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CASE REPORT
Osteolytic primary bone lymphoma in the multiple bones
Shusuke Yagi1,2,3, Robert Zheng1, Seiichi Nishiyama3, Yutaka Kawabata1, Takayuki Ise1, Kosuke Sugiura4,Haruhiko Yoshinari4, Toshihiko Nishisho4, Yoshimi Bando5, Kumiko Kagawa6, Daiju Fukuda1, Tomohiro Soga2,3,7,
Yoshihito Saijo1, Kenya Kusunose1, Koji Yamaguchi1, Hirotsugu Yamada1, Takeshi Soeki1, Tetsuzo Wakatsuki1,Shinji Kawahito2,3,7, Masashi Akaike8, and Masataka Sata1
1
Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan, 2Department ofCommunity Medicine and Human Resource Development, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan,3Shikoku Central Hospital, Ehime, Japan, 4Department of Orthopedic Surgery, Tokushima University Graduate School of Biomedical Sciences,Tokushima, Japan, 5Division of Pathology, Tokushima University Hospital, Tokushima, Japan, 6Department of Hematology, Endocrinology andMetabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan, 7Department of Anesthesiology, Tokushima
University Graduate School of Biomedical Sciences, Tokushima, Japan, 8Department of Medical Education, Tokushima University Graduate
School of Biomedical Sciences, Tokushima, Japan

Abstract : Primary non-Hodgkin bone lymphoma (PBL) can involve solitary or multiple destructive bone lesions
such as those of the femur or pelvis humerus, and some cases have osteolytic lesions. PBL is a rare disease inadults. Thus, PBL is rarely considered a differential diagnosis of the osteolytic tumor. In addition, PBL can be underdiagnosed because patients do not experience symptoms or show objective abnormalities in the early stage.
Here, we reported an elderly patient with PBL in multiple bones, including the cranial and femoral bones thatwere fractured due to falling. J. Med. Invest. 66 : 347-350, August, 2019
Keywords : diffuse large B-cell lymphoma, head tumor, differential diagnosis

INTRODUCTION
Primary non-Hodgkin bone lymphoma (PBL) is a rare disease that accounts for < 2% of all lymphomas in adults (1). PBL
is estimated to account for 3%–7% of primary bone tumors and3%–5% of all extranodal non-Hodgkin lymphomas (2). PBL caninvolve solitary or multiple destructive bone lesions such asthose of the femur or pelvis humerus, and some cases have osteolytic lesions. However, PBL in the cranial vault is extremelyrare (3). PBL is rarely considered a differential diagnosis of theosteolytic tumor. PBL, especially diffuse large B-cell lymphoma (DLBCL), exhibits a better response rate for therapy andbetter prognosis if treated early with chemotherapy or radiotherapy than primary nodal or extranodal DLBCL at othersites (4). Thus, accurate early diagnosis is crucial for treatment.
However, PBL can be underdiagnosed because patients do notexperience symptoms or show objective abnormalities in theearly stage.
Here, we reported an elderly patient with PBL in multiple
bones, including the cranial and femoral bones that were fractured due to falling.

CASE
An 89-year-old woman presented to our hospital because ofpain in her right hip after falling. She had severe aortic valve
stenosis without symptoms. No abnormal neurological and objective findings on the head were noted. Computed tomography(CT) revealed that her right femoral shaft was completely broken
Received for publication January 29, 2019 ; accepted May 26, 2019.
Address correspondence and reprint requests to Shusuke Yagi, MD,PhD, Department of Cardiovascular Medicine, Tokushima University
Graduate School of Biomedical Sciences, Tokushima, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan and Fax : +81-88-633-7894.

