Retrospective analysis of primary pulmonary lymphoma cases from Polish Lymphoma Research Group centers reveals associations between initial symptoms and outcomes

Abstract

Primary pulmonary lymphoma (PPL) is a rare extranodal lymphoma, accounting for only 0.4% of all lymphomas. We conducted a retrospective analysis of 78 patients with PPL treated at 15 tertiary care hematooncology centers in Poland. The study revealed a high incidence of aggressive B-cell lymphoma (42%), although this may reflect the specificity of participating centers. A high prevalence of pleural effusion and dyspnea at the time of diagnosis was found to be associated with worse overall survival in all PPL patients. Dyspnea and bilateral lung lesions at presentation were associated with a lack of complete remission, while the presence of cough was associated with shorter time to disease progression or relapse. Although the progression-free survival did not differ significantly between patients with low- versus high-grade B-cell PPLs, those with indolent PPLs exhibited superior overall survival. To the best of our knowledge, this study is the first multicenter retrospective analysis of PPL in Central Europe involving such a large cohort of patients.

Introduction

Primary pulmonary lymphoma (PPL) is a rare (3–4%) presentation of extranodal lymphoma, accounting for 0.4% of all lymphomas. The main diagnostic criteria for PPL include clonal lymphoid proliferation with lung involvement and the absence of extrapulmonary manifestation (no evidence of mediastinal lymphadenopathy and no extrathoracic disease in clinical stage work-up, including bone marrow examination)¹. According to available evidence¹, the most frequent histology is mucosa-associated lymphoid tissue-type lymphoma (MALT), which is diagnosed in 70–90% of PPL cases. Aggressive PPLs, such as diffuse large B-cell lymphoma (DLBCL), account for 12–20% of cases. PPL affects older population with maximum incidence in the 6th -7th decades of life, and a 1:1 female to male ratio¹.

The etiology of PPL remains unknown. However, in bronchus-associated lymphoid tissue (BALT), chronic antigenic stimulation caused by infection, smoking or autoimmune disease is postulated to play an important role². Approximately 15% of patients with MALT PPLs are diagnosed with autoimmune diseases: rheumatoid arthritis, lupus erythematosus, or Sjögren’s syndrome³.

The diagnosis of PPL should be established through histopathological evaluation of lung tissue obtained during bronchoscopy, thoracoscopic surgery, or thoracotomy. The symptoms of PPL are non-specific and may include cough, dyspnea, chest pain, and occasionally hemoptysis⁴. In radiological imaging, PPL presents as consolidations, masses, or nodules that can occur bilaterally or unilaterally. Computed tomography (CT) imaging reveals multiple nodules, masses, areas of consolidation, and air bronchograms in nearly 50% of patients⁵. Nodules exhibit a peribronchovascular distribution and may converge into pseudo-tumoral masses and excavate, or they can migrate or disappear (the “wax and wane” sign). Hilar and mediastinal lymphadenopathy is observed in 30% of patients with advanced-stage PPL. Pleural effusion is present in less than 10% of cases⁴.

A therapeutic consensus for PPL has not yet been established. Treatment options range from a watch-and-wait strategy for indolent histology, surgery, immunotherapy, to more intensive immunochemotherapy, and/or radiation for aggressive PPL. The outcome in MALT-type PPLs is favorable, with an overall survival rate of about 90% at 10 years³.

High-grade B-cell non-Hodgkin lymphoma (NHL) accounts for 11–19% of cases of PPL. The incidence of high-grade PPL may be underestimated, as it can rapidly spread to the mediastinum or extra-thoracic areas. High-grade PPLs occur both in immunocompetent patients and in immunocompromised subjects such as those with HIV infection, after solid organ transplantation or with Sjögren’s syndrome. Epstein-Barr virus has been implicated in the onset of some high-grade B-cell PPLs^6,7. Unlike patients with MALT, those diagnosed with high-grade PPLs usually present with B symptoms, such as weight loss or fever. Radiological investigations usually reveal a single pulmonary mass, frequently with an area of necrosis that leads to a cavitated pulmonary mass. Atelectasis and pleural effusions are also prevalent^8,9. The median survival time for patients with high-grade B NHL is 8 to 10 years, which is poorer compared to those with low-grade PPLs.

In this retrospective study of the Polish Lymphoma Research Group, we analyzed the diversity of histopathologic types, as well as clinical manifestations of PPL and investigated potential factors associated with treatment response, progression-free survival, and overall survival in a large cohort of Polish patients diagnosed with PPL.

Methods

Study protocol

We retrospectively reviewed the clinical data of adult patients with primary pulmonary lymphoma treated at 15 Polish tertiary care hematooncology centers affiliated with the Polish Lymphoma Research Group (PLRG). Patients treated for PPL between January 2000 and December 2018 were included based on the information provided by the centers. The data obtained from the centers were verified and the patients with uncertain localization (in whom PPL could not have been reliably confirmed) were excluded before data analysis. Patients were included in the study provided that a lung tissue specimen had been obtained, and PPL had been diagnosed by histopathological examination. Patient clinical data were derived from their medical records. Treatment responses were classified according to the International Working Group criteria for malignant lymphoma¹⁰. Follow-up data were obtained from outpatient clinic records or via phone calls at 3, 6 and 12 months post-treatment.

