Successful Treatment of Diffuse Large B-cell Lymphoma Involving Multiple Renal and Bone Infiltrations Presenting with Giant Cell Arteritis-like Manifestations

Abstract

We herein report a case of diffuse large B-cell lymphoma (DLBCL) involving multiple renal and bone infiltrations presenting with giant cell arteritis (GCA)-like manifestations. One month prior, the present patient had left-sided temporal headache, jaw claudication, and renal failure. The patient was diagnosed with DLBCL based on a renal biopsy. After rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone plus intrathecal methotrexate/cytarabine/prednisone and rituximab, high-dose methotrexate, and cytarabine chemotherapy, the patient's clinical manifestations improved, and complete remission was achieved. DLBCL rarely but occasionally presents with GCA-like manifestations or multiple renal and bone infiltrations, highlighting the need for prompt and aggressive combination chemotherapy.

Introduction

Giant cell arteritis (GCA) is a common form of primary systemic vasculitis that mainly affects large and medium-sized vessels in older adults (1). Its clinical symptoms include temporal headaches, jaw claudication, and thickened temporal arteries. Furthermore, in severe cases, visual disturbance and stroke are also observed as a consequence of inflammatory vascular obliteration (2). The definitive diagnosis of GCA is based on a temporal artery biopsy, which may not always demonstrate the presence of giant cells. In addition, the clinical diagnosis of GCA is often difficult because no GCA-specific autoantibodies are known (1,2).

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma (3). It usually presents with a fever, night sweats, and weight loss, known as B symptoms, and is frequently discovered by palpating superficial lymph nodes (4,5). However, hematogenous spread rarely involves renal or bone lesions (6-13), and only a few cases of malignant lymphoma with GCA-like presentations have been reported (14-22).

We herein report a case of DLBCL involving multiple renal and bone infiltrations presenting with GCA-like manifestations that was successfully treated with a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus intrathecal methotrexate/cytarabine/prednisone and rituximab, high-dose methotrexate, and cytarabine (R-MA) chemotherapy.

Case Report

A 63-year-old Japanese man with a 1-month history of new-onset left temporal headache, jaw claudication, and left eyelid ptosis was admitted to our hospital. He had a history of migraine diagnosed at 20 years old.

On admission, his body weight was 58.6 kg (body mass index, 23.1 kg/m²). He was febrile (37.3°C), and his blood pressure was 130/84 mmHg. The palpebral conjunctiva appeared anemic, and left temporal headache was observed. He had tenderness in the left temporal artery, with no palpable pulse, jaw claudication, or left mandibular pain. The superficial lymph nodes and hepatosplenomegaly were not palpable. Pain was observed in the right hip joint. There were no remarkable symptoms, such as difficulty raising the shoulder joint, and no signs suggestive of polymyalgia rheumatica were observed. The neurological findings showed left eyelid ptosis and diplopia, but no other abnormalities were observed.

Laboratory test results were as follows: white blood cell count, 10,910 /μL; hemoglobin, 11.3 g/dL; platelet count, 491,000 /μL; and erythrocyte sedimentation rate (ESR), 56 mm/h. The serum concentration of total protein was 5.1 g/dL, albumin level was 3.1 g/dL, IgG level was 660 mg/dL, IgA level was 36 mg/dL, IgM level was 105 mg/dL, lactate dehydrogenase (LD) level was 312 mg/dL, C-reactive protein level was 2.3 mg/dL, serum creatinine (sCr) level was 1.7 mg/dL, calcium level was 8.9 mg/dL, and soluble interleukin-2 receptor (sIL-2R) was 3,854 U/mL. Tests for rheumatoid factor, antinuclear antibodies, antineutrophil cytoplasmic antibodies, cryoglobulin, circulating immune complexes, hepatitis B surface antigens, and hepatitis C virus antibodies were negative, and the serum C3 and C4 levels were normal. Urinalysis results were negative for protein, occult blood, and Bence Jones protein. N-acetyl-β-D-glucosaminidase (NAG) levels of 18.6 IU/L and β2-microglobulin (β2-MG) levels of 23,163 μg/L were observed. Electrophoresis of serum proteins showed no M-protein spikes. Roentgenograms of the chest and skeleton were normal.