and that her thin bone cortex was filled with a high-intensity
tumor at the site of fracture ; osteolytic tumors were also notedin the bilateral scapula and lumbar spine bones (Figure 1A, B,C, D, E). Whole-body bone scintigram showed accumulation oftechnetium-99m-methylene-diphosphonate (MDP) in the head,shoulders, lumbar spine bones, and right femur (Figure 1F) ; thisindicated that the fracture in her fragile femur was a pathological fracture caused by tumor invasion and induced by the trauma
of falling. She received skeletal traction of the right leg, followed
by transcatheter aortic valve implantation before the operationof the fracture, which was successful. Her broken femoral shaft
was fixed with a nail device. After the operation for the fracture,
she experienced drowsiness without any focal neurological signs.
Head CT showed an osteolytic tumor on the right temporal andleft back of the head (Figure 2 A, B, C, D). The head tumor was
mildly tender and overlaid by healthy skin. T1- (Figure 2E) andT2-weighted (Figure 2F) magnetic resonance images showed
iso-intensity and low intensity of the tumor, respectively, andthe dura structure was maintained. A CT image of the wholebody showed neither lymphadenopathy nor any evidence of systemic involvement and pathological fracture. Blood examination
results revealed elevated ALP, LDH, and soluble interleukin-2receptor levels at 423 IU/L, 400 IU/L, and 5490 U/mL (upperlimit < 519 pmol/L), respectively. Decreased serum total protein
and albumin levels of 5.9 g/dL and 2.9 g/dL, respectively, werenoted, with no M-protein (IgG 903 mg/dL, IgA 200 mg/dL, IgM
38 mg/dL, kappa 18 mg/dL, or lamda 78 mg/dL). No monoclonalprotein was detected by protein electrophoresis of the serum andurine. Normocalcemia (albumin-adjusted calcium 9.6 mg/dL)
with increased parathyroid hormone-related protein-C levels at6.5 pmol/L (upper limit < 1.1 pmol/L) were also noted. Increasedbone markers of type I collagen carboxyterminal telopeptide(ICTP) of 20 ng/mL (upper limit < 4.5 ng/mL), tartrate-resistantacid phosphatase isoform 5b (TRACP 5b) of 534 mU/dL (upperlimit 420 mU/dL), and urinary deoxypyridinoline of 79 nmol/mM・creatinine (upper limit < 7.6 nmol/mM・creatinine) weredetected, although bone-APL was within normal limits of 20.3

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S. Yagi, et al. Osteolytic bone lymphoma

Figure 1. Computed tomography showing fracture of the right femoral shaft (A : arrow), the thin bone cortex (B : arrow)filled with a high-intensity tumor (C : arrow) at the fracture site, and osteolytic tumors in the bilateral scapula (D: arrow)and lumbar spine bones (E : arrow). Whole-body bone scintigram showing accumulation of technetium-99m-methylenediphosphonate in the head, shoulders, lumbar spine bones, and right femur (F).

Figure 2. Computed tomography showing osteolytic tumors in the right temporal bone, left occipital bone (A, B, C), andsphenoid bone (D : arrow). T1-weighted (E) and T2-weighted magnetic resonance imaging (F) showing iso-intensity and low
intensity of the tumor, respectively.

The Journal of Medical Investigation Vol. 66 August 2019
μg/L (upper limit < 22.6 μg/L). Serological test results werenegative for Epstein-Barr (EB) virus early antigen (EBEA) antibody (IgG) and anti-viral capsid antigen (VCA) IgM and werepositive for EB virus nuclear antigen IgG and anti-VCA IgG,
indicating that the patient was infected with EB virus, although
PCR of EB virus-DNA with the peripheral blood sample was
not performed. Biopsy of the right temporal soft tissue revealed
diffuse growth pattern with large cells (Figure 3A) and positivity for CD20 (Figure 3B), a B-cell marker ; B-cell lymphoma 2(BCL-2), an anti-apoptosis factor regulating B-cell development
and differentiation (Figure 3C). Furthermore, multiple myeloma
oncogene 1 (MUM-1) (Figure 3D) and negativity for CD3, CD5,CD10, CD30, and PD-L1 were noted. The tumor cells included
Ki-67-positive cells with a Ki labeling index of 80% (Figure 3E),indicating highly proliferative potential. In situ hybridizationof small RNAs of EB virus showed positive cells for EB virus
infection (Figure 3F). Bone marrow aspiration and bone marrow biopsy were not performed. The lesion was localized in thebones ; thus, we diagnosed her as having PBL of EBV-positive
DLBCL of the elderly. Clinical stage of the patient was IV EB
with a B-symptom of weight loss. The international prognostic
index was 5, indicating a high risk. The best supportive carerather than chemotherapy or radiation therapy was selected, andher general condition worsened after the successful operationof the femoral fracture. The level of ALP increased to 661 IU/L
from 571 IU/L during the course, indicating progression of bonedisease. She died 9 weeks after admission.

