Case report: Pulmonary extranodal mucosa-associated lymphoid tissue lymphoma with eosinophilia diagnosed via exclusion using metagenomic next-generation sequencing

Abstract

Pulmonary extranodal mucosa-associated lymphoid tissue lymphoma (MALToma) is a slow-growing lymphoma often misdiagnosed or undiagnosed due to its nonspecific clinical symptoms. A man in his late 30s initially presented with cough, sputum production, and chest pain, which improved after antibiotic treatment. A definitive diagnosis of pulmonary MALToma was established via bronchoscopic biopsy. Following the exclusion of alternative diagnoses through metagenomic next-generation sequencing of bronchoalveolar lavage fluid, the marked eosinophilia and diverse chest computed tomography findings highlight the need for clinical awareness of this disease.

Introduction

Lymphomas originating from the lymph nodes and lymphoid tissues are classified into Hodgkin’s and non-Hodgkin’s types. Marginal zone lymphoma, a B-cell–derived subtype of non-Hodgkin’s lymphoma, includes extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALToma), splenic marginal zone lymphoma, and nodal marginal zone lymphoma.

Pulmonary MALToma, also referred to as bronchus-associated lymphoid tissue lymphoma, arises from the bronchus-associated lymphoid tissue. Although primary pulmonary lymphomas constitute only 0.5%–1% of all primary lung tumors, pulmonary MALToma comprises 58%–87% of pulmonary lymphomas. ¹ At diagnosis, 37.5%–50% of patients with pulmonary MALToma are asymptomatic. ² Common symptoms, such as cough, sputum production, chest pain, or dyspnea, are nonspecific and frequently result in misdiagnoses, including interstitial lung disease, pneumonia, or tuberculosis. Eosinophilia secondary to pulmonary MALToma has rarely been reported in the literature. Pulmonary MALToma should be considered when clinically significant eosinophilia is accompanied by diverse computed tomography (CT) findings, following the exclusion of alternative diagnoses through metagenomic next-generation sequencing (mNGS). Here, we report the case of a patient with pulmonary MALToma treated at our hospital to enhance the clinical awareness and understanding of this condition.

Case presentation

In May 2023, a male in his late 30s presented to the Department of Respiratory Medicine, Shenzhen Longgang Central Hospital, Shenzhen, China, with a 26-day history of cough, sputum production, and chest pain. The symptoms developed acutely without an identifiable cause. The patient reported a cough producing yellow-black sputum, accompanied by right-sided chest pain, chills, and fever. His medical history included hepatic hemangioma and hepatitis B. At an outside hospital, he had been treated for a suspected lung abscess after a chest X-ray revealed patchy, dense inflammatory infiltration with a central lucent cavity in the right lung. His symptoms partially improved following antibiotic therapy.

The patient presented to our hospital with recurrent chest pain, dyspnea, and white mucus sputum. On admission, physical examination revealed no palpable superficial lymph nodes. Despite the symptoms, the patient reported normal sleep and appetite without weight loss. Auscultation detected coarse breath sounds; however, heart and lung examinations revealed no other abnormalities. Key laboratory findings on admission included a normal white blood cell count and normal neutrophil ratio. However, the lymphocyte ratio was 9.9% (reference range: 20%–50%), eosinophil ratio was elevated at 11.8% (reference range: 0.4%–8%), erythrocyte sedimentation rate was 37 mm/h (reference range: 0–15 mm/h), and the high-sensitivity C-reactive protein level was 28.23 mg/L (reference range: 0–10 mg/L). CT revealed bilateral lung inflammation, consolidation in the right middle lobe with air bronchograms, localized pleural thickening on the right, and a nodular density (16 × 10 mm) above the right diaphragm (Figure 1). Coagulation and liver and kidney function tests as well as routine urine analysis all showed normal findings. Syphilis and human immunodeficiency virus antibody test results were negative, as was the result of acid-fast staining for tuberculosis. Sputum cultures revealed no fungal growth; smears detected both gram-positive and gram-negative bacteria, although no clinically significant bacterial colonies were identified. The initial diagnosis was “lung abscess with pneumonia.” After discussion of the findings and acquisition of informed consent, the patient began a 4-day course of anti-infective therapy with intravenous piperacillin–tazobactam (4.5 g every 8 h) and intravenous moxifloxacin (0.4 g once daily).

Figure 1.

Chest CT scans. (a) Lung window: Consolidation in the right middle lobe with air bronchogram and localized pleural thickening on the right; (b) Mediastinal window: minimal right pleural effusion; (c) Lung window: pulmonary bulla approximately 14 mm in diameter in the dorsal segment of the left lower lobe and (d) Mediastinal window: enlarged lymph node above the right diaphragm, measuring approximately 16 × 10 mm. CT: computed tomography.

