Intravascular Large B-cell Lymphoma Presenting as Pulmonary Ground-glass Nodules That Progressed Slowly over Several Months with No Overt Symptoms

Abstract

A 74-year-old man with no overt symptoms was referred for a chest computed tomography (CT) that revealed multiple bilaterally pulmonary ground-glass nodules (GGNs) with subtle changes in size over eight months. Surgical lung biopsies were performed in the left upper lobe. A pathologic study confirmed the intravascular large B-cell lymphoma (IVLBCL). This lesion was a nodule-like cluster of atypical cells, meaning that it had been localized for several months. Pulmonary IVLBCL may form focal lesions presenting as GGN on chest CT and progress slowly without apparent symptoms.

Introduction

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal large B-cell lymphoma characterized by the selective proliferation of lymphoma cells within the lumen of small blood vessels in various organs (1). IVLBCL commonly involves the skin and central nervous system (CNS), and approximately 55-76% of patients present with some B symptoms, especially a fever (2). Although autopsy findings revealed that intravascular lymphoma often involves the lungs, early presentation of the lungs has rarely been reported because of diagnostic difficulties (3,4). The most common radiological finding of pulmonary IVLBCL is diffuse ground-glass opacities in both lungs with an increased ¹⁸F-fluorodeoxyglucose (FDG) uptake on positron emission tomography combined with computed tomography (PET/CT) (5), sometimes accompanied by pleural effusion and pulmonary hypertension (6).

The differential diagnosis of pulmonary ground-glass nodules (GGNs) includes neoplasms, infections, and immune-mediated diseases (7), but there are limited reports of IVLBCL presenting exclusively with GGNs.

We herein report an atypical case of IVLBCL with multiple GGNs and slow progression without overt symptoms.

Case Report

An asymptomatic 74-year-old man with a smoking history (20 cigarettes/day, 50 years) was referred to our department for a definitive diagnosis of multiple bilateral pulmonary GGNs. Eight months before his referral, he underwent CT and PET/CT to evaluate a pancreatic cyst. Malignancy findings on CT and PET/CT were negative, and the patient remained under observation. He had no family history or exposure to occupational or environmental particles but had undergone percutaneous coronary intervention for angina pectoris. There was no rale in the bilateral lungs, and no surface lymphadenopathy or hepatosplenomegaly was found.

Percutaneous oxygen saturation was 96% while breathing ambient air, and the body temperature was 36.2°C. Laboratory studies showed abnormalities: the hemoglobin level was 11.4 g/dL, the lactate dehydrogenase (LDH) level was 238 U/L, and the C-reactive protein (CRP) level was 0.6 mg/dL. No atypical cells were detected in the peripheral blood. Cryptococcal antigen was negative, and tumor markers, including carcinoembryonic antigen, cytokeratin fragment, and pro-gastrin-releasing peptide, were within the normal range.

Chest CT showed multiple bilateral GGNs with subtle changes in size over eight months (Fig. 1a, 1c). PET/CT performed eight months earlier demonstrated the accumulation of ¹⁸FDG only in a nodule in the left upper lobe (Fig. 1b), which had been slightly enlarged for eight months. Differential diagnoses included multiple primary lung cancer, metastatic lung tumor, and chronic infection. Therefore, the patient underwent wedge resection of two nodules in the left upper lobe (arrows in Fig. 1) with video-assisted thoracic surgery.

Figure 1.

Chest computed tomography (CT) and positron emission tomography (PET)-CT. (a, b) Eight months before the visit. CT showed ground-glass nodules (GGNs) bilaterally, and PET-CT demonstrated an abnormal accumulation in the GGN of the left S¹⁺² (SUV_max 2.5). The nodules varied in size from 5 to 14 mm. (c) At the referral visit. The GGNs in the left upper and right middle lobes were slightly enlarged, ranging in size from 11 to 16 mm. A surgical lung biopsy was performed on two pulmonary nodules (arrows). SUV_max: maximum standardized uptake value

In one part of the specimen (blue arrow in Fig. 1c), clusters of atypical tumor cells were identified in the lumina of the small pulmonary vessels, including capillary vessels and pulmonary arteries (Fig. 2). The lesion was a nodule-like cluster of atypical cells, and the boundary between the lesion and the normal lung was apparent. Immunohistochemically, these atypical cells were positive for CD20, CD79α, BCL2, BCL6, c-Myc, and MUM1, negative for CD3, CD5, and CD10, and had a Ki-67 proliferation index of ＞50% (Fig. 2e-f). The patient was diagnosed with IVLBCL. No tumor cells were identified in the other specimen (red arrow in Fig. 1c), suggesting that the resected lung specimen did not contain the nodule.

Figure 2.

Hematoxylin and Eosin staining (a-c), Elastica van Gieson (EVG) staining (d), and immunohistochemical staining (e, f) of the lung biopsy. (a) Loupe image of a specimen. (b, c) Magnification shows small vessels filled with atypical cells with prominent nucleoli (original magnification, ×20, ×200, respectively). (d) EVG staining shows no pattern of pulmonary fibrosis (×200). (e) Anti-CD31 immunostaining, highlighting the vascular structures (×200). (f) Immunohistochemistry showed positivity for CD20 (×200).

Soluble interleukin 2 receptor (sIL-2R) was measured and elevated at 1,277 U/mL. After the diagnosis of IVLBCL, PET/CT was reexamined and showed that the left adrenal gland, which had not been enlarged previously, had grown and now showed the accumulation of ¹⁸FDG (Fig. 3). A bone marrow biopsy showed no evidence of bone marrow involvement. Transthoracic echocardiography showed a peak tricuspid regurgitation velocity (TRV) of 2.6 m/s and no other signs of pulmonary hypertension. The patient had no significant symptoms during postdiagnostic evaluations. The introduction of IVLBCL treatment was postponed because coronary angiography for angina pectoris had been scheduled at another hospital.