The following Ann Arbor classification for pulmonary lymphomas was used for staging¹¹:

• IE: Lung only, could be bilateral.

• II1E: Lung and hilar lymph nodes.

• II2E: Lung and mediastinal lymph nodes.

• II2EW: Lung and chest wall or diaphragm.

• III: Lung and lymph nodes below the diaphragm.

• IV: Diffuse.

For data consistency, the staging was reported reflecting the advancement of the disease at admission to the tertiary care centers participating in the study.

Ethics

We have received the approval from the Jagiellonian University Ethics Committee (the decision no. 1072.6120.282.2020, dated 28 October 2020) for conducting this study. All methods were performed in accordance with the relevant guidelines and regulations as outlined in the Declaration of Helsinki. The need for informed consent was waived by the Jagiellonian University Ethics Committee due to the retrospective nature of this study.

Statistical analysis

The number of patients and the percentages of the respective groups were reported for each category. Median (lower-upper quartile) were reported for quantitative variables due to skewed or bimodal distributions; minimum – maximum were additionally given for selected variables. Contingency tables were analyzed using the chi-squared test. For quantitative variables, differences between groups were assessed with the t-test or Mann-Whitney U test, depending on the distribution of the variable (assessed with Shapiro-Wilk’s test). Overall survival times were calculated from the date of diagnosis until death from any cause or last follow-up. For PPL-specific survival, only observations ending with death due to PPL were considered complete. Progression-free survival (PFS) times were calculated from the date of diagnosis until progression, relapse, death, or the end of the study, whichever occurred first. Survival times were estimated with the Kaplan-Meier method and compared using the log-rank test. Cox proportional regression was used to examine the associations between the clinical data and survival. Logistic regression was used to analyze the associations between clinical data and treatment response. Both the Cox regression and the logistic regression models were adjusted for diagnosis (aggressive versus indolent B-cell PPL) and stage at admission, as specified in the results. All statistical tests were two-tailed, and p < 0.05 indicated significant results. Statistical analyses were performed using Statistica 12.0 software (StatSoft, Tulsa, OK, USA).

Results

Patients’ characteristics

The initial database included 88 patients; however, in case of 10, the diagnosis of PPL could not have been reliably confirmed and therefore those patients were excluded from further analysis upon data review (Fig. 1). The study included 78 patients, 28 (36%) women and 50 (62%) men, aged 26 to 88 years, with a median age of 62 (51; 72) years. The age distribution was bimodal, with maxima at 57 and 72 years. Indolent low-grade B-cell non-Hodgkin lymphoma – MALT was diagnosed in 43 patients (55%). Aggressive B-cell lymphomas were diagnosed in 33 patients (42%): the histological types included DLBCL in 24 patients (31%), mantle cell lymphoma (MCL) in 4 (5%), Hodgkin lymphoma (HL) in 3 (4%), primary mediastinal large B-cell lymphoma (PMBCL) in 1 (1%), and plasmablastic lymphoma in 1 patient (1%). Two patients (3%) had T-cell lymphomas.

Fig. 1 [Images not available. See PDF.]

The flowchart summarizing the process of patients’ selection and data analysis. CT, computed tomography; PPL, primary pulmonary lymphoma.

In subsequent analyses, the clinical data and the data on treatment were compared between patients with low- and high-grade B-cell PPLs. As the number of patients with T-cell PPL was low, we reported the data of the two patients, but we did not include them in the statistical analysis (Fig. 1).

Clinical manifestation of the disease and initial assessment

The main clinical symptoms of PPL included cough in 53 patients (68% of the study group), dyspnea in 36 (46%), fever in 29 (37%), and hemoptysis in 10 (13%). Twelve patients (15%) were asymptomatic. Atelectasis was observed in 24 patients (31%), and a pleural effusion was noted in 22 (28%). We did not observe significant differences in the prevalence of symptoms and signs between patients with indolent and aggressive B-cell PPLs (Table 1).

Table 1. Baseline characteristics of 78 studied patients with primary pulmonary lymphomas according to histopathologic diagnosis.

