Non-resolving pneumonia: primary pulmonary MALT lymphoma

Abstract

Mucosa-associated lymphoid tissue (MALT) lymphoma is an uncommon extranodal low-grade B-cell lymphoma. Pulmonary MALT lymphomas originate from bronchial MALT and are also referred to as bronchial-associated lymphoid tissue lymphomas. MALT lymphomas of the lung are slow-growing tumours and usually present as asymptomatic chronic alveolar opacities visible on chest radiographs or with non-specific pulmonary symptoms. Here we described a case of a male patient in his early 50s with cough and chest pain for 4 years. His CT chest scan showed consolidation in the lingula and left lower lobe. Histopathology of the specimen obtained from cryobiopsy of the lung lesion showed a dense monomorphic lymphoid infiltrate, and immunohistochemistry confirmed the diagnosis of MALT lymphoma. The prognosis of pulmonary MALT lymphomas is good with >80% 5-year survival rates. This case highlights that MALT lymphoma should be considered as a differential diagnosis while evaluating cases with non-resolving consolidation.

Background

Primary pulmonary lymphomas (PPL) are extremely rare, comprising only 0.5–1.0%¹ of all primary lung malignancies and only 0.4% of all lymphomas.^{2 3} The reported sub-types of primary pulmonary lymphomas include mucosa-associated lymphoid tissue (MALT) lymphoma, diffuse large B-cell lymphoma, lymphoplasmacytic lymphomas and anaplastic large cell lymphoma.⁴ MALT lymphoma often occurs in the sixth and seventh decades of life, with no gender predominance,⁵ frequently in patients with chronic inflammatory or infectious background.

Case presentation

We present the case of a male patient in his early 50s, who came to us with complaints of dry cough, chest pain and shortness of breath on exertion for 4 years. He was a never smoker and consumed alcohol occasionally. His cough was insidious in onset, intermittent, and dry and was not associated with any seasonal, postural or diurnal variations. Chest pain was left-sided, dragging type, not severe enough to disturb his sleep or activities of daily living and was relieved by non-opioid analgesics. Dyspnoea was insidious in onset, mMRC grade one and was not associated with orthopnoea or paroxysmal nocturnal dyspnoea. He did not have any fever, hemoptysis, appetite loss or weight loss. His medical history was significant for pulmonary tuberculosis 6 years ago which was confirmed microbiologically by sputum acid-fast bacillus (AFB) smear positivity. He was treated with appropriate antitubercular therapy for 6 months.

Before his presentation to our centre, over the past 4 years, he was evaluated twice for the above complaints. He was found to have an opacity in the left hilar region on a chest radiogram (figure 1A) and underwent bronchoscopy. Broncho-alveolar lavage (BAL) was performed, and samples were sent for bacterial culture, fungal smear and AFB smear, which were all negative. He was prescribed antibiotics, cough suppressants and supportive medications, but there was no improvement in his condition. He then went to another hospital after 1 year due to similar complaints. Chest radiograms were taken showing opacity in the left hilar region (figure 1B,C), and he again underwent BAL. Cytology of the BAL fluid showed predominantly lymphocytes (lymphocytes, 100%). Bacterial culture and AFB smear were negative. He was then referred to our hospital for further evaluation.

Figure 1.

(A)(B)(C) Serial chest radiographs over 4 years showing a stable left-sided hilar opacity and linear opacity in the right mid zone regressing over time. (D) Chest radiograph at presentation showed a persistent opacity in the left hilar region. (E) HRCT chest scan showing consolidation with air bronchograms in the lingula. (F) HRCT chest scan showing consolidation in the left lower lobe. (G) PET-CT image of the lingula showing solid soft tissue density consolidation with an increased FDG uptake (SUVmax 6.0). (H) PET-CT image of the left lower lobe showing solid soft tissue density consolidation with an increased FDG uptake (SUVmax 4.3). HRCT, high-resolution CT; PET-CT, positron emission tomography-CT.

At presentation to our centre, he was afebrile, with a pulse rate of 84 beats per minute; blood pressure, 120/70 mm Hg; room air saturation, 98%; and a respiratory rate of 14 breaths per minute. On general examination, there was no pallor, clubbing, cyanosis, icterus or peripheral lymphadenopathy. On respiratory system examination, there were crackles in the left mammary area. Cardiovascular, gastrointestinal and central nervous system examinations were all normal.