After the initiation of anti-infective therapy, the patient experienced substantial improvement in cough and sputum production; chest pain was almost completely resolved. A follow-up sputum smear revealed no bacterial growth. Bronchoscopy revealed smooth, mildly congested mucosa in both the left and right main bronchi; although a small amount of white secretion was observed, no evidence of a tumor or bleeding was noted. Bronchoalveolar lavage was performed, and mNGS of the lavage fluid detected no pathogens, effectively ruling out infectious lung diseases.

Further laboratory tests revealed persistent eosinophilia, with an eosinophil ratio of 12.7% (reference range: 0.4%–8%) and an absolute eosinophil count of 0.91 × 10⁹/L (reference range: 0.02–0.52 × 10⁹/L). After exclusion of surgical contraindications, the patient underwent bronchoscopic biopsy of the right middle lobe under general anesthesia. Histological analysis revealed extensive lymphocytic infiltration of the bronchial mucosa; some cells displayed mononuclear-like morphology. Immunohistochemical staining showed that the tumor cells were positive for CD20, CD79a, Bcl-2, Kappa (most cells), Lambda (some cells), cytokeratin, CD21, and CD23, and negative for CD3 and CD5. The Ki-67 proliferation index was approximately 10%, consistent with low-grade malignancy (Figure 2). These findings supported a diagnosis of pulmonary extranodal marginal zone lymphoma of MALToma.

Figure 2.

Morphology and immunohistochemistry. (a) The endobronchial biopsy specimen revealed diffuse lymphocytic infiltration (hematoxylin–eosin, 40×); (b) no distinct lymphoid follicle structures were identified, and neoplastic cells infiltrated the bronchial mucosal epithelium, forming lymphoepithelial lesions (hematoxylin–eosin, 100×); (c) immunohistochemical analysis of CD20 demonstrated diffuse positivity in tumor cells (40×) and (d) immunohistochemical analysis of cytokeratin showed diffuse growth of neoplastic lymphocytes invading the bronchial epithelium (40×).

The patient underwent 17 sessions of localized radiotherapy without additional treatments such as chemotherapy or surgery. This approach resulted in marked reductions in both lesion size and consolidation. Follow-up CT scans performed every 3–6 months over the subsequent 17 months revealed no evidence of disease recurrence. All patient identifiers have been removed from this report. Written informed consent for publication of this case report was obtained from the patient. This report was prepared in accordance with the Case Report (CARE) guidelines. ³

Discussion

MALToma is a subtype of non-Hodgkin’s lymphoma that arises from the marginal zone of the extranodal mucosa-associated lymphoid tissue. Pulmonary MALToma is primarily composed of small B lymphocytes, including small lymphocytes, marginal zone cells, monocyte-like cells, scattered immunoblasts, and centrocyte-like cells. In some cases, it can differentiate into lymphoplasmacytic forms. ⁴ Pulmonary MALToma is more frequently diagnosed in middle-aged and older individuals. ⁵ Research indicates that chronic inflammation caused by bacterial or viral infections as well as autoimmune conditions (e.g. systemic lupus erythematosus, Sjögren’s syndrome, and Hashimoto’s thyroiditis) plays a key role in the development and progression of MALToma. ⁵ Recent studies have also explored the molecular and genetic mechanisms underlying MALToma. These studies have reported a strong association between the upregulation of the nuclear factor-kB pathway and its pathogenesis. ⁶ Approximately 50% of patients with pulmonary MALToma are asymptomatic at the time of diagnosis. Symptomatic cases often involve nonspecific respiratory symptoms such as cough, dyspnea, sputum production, or chest pain, without distinctive clinical features. ⁵ In rare instances, when the tumor exhibits aggressive behavior, a small percentage of patients may experience symptoms of lymphoma, including weight loss, night sweats, and fever. ⁷ In the present case, a middle-aged man presented with cough, sputum production, and chest pain, consistent with the clinical profile described in the literature for pulmonary MALToma.

mNGS is a diagnostic method that identifies nucleic acids in a sample by comparing them to a database of known pathogenic microorganisms. Its high sensitivity, broad range, and unbiased approach make it an effective tool for detecting atypical pathogens. In this case, mNGS analysis of the bronchoalveolar lavage fluid did not detect any clinically significant pathogens, effectively ruling out bacterial, fungal, viral, or parasitic infections as the cause of the patient’s lung disease. B cells proliferate in the germinal centers of lymphoid tissues, where they undergo somatic hypermutation and class-switch recombination before differentiating into plasma cells or memory B cells. Previous studies have indicated that eosinophilia may be relatively common in B-cell lymphomas that have undergone germinal center differentiation. ⁸ Because MALToma originates from memory B cells in the post-germinal center marginal zone, we hypothesized that it leads to abnormal eosinophilia. In the present case, the patient exhibited an eosinophil ratio of 12.7% (reference range: 0.4%–8%) and an absolute eosinophil count of 0.91 × 10⁹/L (reference range: 0.02–0.52 × 10⁹/L), findings consistent with our hypothesis. We propose that eosinophilia could serve as a distinguishing feature of pulmonary MALToma. In contrast, eosinophil levels are typically not elevated in inflammatory conditions such as lung abscesses or pneumonia, further supporting this observation. However, given the limited number of relevant published cases, this potential association warrants further validation.

