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Clinical Case Report
1
Medicine®
Rectourethral fistula after external beam
radiotherapy for prostate cancer in a patient with
thromboangiitis obliterans
A case report
KeiichiOhira, MDa,* , KentaKonishi, MDa, ShuheiAramaki, MDa, RyoKokubo, MDa, KouheiWakabayashi, MDa,
MasanoriHirata, MDa, MichikoImai, MDb, KatsumasaNakamura, MD, PhDa
Abstract
Introduction: Thromboangiitis obliterans (TAO) is a rare disease of unknown cause that causes segmental vasculitis in peripheral
blood vessels. It is uncertain whether its presence causes serious adverse events in patients receiving external beam radiotherapy.
Patient concerns: A 73-year-old Japanese man with prostate cancer underwent external beam radiotherapy.
Diagnosis: After completion of radiotherapy, fingertip pain occurred, leading to the diagnosis of TAO.
Interventions: The patient was instructed to stop smoking, but was unable to do so.
Outcomes: Nine months after the completion of radiotherapy, fecaluria appeared, and a rectourethral fistula was diagnosed
by contrast enema. The patient’s TAO was poorly controlled, and the patient died from aspiration pneumonia 33 months after
completion of the radiotherapy regimen. No tumor recurrence was observed during this process, and there were no risk factors
other than TAO that may have formed a rectourethral fistula.
Lessons: This is the first report of rectourethral fistula caused by external beam radiotherapy for prostate cancer in which TAO
was suspected to be involved. Although little is known about the relationship between TAO and radiotherapy, it should be noted
that radiotherapy itself may increase the risk of normal tissue toxicity in patients with TAO.
Abbreviations: PSA = prostate-specific antigen, TAO = thromboangiitis obliterans.
Keywords: adverse event, prostate cancer, radiotherapy, rectourethral fistula, thromboangiitis obliterans
1. Introduction
Thromboangiitis obliterans (TAO) is a rare disease of unknown
cause that mainly causes segmental vasculitis in peripheral ves-
sels. It is characterized by a predilection for the arteries of the
lower extremities and is more common in men in their 20s
to 40s, especially in smokers. The most common symptoms
are coldness and paresthesia associated with peripheral isch-
emia in the extremities, but in rare cases, ischemia occurs in
visceral vessels. Serious adverse events of radiotherapy have
been reported in patients with vasculitis syndrome; however,
few such events have been reported in individuals with TAO.
We report a case of a patient with a rectourethral stula after
prostate cancer radiotherapy in which TAO was suspected to
be involved.
2. Case report
A 73-year-old Japanese man was referred to our hospital
because of a prostate-specic antigen (PSA) value of 837.8 ng/
mL, and was diagnosed with prostate cancer (clinical stage
T3aN0M0, Gleason score of 8). The patient’s medical history
was unremarkable. After 4 months of hormone therapy, radio-
therapy was performed with a total dose of 74 Gy in 37 frac-
tions for the prostate and the proximal part of the seminal
Funding: The authors did not receive any funding for this case report.
Consent for publication: Informed consent was not obtained from the patient
because he died and no relatives were available. Therefore, the institutional review
board of our hospital has owned the responsibility for the anonymization of the
patient, and the requirement for informed consent was waived.
The authors have no conflicts of interest to disclose.
Disclosure: Authors have no relevant financial or nonfinancial relationships to
disclose.
Declaration: This case report was conducted under the Declaration of Helsinki.
Disclaimer: I certify that the opinions expressed herein are only those of
the authors. They do not represent the official views of the aforementioned
institutions.
Data Access Statement: All data generated or analyzed during this study are included
in this article. Further inquiries can be directed to the corresponding author.
Ethics approval and consent to participate: This case report was written in
accordance with the ethical committee of Hamamatsu University School of Medicine.
Publication history: This manuscript was previously posted to Research Square:
doi: https://doi.org/10.21203/rs.3.rs-1464211/v1”.
a Department of Radiology, Hamamatsu University School of Medicine, Shizuoka,
Japan, b Department of Radiation Oncology, Iwata City Hospital, Shizuoka, Japan.
*Correspondence: Keiichi Ohira, Department of Radiology, Hamamatsu University
School of Medicine, Shizuoka, Japan (e-mail: ohiradon@hotmail.com).
Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the Creative Commons
Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
How to cite this article: Ohira K, Konishi K, Aramaki S, Kokubo R, WakabayashiK,
Hirata M, Imai M, Nakamura K. Rectourethral fistula after external beam
radiotherapy for prostate cancer in a patient with thromboangiitis obliterans:
acase report. Medicine 2022;101:34(e30343).
Received: 15 June 2022 / Accepted: 20 July 2022
http://dx.doi.org/10.1097/MD.0000000000030343
2
Ohira et al. • Medicine (2022) 101:34 Medicine
vesicles with volumetric modulated arc therapy (Fig.1). The
accumulated dose to the rectum and bladder were considered
to be acceptable within the dose constraints widely recom-
mended. No obvious adverse events were observed during
radiotherapy.
Two months after the completion of radiotherapy, he reported
experiencing pain in his ngertips and purpura at the ngertips.
A vascular surgeon diagnosed TAO on the basis of the patient’s
physical and computed tomography ndings. The patient was
instructed to stop smoking but was unable to do so.
Four months after the completion of radiotherapy, the
patient complained of discomfort in the anus. Lower endos-
copy revealed many ulcers on the anterior wall of the lower
rectum. Steroid suppositories were prescribed on the basis of
the diagnosis of radiation proctitis. However, the patient sub-
sequently experienced pain in the toes, and antiplatelet agents
and prostaglandin E1 were prescribed for this apparent exac-
erbation of TAO.
Nine months after the completion of radiotherapy, faecaluria
developed, and after the administration of a contrast enema,
a rectourethral stula was diagnosed (Fig.2). The stula was
treated with colostomy and cystostomy. The patient’s TAO was
poorly controlled, and his clinical status declined because of
ischemic necrosis of the toes. At 33 months after completion of
the radiotherapy regimen, the patient died of aspiration pneu-
monia. During this process, there were no ndings suggestive of
tumor recurrence, including PSA level.
3. Discussion
Thromboangiitis obliterans, also known as Buerger disease, is a
disease of unknown etiology that occurs mostly in young adult
men. TAO has been described as rare in Western Europe and the
United States but relatively common in Japan, Korea, Southeast
Asia, and the Middle East.[1] Although in some countries, the
prevalence of TAO has apparently been decreasing in recent
years. For example, the prevalence in Japan is now 7–10 cases
per million, which is almost the same as that in Western coun-
tries.[2] The initial symptoms of TAO are coldness, numbness,
and pain in the extremities. As the disease progresses, ulcers
and gangrene occur. It has been reported that >90% of TAO
patients have a history of smoking. Smoking cessation is effec-
tive in controlling disease progression, and smoking often leads
to progression.[2–6] The effects of TAO are most common in the
arteries of the extremities; however, lesions in visceral arteries
such as mesenteric arteries, renal arteries, coronary arteries, and
cerebral arteries have also been reported.[7–11]
There are no international criteria for TAO, but various diag-
nostic criteria have been proposed.[1,12] In Japan, Shiono clinical
criteria are often used: history of smoking, onset under the age
of 50, occlusive lesions beyond the popliteal artery, involve-
ment of the upper limb arteries or migratory phlebitis, and no
risk factors for atherosclerosis other than smoking.[13] It be
easily diagnosed if a patient meets all the 5 criteria. However,
in clinical practice, patients often meet only some of these cri-
teria. Therefore, when Shiono criteria are used, TAO can be
diagnosed if the patient’s clinical symptoms, vascular images,
and histopathology are consistent, and differential diagnoses
are ruled out.[14]
A rectourethral stula occurred in the present patient.
Rectourethral stula is a quite rare adverse event of radiother-
apy for prostate cancer, and has been reported to be caused by
brachytherapy for prostate cancer. Shakespeare et al assessed
1455 patients treated with brachytherapy or brachytherapy
combined with external beam radiotherapy to investigate the
incidence of rectourethral stulas, and they identied 3 (0.2%)
patients with rectourethral stulas,[15] whereas Zelefsky et al
evaluated rectal and urethral adverse events in 561 prostate can-
cer patients treated with 81 Gy intensity-modulated radiother-
apy.[16] Despite the relatively large number of patients, no grade
4 adverse events (including rectourethral stula) were observed.
