Advances in Molecular Imaging, 2011, 1, 12-15
doi:10.4236/ami.2011.11002 Published Online April 2011 (http://www.SciRP.o rg/journal/ami)
Copyright © 2011 SciRes . AMI
Incidental Uptake of In-111 Ibritumomab Tiuxetan in
Surgically Tre ated Fracture
Hidenari Hirata1, Makoto Nakagawa1, Koichiro Abe2, Takashi Okafuji1, Kenji Shinozaki1,
Ilseung Choi3, Naokuni Uike3, Shuji Sakai1
1Department of Radiology, National Kyushu Cancer Center, Fukuoka, Japan
2Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu Universit y, Fukuoka, Japan
3Department of Hematology, National Kyushu Cancer Center, Fukuoka, Japan
Received March 5, 2011; Revised April 5, 2011; Accepted April 30, 2011
In-111 ibritumomab tiuxetan pretherapy imaging is performed prior to radioimmunotherapy with Y-90 ibri-
tumomab tiuxetan in patients with lymphoma in order to estimate the biodistribution of the radiolabeled an-
tibodies. We report the case of a 61-year-old woman with relapsed follicular lymphoma. In-111 ibritumomab
tiuxetan pretherapy imaging showed tracer accumulation in a surgically treated fracture of the left calcaneus
as well as in the involved lesions. The patient had fractured her left calcaneus 6 months before the radioim-
munotherapy, and fracture of the left calcaneus without lymphoma involvement had been revealed opera-
tively at that time. Clinical features and magnetic resonance imaging (MRI) indicated an inflammatory re-
sponse in the left heel. We concluded that this inflammation played an important role in the uptake on pre-
therapy imaging. It should be kept in mind that the inflammation is a differential diagnosis of lymphoma in-
volvement in In-111 ibritumomab tiuxetan pretherapy imaging. To the best of our knowledge, this is the first
case report of In-111 ibritumomab tiuxetan uptake in a surgically treated fracture.
Keywords: In-111, Ibritumomab, Fracture, Lymphoma
1. Introduction
In January 2008, radioimmunotherapy with Y-90 ibritu-
momab tiu xeta n was a ppr ove d in J apa n. T his is a n ef fec-
tive treatment for refractory or relapsed non-Hodgkin’s
lymphoma [1]. It is composed of a radionuclide conju-
gated to the monoclonal antibody targeting CD20 on the
surface of lymphocytes. The beta emission from Y-90
induces cellular damage in the target. In ad dition to that,
radiation damage can be achieved in neighboring cells
that not express the antigen or that compose poorly vas-
cularized bulky tumors. The main toxicity is myelosup-
pression. In order to predict toxicities, estimating the
biodistribution of the radiolabeled antibodies is impor-
tant. The gamma emitter In-111-labeled ibritumomab
tiuxetan is generally administered prior to the pure beta
emitter Y-90-labeled ibritumomab tiuxetan because of
the impossibility of obtaining a drug distribution image
by the beta emitter. Patients with altered biodistribution
(e.g. prominent bone marrow uptake) on In-111 ibritu-
momab tiuxetan pretherapy imaging cannot receive Y-90
ibritumomab tiuxetan.
Here we report a patient who underwent radioimmu-
notherapy with Y-90 ibritumomab tiuxetan for relapsed
follicular lymphoma. In this patient, pretherapy imaging
using In-111 ibritumomab tiuxetan demonstrated uptake
not only in the involved lesions, but also in a surgically
treated fracture. To the best of our knowledge, this is the
first case report of In-111 ibritumomab tiuxetan uptake
in a surgically treated fracture.