His complete blood picture was normal with haemoglobin of 150 g/L; total white blood cell count, 6.94 x 10⁹ /L; and platelet count, 235 × 10⁹/L. Erythrocyte sedimentation rate, C-reactive protein, liver function tests and renal function tests were within normal limits. Chest radiograph (CXR) showed an opacity in the left hilar region (figure 1D). Similar opacity was seen in his previous CXRs, and it appeared to remain stable over the last 3 years. His serial radiographs also showed an opacity in the right mid-zone. This lesion had developed 6 years ago when he was diagnosed with pulmonary tuberculosis. He took antituberculosis medication for 6 months after which this opacity has consistently regressed over the years (figure 1A–D). He underwent a high-resolution CT (HRCT) of the chest, which showed consolidation with air bronchograms in the lingula and left lower lobe (figure 1E,F) and fibrotic densities in the right middle lobe with traction bronchiectatic changes (online supplemental figure 1A).

The patient then underwent flexible bronchoscopy under general anaesthesia. The lesion in the lingula was localised using radial endobronchial ultrasonography (EBUS) (Olympus UM-S20-20R) (figure 2A). A broncho-alveolar lavage sampling and cryobiopsy of the lesion (ERBE cryoprobe 1.1 mm) were performed. The lesion in the right middle lobe was not biopsied as it was fibrotic and appeared as tuberculosis sequelae. BAL was sent for bacterial culture, AFB smear, Xpert mycobacterium tuberculosis (MTB)/Rif assay, MTB culture and fungal smear, which were all negative. Histopathological examination of the cryobiopsy sample revealed a dense diffuse and nodular atypical lymphoid infiltrate composed of monotonous small lymphocytes seen infiltrating the bronchiolar epithelium (lymphoepithelial lesions) and alveolar septa (figure 2B). On immunohistochemistry, the atypical cells were found to be diffusely positive for CD20, focally positive for bcl2 and CD3 (figure 2C–E) and negative for CD10, bcl6, MUM1, CD30, kappa and lambda light chains. Ki 67 proliferation index was 12–15% in the highest proliferating areas (figure 2F). A final diagnosis of extra-nodal marginal zone lymphoma of MALT involving the lung was made.

Figure 2.

(A) Radial EBUS showing a concentric image of the lesion in the lingula. (B) Histopathologic examination of the lung biopsy showed dense diffuse and nodular infiltrate of monomorphic atypical lymphoid cells effacing the lung architecture (H&E, 10x magnification). (C) Immunohistochemical examination showing diffuse staining of CD20 in atypical lymphoid cells (40x magnification). (D) Immunohistochemical examination showing focal positivity of bcl2 in atypical lymphoid cells (40x magnification). (E) Immunohistochemical examination showing background reactive T-lymphocytes positive for CD3 (40x magnification). (F) Immunohistochemical examination showing Ki-67 proliferation index of 12–15% in the highest proliferating areas (40x magnification). EBUS, endobronchial ultrasonography.

A ¹⁸flouro-2-deoxy-D glucose (FDG) positron emission tomography (PET) was performed after the biopsy, which showed increased heterogeneous FDG uptake in the lesion in superior lingula (SUVmax 6.0), mild heterogenous FDG uptake in the left lower lobe lesion (SUVmax 4.3) (figure 1G,H) and non-FDG avid fibrotic densities with traction bronchiectatic changes in the right middle lobe (online supplemental figure 1B). There was no FDG uptake elsewhere in the body. A final diagnosis of low-grade primary pulmonary non-Hodgkin’s lymphoma (NHL) was confirmed.

Differential diagnosis

As this is a case of non-resolving pneumonia in a treated case of pulmonary tuberculosis, the differential diagnoses would include both infectious and non-infectious causes. Infections presenting as non-resolving pneumonia are tuberculosis, non-tuberculous mycobacteria, brucellosis, nocardiosis and actinomycosis. Non-infectious causes of a non-resolving pneumonia include carcinoma lung, organising pneumonia, nodular or diffuse lymphoid hyperplasia, lymphocytic interstitial pneumonia and lymphomas. Endobronchial obstruction can also lead to persistent distal post-obstructive pneumonia. Differentiation among various causes of non-resolving pneumonia can be performed by bronchoscopy. In the index case, there was no proximal endobronchial obstruction. The lesion was localised by an EBUS probe, and samples were obtained for microbiological tests and histopathology. Microbiological tests were negative for all infectious conditions, and a biopsy confirmed pulmonary MALT lymphoma in the index case.