To our knowledge, there have been no published reports on
Figure 1. Dose distributions in the axial slice (a) and sagittal slice (b). The isodose lines indicate the percentage of the prescribed dose of 74 Gy.
Figure 2. The fistula between the patient’s bladder and rectum, confirmed
by contrast enema.
3
Ohira et al. • Medicine (2022) 101:34 www.md-journal.com
rectourethral stulas induced by external beam radiotherapy
alone for prostate cancer.
We speculate that the patient’s TAO itself enhanced the
adverse events associated with radiotherapy. There is a case
report by Barkhuysen et al that may support this hypothe-
sis.[17] They reported severe radiation osteonecrosis follow-
ing radiotherapy for a squamous cell carcinoma of the soft
palate in a patient with TAO. They applied an accelerated
fractionation scheme with a total dose of 68 Gy given in 34
fractions, and grade 4 mucositis developed even at 28 Gy.
They also reported that intractable intraoral ulcers devel-
oped 1 month after radiotherapy, and maxillary bone expo-
sure and oral maxillary sinus fistulas developed 2 months
after radiotherapy. Although the total dose was not markedly
high, serious adverse events occurred from a relatively early
period, as in our patient’s case. Barkhuysen et al hypothe-
sized that normal tissues in TAO patients may have impaired
the ability to recover from radiation damage, and they noted
that autoantibodies such as anticollagen and antiendothe-
lial cell autoantibodies are expressed in TAO patients as evi-
dence of this.
There are scattered reports of adverse events associated with
radiotherapy in patients with vasculitis, particularly those asso-
ciated with collagen disease. Lin et al evaluated the adverse
events of radiotherapy in 73 patients with collagen vascular
diseases, and reported that all 73 patients had signicantly
more late adverse events and that the adverse events tended to
be more severe compared to controls.[18] Wo et al reviewed 3
case-controlled studies of 61, 38, and 36 cases and 1 retrospec-
tive study of 209 cases. They stated that there was no signicant
increased incidence of acute or late adverse events in the stud-
ies, but there was a trend toward more fatal late adverse events
such as necrosis and obstruction of the bowel, bladder necrosis,
and pericarditis.[19–23] Although the precise risk and frequency
of adverse events for collagen vascular diseases remain unclear,
when clinicians consider using radiotherapy for patients with
vasculitis, they should be aware that there can be a high risk
of increased adverse events, and caution should be exercised in
irradiating.
Regarding the potential mechanisms underlying such adverse
effects, it has been speculated that microvascular damage caused
by radiotherapy and collagen vascular disease might be addi-
tive.[24] If so, it cannot be denied that TAO, which similarly
produces thrombotic ischemia, may have the potential to cause
serious side effects in radiotherapy. Of course, the mechanisms
of vascular damage in TAO and other forms of vasculitis differ,
and it may thus not be possible to directly compare the mecha-
nisms. However, all these mechanisms have in common the fact
that inammation of blood vessels results in ischemia in the ves-
sels’ dominant regions, and if the reduction of blood ow due
to radiotherapy is combined with this, the recovery of normal
tissues may be hindered.
The lack of reports on adverse events after radiotherapy
in patients with TAO may be due to the rarity of this disease.
Further investigations and accumulation of case reports are
needed to establish the relationship between TAO and severe
adverse events after radiotherapy.
4. Conclusions
We report the case of an elderly male smoker with TAO who
developed a rectourethral stula induced by radiotherapy. When
patients with TAO are treated, oncologists should be aware of
the potential increased risk of normal tissue toxicity and follow
up carefully over the long term.
Acknowledgments
The authors would like to thank KN International and PaperPal
PreFlight service for English language editing.
Authors’ contributions
Conceptualization: Keiichi Ohira, Katsumasa Nakamura
Investigation: Keiichi Ohira, Kouhei Wakabayashi, Michiko Imai
Supervision: Keiichi Ohira, Katsumasa Nakamura, Michiko Imai
Visualization: Keiichi Ohira
Writing—original draft: Keiichi Ohira
Writing—review & editing: Keiichi Ohira, Kenta Konishi, Shuhei
Aramaki, Ryo Kokubo, Masanori Hirata, Katsumasa Nakamura.
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