Characteristic	Low-grade B-cell PPL (N = 43)	High-grade B-cell PPL (N = 33)	T-cell PPL (N = 2)
Age (years), median (lower; upper quartile), minimum – maximum	63 (52; 72), 29–52	63 (51; 73), 26–88	53, 48–58
Male sex, N (%)	14 (33)	12 (36)	2 (100)
Main symptoms
Asymptomatic, N (%)	8 (21)	4 (12)	0
Cough, N (%)	28 (65)	23 (70)	2 (100)
Dyspnea, N (%)	17 (40)	18 (55)	1 (50)
Hemoptysis, N (%)	5 (12)	4 (12)	1 (50)
Fever, N (%)	12 (28)	16 (48)	1 (50)
Working diagnosis upon admission
Lung cancer, N (%)	13 (30)	16 (48)	1 (50)
Pulmonary infection, N (%)	15 (35)*	4 (12)*	1 (50)
Lymphoma, N (%)	0	4 (12)	0
Sarcoidosis, autoimmune disease, N (%)	2 (5)	2 (6)	0
Unknown, N (%)	13 (30)	7 (21)	0
PPL diagnosis confirmed in
Broncho-/mediastino-/thoracoscopic biopsy, N (%)	8 (19)	5 (15)	0
Open biopsy/partial resection, N (%)	6 (14)	4 (12)	1 (50)
Tumor resection, lobectomy, N (%)	8 (19)	6 (18)	0
Extrapulmonary lesion biopsy, N (%)	0	3 (9)	0
Unknown, N (%)	21 (49)	15 (45)	1 (50)
Stage in Ann Arbor PPL classification:
IE, N (%)	16 (37)*	3 (9)*	0
II1E, N (%)	1 (2)	0	0
II2E, N (%)	17 (40)	13 (39)	2 (100)
II2EW, N (%)	3 (7)*	9 (27)*	0
III, N (%)	0	0	0
IV, N (%)	5 (12)	8 (24)	0
Unknown, N (%)	1 (2)	0	0

*Significant difference between patients with low- and high-grade B-cell PPLs (p < 0.05).

N, number of patients; PPL, primary pulmonary lymphoma.

Similarly, most findings from the chest CT scans did not differ significantly between the low- and high-grade B-cell PPLs (Table 2). For the purpose of this study, the main CT findings were divided into three categories: a single tumor, diffuse infiltrates or areas of consolidation, and multiple nodules. Peribronchial or perivascular thickening was also reported in addition to the main findings. Patients with indolent and aggressive B-cell PPLs did not differ significantly with respect to the patterns of pulmonary infiltration, tumor size, or unilateral versus bilateral localization of lung lesions. However, DLBCLs more often manifested as single tumors (in 12 of 24 patients; 50%) and less often as infiltrates/areas of consolidation (in 5 patients; 21%) than indolent PPLs (p = 0.044). The involvement of mediastinal lymph nodes was more prevalent in aggressive PPLs (p = 0.007; Table 2).

Table 2. Imaging (computed tomography, CT) findings among 78 studied patients with primary pulmonary lymphomas according to histopathological diagnosis.

CT finding	Low-grade B-cell PPL (N = 43)	High-grade B-cell PPL (N = 33)	T-cell PPL (N = 2)
Tumor, N (%)	15 (35)	16 (48)	1 (50)
Infiltrates or areas of consolidation, N (%)	22 (51)	10 (30)	1 (50)
Nodules, N (%)	6 (14)	7 (21)	0
Peribronchial/perivascular thickening, N (%)	5 (12)	2 (6)	0
Maximum tumor diameter (mm), median (lower; upper quartile)	49 (35; 71)	55 (31; 75)	32
Unilateral localization, N (%)	29 (67)	19 (58)	1 (50)
Bilateral localization, N (%)	14 (33)	14 (42)	1 (50)
Atelectasis, N (%)	13 (30)	10 (30)	1 (50)
Pleural effusion, N (%)	9 (21)	13 (39)	0
Mediastinal lymphadenopathy, N (%)	27 (63)*	30 (91)*	2 (100)

*Significant difference between patients with low- and high-grade B-cell PPLs (p < 0.05).

CT, computed tomography; N, number of patients; PPL, primary pulmonary lymphoma.

The initial running diagnosis, based on patients’ symptoms and imaging results, was most commonly lung cancer (30 patients, 38% of the study group) or pneumonia (20 patients, 26%). Lymphoma was initially suspected in 4 patients with aggressive B-cell lymphomas. Patients with MALT were more frequently suspected of having pulmonary infection (p = 0.006; Table 1), whereas the suspicion of neoplasm (cancer or lymphoma) was more prevalent in those with aggressive B-cell lymphomas (p = 0.011). Additionally, sarcoidosis or autoimmune diseases were suspected in individual cases (Table 1).

The final diagnosis was established through histopathological examination of tissue samples collected by either biopsy (via bronchoscopy, mediastinoscopy or thoracoscopy) or partial or total surgical resection of lung lesions. No differences were found between patients with indolent and aggressive PPLs regarding the proportion of biopsies on broncho- or mediastinoscopy and surgical resections (Table 2).

Stage IE PPL was diagnosed upon admission to the tertiary care centers in 19 patients (24% of the study group), stage II1E in 1 (1%), stage II2E in 32 (41%), stage II2EW in 12 (15%) and stage IV in 13 (17%). Stage IE was more often diagnosed in patients with low-grade PPL than in high-grade B-cell PPL patients, while stage II2EW was significantly more prevalent in those with aggressive B-cell PPL (p = 0.004 and p = 0.018; Table 1).