Plain abdominal computed tomography (CT) revealed bilateral renal enlargement, right hydroureter, and a suspected lesion with a soft tissue shadow around the abdominal aorta (Fig. 1A). In addition, fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT revealed no accumulation of FDG in the suspected lesion with a soft tissue shadow around the abdominal aorta but did show a high FDG uptake in the bilateral kidneys, base of the skull, left mandible, bilateral humerus, femur, tibia, vertebral bones, and mediastinal and lesser curvature lymph nodes (Fig. 1C, 2A, C). Brain magnetic resonance imaging (MRI) revealed high-intensity areas at the skull base on both sides on diffusion-weighted imaging, indicating infiltration into the cranial nerves (trigeminal and oculomotor nerves). The symptoms of left-sided headache, jaw deviation and pain, ptosis, and diplopia are attributed to trigeminal and oculomotor neuropathies, which are caused by skull base infiltration by DLBCL.

Figure 1.

Axial section of the plain abdominal computed tomography (CT) scan showing bilateral renal enlargement, right hydroureter, and suspected lesion with soft tissue shadow around the abdominal aorta (A). The abnormalities were ameliorated after combination chemotherapy (B). Axial section of the fluorodeoxyglucose (FDG)-positron emission tomography/CT revealing no FDG accumulation in the suspected lesion with a soft tissue shadow around the abdominal aorta but a high FDG uptake in both kidneys and the left adrenal gland (C). The uptakes decreased after combination chemotherapy (D).

Figure 2.

Coronal section of the fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography revealing a high FDG uptake in the bilateral kidneys, base of the skull, left mandible, bilateral humerus, femur, tibia, vertebral bones, and mediastinal and lesser curvature lymph nodes (A, C). The uptakes were ameliorated after treatment (B, D). The arrows indicate the locations of the main lesions.

The patient had unexplained progressive renal dysfunction, but imaging studies did not reveal any renal atrophy, and the course of the condition was unusual for chronic kidney disease. A renal biopsy was performed to clarify the cause of this renal dysfunction on day 17 of hospitalization. He was continuously febrile and showed loss of appetite and body weight; thus, moderate-dosage (25 mg/day) prednisolone was administered to prevent further progressive renal failure and worsening of the patient's condition on day 24 of hospitalization. However, these symptoms did not respond to moderate doses of prednisolone.

Renal histopathological findings showed the replacement of the tubulointerstitium by infiltrating lymphocytes (Fig. 3A, B). Immunostaining for CD20 (Fig. 3C) was strongly positive for medium-to-large infiltrating lymphocytes. Staining for CD3 (Fig. 3D) and CD5 (Fig. 3E) revealed occasional non-neoplastic cells with positive staining. Neoplastic cells showed no immunoreactivity for CD10 (Fig. 3F) or CD68 (Fig. 3G). B-cell CLL/lymphoma 6 was partially positive, and E3 ubiquitin-protein ligase MIB1 showed a high labeling rate of >50% (data not shown). A few CD138 plasma cells were observed (Fig. 3H), and no significant IgG4-positive cells were observed among the IgG-positive cells (Fig. 3I, J). No significant difference was observed between the kappa and lambda light chains (Fig. 3K, L). The glomeruli showed almost normal findings without any proliferation or deposition. Direct immunofluorescence staining for C3, C4, IgG, IgA, IgM, kappa, and lambda light chains revealed no significant deposition in either the glomeruli or tubules (data not shown). Given the above examination results, the patient was eventually diagnosed with DLBCL (IV) based on the pathological findings and the Ann Arbor staging system (23).

Figure 3.

Representative photomicrographs from immunohistopathological analyses of renal biopsy tissue sections, showing a diffuse population of large, atypical cells with irregular nuclei, prominent nucleoli, and increased mitotic activity (A and B: Hematoxylin and Eosin staining). Strong and diffuse immunostaining for CD20 in atypical infiltrating lymphocytes (C). Only occasional immunostaining for CD3 and CD5 in non-neoplastic cells is shown (D, E). No immunoreactivity of neoplastic cells to CD10 and CD68 is observed (F, G). A few CD138 plasma cells are observed (H). No significant IgG4-positive cells among the IgG-positive cells are shown (I, J). No significant differences are observed between kappa and lambda light chains (K, L). A: high-power field; B-L: low-power field.