2. Case Report
A 61-year-old woman was diagnosed with stage IVA
follicular lymphoma, and complete remission was at-
tained after eight cycles of R-CHOP (rituximab, cyclo-
phosphamide, doxorubicin, vincristine, and prednisolone)
chemotherapy in another hospital. Four years after fi-
nishing R-CHOP chemotherapy, computed tomography
(CT) demonstrated enlargement of her mesenteric and
left internal iliac lymph nodes. During a 5-month “wait-
and-see” period, CT showed an increase in the size of
Copyright © 2011 SciRes . AMI
these l ymph no des. Finall y, she was ad mitted to our ho s-
pital to receive radioimmunotherapy with Y-90 ibritu-
momab tiuxetan. Laboratory data on admission (Tab le 1 )
including common blood count and blood chemistry
were within normal limits except that the serum level of
solub le i nte rl e uki n -2 receptor ( sI L2 R) was 639 U/ml (the
upper normal limit is 570 U/ml). F-18 fluorodeoxyglu-
cose (FDG) positron emission tomography (PET)/CT
performed on the whole-body, except below the knees,
showed abnormal uptake in the paraaortic, mesenteric,
and left iliac lymph nodes. The maximal standardized
uptake value (SUV max) among these lymph nodes was
Initially, she received rituximab at a dose of 250
mg/ m 2 t o pr event In -111 labeled antibodies from binding
to the CD20 antigens of normal B cells [2]. Subsequently,
In-111 ibritumomab tiuxetan at a dose of 130MBq (the
radiochemical purity was 98.8%) was administered in
order to determine the indication of radioimmunotherapy
with Y-90 ibritumomab tiuxetan. Whole-body anterior
and posterior gamma camera scans were obtained at 48
hours after injection. These images demonstrated tracer
accumulation in the paraaortic, mesenteric, and left iliac
lesions compatible with the relapse of lymphoma dem-
onstrated on the PET/CT. Furthermore, there was tracer
accumulation in the left heel (Figure 1(a)). These find-
ings on 48-hour images were same as those on 72-hour
images obtained to assess tracer accumulation in the left
heel (Figure 1(b)). She complained of chronic left heel
pain on admission because she had missed a step and
fractured her left calcaneus 6 months prior to admission.
Radiograph on admission had demonstrated a faint scle-
rotic band in the fracture site. MRI was performed sub-
sequently to confirm the cause of uptake in the left heel.
Fat-suppressed T2-weighted MR images showed a hy-
pointense line of the left calcaneus coincident with the
fracture line, which was surrounded by an ill-defined
high -s i g na l-intensity area (Figure 2). These findings
represent the fracture associated with bone marrow ede-
ma and suggested an inflammatory response at the bone
fracture site [3]. Moreover, the surgical treatment per-
formed following the fracture revealed that there was no
lymphomatous tis sue there. Thus, we concluded t hat up-
take i n the le ft heel o n In-111 ibritumomab tiuxetan pre-
therapy imaging represented a surgically treated fracture
with chronic inflammation. Radioimmunotherapy with
Y-90 ibritumomab tiuxetan was performed 7 days fol-
lo wing i nje ctio n of I n-111 ibritumomab tiuxetan, and the
patient was discharged without any adverse reactions.
PET/CT obtained 9 weeks after injection of Y-90 ibri-
tumomab tiuxetan demonstrated that complete remission
was achieved. Her left heel pain improved gradually. She
had no pain as of 4 months after radioimmunotherapy.
Table 1. L ab orat ory data on ad miss io n
WBC 4430 /μl LDH 189 IU/l
neutro 73.0% CRP 0.07 mg/dl
lymph 24.0% sIL2R 639 U/ml
momo 2.0%
RBC 389 × 104/μl
Ht 35. 9%
Hb 12.1 g/dl
Plt 1 8. 4 × 10 4/μl
Figure 1. Whole-body anterior and posterior gamma cam-
era scans at 48 h (a) and 72 h (b) after administration of
In-111 ibritumomab tiuxetan show uptake in the left heel
(arrows) in addition to that in the paraaortic, mesenteric,
and le ft i liac lesi on s, a nd t hese fi nding s are co mpat ibl e w ith
the relapse of lymphoma demonstrated on the PET/CT.
Copyright © 2011 SciRes . A MI
Figure 2. A sagittal fat-suppressed T2-weighted MR image
clearly depicts a hypointense line of the left cal caneus coin-
cident with the fracture line (arr o w), w hich was surrounded
by an ill-defined high-signal-intensity area. These findings
represent the surgically treated fracture associated with
bone marrow edema and suggested an inflammatory re-
sponse at the bone fracture site.