Treatment and response

A variety of therapeutic options were employed among the studied PPL patients, depending on the histological diagnosis (Table 3). In most patients, treatment was initiated within one month of diagnosis. The time from diagnosis to treatment initiation was associated neither with diagnosis of indolent versus aggressive PPL, nor with the stage of the disease. However, there were three patients with MALT in whom the treatment was deferred for more than three months (with a maximum of 23 months) as part of a watch-and-wait strategy.

Table 3. Treatment, response, and survival of 78 studied patients with primary pulmonary lymphomas according to histopathological diagnosis.

	Low-grade B-cell PPL (N = 43)	High-grade B-cell PPL (N = 33)	T-cell PPL (N = 2)
Observation only, N (%)	2 (5)	0	0
Early death, no treatment received, N (%)	0	1 (3)	0
Surgery, N (%)	19 (44)*	4 (12)*	1 (50)
Plus observation, N (%)	8 (19)*	0*	0
Plus chemotherapy, N (%)	11 (26)	4 (12)	1 (50)
Chemotherapy, N (%)	33 (77)*	31 (94)*	2 (100)
Radiotherapy, N (%)	0*	4 (12)*	0
Schemes of chemotherapy
Rituximab + CHT without anthracyclines, N (%)	17 (40)*	1(3)*	0
Rituximab + CHT with anthracyclines, N (%)	9 (21)*	25 (76)*	0
CHT without rituximab, N (%)	7 (16)	5 (15)	2 (100)
Anthracyclines, N (%)	11 (26)*	27 (82)*	2 (100)
Time from diagnosis to start treatment (days), median (lower; upper quartile)	29 (1; 49)	21 (4; 31)	NA
Duration of follow-up (months), median (lower; upper quartile), minimum-maximum	45 (15; 77), 5–192*	16 (8; 48), 1–126*	NA, 5–21
Treatment response
CR, N (%)	28 (63)	18 (55)	1 (50)
PR, N (%)	13 (30)	12 (36)	0
SD, N (%)	1 (2)	0	0
PD, N (%)	1 (2)	3 (9)	0
Unknown, N (%)	0	0	1 (50)
Relapse/progression, N (%)	14 (33)	11 (33)	0
PFS (months), median (lower; upper quartile)	75 (34; NR)	48 (19; NR)	NA
5-year PFS (95% confidence interval), %	65 (46–84)	41 (14–68)
Death, N (%)	3 (7)	7 (21)	0
Lymphoma as a cause, N (%)	1 (2)	4 (12)	0
Overall survival (months), median (lower; upper quartile)	NR (NR; NR)*	NR (41; NR)*	NA
5-year OS (95% confidence interval), %	94 (86–100)	68 (43–92)

*Significant difference between patients with low- and high-grade B-cell PPLs (p < 0.05).

CHT, chemotherapy; CR, complete remission; N, number of patients; NA, not applicable; PFS, progression-free survival; PD, progressive disease; PPL, primary pulmonary lymphoma; PR, partial remission; SD, stable disease.

The most common treatment was chemotherapy administered in 65 patients (83% of the study group). Chemotherapy was more commonly used in high-grade than in low-grade B-cell lymphomas (p = 0.042), and chemotherapy regimens differed significantly between the groups (p < 0.001; Table 3). Regimens including rituximab without anthracyclines (R B, R FC, R CVP) were most often used for low-grade PPLs, whereas regimens including both rituximab and anthracyclines (R CHOP, R DAEPOCH) were applied for high-grade B-cell PPLs (Table 3). No patient received rituximab monotherapy as first-line treatment.

Total surgical resection of the lung lesions was performed in 24 studied patients (31%), significantly more commonly in low-grade than high-grade B-cell lymphomas (p = 0.003; Table 3). In eight patients with MALT PPLs, surgery was the only treatment, followed by careful observation, while eleven patients with MALT PPLs were further treated with chemotherapy. Of those treated solely with surgery, five patients were in stage IE, two in stage II2E and one in stage II2EW. In contrast, all four patients with aggressive B-cell lymphomas who underwent surgery also received chemotherapy (Table 3).

Radiotherapy was used in the treatment of 4 patients with advanced aggressive B-cell PPLs (three stage IV, one stage II2EW), including two patients with DLBCL and two with MCL (Table 3). Three of these patients received radiotherapy following surgical resection of the pulmonary lesions, and one was treated with radiotherapy alone.

Three patients did not receive anti-neoplastic treatment (Table 3). This group included two patients with MALT PPLs and one with DLBCL. Stage 1E and II2E MALT patients were carefully observed for 43 and 46 months and did not progress until the end of the study. The patient with DLBCL was diagnosed with stage IV and died one month after diagnosis without receiving anti-lymphoma treatment.

The first-line treatment resulted in complete remission in most patients (47; 60% of the group) and partial remission in further 25 patients (32%). One patient (1%) had stable disease, and four (5%) progressed during the first-line treatment. No significant differences were observed in treatment response between patients with indolent and aggressive B-cell PPLs (Table 3).