The international prognostic index score was 5, indicating a high risk of DLBCL (24). R-CHOP and intrathecal injections of methotrexate, cytarabine, and prednisone chemotherapy were administered on day 45 of hospitalization. The chemotherapy drug dosages were as follows: rituximab, 375 mg/m² on day 1; cyclophosphamide, 750 mg/m² on day 2; liposomal doxorubicin, 50 mg/m² on day 2; vincristine, 1.4 mg/m² on day 2; prednisolone, 60 mg/m² on days 2-6; methotrexate, 15 mg/body on day 1; cytarabine, 40 mg/body on day 1; prednisone 10 mg/body on day 1. This treatment regimen is accompanied by supportive symptomatic treatment for pain control, infection prevention, and transfusion of blood products.

Following the first cycle of chemotherapy, the left-sided headache, jaw claudication and pain, ptosis, diplopia, and cranial nerve infiltration of DLBCL observed on brain MRI were ameliorated, and the abnormal levels of sCr, LD, sIL-2R, urinary NAG, and β2-MG gradually returned to almost normal values. The patient was then administered R-MA chemotherapy (rituximab 375 mg/m² on day 1, methotrexate 1,000 mg/m² on day 2, and cytarabine 3,000 mg/m² on day 3) for prophylaxis against lymphoma central nervous system infiltration, followed by a second cycle of R-CHOP chemotherapy. The patient was discharged on day 110 of hospitalization (Fig. 4).

Figure 4.

Serum soluble interleukin-2 receptor, lactate dehydrogenase, and creatinine levels and therapy during hospitalization. sCr: serum creatinine, sIL-2R: soluble interleukin-2 receptor, sLD: serum lactate dehydrogenase, MTX: methotrexate, PSL: prednisolone, R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, R-MA: rituximab, high-dose methotrexate, and cytarabine

Finally, the patient achieved complete remission after four cycles of R-CHOP: three cycles of intrathecal injection of methotrexate, cytarabine, and prednisone, and two cycles of R-MA chemotherapy at the hospital according to the interim response evaluation by FDG-PET/CT (Fig. 1D, 2B, D). Furthermore, bilateral renal enlargement and right hydroureter were ameliorated on abdominal CT (Fig. 1B). No relapse occurred within 18 months of the onset of DLBCL.

Discussion

Lymphomatous involvement of the genitourinary tract is a rare occurrence. It has been estimated that malignant lymphoma of the genitourinary tract occurs in 3-6% of cases (13). The diagnosis of DLBCL based on a renal biopsy is rare because kidney tissue lacks lymphoid elements, and the mechanism of origin of renal lymphomatous involvement is poorly understood (6-13). Dense tumor cell infiltration of the tubulointerstitium in both kidneys may cause compression of the tubules, subsequently enlarging the kidneys and impairing the renal function. In the present case, an early diagnosis was made using a renal biopsy. In addition, prompt intensive intervention with combination chemotherapy markedly improved not only the renal swelling and renal failure but also multiple bone lesions and GCA-like manifestations.

Our literature search showed that cases of DLBCL with multiple renal and bone infiltrations were rare, with only nine total cases noted, including the present case (6-13). Table 1 summarizes the patient characteristics. The average age was 57.0 (range, 24-75) years old, and the majority were men (7/9, 77.8%). The most common initial symptoms were bone, joint, or back pain (7/9, 77.8%), followed by a high fever and body weight loss (4/9, 44.4%). The superficial lymph nodes were palpable in only 2/9 cases (22.2%). The biopsy sites with a diagnosis of DLBCL were the kidney or bone marrow (3/9, 33.3%), lymph nodes (2/9, 22.2%), and the liver (1/9, 11.1%). The initial treatment for all patients was R-CHOP chemotherapy. Importantly, of the 9 patients reported, 4 survived (44.4%) and 5 died (55.6%), indicating a poor prognosis. In addition, regarding the renal function of the 5 deceased cases, 3 had serum creatinine levels ranging from 1.5 to 9.2 mg/dL, showing no consistent trend (the other 2 cases were not described). Therefore, there was no direct association between the severity of renal dysfunction and cause of death. Furthermore, among the five cases, four experienced an acute exacerbation of DLBCL, and the 5th case is different from the 4th case because besides an acute exacerbation, it also had sepsis.