Pulmonary consolidation is the most common imaging feature of MALToma. ⁹ However, the disease may also present as unilateral or bilateral pulmonary nodules, air bronchograms, and surrounding ground-glass nodules.^10,11 Pulmonary consolidation and ground-glass opacities are typically associated with tumor infiltration into the surrounding pulmonary interstitium.^9,12 When tumor cells invade the alveolar walls and occupy the alveolar spaces, mass lesions become apparent. The formation of air bronchograms occurs when tumor infiltration extends into the interstitial spaces surrounding the bronchial walls without causing bronchial wall destruction. ¹³ Mediastinal or hilar lymphadenopathy is observed in approximately 30% of the patients, whereas pleural effusion occurs in approximately 10%.^12,14 Pulmonary bullae, although uncommon, can develop when lymphoma invades the bronchial wall, leading to bronchial narrowing, valvular obstruction, air trapping, and eventual bulla formation. ¹⁵ In this case, the lesions displayed multiple and polymorphic features, with several imaging manifestations simultaneously evident on lung CT, including right lung consolidation with bronchial inflation; a small amount of right-sided pleural effusion; an isodense nodular shadow (approximately 16 × 10 mm) above the right diaphragm, suggestive of lymph node enlargement; and a round translucent shadow in the dorsal segment of the left lower lobe, consistent with bulla formation. These findings illustrate the polymorphic nature of pulmonary MALToma, which includes diverse radiological features that can aid in diagnosis.

The diagnosis of pulmonary MALToma is confirmed through histopathological examination. Microscopically, the tumor predominantly comprises small B lymphocytes, interspersed with monocyte-like B cells and centrocyte-like cells. When tumor cells infiltrate the bronchial mucosa, they form characteristic lymphoepithelial lesions. ⁴ Immunohistochemistry typically demonstrates positive staining for B-cell markers, including CD79a, CD19, CD20, CD22, and Bcl-2. ⁸ Tumor cells usually lack staining for T-cell markers such as CD3 and CD5. ⁸ Additionally, proliferating follicular dendritic cell networks exhibit positive staining for CD21 and CD23. ¹⁶ In this case, the Ki-67 proliferation index was less than 20%, indicating a low-grade malignancy. ⁸

Treatment options for pulmonary MALToma include observation, surgery, radiotherapy, chemotherapy, immunotherapy, and biological therapy. Because MALToma can sometimes regress spontaneously, observation is the preferred approach for asymptomatic patients. ¹⁷ Some reports have indicated that surgical resection may be considered the optimal treatment for localized pulmonary MALToma. ¹⁸ However, other research has indicated no difference in overall survival between patients undergoing surgery and those receiving chemotherapy. Considering the risks of surgery and the importance of preserving lung function, chemotherapy may be prioritized as the first-line treatment for localized pulmonary MALToma. ¹⁸ Radiotherapy should be considered in patients with localized disease who cannot undergo surgery. ⁵ Chemotherapy is recommended in patients with bilateral or extrathoracic disease or in recurrent or progressive cases. The cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen is widely used as first-line treatment. ⁵ Rituximab can also be used as a first-line immunotherapeutic agent. In a study by Okamura et al., eight patients with pulmonary MALToma were treated with rituximab; five achieved complete remission, one showed partial remission, and two maintained stable disease, demonstrating its efficacy in the management of pulmonary MALToma. ¹⁹ As an indolent lymphoma, MALToma generally has a favorable prognosis, with 5- and 10-year overall survival rates of 90% and 72%, respectively. Performance status and age are the only known unfavorable prognostic factors. ⁷

Conclusions

Pulmonary MALToma belongs to the category of indolent lymphomas. The initial symptoms lack specificity, and lung tissue biopsy and immunohistochemistry are required for a definite diagnosis. Therefore, the misdiagnosis rate is relatively high in clinical practice. Clinicians should enhance their understanding of this disease. Pulmonary MALToma should be considered in patients presenting with elevated eosinophil levels in conjunction with characteristic imaging features—such as pulmonary consolidation, air bronchogram, and ground-glass miliary nodules surrounding the lesion—in the absence of definitive clinical or laboratory evidence of infection.