Survival and predictors of outcome

For the entire study group, the follow-up period ranged from 1 to 126 months with a median (lower; upper quartile) of 33 (11; 62) months. It was significantly longer in patients with indolent versus aggressive B-cell PPLs (p = 0.022; Table 3). During the follow-up, progression or relapse was observed in one-third of patients in both groups, and progression-free survival did not differ significantly between patients with low- and high-grade B-cell PPLs (Table 3; Fig. 2). Following disease relapse, chemoimmunotherapy was used in the majority of MALT patients, while high-grade B-cell lymphomas were treated with second line chemotherapy (including salvage therapy and high-dose therapy with subsequent auto-stem cell transplantation in four patients) or immunotherapy (in two patients).

Fig. 2 [Images not available. See PDF.]

Overall (A), PPL-specific (B) and progression-free (C) survival among patients with low-grade (solid line) and high-grade (dashed line) B-cell primary pulmonary lymphomas. Censored observations are marked with crosses; p-values in log-rank test are shown on the graphs. PFS, progression-free survival; PPL, primary pulmonary lymphoma.

Ten patients died during the follow-up, including three with MALT and seven with aggressive B-cell lymphomas (Table 3). Five of the deaths were caused by lymphoma, the other five were associated with (mostly cardiovascular) comorbidities (two of those patient received anthracyclines, which may suggest anthracycline-induced cardiotoxicity as a probable cause of death). Overall survival was significantly better in patients with indolent PPLs (Table 3; Fig. 2).

In B-cell PPLs, a statistically significant association was observed between the response to first-line treatment and overall survival. This association was independent of the diagnosis of high- versus low-grade PPL and the stage of the disease (Fig. 3). Five-year survival was observed in 96% (90-100%) of patients with complete remission and 73% (51-95%) of patients with partial remission or stable disease, respectively. Only one of the four patients with progressive disease survived one year from the diagnosis (specifically, 13 months); median overall survival in this group was 2 months. Further progression or relapse were also associated with poor survival (Fig. 3), again, independently of the diagnosis and the stage. Five-year survival was observed in 83% (65-100%) of patients with progression or relapse following initial response to first-line treatment and in 93% (85-100%) of those who did not experience relapse or progression. In the group of patients with MALT PPLs, we did not observe any significant associations between treatment modalities (surgery, chemotherapy, various chemotherapy regimens, or rituximab use) and progression-free or overall survival. In contrast, among patients with high-grade B-cell lymphomas, chemotherapy regimens including anthracyclines together with rituximab were associated with improved overall survival: HR 0.09 (0.01–0.96); p = 0.045. However, the association of such treatment with PFS was non-significant: HR 0.12 (0.01–1.33); p = 0.084. Complete remission was achieved in 16 (64%) of 25 patients with high-grade B-cell PPLs who were treated with anthracyclines and rituximab versus two (25%) of eight treated otherwise (p = 0.054).

Fig. 3 [Images not available. See PDF.]

Overall survival in patients with B-cell primary pulmonary lymphomas depending on response to first-line treatment (A) and further progression or relapse (B). Censored observations are marked with crosses. Hazard ratios (HR) are adjusted for diagnosis of high-grade versus low-grade B-cell lymphoma and the stage of the disease and are reported with 95% confidence intervals (in brackets).

Based on the results presented, we identified several factors associated with clinical outcomes. Dyspnea and bilateral lung lesions were significantly correlated with the absence of complete remission. Cough was the only symptom significantly associated with time to progression or relapse. Dyspnea and pleural effusion were associated with worse overall survival (Table 4). All of these associations were independent of the diagnosis of aggressive versus indolent B-cell PPL and PPL stage.

Table 4. Predictors of outcome in 76 patients with B-cell primary pulmonary lymphoma. The logistic regression and Cox regression models were adjusted for diagnosis (high-grade B-cell PPL versus low-grade B-cell PPL) and the disease stage at diagnosis.

Predictor variable	Logistic regression	Cox regression
	Adjusted OR (95% CI) for lack of complete remission; p-value	Adjusted HR (95% CI) for progression/relapse; p-value	Adjusted HR (95% CI) for death from any cause; p-value
Cough	1.95 (0.52–7.30); p = 0.3	4.22 (1.09–16.38); p = 0.037*	1.57 (0.28–8.86); p = 0.6
Dyspnea	3.48 (1.21–9.96); p = 0.018*	1.79 (0.78–4.13); p = 0.2	13.67 (1.52–122.6); p = 0.019*
Pleural effusion	0.79 (0.26–2.39); p = 0.7	1.55 (0.61–3.94); p = 0.4	4.39 (1.15–16.71); p = 0.030*
Bilateral lesions	3.08 (1.10–8.64); p = 0.030*	1.95 (0.83–4.59); p = 0.1	0.70 (0.18–2.72); p = 0.6

*Statistically significant results (p < 0.05).

CI, confidence interval; CR, complete remission; HR, hazard ratio; OR, odds ratio; PD, progressive disease; PR, partial remission; SD, stable disease.

