters. Finally, the small sample size may have introduced bias.

Conclusions

In conclusion, this study provides a comprehensive analysis of the imaging features and metabolic characteristics of PPLs. Our findings highlight the differences between pathological subtypes of PPL in terms of PET/CT features. PPL generally has a good prognosis but is not highly responsive to treatment. In addition, functional ¹⁸F-FDG PET/CT imaging readily reflects tumor cell activity before morphology changes. PET/CT plays a unique and essential role in diagnosing, staging, and evaluating the treatment response in patients with PPL. As radiomics and artificial intelligence (AI) continue to advance, these technologies may further increase the utility of PET/CT in managing this rare disease.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-922/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-922/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-922/prf

Funding: This study has received funding by the Scientific Research Fund of Yunnan Province Educational Department (No. 2024J0357), Technology Plan Project of Yunnan Province (No. 202101AY070001-180), and Xing Dian Ying Cai Support Plan and Kunming Medical University Chengfeng Project.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-922/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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Boards at The Third Affiliated Hospital of Kunming Medical University (No. KYLX2025-151) and individual consent for this retrospective analysis was waived.

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/.

References

1. Hu M, Gu W, Chen S, et al. Clinical Analysis of 50 Cases of Primary Pulmonary Lymphoma: A Retrospective Study and Literature Review. Technol Cancer Res Treat 2022;21:15330338221075529. [Crossref] [PubMed]
2. Miller DL, Allen MS. Rare pulmonary neoplasms. Mayo Clin Proc 1993;68:492-8. [Crossref] [PubMed]
3. William J, Variakojis D, Yeldandi A, et al. Lymphoproliferative neoplasms of the lung: a review. Arch Pathol Lab Med 2013;137:382-91. [Crossref] [PubMed]
4. Otero Lozano D, Blanco Ramos M, Sacristán Robles L, et al. Primary pulmonary lymphoma: a surgical series. Indian J Thorac Cardiovasc Surg 2025;41:156-61. [Crossref] [PubMed]
5. Piña-Oviedo S, Weissferdt A, Kalhor N, et al. Primary Pulmonary Lymphomas. Adv Anat Pathol 2015;22:355-75. [Crossref] [PubMed]
6. Cadranel J, Wislez M, Antoine M. Primary pulmonary lymphoma. Eur Respir J 2002;20:750-62. [Crossref] [PubMed]
7. Graham BB, Mathisen DJ, Mark EJ, et al. Primary pulmonary lymphoma. Ann Thorac Surg 2005;80:1248-53. [Crossref] [PubMed]
8. Carter BW, Wu CC, Khorashadi L, et al. Multimodality imaging of cardiothoracic lymphoma. Eur J Radiol 2014;83:1470-82. [Crossref] [PubMed]
9. Cardenas-Garcia J, Talwar A, Shah R, et al. Update in primary pulmonary lymphomas. Curr Opin Pulm Med 2015;21:333-7. [Crossref] [PubMed]
10. Majid N. Primary pulmonary lymphoma: About five cases and literature review. Lung India 2014;31:53-5. [Crossref] [PubMed]
11. Dong Y, Zeng M, Zhang B, et al. Significance of imaging and clinical features in the differentiation between primary and secondary pulmonary lymphoma. Oncol Lett 2017;14:6224-30. [Crossref] [PubMed]
12. Yao D, Zhang L, Wu PL, et al. Clinical and misdiagnosed analysis of primary pulmonary lymphoma: a retrospective study. BMC Cancer 2018;18:281. [Crossref] [PubMed]
13. He H, Tan F, Xue Q, et al. Clinicopathological characteristics and prognostic factors of primary pulmonary lymphoma. J Thorac Dis 2021;13:1106-17. [Crossref] [PubMed]
