Successful Treatment of Malignant Priapism by Radiotherapy: Report of a Case, Review of the Literature, and Treatment Recommendations

Malignant priapism is a condition of painful induration and erection of the penis secondary to metastatic infiltration by a neoplasm. This condition is associated with a poor prognosis. We report on a case of an 87-year-old man who presented with a painful, partially erected penis subsequent to a diagnosis of metastatic Gleason 4+5 prostate cancer. Magnetic resonance imaging (MRI) showed diffuse bilateral infiltration of his corpora cavernosa. The core biopsy of the penile nodule revealed it to be a poorly differentiated carcinoma consistent with prostatic origin. The patient’s symptoms were completely resolved after treatment with high-dose palliative conformal radiotherapy (40Gy in 16 fractions). We systemically reviewed clinical reports of palliative radiotherapy for malignant priapism with the aim to gain more information on the management of this rare condition.


Introduction
Penile metastasis is a rare phenomenon, first described in 1870 by Eberth. Since then, about 460 cases have been reported in the literature [1][2][3]. The most common causes of this condition are genitourinary (especially prostate and bladder primaries) and recto-sigmoid primary malignancies [4]. About 20-30% of patients with penile metastasis reported in the literature presented with priapism [5][6]. Malignant priapism is a condition of painful induration and erection of the penis secondary to metastatic infiltration by a neoplasm. Here, we describe a case of malignant priapism secondary to prostate adenocarcinoma. The patient achieved longlasting symptomatic relief after receiving high-dose palliative radiotherapy to the penis.

Case Presentation
An 87-year-old man with metastatic prostate adenocarcinoma presented with painful and persistent partially erected penis He was previously diagnosed with prostate cancer in 1998 with a prostate-specific antigen (PSA) of 70 µg/L and T3 disease. It was unclear if he had metastatic disease at the time of diagnosis, The patient had been continuously treated with hormonal therapy since his initial diagnosis of prostate cancer. Upon presentation, the patient had low volume bony disease on the seventh cervical spine, first thoracic spine, left femur, and right tibia on a whole-body bone scan. We instituted treatment with leuprorelin and bicalutamide. The patient's PSA was reduced to 0.75 µg/L. Figure 1 shows the magnetic resonance imaging (MRI) scan. 1 2 3 3, 4 3, 4 Immunohistochemistry showed tumor cells with positive staining for CK7 and CK20 ( Figure 2, panel B), as well as very focal positive staining for PSMA ( Figure 2, panel C). GATA3, CK5/6, p63, and PSA stains returned negative. Whilst the presence of staining for CK7 and CK20 is unusual for prostatic adenocarcinoma, a previous prostatic biopsy had shown a similar immunohistochemical staining profile (i.e. with positive staining for CK7, CK20, PSMA, PSAP, and focal staining for PSA); hence, the penile mass biopsy was favored to be metastatic prostatic adenocarcinoma.
The patient had previously received high-dose palliative radiotherapy to the prostate primary (60Gy in 30 fractions). The patient remained to have good performance status. Therefore, we chose to use volumetric modulated arc therapy (VMAT) to deliver moderately hypofractionated high-dose radiotherapy to the penis with the aim to reduce damage to normal pelvic tissue. The patient was treated in a supine position with a 1 cm bolus administered to the penis. The air gap was filled with wet gauze. We initially planned to deliver doses up to 50Gy in 20 fractions. The radiation dosimetry is shown in Figure 3. The dose-volume histogram (DVH) of the current plan is shown in Figure 4, panel A.

FIGURE 4: Dose-volume histogram (DVH) of bladder and rectum
A) The current course of radiotherapy. B) Combined DVH of the current plan with previous pelvic radiotherapy.
The bladder and rectum received a very low dose wash. The combined DVH of the bladder and rectum from two courses of pelvic radiotherapy is shown in Figure 4, panel B. Both the bladder and rectum met the dose constraints as per our departmental policy. Daily cone-beam CTs were used for treatment setup verification. However, the patient developed a grade 3 skin reaction of the penis and thus treatment was ceased at 40Gy.
The patient achieved complete symptomatic relief and acute skin toxicity was resolved at two months postradiotherapy. The patient was switched to androgen depression therapy with abiraterone. At nine months post-radiotherapy, his PSA remains at a low level (0.13 µg/L). He remains symptom-free and maintains excellent urinary function. He further reports a good quality of life at nine months post-radiotherapy.