Discussion

Primary non-Hodgkin lymphoma of the lung is a rare disease, in contrast to secondary involvement of the lungs by lymphoma, which has an incidence of 25–44%¹². Considering the low prevalence of PPL, the analysis of the records of 15 Polish hematooncology centers over an 18-year period allowed us to present data on a relatively large series of 78 cases. To our knowledge, this represents the largest multicenter study on primary pulmonary lymphoma in Central Europe.

Due to the varied clinical presentation and nonspecific symptoms, which can mimic other disorders such as pneumonia, lung cancer, tuberculosis or interstitial lung disease, the diagnosis of PPL remains a challenge. In particular, the diagnosis of aggressive PPL may be underestimated due to the high number of advanced stages on admission, which may suggest another primary lymphoma localization. Our study demonstrated a high incidence of aggressive B-cell lymphoma (42%) among all diagnosed cases of PPL. This finding, however, may represent the inclusion bias associated with the specificity of the tertiary care centers which participated in the study, and the fact that some patients with indolent disease might have not been referred to the tertiary-care centers.

In the case of the most commonly diagnosed aggressive B-cell lymphoma, DLBCL (31%), the specific clinical presentation consisted mainly of solid tumors with a higher incidence of mediastinal lymph node involvement. Furthermore, stage II2EW was significantly more common in patients with aggressive B-cell PPL, which may affect proper, timely diagnosis as well as clinical outcome and prognosis. In previous studies, most cases of primary pulmonary lymphoma have been reported to be of indolent, MALT histology^1,13. The high proportion of aggressive B-cell lymphomas in our study may be related to the fact that they were diagnosed in highly specialized centers with rapid access to diagnostic imaging and histopathological evaluation. The challenges in diagnosing aggressive primary pulmonary lymphoma may stem from the rapid spread of high-grade PPLs to extra-thoracic areas, potentially leading to an underestimation of the true incidence of PPL¹⁴. Notably, despite the high incidence of aggressive PPLs observed in our study, the histories and medical documentation of our patients did not suggest any primary or inherited immunodeficiencies.

The age distribution of our patients was consistent with previous reports, with two peaks in the fifth and seventh decades of life¹¹. According to prior case series, 37.5–50% of patients with MALT-type PPL were asymptomatic, while those with aggressive histology were usually symptomatic at presentation^4,10. However, in our cohort, only 15% of patients were asymptomatic at diagnosis, and we observed no statistically significant differences in the incidence of symptoms and signs between patients with indolent and aggressive PPLs. Both indolent and aggressive PPL were more frequently symptomatic in our study than in previous reports^4,11.

Furthermore, the incidence of pleural effusions was higher than published data for both groups analyzed⁴. The presence of pleural effusion at the initial presentation of PPL may make it difficult to differentiate lymphoma from pneumonia, tuberculosis, or lung cancer^12,15.

A high prevalence of pleural effusion, as well as dyspnea at the time of diagnosis, were found to be associated with worse overall survival in both low- and high-grade PPL patients. We showed that dyspnea and bilateral lung lesions at presentation were linked to a lack of complete remission, whereas the presence of cough was associated with shorter time to disease progression or relapse in all studied patients with PPL (Fig. 4). In the absence of well-defined prognostic risk factors in this particular group of patients, our results appear to have clinical relevance.

Fig. 4 [Images not available. See PDF.]

Summary of the assessment and treatment of patients with PPL. The symptoms and radiological signs which were found in our study to be associated with worse outcome or more aggressive histology are shown in italics.

The imaging manifestations of PPL are complex, with various findings observed, and there is no typical presentation. CT imaging of MALT PPL often reveals multiple nodules, masses, and areas of consolidation with air bronchograms. In addition, clinicians should be aware of the “wax and wane” phenomenon, the presence of cavitated pulmonary masses and atelectasis in aggressive PPL, as these features may facilitate faster diagnosis^8,9.

In our study, most chest CT findings did not reveal significant differences between low- and high-grade PPLs in terms of pulmonary infiltration patterns, tumor size, or unilateral versus bilateral localization of lung lesions. However, compared to indolent PPLs, DLBCLs manifested more frequently as single tumors and less frequently as infiltrates/areas of consolidation. Mediastinal lymph node involvement was more common in aggressive PPLs (Fig. 4).

The role of positron emission tomography-computed tomography (PET-CT) in imaging PPL appears limited. Indolent and slow-growing MALT lymphoma is characterized by low fluorodeoxyglucose (FDG) uptake and a multifocal presentation pattern. According to the literature, absence of FDG uptake is observed in approximately 20% of patients, and maximum standardized uptake values are below 5³. For that reasons, PET-CT was used only in single cases included in our retrospective analysis. Nonetheless, recent guidelines^16,17 increasingly emphasize the role of PET-CT, particularly in cases where local therapy is planned, to exclude disseminated disease. PET-CT is also recommended when clinical data suggest possible disease transformation, and for selecting the optimal lymph node for biopsy. The unusual localization, atypical clinical manifestations, and complex, nonspecific imaging findings make it difficult to differentiate PPL from other lung pathologies. Consequently, the disease can often be initially misdiagnosed as pneumonia, lung cancer, tuberculosis, or sarcoidosis. PPL, particularly MALT, should be considered in the differential diagnosis of nonresolving pneumonia, defined as the presence of focal infiltrates associated with symptoms of acute pulmonary infection and no clinical improvement or resolution of infiltrates within 12 weeks despite at least 10 days of antibiotic therapy^18,19.

