Thromboangiitis obliterans, also known as Buerger's disease, is a disease of unknown aetiology 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]. 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 in Western countries [2]. The initial symptoms of TAO are coldness, numbness, and pain in the extremities, and as the disease progresses, ulcers and gangrene occur. It has been reported that >90% of patients with TAO have a history of smoking. Smoking cessation is effective in controlling the progression of the disease, and smoking often leads to progression [2–6]. The effects of TAO are most common in the arteries of the extremities, but 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 diagnostic criteria have been proposed [1, 12]. In Japan, Shiono's clinical criteria are often used: history of smoking, onset under age 50, occlusive lesions beyond the popliteal artery, involvement of the upper limb arteries or migratory phlebitis, and no risk factors for atherosclerosis other than smoking [13]. It is easy to diagnose TAO if a patient meets all five of these criteria. However, in actual clinical practice, a patient often meets only some of the criteria. Therefore, when Shiono's 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 fistula occurred in the present patient's case; a rectourethral fistula is a quite rare adverse event of radiotherapy 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 fistulas, and they identified three (0.2%) patients with rectourethral fistula [15]. Whereas Zelefsky et al. evaluated rectal and urethral adverse events in 561 prostate cancer patients treated with 81 Gy intensity-modulated radiotherapy [16], and despite this relatively large number of patients, no grade 4 adverse events (including rectourethral fistula) were observed. To our knowledge, there have been no published reports on a rectourethral fistula induced by external beam radiotherapy alone for prostate cancer.
We speculate that the patient's TAO itself enhanced the adverse events of radiotherapy. There is a case report by Barkhuysen et al. that may support this hypothesis [17]. They reported severe radiation osteonecrosis following radiotherapy for a squamous cell carcinoma of the soft palate in a TAO patient. They applied an accelerated fractionation scheme with a total dose of 68 Gy given in 34 fractions, and then grade 4 mucositis developed even at 28 Gy. They also reported that intractable intraoral ulcers developed 1 month after the radiotherapy, and maxillary bone exposure and oral maxillary sinus fistulas developed 2 months after the 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. hypothesized that normal tissues in TAO patients may have impaired the ability to recover from radiation damage, and they noted that autoantibodies such as anti-collagen and anti-endothelial cell autoantibodies are expressed in TAO patients as evidence of this.
There are scattered reports of adverse events associated with radiotherapy for patients with vasculitis, especially associated 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 significantly more late adverse events and that the adverse events tended to be more severe compared to controls [18]. Wo et al. reviewed three case-controlled studies of 61, 38, and 36 cases and one retrospective study of 209 cases. They stated that there was no significant increased incidence of acute or late adverse events in the studies, 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 the adverse effects, it has been speculated that the microvascular damage caused by radiotherapy and collagen vascular disease might be additive [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 make direct comparisons of the mechanisms. However, these mechanisms all have in common the fact that inflammation of blood vessels results in ischemia in the vessels' dominant regions, and if the reduction of blood flow due to radiotherapy is combined with this, the recovery of normal tissues may be hindered.
The lack of reports of adverse events after radiotherapy in TAO patients may be due to the rarity of this disease. Further investigations and the accumulation of case reports are needed to establish the relationship between TAO and severe adverse events after radiotherapy.