Treatment

The staging of MALT lymphomas is similar to the staging of other NHLs. As the PET-CT showed no uptake in any other organ or lymph nodes, this patient with pulmonary MALT lymphoma was classified as stage 1E where lymphoma is present in one area or organs other than the lymph nodes. The patient was referred to the oncology centre, and after a multi-disciplinary tumour board meeting, chemotherapy with rituximab and chlorambucil was initiated. He completed two cycles of chemotherapy.

Outcome and follow-up

He completed two cycles of chemotherapy and is due for the next four cycles. His cough and chest pain have improved at the last follow-up.

Discussion

Lymphomas can involve the lung parenchyma in three ways: (1) haematogenous dissemination of NHL or Hodgkin’s disease (HD), (2) contiguous invasion from a hilar or mediastinal nodal disease and (3) primary pulmonary involvement.⁶

PPL is defined as clonal lymphoid proliferation affecting one or both lungs (parenchyma and/or bronchi) in a patient without detectable extrapulmonary involvement at diagnosis or during the subsequent 3 months.^{1 2} PPL represent <1% of NHL, 0.5–1% of primary pulmonary malignancies and only 0.4% of all lymphomas.^7–9 The types of PPL reported so far include (1) MALT lymphoma, (2) diffuse large B-cell lymphoma, (3) lymphoplasmacytic lymphomas and (4) anaplastic large-cell lymphoma.

MALT lymphoma is considered a low-grade B-cell extranodal lymphoma. It can originate in different organs. The most common sites involved are the gastrointestinal tract, salivary glands, orbit and thyroid gland. Lung involvement is considered uncommon. Chronic infections have been suggested as a possible cause of MALT lymphoma. The association between gastric MALT lymphoma and Helicobacter pylori is well described.¹⁰ The association between Borrelia burgdorferi and cutaneous MALT lymphoma, hepatitis C virus and hepatic MALT lymphoma, and Chlamydia psittaci and ocular adnexal MALT lymphoma are other suspected links between infection and MALT lymphomas.^11–14 The association between pulmonary MALT lymphoma and chronic pulmonary infection has to be evaluated further. Infections like Mycobacterium tuberculosis, Epstein-Barr virus and human herpes virus 8 have been implicated in high-grade lymphoma with primary lung lesions.¹⁵ People infected with tuberculosis can develop lymphoma more frequently compared with non-infected individuals.¹⁶ In highly tuberculosis-prevalent countries, it is also not uncommon to diagnose pulmonary lymphoma and tuberculosis concurrently.¹⁷ Increased risk of lymphoma is also seen in patients with sarcoidosis, attributed to the involvement of the reticuloendothelial system and immunological deficiencies.^{18 19}

Patients with pulmonary MALT lymphomas have non-specific symptoms, and nearly one-third of patients may be asymptomatic at the time of diagnosis. They generally present with cough, chest pain, fatigue, dyspnoea, fever and haemoptysis. The radiological findings of MALT lymphoma are also non-specific. The most common HRCT findings are nodules, followed by mass lesions and consolidations; rarely hilar and mediastinal lymphadenopathy and pleural effusions may be seen.^{20 21} PET-CT has a limited role in primary pulmonary MALT lymphoma. Low FDG uptake is seen in 80% of patients and no uptake in nearly 20% of patients.²² The non-specific symptoms and radiological presentation make the diagnosis of pulmonary MALT lymphoma difficult. Our patient presented with non-specific symptoms and consolidation on the HRCT chest, which led to a delay in the diagnosis.

The diagnosis of primary pulmonary MALT lymphoma requires a biopsy, which is usually obtained by invasive procedures such as surgical resection, transbronchial lung biopsy or a CT‐guided transthoracic lung biopsy. The diagnosis of our case as MALT lymphoma was confirmed by radial EBUS-guided transbronchial lung cryobiopsy. While performing a transbronchial lung biopsy, the addition of radial EBUS helps in better localisation of the peripheral pulmonary lesions, and performing a cryobiopsy gives larger tissue as compared with a conventional forceps biopsy.