Table 1.

Diffuse Large B-cell Lymphoma with Multiple Renal and Bone Infiltrations.

Age/Sex	Initial symptoms	Serum creatinine (mg/dL)	Lymphade-nopathy	Biopsy	Treatment	Time from symptom onset to admission	Outcome	Reference
75/M	Left-side shoulder pain	5.4	No	Liver	R-CHOP	1 month	Recovered	(6)
24/M	Anemia, back pain	ND (elevated)	Systemic lymph nodes	Bone marrow	R-CHOP	2 months	Died	(7)
73/M	Fever, anemia, splenomegaly	ND	Parabronchial lymph nodes	Bone marrow	R-CHOP	17 months	Died	(8)
67/F	Epigastric pain, vomiting, nausea	6.4	No	Kidney	R-CHOP	0.5 month	Recovered	(9)
45/M	Fever, polyarthralgia, polyuria, easy fatigability, weight loss	3.4	Neck lymph nodes	Lymph node	Bortezomib R-CHOP	ND	Died	(10)
69/M	Fatigue, anorexia, weight loss, generalized body aches	1.3	No	Bone marrow	R-CHOP	0.5 month	Recovered	(11)
51/M	Fever, left-side flank pain	1.5	No	Kidney	R-CHOP	2 months	Died	(12)
46/F	Left-side knee pain	9.2	Inguinal lymph nodes	Lymph node	COP	5 months	Died	(13)
63/M	Left-side temporal headache, eyelid ptosis, jaw claudication	1.7	Mediastinal and lesser curvature lymph nodes	Kidney	R-CHOP R-MA Intrathecal MTX/cytarabine/PSL	1 month	Recovered	Our case

M: male, F: female, MTX: methotrexate, PSL: prednisolone, R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, R-MA: rituximab, high-dose methotrexate, and cytarabine, ND: not described

Notably, all four surviving patients were hospitalized within one month after the initial symptom onset, whereas four of the deceased patients were hospitalized two months or later after the initial symptoms were noted (the details of one case were not described). These results indicate that the period from the initial symptom onset to admission may affect the prognosis of DLBCL patients with multiple renal and bone infiltrations. It will be necessary to accumulate and evaluate evidence from more cases in future studies to confirm these findings.

The manifestation of malignant lymphoma mimics rheumatic diseases (18,25). Only 10 case reports, including ours, have specifically described malignant lymphomas presenting with GCA-like symptoms (Table 2). The average age was 72.8 (range, 57-89) years old, and the majority were men (8/10, 80.0%). The most common initial symptom was headache (7/10, 70%), followed by visual disturbances (5/10, 50.0%), weight loss, and jaw claudication (3/10, 30%). The confirmed biopsy site was the temporal artery (2/10, 20%), followed by the paranasal sinuses, skin, brain, bone, mediastinal tissue, and kidneys (1/10, 10.0% each). Malignant lymphoma was classified as DLBCL in 5 of the 10 patients. In addition, 6/10 patients (60.0%) were treated with chemotherapy, such as R-CHOP. Importantly, 4/9 patients (44.4%) died, showing high mortality rates (details of 1 case were not described). Therefore, malignant lymphoma, especially DLBCL, rarely but occasionally presents with GCA-like manifestations, and such patients have a poor prognosis.

Table 2.

Malignant Lymphoma Presenting with Giant Cell Arteritis-like Manifestations.