3. Discussion
We present here a case in which In-111 ibritumomab
tiuxetan accumulated in a surgically treated fracture
where inflammatory response was suspected to be per-
sistent. To the best of our knowledge, there has been no
report which showed In-111 ibritumomab tiuxetan up-
take i n in fl ammato ry sites during ra dio immu not herapy.
The mechanism of In-111 ibritumomab tiuxetan ac-
cumulation at the inflammatory site is still unknown.
However, one possible explanation would be that this
accumulation is due to the nonspecific accumulation of
In-111 labeled antibody at the inflammatory site. Wegener
et al. demonstrated that In-111 labeled nonspecific po-
lyclonal immunoglobulin (IgG) scintigraphy is useful for
detecting infla mmator y and infectiou s foci [4] . However,
the exact mechanism of the uptake of In-111 labeled
human nonspecific IgG in inflammatory foci remains to
be clarified.
Another possibility might be that the accumulation of
In-111 ibritumomab tiuxetan is caused by accumulation
of fr ee In-111 in the inflammatory site. Indeed, there are
a few descriptions of In-111 chloride uptake in both in-
fected and noninfected ununited fracture sites [5,6], and
in other inflammatory conditions such as abscess [7]. In
the radiolabeling process of In-111 ibritumomab tiuxetan,
small amounts of free In-111 chloride might dissociate
from anti-CD20 antibodies. Moreover, Claessens et al.
reported that local retention of free In-111 in the in-
flammatory foci after dissociation from IgG was the
most probable mechanism of In-111 labeled nonspecific
polyclonal IgG uptake at the inflammatory site [8].
However, almost all free In-111 chloride should have
bound to the diethylenetriaminepentaacetic acid (DTPA)
included in the provided formulation buffer and then
been excreted in the urine immediately after injection [9].
In addition, In-111 labeled antibodies are thought to be
quite stable. Chinn PC et al. indicated that the average
loss of Y -90 from the conjugate was 1% per day in the in
vitro stabilit y o f Y-90 ibritumomab tiuxetan at 37˚C [10],
although the in vivo stability of In-111 ibritumomab
tiuxetan has not been reported. Therefore, the amount of
free In-111 chloride present would seem to be negligible.
We also suspected that the inflammatory response in-
creased vascular permeability in the left heel and pro
moted the uptake there. To assess the increased blood
flow in the left heel, whole-body anterior and posterior
images were obtained at 72 hours after administration of
In-111 ibritumomab tiuxetan. Although the radioactivity
of mediastinal blood pool weakened on 72-hour images,
tracer accumulation in the left heel on 72-hour images
was the same as that on 48-hour i ma ges (Figure 1(a) and
(b)). This indicated that uptake in the left heel was not
merely a result of the increase of the blood pool.
The possibility of lymphoma involvement in the left
calcaneus fracture site cannot be completely denied.
However, the clinical course and MRI findings were
compatible with inflammatory response. Moreover, the
surgical approach had already revealed a fracture of the
left calcaneus without involvement of lymphoma, al-
though it was 6 months before the radioimmunotherapy.
Biopsy of the left calcaneus would not be useful, since
the presence or absence of lymphoma would not affect
the decision to perform radioimmunotherapy. If whole-
body PET/CT including the tips of the toes had been
performed on admission, it might have demonstrated
uptake in the left heel. However, it would be quite diffi-
cult to differentiate an inflammatory response from in-
volvement of lymphoma o n PET/CT.
In conclusion, we experienced a case in which In-111
ibritumomab tiuxetan was accumulated in the inflamma-
tory site following the surgical treatment of fracture.
When we encountered unusual or unexpected uptake in
In-111 ibritumomab tiuxetan pretherapy imaging, it
should be kep t in mind that inflammation is a differe ntial
diagnosis of lymphoma involvement.
4. Referen ces
[1] K. Tobinai, T. Watanabe, M. Ogura, Y. Morishima, T.