Discussion
We carried out a structured literature search regarding malignant priapism and its treatment. The search was limited to English language literature available on the MEDLINE database and to case reports occurring between January 1940 and December 2018. The search terms included priapism, penile, metastasis, radiotherapy, and radiation.
We identified 42 cases reports of malignant priapism secondary to prostate adenocarcinoma, urothelial carcinoma, renal cell carcinoma, rectal adenocarcinoma, caecal carcinoma, oesophageal carcinoma, nonsmall cell lung cancer, chondrosarcoma, chordoma, melanoma, and lymphoma ( Table 1).  The details of the reviewed case reports are described in Table 2.   Malignant priapism is a rare phenomenon with a poor prognosis [5]. It is unlikely a large prospective study for this condition will be conducted, therefore, management of this condition remains challenging. We reported a case of malignant priapism, secondary to prostate adenocarcinoma, which was successfully treated with high-dose palliative radiotherapy (40Gy in 16 fractions using the VMAT technique). We report that the patient achieved long-lasting symptomatic relief, and the acute toxicity from high-dose palliative radiotherapy was tolerable.

Primary Histopathology
There has been significant improvement in outcomes in patients with metastatic prostate cancer owing to advances in systemic androgen deprivation therapies [46]. However, androgen blockage does not address local symptoms, unlike radiotherapy. There are 13 case reports of malignant priapism secondary to prostate adenocarcinoma, among whom five patients received palliative radiotherapy for priapism symptoms ( Table  1). All the patients received concurrent hormonal therapy ( Table 2). Unfortunately, only two case reports included brief descriptions of radiation dose fractionation [12][13]. Local symptom control was achieved by administering 35Gy in 14 fractions using the 3D conformal technique [12] to the penis in one case and 40Gy in the other report (fractionation and technique were not described) [13]. Similarly, it has been reported that complete relief pain and priapism can be achieved by locally administering 30Gy in 10 fractions in metastatic bladder urothelial carcinoma [21] and metastatic rectal adenocarcinoma [32] using the 3D conformal technique. On the contrary, priapism symptoms were only partially relieved in earlier case reports [20,28], even with a higher dose (56Gy) [20]. To reconcile the results, it is plausible that the modern conformal radiotherapy technique is better than the field-based technique in terms of ensuring coverage of target and avoiding hotspots or high doses to the organs at risk given the palliative nature of the treatment.
Various doses and fractionations have been reported in the successful treatment of even rarer causes of secondary malignant priapism ( Table 3). High-dose radiotherapy (60Gy in 30 fractions) partially relieved priapism symptoms in non-small cell lung cancer, but the acute toxicities were not described in detail [40]. Hypo-fractionated radiotherapy is effective in control priapism secondary to melanoma [44] but not soft tissue neoplasm [42][43]. In sum, these case reports demonstrate that high-dose palliative external beam radiotherapy is an effective palliative option for priapism. However, this option has been relatively underutilized. Only 16 out of 42 malignant priapism cases were reported to be treated with palliative radiotherapy according to our review.
One reason that palliative radiotherapy may be underutilized is that the traditional patient setup is challenging. In the present case, it was very difficult for the patient to tolerate the initial treatment setup, which used a traditional plastic block or wax to hold the penis, due to significant pain. Furthermore, the patient had previously received high-dose radiotherapy to the pelvis. In this case, we used the VMAT technique to overcome these issues. The VMAT setup is simple and comfortable for the patient. Our setup is also reproducible, as we use imaging guidance.
To summarize, the paucity of literature regarding the successful treatment of malignant priapism via radiotherapy means that the optimal radiation dose and fractionation to use is unknown. We recommend high-dose palliative radiotherapy (40-50Gy) for malignant priapism secondary to prostate cancer to achieve durable local control. This dosage was shown to be effective in the current case report and a further two other reports [12][13]. This dose may also be effective for other common causes of malignant priapism (e.g. urothelial carcinoma or rectal carcinoma). The VMAT radiotherapy technique is preferred for two reasons. First, it allows for a simple patient setup and avoids additional stress to the patient. Secondly, malignant priapism is primarily caused by genitourinary or lower gastrointestinal malignancies. Patients with genitourinary or lower gastrointestinal malignancies typically receive high-dose radiotherapy as part of their initial treatment or may require further palliative pelvic radiotherapy. VMAT helps minimize damage to normal pelvic tissues caused by retreatment of radiotherapy.

Conclusions
Malignant priapism is a rare clinical presentation in patients with metastatic carcinoma. High-dose palliative radiotherapy is an effective treatment for symptomatic relief. Patients need to be monitored closely during treatment to avoid excessive toxicity from radiotherapy.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.