Age/Sex	Initial symptoms	Biopsy	Classification of malignant lymphoma	Treatment	Outcome	Reference
79/M	Right-side eye and temple pain, blurring of vision, visual loss	Temporal artery	Perivascular mantle cell lymphoma	PSL 60 mg/day	Died	(14)
89/M	Left-side headache, visual loss	Paranasal sinuses	DLBCL	PSL 1 mg/kg/day CHOP Radiotherapy	Recovered	(15)
73/F	Frontotemporal headaches, jaw claudication, visual disturbance, vertigo, fever, night sweats, weight loss	Temporal artery	Perivascular marginal, zone lymphoma	Radiotherapy	ND	(16)
69/M	Right-side visual loss and proptosis	(Autopsy)	Intravascular large B-cell lymphoma	PSL 60 mg/day	Died	(17)
83/M	Fever, weight loss, headache, shoulder stiffness, erythematous skin lesions, gait disturbance	Skin	Anaplastic large T-cell lymphoma	PSL 60 mg/day Chemotherapy	Recovered	(18)
68/M	Left-side visual loss	Brain	Intravascular lymphoma	MR-CHOP	Died	(19)
57/M	Bilateral frontal headaches, weight loss	Bone	DLBCL	MR-CHOP	Recovered	(20)
67/M	Right-side retro-orbital pain	Mediastinal tissue	DLBCL	PSL 60 mg/day R-CHOP plus Intrathecal MTX	Died	(21)
80/F	Left-side visual loss, anorexia, headache, jaw claudication	(Autopsy)	DLBCL	MP 500 mg/day MTX	Died	(22)
63/M	Left-side temporal headache, eyelid ptosis, jaw claudication	Kidney	DLBCL	R-CHOP R-MA Intrathecal MTX/cytarabine/PSL	Recovered	Our case

M: male, F: female, DLBCL: diffuse large B-cell lymphoma, PSL: prednisolone, MTX: methotrexate, CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone, MR-CHOP: high-dose methotrexate with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, MP: methylprednisolone, R-MA: rituximab and high-dose methotrexate, and cytarabine, ND: not described

The gold-standard method for making the definitive diagnosis of GCA is a temporal artery biopsy (26,27). The classification criteria established by the American College of Rheumatology consist of 5 items: (1) onset at ≥50 years old (2) new-onset headache, (3) temporal artery tenderness or decreased palpability, (4) elevated ESR (≥50 mm/h), and (5) GCA-specific pathological features on a temporal artery biopsy (28). When ≥3 of these criteria are satisfied, the sensitivity for distinguishing GCA from other forms of vasculitis is high (93.5%), as is the specificity (91.2%) (28). The present patient met all four of the GCA classification criteria.

However, our patient had unexplained renal failure. Therefore, we deemed exclusion of other diseases necessary and performed FDG-PET/CT and a renal biopsy. Finally, we diagnosed the patient with DLBCL with a GCA-like manifestation.

In Japan, FDG-PET/CT is covered by health insurance for all malignant tumors, including malignant lymphoma, epilepsy, cardiac sarcoidosis, ischemic heart disease, and large-vessel vasculitis (GCA or Takayasu arteritis). In the current case, FDG-PET/CT was performed, and a high FDG accumulation was observed bilaterally in the kidneys, multiple bone lesions, and lymph nodes. FDG often accumulates more markedly in reticuloendothelial lesions in malignant lymphoma and in large- and medium-sized arterial lesions in GCA than in normal tissues (29). Therefore, FDG-PET/CT is useful for differentiating malignant lymphoma from GCA as well as for staging malignant lymphoma or visualizing GCA activity. In addition, high-resolution MRI with MR angiography (MRA) enables visualization of the temporal arteries and detection of mural edema using a contrast agent (30). A systematic review and meta-analysis comparing MRI findings to the clinical diagnosis of cranial GCA reported a sensitivity of 73% and specificity of 88% (31). Consequently, high-resolution MRI with MRA is regarded as an invaluable diagnostic tool for cranial GCA.

In conclusion, we encountered a case of DLBCL resembling GCA with multiple renal and bone infiltrations that was successfully treated with prompt and aggressive combination chemotherapy. DLBCL rarely but occasionally presents with GCA-like manifestations. Its early diagnosis and treatment using FDG-PET/CT and an appropriate biopsy are important for improving the disease prognosis.

Informed consent was obtained from the patient for publication of this case report.

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