Figure 3.

Chest computed tomography (CT) and positron emission tomography (PET)-CT findings before and after treatment. At the diagnosis of lymphoma, a pulmonary ground-glass nodule (GGN) (red arrow) and left adrenal lesion (blue arrow) were detected. At the time of the emergency department visit, no enlargement of the GGN or other additional abnormalities were observed. After chemotherapy, the GGN and the left adrenal tumor shrank.

One month after the diagnosis, the patient was admitted to the emergency department (ED) due to rapidly progressive dyspnea without a fever over three days. Percutaneous oxygen saturation and partial pressure of arterial oxygen while breathing ambient air were 99% and 98.3 mmHg, respectively. Laboratory tests at the ED showed a hemoglobin level of 10.8 g/dL, LDH level of 230 U/L, and CRP level of 6.48 mg/dL, and no apparent liver, renal, or coagulation abnormalities were noted. In addition, there was no notable decrease in white blood cell or platelet counts. No bone marrow examination was performed. Emergency CT showed no enlargement of known lung and adrenal lesions or other additional abnormalities. The TRV was mildly elevated at 2.9 m/s, but chest imaging was considered negative for pulmonary edema. There were no electrocardiographic abnormalities or elevated myocardial enzymes suggestive of myocardial ischemia.

Even without significant changes in the laboratory and radiological study, worsening symptoms and an elevated sIL-2R level (2,729 U/mL) suggested IVLBCL progression. Therefore, the patient underwent rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy in combination with intrathecal methotrexate (IT-MTX). After six cycles of R-CHOP and three cycles of IT-MTX, the sIL-2R level normalized, the left adrenal lesion shrank, and the ¹⁸FDG accumulation in the left adrenal gland disappeared. The remaining multiple pulmonary nodules showed improvement on chest CT (Fig. 3).

The patient is still under follow-up and has been progression-free for six months since treatment completion.

Discussion

We reported a case of IVLBCL with pulmonary GGNs in which a pathological examination revealed that the intravascular lymphoma cells were not diffusely distributed but localized to an area. GGNs refer to focal and nodular ground shadows. They can be differentiated from various diseases, including tumor lesions such as lung adenocarcinoma and inflammatory changes such as infection and immune abnormalities (7). In this case, GGNs were discovered incidentally while examining a pancreatic cyst. The patient was an older man with a smoking history; lung adenocarcinoma was the primary differential diagnosis. However, a surgical lung biopsy unexpectedly diagnosed IVLBCL.

IVLBCL commonly affects the skin and central nervous system, and symptoms at presentation are based on the site of involvement. Approximately 55% and 76% of patients present with some B symptoms, especially a fever (2), and a Japanese single-center retrospective study found a persistent fever in 97.6% of patients (8). In contrast, when diagnosed incidentally, as in our case, patients may have no overt symptoms (2).

Pulmonary lesions are relatively frequent in IVLBCL patients. An autopsy review revealed pulmonary involvement in approximately 60% of cases (5), and a single-center study found diffuse ground-glass opacities on chest CT in 23.8% of patients (8). Typical chest CT findings in pulmonary IVLBCL are diffuse ground-glass opacities and multiple nodules in the bilateral lungs (6,9), and PET/CT often shows a diffuse uptake in both lungs (9). As Nakazato et al. diagnosed PET-negative pulmonary IVLBCL on a random transbronchial lung biopsy (10), the absence of an ¹⁸FDG uptake does not rule out lung involvement, making the diagnosis of pulmonary IVLBCL more difficult. It is rare for pulmonary IVLBCL to present with GGNs. However, Satoh et al. reported IVLBCL presenting as GGNs on chest CT (11). In the present case, PET/CT showed a diffuse ¹⁸FDG accumulation in the bilateral lungs, and a pathological examination revealed the diffuse spread of atypical lymphocytes in the alveolar septal walls. Our case, which presented as a GGN without a diffuse ¹⁸FDG accumulation in the lungs, is an unusual presentation that has not been previously reported.

Interestingly, upon a review of the loupe image of the present case (Fig. 2a), no atypical lymphocytes were histologically observed in the normal lung surrounding the lesion. The boundary between the normal alveolar area and the IVLBCL lesion was clear, and all lymphoma cells in the lesion were confined to the intravascular space without extravascular invasion. There was no accumulation of ¹⁸FDG in either lung field or in the unresected lung GGNs. Since the GGNs resolved after lymphoma treatment, lymphoma cells may coexist in the lung nodules without the uptake of ¹⁸FDG. A biopsy was not performed in the right lung or left lower lobe, making it difficult to confirm whether or not IVLBCL was diffusely disseminated in these lobes. However, since the two biopsied sites did not show diffuse lesions and there was no clinical evidence of respiratory failure or pulmonary hypertension, we considered the present case to be consistent with localized lesions.

Conclusion

The present case demonstrated that IVLBCL formed a focal lesion in the lung that appeared as a GGN on chest CT and remained stable for several months without overt symptoms. IVLBCL has various pathogenetic features, and lung involvement often develops into nonspecific lesions. Therefore, pulmonologists should consider IVLBCL in the differential diagnosis of pulmonary nodules, even if PET/CT does not show a diffuse ¹⁸FDG accumulation in the lung.

The authors state that they have no Conflict of Interest (COI).