Unlike lung cancer, PPL, especially with MALT histology, is often negative on cytologic examination of bronchoalveolar lavage or pleural effusion, due to the localization of the lymphoma in parenchymal tissue. In some patients, the diagnosis can be established through histopathological examination of tissue samples obtained by minimally invasive procedures, such as transbronchial biopsy or CT-guided transbronchial biopsy^3,20. Cryobiopsy techniques are promising tools that enhance diagnostic efficacy²¹. Nevertheless, in a significant percentage of patients, surgical resection of the lesional lung tissue will be necessary to establish the diagnosis. In certain cases, particularly those with MALT PPLs, surgical resection may also be the only treatment option. As observed in our subgroup of patients with MALT PPLs, such treatment, without subsequent chemotherapy, can be effective.

The treatment options for PPL include a watch-and-wait strategy, surgery, immunotherapy or chemoimmunotherapy. The role of radiotherapy in the treatment of PPLs is limited due to the risk of lung injury, which can worsen lung function, e.g. radiation pneumonitis.

In our study, the majority of patients with PPL (regardless of lymphoma type, whether indolent or aggressive) achieved complete (60%) or partial response (32%) after the first-line treatment, which in most patients (83%) involved chemotherapy. The intensive first line treatment used in our patients with MALT lymphoma might be explained by relatively advanced disease, and may also reflect the fact that rituximab was not available in Poland in this indication until 2006. One of the most significant findings in our study was the impact of response to first-line treatment on overall survival, regardless of the histopathological type of PPLs. We also found that progression-free survival did not differ significantly between patients with low- versus high-grade B-cell PPLs; however, patients with indolent PPLs had superior overall survival. Our analysis did not show significant differences in the effectiveness of different treatment strategies in patients with MALT. However, the results are limited by low numbers of patients treated with different strategies, which precluded the reliable statistical analysis adjusted for the confounders. It must be underlined that the choice of treatment strategies was affected by many factors like comorbidities, the centers’ experiences, the availability and reimbursement of medications (changing over the studied period), which also reflects the lack of clinical guidelines in this rare disease at the time of patients’ treatment.

The prognosis of PPLs is favorable. In our study, 10-year overall survival was observed in almost 80% of the group, which is consistent with previous reports.

Conclusions

Our study highlighted the high incidence of aggressive B-cell lymphoma among patients diagnosed with PPL and emphasized the significant role of response to first-line therapy on overall survival, regardless of the histopathological type of PPL. A high prevalence of pleural effusion and dyspnea at the time of diagnosis is associated with worse overall survival in both low- and high-grade PPL patients. Dyspnea and bilateral lung lesions at initial presentation were found to negatively impact the achievement of complete remission, while the presence of cough is associated with a shorter time to disease progression or relapse in PPL patients. Progression-free survival did not differ between patients with low- and high-grade B-cell PPL, whereas patients with indolent PPLs exhibited superior overall survival.

Acknowledgements

We would like to acknowledge the significant contribution of Dr Wojciech Spychałowicz, who was involved in the data collection for this research but passed away before the completion of the paper.

Author contributions

The authors contributed to the study as follows: AG was responsible for the conceptualization, data collection, data analysis, linguistic editing, manuscript preparation, coordination, and final approval. PD contributed to data analysis, linguistic editing, manuscript preparation, coordination, and final approval. EK handled linguistic editing, manuscript preparation, and final approval. JRJ, DZC, WKP, GS, RGK, MW, MM, PK, EK, and MH were involved in data collection and gave final approval. JDS contributed to data collection, manuscript preparation, and final approval. AK and DG were both involved in manuscript preparation, linguistic editing, and final approval. EPK contributed to data collection and final approval. SG, JMZ, and TW were responsible for the conceptualization and gave final approval. All authors reviewed the manuscript.

Funding

This research received no external funding. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The article processing charge was funded jointly by Jagiellonian University Medical College and Polish Lymphoma Research Group.

Data availability

The data used and analyzed in the current study are available from the corresponding author upon reasonable request. Due to privacy and ethical restrictions, the data cannot be made publicly available. Anonymized data may be shared with researchers subject to prior approval from the Jagiellonian University Medical College Ethics Committee.