349

DISCUSSION
The differential diagnosis of the osteolytic lesion includes
secondary bone involvement of the systemic lymphoma, bonemetastasis from neoplasm, and multiple myeloma. The patient
was infected with EB virus, and thus, the differential diagnosisof EB-related malignancy also included Hodgkin lymphoma andBurkitt lymphoma. Imaging studies, including CT and scintigraphy, revealed no primary lesion of the malignant tumor, andblood examination and results showed no evidence of multiple
myeloma. In addition, tumor cells were negative for CD138, indicating no differentiation of plasma cells. Immunohistochemistry
for light chain kappa and lambda staining showed no dominancy
for either immunoglobulin. Thus, we excluded CD20-positive
myeloma. Histopathological analysis showed no presence ofReed-Sternberg cells and no appearance of a “starry-sky” pattern. Immunophenotype analysis distinguished DLBCL from
Hodgkin lymphoma and Burkitt lymphoma. Thus, we diagnosed
her as PBL of EBV-positive DLBCL of the elderly.
T2-weighted MR imaging characteristics of primary lymphoma of bone vary and do not seem to be a simple reflection ofhistologic findings of lymphoma (5). In this case, the intensity oftumorous lesions was low in T2-weighted MRI. MRI of DLBCLwith a high nuclear/cytoplasm ratio and hypercellularity could
cause decreased extracellular fluid concentration and small
intratumoral edema which results in low signal on t2-weighted
images (6).
The precise mechanism of osteolysis remains unclear ; however, the increased expression of osteoclast-activating factors,

Figure 3. Hematoxylin and eosin staining (A) of the biopsy obtained from the head tumor showing diffuse growth
patterns with large cells. Immunohistochemical analysis showing positive results for CD20 (B), BCL-2 (C), MUM-1 (D),and high Ki-67 labeling index (E). In situ hybridization of the small RNAs of EB virus showing positive cells for EB
virus infection (F) (Barr : 100 µm).

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S. Yagi, et al. Osteolytic bone lymphoma

including MIP-1α, MIP-1β, and RANKL, was observed in theRNA derived from the patient’s lymphoma cells. In addition,
increased protein levels of RANKL and osteoprotegerin, a key
regulator of osteoclastogenesis, from the patient’s lymphoma
cells were sharply decreased after the chemotherapy (7, 8). Thus,
the secretion of osteoclast-activating factors by tumor cells (and/or bone marrow stromal cells) might be involved in the mechanism of osteolysis in some malignant lymphoma cases (9).
Anthracycline-based chemotherapy and radiation therapy arerecommended for treating PBL (4). The destructive bone involvement in the cranial vault could be regenerated after therapy(10). However, we did not recommend such aggressive therapies,
but suggested best supportive care to our patient because of her
older age.
The prognosis of PBL is relatively better than that of otherlymphoma types (4). Patients with advanced-stage DLBCL andskeletal involvement show a 65% complete remission rate (11),with 5-year progression-free and overall survival rates of 54%
and 59%, respectively (12), and bone involvement does not seemto be an adverse prognostic factor (4). However, her general condition progressively worsened after the operation of the fracture.
High proliferative potentials with high Ki-67 labeling index
might be involved in her progressive poor general condition,
which was different from gradual proliferative tumors, such as
multiple myeloma.
Although the patient visited several clinics for medical problems, including common cold and aortic valve stenosis, the headtumor was not detected. Furthermore, PBL can be underdiagnosed because skull tumors may be covered by hair. Little
symptoms are exhibited because the dura structure was maintained and brain invasion by the tumor is rare (13). Thus, carefulinspection and palpation of the head, especially during the firstvisit, are essential even when patients have no head complaints
in order to make an early diagnosis. In addition, osteolytic PBL
should be included as a differential diagnosis in cases of femoral
shaft fractures, even if these fractures occur after falling.

CONFLICT OF INTEREST
The authors have no conflicts of interest to disclose.

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