14. Zhang XY, Gu DM, Guo JJ, et al. Primary Pulmonary Lymphoma: A Retrospective Analysis of 27 Cases in a Single Tertiary Hospital. Am J Med Sci 2019;357:316-22. [Crossref] [PubMed]
15. King LJ, Padley SP, Wotherspoon AC, et al. Pulmonary MALT lymphoma: imaging findings in 24 cases. Eur Radiol 2000;10:1932-8. [Crossref] [PubMed]
16. Cozzi D, Dini C, Mungai F, et al. Primary pulmonary lymphoma: imaging findings in 30 cases. Radiol Med 2019;124:1262-9. [Crossref] [PubMed]
17. Yang X, Xu X, Song B, et al. Misdiagnosis of primary pleural DLBCL as tuberculosis: A case report and literature review. Mol Clin Oncol 2018;8:729-32. [Crossref] [PubMed]
18. Li S, Wang L, Chang N, et al. Differential clinical and CT imaging features of pneumonic-type primary pulmonary lymphoma and pneumonia: a retrospective multicentre observational study. BMJ Open 2023;13:e077198. [Crossref] [PubMed]
19. Hussain A, Soman R, Goyal A, et al. Primary Pulmonary Marginal Cell Lymphoma: Your Eyes See Only What Your Mind Knows. Turk Thorac J 2021;22:271-3. [Crossref] [PubMed]
20. Cheson BD. PET/CT in Lymphoma: Current Overview and Future Directions. Semin Nucl Med 2018;48:76-81. [Crossref] [PubMed]
21. Ceriani L, Milan L, Martelli M, et al. Metabolic heterogeneity on baseline 18FDG-PET/CT scan is a predictor of outcome in primary mediastinal B-cell lymphoma. Blood 2018;132:179-86. [Crossref] [PubMed]
22. Cottereau AS, Meignan M, Nioche C, et al. Risk stratification in diffuse large B-cell lymphoma using lesion dissemination and metabolic tumor burden calculated from baseline PET/CT Ann Oncol 2021;32:404-11. [Crossref] [PubMed]
23. Gallamini A, Kurlapski M, Zaucha JM. FDG-PET/CT for the Management of Post-Chemotherapy Residual Mass in Hodgkin lymphoma. Cancers (Basel) 2021;13:3952. [Crossref] [PubMed]
24. Xie X, Zhang L, Wu M, et al. A retrospective study on the clinical characteristics and radiological features of primary pulmonary lymphoma. Transl Cancer Res 2020;9:1969-77. [Crossref] [PubMed]
25. Wang Y, Han J, Zhang F, et al. Comparison of radiologic characteristics and pathological presentations of primary pulmonary lymphoma in 22 patients. J Int Med Res 2020;48:300060519879854. [Crossref] [PubMed]
26. Mettler J, Müller H, Voltin CA, et al. Metabolic Tumour Volume for Response Prediction in Advanced-Stage Hodgkin Lymphoma. J Nucl Med 2018;60:207-11. [Crossref] [PubMed]
27. Driessen J, Zwezerijnen GJC, Schöder H, et al. The Impact of Semiautomatic Segmentation Methods on Metabolic Tumor Volume, Intensity, and Dissemination Radiomics in (18)F-FDG PET Scans of Patients with Classical Hodgkin Lymphoma. J Nucl Med 2022;63:1424-30. [Crossref] [PubMed]
28. Toledano MN, Desbordes P, Banjar A, et al. Combination of baseline FDG PET/CT total metabolic tumour volume and gene expression profile have a robust predictive value in patients with diffuse large B-cell lymphoma. Eur J Nucl Med Mol Imaging 2018;45:680-8. [Crossref] [PubMed]
29. Pu Y, Wang C, Xie R, et al. Role of 18F-fluorodeoxyglucose PET/computed tomography in the diagnosis and treatment response assessment of primary bone lymphoma. Nucl Med Commun 2023;44:318-29. [Crossref] [PubMed]
30. Ferraro P, Trastek VF, Adlakha H, et al. Primary non-Hodgkin's lymphoma of the lung. Ann Thorac Surg 2000;69:993-7. [Crossref] [PubMed]
31. Itti E, Meignan M, Berriolo-Riedinger A, et al. An international confirmatory study of the prognostic value of early PET/CT in diffuse large B-cell lymphoma: comparison between Deauville criteria and ΔSUVmax. Eur J Nucl Med Mol Imaging 2013;40:1312-20. [Crossref] [PubMed]