Declarations

Competing interests

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

1. Majid, N et al. Primary pulmonary lymphoma: about five cases and literature review. Lung India; 2014; 31, pp. 53-55. [DOI: https://dx.doi.org/10.4103/0970-2113.125909]

2. Bi, L; Li, J; Dan, W; Lu, Z. Pulmonary MALT lymphoma: A case report and review of the literature. Exp. Ther. Med.; 2015; 9, pp. 147-150. [DOI: https://dx.doi.org/10.3892/etm.2014.2072]

3. Borie, R et al. Clinical characteristic and prognostic factors of pulmonary MALT lymphoma. Eur. Respir J.; 2009; 34, pp. 1408-1416. [DOI: https://dx.doi.org/10.1183/09031936.00039309]

4. Cadranel, J; Wislez, M; Antoine, M. Primary pulmonary lymphoma. Eur. Respir J.; 2002; 20, pp. 750-762. [DOI: https://dx.doi.org/10.1183/09031936.02.00404102]

5. Korzan, S., Mutneja, R. & Lahiri, B. Patient with lung consolidation and hypercalcemia: Primary Pulmonary Lymphoma. Chest Annual Meeting, Los Angeles 2016. Chest.150, 753A (2016).

6. Cheson, BD et al. Recommendation for initial evaluation, staging and response assessment of hodgkin and non-Hodgkin lymphoma: the Lugano classification. J. Clin. Oncol.; 2014; 32, pp. 3959-3069. [DOI: https://dx.doi.org/10.1200/JCO.2013.54.8800]

7. Cadranel, J. & Cordier, J. F. Primary pulmonary lymphoma. Orphanet Encyclopediahttps://www.orpha.net/en/disease/detail/2420 (2004).

8. Cordier, JF et al. Primary pulmonary lymphomas. A clinical study of 70 cases in nonimmunocompromised patients. Chest; 1993; 103, pp. 201-208. [DOI: https://dx.doi.org/10.1378/chest.103.1.201]

9. Martinez Rivera, C et al. Primary pulmonary lymphoma presenting as pulmonary mass with cavitation. Arch. Bronconeumol.; 2004; 40, pp. 94-96. [DOI: https://dx.doi.org/10.1016/s1579-2129(06)60201-2]

10. Gupta, S; Goel, K; Kaur, J. MALT lymphoma diagnosed on transbronchial lung biopsy: A case report. J. Pulmonar Respirat Med.; 2012; 2, pp. 117-119.

11. Parissis, H. Forty years literature review of primary lung lymphoma. J. Cardiothorac. Surg.; 2011; 6, pp. 23-31. [DOI: https://dx.doi.org/10.1186/1749-8090-6-23]

12. Ferraro, P et al. Primary non-Hodgkin’s lymphoma of the lung. Ann. Thorac. Surg.; 2000; 69, pp. 993-997. [DOI: https://dx.doi.org/10.1016/s0003-4975(99)01535-0]

13. Hu, M; Gu, W; Chen, S; Mei, J; Wang, W. Clinical analysis of 50 cases of primary pulmonary lymphoma: A retrospective study and literature review. Technol. Cancer Res. Treat.; 2022; 21, 15330338221075529. [DOI: https://dx.doi.org/10.1177/15330338221075529]

14. Hadda, V et al. Pulmonary lymphoma mimicking metastases: a case report. Cases J.; 2009; 2, pp. 7081-7084. [DOI: https://dx.doi.org/10.1186/1757-1626-2-7081]

15. Wang, B; Zhang, C; Wang, B; Zhang, L. Comparisons of surgery and/or chemotherapy in the treatment of primary pulmonary mucosa - Associated lymphoid tissue lymphoma. Ann. Thorac. Cardiovasc. Surg.; 2014; 21, pp. 109-113. [DOI: https://dx.doi.org/10.5761/atcs.oa.14-00145]

16. Alderuccio, JP et al. A roadmap for clinical trial design in marginal zone lymphoma. Am. J. Hematol.; 2022; 97, pp. 1398-1403. [DOI: https://dx.doi.org/10.1002/ajh.26706]

17. Walewska, R et al. Guideline for the diagnosis and management of marginal zone lymphomas: A British society of haematology guideline. Br. J. Haematol.; 2024; 204, pp. 86-107. [DOI: https://dx.doi.org/10.1111/bjh.19064]

18. Cherian, SV; Thampy, E; Mauzo, SH. Primary pulmonary lymphoma: a case of unresolving pneumonia. Am. J. Med.; 2014; 127, pp. 3-4. [DOI: https://dx.doi.org/10.1016/j.amjmed.2013.09.034]

19. Rajagopala, S; Singh, N; Nada, R; Gupta, D. An unusual cause of non-resolving pneumonia. Respir Care; 2009; 54, pp. 1266-1269.

20. Nahorecki, A et al. Primary pulmonary MALT lymphoma – case report and literature overview. Eur. Rev. Med. Pharmacol. Sci.; 2016; 20, pp. 2065-2069.

21. Nogawa, H et al. Transbronchial cryobiopsy using an ultrathin cryoprobe with a guide sheath for the diagnosis of pulmonary mucosa-associated lymphoid tissue lymphoma. J. Thorac. Dis.; 2023; 15, pp. 7123-7129. [DOI: https://dx.doi.org/10.21037/jtd-23-1074]