Background
Primary pulmonary lymphoma (PPL), as an uncommon disease, affects the lung occuring over a broad clinical and pathologic spectrum. PPL, with a low incidence, comprises < 1% [
1] of all non-Hodgkin’s lymphoma (NHL), and 0.5% of all primary pulmonary malignant tumors [
2,
3]. Traditionally, it has been defined as a clonal lymphoid proliferation affecting one or both lungs (parenchyma and/or bronchi) in a patient with no clinical, pathological, or radiographic evidence of lymphoma elsewhere, either in the past, or at present, or for 3 months after presentation [
4,
5]. The vast majority are type of low-grade mucosa-associated lymphoid tissue [
6‐
10]. Although there have been several retrospective reports, few studies were investigated in the Asian population [
8‐
10].
PPL usually occurs with nonspecific clinical features, is highly misdiagnosed in clinic. In order to provide a better understanding of this disease, increase the accuracy of early diagnosis and minimize misdiagnosis, this research was to analyze and summarize the misdiagnosis reasons of PPL based on the clinical features, the laboratory and imaging examinations, and the pathologic characteristics of PPL cases from our hospital during April 2010 to May 2016 while referring to relative literature.
Discussion
PPL [
11,
12], as an extremely rare disease, represented less than 1% of lung malignancies, and less than 1% of non-Hodgkin’s lymphoma (NHL) and accounting for only 3.6% of extranodal lymphomas. There were almost one third of patients (31.6%) with no symptoms in our research. PPL, with a low incidence, usually occured with nonspecific clinical features, and was highly misdiagnosed in clinic. In our research, 13 patients (68.4%) were misdiagnosed as pneumonia, lung cancer, tuberculosis before confirming. The present study analyzes the clinical features, laboratory and imaging data, pathologic characteristics, and summarize misdiagnosis reasons of PPL cases. Aims to provide a better understanding and increase the accuracy of early diagnosis and minimize the misdiagnosis of PPL.
The symptoms and physical signs of pulmonary lymphoma were highly heterogeneous. In our research, 11 male and eight female patients were described with a mean age of 51.8 years old (range 19 to 71 years). It occured most commonly around the age of 50–70 years, although rare cases of younger age of onset had been reported. LDH exam showed 4 cases (21%) elevation, and β2 microglobulin exam showed 2 (10.5%) elevation in these 19 patients. Laboratory tests showed no-specific.
Low grade B-cell PPL, as most commonly in PPL, formed almost 85–90% of all reported cases, out of which almost all cases correspond to MALT-type NHL [
13‐
15]. The recent delineation of new pathologic entities such as low-grade malignant lymphoma of mucosa-associated lymphoid tissue (MALT type) had aided in the understanding of the pathophysiology, clinical course, and management of patients with pulmonary lymphoma. Ahmed [
16] reported no clinical symptoms in the MALT lymphoma diagnosis was about 40.9%. While 63.2% (12/19) MALT lymphoma were found in our study. The pathology of the six cases with no symptoms were confirmed MALT-type in our study. Nearly half of reported cases of MALT-type had been asymptomatic at presentation, while in the others, the presentation had been associated with non specific respiratory symptoms.
The radiographic presentation of PPL was not specific, but variable. The same as Bae et al.’s reported [
17], single or multiple nodules or areas of consolidation were the main patterns of radiographic abnormalities in our study, accounted for 47.4%. We found that 26.3%of patients presented pneumonia-like, with air space consolidation with or without air bronchogram. Other [
16‐
18] radiographic presentation of PPL were pleural effusion, mixed-type, multiple nodules etc. In previous case reports, PPL may appear as a single nodule, as multiple nodules or as cavitated lesions [
6]. Cavitated lesions had a wide differential diagnosis including granulomatous diseases (Wegener’s granulomatosis), tuberculosis, necrotic pneumonia, pulmonary Gram-negative organisms, anaerobic bacteria or fungal infections, pulmonary abscess, evacuated hydatid cysts, septic emboli, inhalational diseases (eg, coal workers’ pneumoconiosis and silicosis), eosinophilic pneumonia, cavitated rheumatoid nodules and neoplastic diseases (primary bronchial carcinoma). Metastatic lung nodules may especially cavitate squamous cell types but also adenocarcinomas, sarcomas, melanomas and osteosarcomas [
7]. Because of the wide differential diagnosis, multiple invasive and noninvasive diagnostic investigations were common. Due to these circumstances, in many cases, the invasive biopsy that confirmed the diagnosis was delayed [
8].
As the clinical features of PPL were poorly defined, most of the patients were initially misdiagnosed as pneumonia, pulmonary tuberculosis, organizing pneumonia and lung cancer. Altough imaging manifestation of PPL had a less specificity [
19‐
22], there were still some hints: 1) Fuzzy shadow at the edge of lung mass with air bronchogram; 2) Lung mass shadow stable for a long time; 3) Pneumonia-like changing without infections clinical and lab manifestation.
Although there had been several retrospective case reports, few studies were investigated in the Asian population. PPLwas commonly misdiagnosed as pneumonia, pulmonary abscess and carcinoma as reported [
9,
10,
23‐
25]. The main cause of misdiagnosis were summarized as follow: 1) The limitation of specialists. All the patients went to the repiratory department because of symptoms or physical findings in lung or air way, some of them accepted anti-infection treatment primarily combined with symptoms, laboratory examination and CT scan. 2) Poor compliance. Some patients didn’t come back for subsequent visit when they felt a little better after anti-infection treatment, and some patients went to other hospitals while the symptoms progressed. 3) Some patients’ chest CT scan showed pneumonia-like or cavity and the report of T-SPOT was positive, but the evidence of infection were negative, given the highly endemic nature of Mycobacterium tuberculosis in China and the fact of chest CT scan, they accepted diagnostic anti-tuberculosis treatment. 4) The similarity of pathological manifestation. In some cases the pathologists were confused because similarity of pathological manifestation of PPL. In our experience, if a patient was elderly and not responsive to treatment, alternative diagnosis should be considered and invasive procedures, such as bronchoscopy, CT-guided percutaneous lung biopsies, and an open thoracotomy or a video-assisted thoracoscopic (VATS) lung biopsy should be performed.
As a consequence, PPL could be diagnosed only by pathologic methods. Previously, the pathological tissue was mainly obtained through the diseased lung surgery, open thoracotomy, under thoracoscopy biopsy. CT guided percutaneous lung biopsy, thoracotomy and flexible fiberoptic bronchoscopy were the common methods in current. In our stury, pathological diagnosis was obtained by CT-guided percutaneous lung biopsies in ten patients, while four patients were confirmed by flexible fiberoptic bronchoscopy, 4 cases were confirmed by surgery, and the other one clinical feature was pleural effusion, confirmed by thoracoscopy. Of the 19 cases, more than half of the patients’ pathology was confirmed by CT guided percutaneous lung biopsy. CT guided percutaneous lung biopsy should be taken actively if the imaging findings did not match the symptoms or the anti-infection treatments to “lung infection” didn’t work. Accurate diagnosis requires adequate tissue sampling with appropriate ancillary pathologic studies.
The therapy of PPL relies on histology [
26,
27]. Surgery, chemotherapy and radiotherapy were the main treatment to PPL, alone or in combination, as well as therapeutic abstention or follow-up alone, had been commonly used. For MALT lymphoma the final results of IELSG-19 have recently been reported suggesting that rituximab+ chlorambucil should probably be the first line of chemotherapy.