The histopathology of MALT lymphoma shows atypical lymphoid infiltrate in the marginal zone of reactive follicles, which extends to interfollicular and intrafollicular regions. In addition, in the lung, MALT lymphoma shows lymphoepithelial lesions in the bronchial/bronchiolar epithelium and the presence of a lymphangitic pattern of infiltration with spread through bronchovascular structures, interlobular septa and visceral pleura. The immunophenotype of MALT cells is positive for pan B-cell markers (CD20, CD3, CD19, CD79a and Pax5) and bcl2 and negative for CD5, CD10, CD23, CD 21, cyclin D1 and BCL6.²³

Treatment options for pulmonary MALT lymphoma are surgery, radiotherapy or chemotherapy with or without anti-CD20 monoclonal antibody therapy.²² Some authors have also suggested a ‘watch and wait’ strategy because spontaneous regression of MALT lymphoma has been reported, especially for primary MALT lymphoma of the lung.²⁴ Primary pulmonary MALT lymphomas generally show no progression, and dissemination takes a longer time.²²

Chemotherapy is indicated in disseminated, bilateral or extrapulmonary disease. Immunotherapy with an anti-CD20 monoclonal antibody (rituximab) is also an option and can be given alone or in combination with chemotherapy.²⁵ A variety of chemotherapeutic agents either single or combined have been proposed for the treatment of primary pulmonary MALT lymphoma, but there is no standard regimen that has been established. Oral alkylating agents like chlorambucil and cyclophosphamide, purine nucleoside analogues like fludarabine, and cladribine can be used as single agents for chemotherapy.²⁶ Chlorambucil-based regimen is the treatment of choice as it has better outcomes and prolonged remission periods.²² The combination of rituximab and chlorambucil was more efficacious and safer as proven in phase three international extranodal lymphoma study groups on gastric and non-gastric MALT lymphomas in comparison with a single agent alone.²⁶ The combination of rituximab and bendamustine as well as rituximab and fludarabine showed higher rates of disease control in small non-randomised trials.²⁶ CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone) and R CHOP regimens are widely used chemotherapeutic options in clinical practice with good disease remission rates.²⁷ Other regimens containing CVP (cyclophosphamide, vincristine and prednisone) also showed significant disease-free survival rates but were inferior to the fludarabine regimen in non-gastric MALT lymphoma.²⁷ The prognosis of primary pulmonary MALT lymphoma is good with 5-year survival rate of more than 85%.²² Poor socioeconomic status and geriatric age group are considered to have a poor prognosis. MALT lymphoma has a high relapse rate (up to 36%), and hence, patients with pulmonary MALT lymphoma should be kept under long-term observation.^{28 29}

Patient’s perspective.

I had dry cough, shortness of breath, chest pain for 4 years. Doctors informed me that I have a patch in my lungs, and I underwent a procedure twice to get a sample from the lungs for reaching diagnosis, but sadly, the doctors were not able to diagnose the reason and I continued to have the symptoms. I was referred to this hospital by my treating physician. Here I underwent a CT scan of the chest and an invasive procedure to get the diagnosis. After the biopsy report, I was told that I have a slow-growing malignancy named MALT lymphoma in my lungs. A PET scan was done to see the extent of the cancer spread. I was apprehensive initially after knowing the diagnosis, but my doctors clearly explained to me the condition treatment and also that prognosis will be good after treatment. I was referred to an oncology centre for further treatment. I completed my two cycles of chemotherapy and under follow-up.

Learning points.

• Primary pulmonary Mucosa-associated lymphoid tissue (MALT) lymphoma is a rare lung neoplasm and should be considered as a differential diagnosis of non-resolving pneumonia.

• It is an indolent tumour with non-specific symptoms and radiology. A high index of suspicion is required to establish a diagnosis.

• The bronchoscopic diagnosis of peripheral pulmonary lesions can be improved by using radial endobronchial ultrasonography for localising the lesion and cryoprobes to obtain larger tissue samples.

• The treatment options for pulmonary MALT lymphomas include surgical resection, chemotherapy or radiation therapy, and the therapy should be decided on a case-to-case basis.

Ethics statements

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