Copyright © 2011 SciRes . AMI
Hotta, K. Ishizawa, K. Itoh, S. Okamoto, M. Taniwaki, N.
Tsukamoto, H. Okumura, T. Terauchi, S. Nawano, M.
Matsusako, Y. Matsuno, S. Nakamura, S. Mori, Y. Oha-
shi, M. Hayashi and K. Endo, “Japanese Phase II Study
of 90Y-Ibritumomab Tiuxetan in Patients with Relapsed
or Refractory Indolent B-Cell Lymphoma,” Cancer
Scien ce, Vol. 100, No. 1, 2009, pp. 158-164.
[2] S. J. Knox, M. L. Goris, K. Trisler, R. Negrin, T. Davis,
T. M. Liles, A. Grillo-López, P. Chinn, C. Varns, S. C.
Ning, S. Fowler, N. Deb, M. Becker, C. Marquez and R.
Levy, “Yttrium-90-Labeled Anti-CD20 Monoclonal An-
tibody Therapy of Recurrent B-Cell Lymphoma,” Clini-
cal Can cer Research , Vol. 2, No. 3, 1996, pp. 457-470.
[3] J. A. Narváez, J. Narváez, R. Ortega, C. Aguilera, A.
Sánch ez and E. And ía, “Pain ful Heel: MR Imaging Find-
ings,” Radiographics, Vol. 20, No. 2, 2000, pp. 333-352.
[4] W. A. Wegener, M. G. Velchik, D. Weiss, S. Ter, A.
Byars, M. Neptune and A. Alavi, “Infectious Imaging
with Indium-111-Labeled Non specific Polyclon al Human
Immunoglobulin,” The Journal of Nuclear Medicine, Vol.
32, No. 11, 1991, pp. 2079-2085.
[5] B. A. Sayle, H . D . F awcet t , W. M . Yud t , S . C . Wan g, J. T.
Mader an d G. Cierny 3rd, “Indium-111 Chloride Imaging
with Ununited Fractures,Clinical Nuclear Medicine,
Vol. 12, No. 3, 1987 , pp. 20 8-209.
[6] H. Oht a, “In-111 Chloride Uptake in Ununited Fractures:
A Case Report,” Kaku Igaku (Japanese Journal of Nuc-
lear Med icine), Vol. 37, No. 2, 20 00, pp. 121-124.
[7] B. A. S ayle, S. B alachand ran an d C. A. Rogers, “Indium-
111 Chloride Imaging in Patients with Suspected Ab-
scesses: Concise Communication,” The Journal of Nuc-
lear Med icine, Vol. 24, No. 12, 1983, pp. 1114-1118.
[8] R. A. Claessens, E. B. Koenders, O. C. Boerman, W. J.
Oyen, G. F. Bor m, J. W. van d er Meer an d F. H. Corstens,
Dissociation of Indium from Indium-111-Labelled Die-
thylene Triamine Penta-Acetic Acid Conjugated Non-
Specific Polyclonal Human Immunoglobulin G in In-
flammatory Foci,” European Journal of Nuclear Medi-
cine, Vol. 22, No. 3, 1995, pp. 212-219.
[9] M. Cremonesi, M. Ferrari, C. M. Grana, A. Vanazzi, M.
Stabin, M. Bartolomei, S. Papi, G. Prisco, G. Martinelli,
G. Paganelli and P. F. Ferrucci, “High-Dose Radioim-
munotherapy with 90Y-Ibritumomab Tiuxetan: Compara-
tive Dosimetric Study for Tailored Treatment,” The
Journal of Nuclear Medicine, Vol. 48, No. 11, 2007, pp.
1871-1879. doi:10.2967/jnumed.107.044016
[10] P. C. Chinn, J. E. Leonard, J. Rosenberg, N. Hanna and D.
R. Anderson, “Preclinical Evaluation of 90Y-Labeled
Anti-CD20 Monoclonal Antibody for Treatment of
Non-Hodgkin ’s Lymphoma,” International Journal of
Oncology, Vol. 15, No. 5, 1999, pp. 1017-1025.