32. Sirajuddin A, Raparia K, Lewis VA, et al. Primary Pulmonary Lymphoid Lesions: Radiologic and Pathologic Findings. Radiographics 2016;36:53-70. [Crossref] [PubMed]
33. Huang J, Lin T, Li ZM, et al. Primary pulmonary non-Hodgkin's lymphoma: a retrospective analysis of 29 cases in a Chinese population. Am J Hematol 2010;85:523-5. [Crossref] [PubMed]
34. Huang H, Lu ZW, Jiang CG, et al. Clinical and prognostic characteristics of pulmonary mucosa-associated lymphoid tissue lymphoma: a retrospective analysis of 23 cases in a Chinese population. Chin Med J (Engl) 2011;124:1026-30.
35. Parissis H. Forty years literature review of primary lung lymphoma. J Cardiothorac Surg 2011;6:23. [Crossref] [PubMed]
36. Ahmed S, Kussick SJ, Siddiqui AK, et al. Bronchial-associated lymphoid tissue lymphoma: a clinical study of a rare disease. Eur J Cancer 2004;40:1320-6. [Crossref] [PubMed]
37. Borie R, Wislez M, Thabut G, et al. Clinical characteristics and prognostic factors of pulmonary MALT lymphoma. Eur Respir J 2009;34:1408-16. [Crossref] [PubMed]
38. Borie R, Wislez M, Antoine M, et al. Clonality and phenotyping analysis of alveolar lymphocytes is suggestive of pulmonary MALT lymphoma. Respir Med 2011;105:1231-7. [Crossref] [PubMed]
39. Peng Y, Qi W, Luo Z, et al. Role of 18F-FDG PET/CT in patients affected by pulmonary primary lymphoma. Front Oncol 2022;12:973109. [Crossref] [PubMed]
40. Dietz M, Chironi G, Claessens YE, et al. COVID-19 pneumonia: relationship between inflammation assessed by whole-body FDG PET/CT and short-term clinical outcome. Eur J Nucl Med Mol Imaging 2021;48:260-8. [Crossref] [PubMed]
41. Erdoğan Y, Özyürek BA, Özmen Ö, et al. The Evaluation of FDG PET/CT Scan Findings in Patients with Organizing Pneumonia Mimicking Lung Cancer. Mol Imaging Radionucl Ther 2015;24:60-5. [Crossref] [PubMed]
42. Uehara T, Takeno M, Hama M, et al. Deep-inspiration breath-hold 18F-FDG-PET/CT is useful for assessment of connective tissue disease associated interstitial pneumonia. Mod Rheumatol 2016;26:121-7. [Crossref] [PubMed]
43. Nooreldeen R, Bach H. Current and Future Development in Lung Cancer Diagnosis. Int J Mol Sci 2021;22:8661. [Crossref] [PubMed]
44. Benboubker L, Valat C, Linassier C, et al. A new serologic index for low-grade non-Hodgkin's lymphoma based on initial CA125 and LDH serum levels. Ann Oncol 2000;11:1485-91. [Crossref] [PubMed]
45. Zanoni L, Bezzi D, Nanni C, et al. PET/CT in Non-Hodgkin Lymphoma: An Update. Semin Nucl Med 2023;53:320-51. [Crossref] [PubMed]
46. Koç ZP, Kara PÖ, Özge C, et al. F-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Images of Severe Primary Lung Lymphoma. Indian J Nucl Med 2020;35:80-1. [Crossref] [PubMed]
47. Dai L, Fan G, Xie T, et al. Single-cell and spatial transcriptomics reveal a high glycolysis B cell and tumor-associated macrophages cluster correlated with poor prognosis and exhausted immune microenvironment in diffuse large B-cell lymphoma. Biomark Res 2024;12:58. [Crossref] [PubMed]
48. Zaucha JM, Chauvie S, Zaucha R, et al. The role of PET/CT in the modern treatment of Hodgkin lymphoma. Cancer Treat Rev 2019;77:44-56. [Crossref] [PubMed]
49. Lin H, Zhou K, Peng Z, et al. Surgery and chemotherapy cannot improve the survival of patients with early-stage mucosa-associated lymphoid tissue derived primary pulmonary lymphoma. Front Oncol 2022;12:965727. [Crossref] [PubMed]