Penile gangrene due to calciphylaxis: a multidisciplinary approach to a complex clinical challenge

Abstract

Penile calciphylaxis is a rare but clinically challenging condition to manage. While multiple treatment options have been proposed, the underlying evidence is anecdotal, and the overall prognosis remains extremely poor. We describe the case of a patient who underwent urgent debridement of a suspected gangrenous penile tip, who was intraoperatively found to have penile calciphylaxis. The necrosis progressed and the patient had a glans amputation. A non-healing wound developed, requiring reconstruction with two skin grafts using foreskin by the plastic and reconstructive surgical unit. The patient was commenced on sodium thiosulfate and his wound had completely healed 2 months following his last operation. We review the literature to determine the biochemical features, management options and outcomes in patients with penile calciphylaxis.

Background

Penile calciphylaxis is a rare presentation of an uncommon systemic disease. Calciphylaxis, in general, has a reported global prevalence rate of 1%–4.1% in haemodialysis patients with end-stage renal failure.^{1 2} While remaining an uncommon condition, there has been a rising prevalence of calciphylaxis because of ongoing advances in dialysis techniques in combination with increasing numbers of patients on prolonged dialysis.^3–5 Penile calciphylaxis was first described by Wood et al in 1997, as a rare cause of penile gangrene.⁶ The prognosis associated with penile calciphylaxis continues to be poor, given the systemic nature of the disease and the associated comorbidities. In 2003, Karpman et al reviewed 34 cases of penile calciphylaxis and found an overall mortality rate of 64%.⁷

Furthermore, the true mortality rates are underestimated, as reflected in a literature review of penile calciphylaxis by Yang et al in 2018.⁸ The poor prognosis associated with the presence of extragenital gangrene in patients with penile calciphylaxis was highlighted by Yang et al, which revealed a higher 3-month mortality rate in patients with extragenital gangrene than in those without extragenital gangrene (60.7% vs 27.8%, p=0.03).⁸ The heterogeneity of the clinical manifestations and poor associated outcomes lead to challenges in decision-making for the treating clinicians, especially regarding aggressive surgical intervention. We describe a rare and clinically challenging case of penile gangrene secondary to calciphylaxis in a patient with diabetic end-stage renal disease.

Case presentation

Urological consultation was sought for a 43-year-old Caucasian man who was found to have a necrotic penile glans and prepuce on a routine admission for haemodialysis. The patient’s medical history included type 2 diabetes mellitus, end-stage renal disease requiring haemodialysis three times per week, obesity, peripheral vascular disease, obstructive sleep apnoea and hypertension. Examination revealed a violaceous 8 mm disc of tissue on the glans with a thick eschar on the remainder of glans and a purulent inner prepuce (figure 1).

Figure 1.

Dry gangrene of glans and prepuce with thick eschar and violaceous changes.

Investigations

Inflammatory markers were found to be elevated (white cell count (WCC) 21 x10⁹/L and C reactive protein (CRP) 150 mg/L). Serum calcium and phosphate levels were within normal limits.

Treatment

The patient underwent urgent surgical debridement for suspected penile gangrene and was found to have poorly vascularised and non-viable segments of the glans penis and inner prepuce. Intraoperative wound swabs and tissue specimens cultured multiple organisms, including Serratia marcescens, Mycoplasma hominis, Coagulase-negative S taphylococcus and Enterococcus faecalis. Histological examination of tissue specimens reported necrosis with calcified vessels consistent with calciphylaxis (figure 2).

Figure 2.

Calcification of tunica media and intimal fibrosis at ×10 magnification.

Two days later, the patient returned to theatre for further debridement and glans amputation. After 2 weeks of frequent wound reviews and negative culture swabs, the plastic and reconstructive surgery unit were consulted for the reconstruction of the penile defect. The foreskin was divided along the ventral aspect and unfurled so as to effect local coverage with the foreskin being used as a skin graft.

Outcome and follow-up

Unfortunately the patient’s disease continued to progress, requiring a return to the theatre 2 months later. Intraoperatively, there were persistent areas of necrotic avascular tissue of the corpora cavernosum necessitating further debridement to bleeding edges at the urethra. Reconstruction of the penile stump was performed 4 days later with a second split skin graft (figure 3). The patient was then commenced on a 1 month course of sodium thiosulfate. The patient was reviewed in the urology and plastic surgery outpatient clinics until his wound had completely healed 2 months after his last operation.

Figure 3.

Following penile stump reconstruction with split skin graft.

One year after the time of presentation with penile calciphylaxis, the patient underwent an emergency laparotomy and right hemicolectomy for a colonic perforation due to caecal calciphylaxis. The patient remains alive at his last follow-up over a year following his initial diagnosis of penile calciphylaxis.

Discussion

Penile calciphylaxis remains a rare cause of penile gangrene. To date, there have been a total of 81 cases of penile calciphylaxis reported in the English language literature, as a result of our MEDLINE review of published case reports searching for ‘penile’, ‘calciphylaxis’ and ‘gangrene’. Clinical suspicion for calciphylaxis should be raised in patients with end-stage renal disease and diabetes. In our review, the presence of end-stage renal disease and diabetes was reported in 77/81 (95%) and 72/81 (89%) of all cases. The average age at onset of penile calciphylaxis was 56 years. Typical clinical features of penile calciphylaxis include progressive violaceous skin lesions overlying tender and indurated, subcutaneous nodules, often affecting the glans penis.^{6 9–11} Diagnosis is made clinically and requires the exclusion of conditions, such as necrotising fasciitis, warfarin skin necrosis, cellulitis, nephrogenic fibrosing dermopathy and cholesterol emboli.^{12 13} Some authors argue that calcium phosphate 70 mg²/dL² is the cut-off for the diagnosis of calciphylaxis.¹⁴ However, many cases of penile calciphylaxis have not been associated with a calcium phosphate level of greater than 70 mg/dL. The systematic review by Budisavljevic et al found elevated levels in only one-third of the 52 reported cases.^15–18 Diagnosis is often confirmed pathologically, as described in the presented case. Pathological characteristics include medial calcification with secondary intimal fibrosis and thrombosis in medium and small dermal and subcutaneous vessels, resulting in ischaemic ulceration and necrosis of the skin.15 17 19 20 However, the exact pathogenesis of calciphylaxis remains elusive.^{17 21–27} Preoperative biopsy is contraindicated in the management of penile calciphylaxis because it may increase the risk of progression to gangrene.²⁸

The role of surgical management is controversial,²⁹ given the systematic nature of the disease and its associated poor prognosis.^{30 31} Of the 81 recorded cases in the literature, 40 (49%) were treated conservatively, 30 (37%) were initially treated expectantly with subsequent delayed surgery following the development of complications and 11 (14%) underwent early surgery (penectomy).³ The majority of patients who develop penile calciphylaxis progress to gangrene and sepsis.^{7 32} A total of 40/81 (49%) of patients were managed conservatively and data regarding time to death were recorded in 24 cases, with a 3.4-month mean time to death. Of the 41 patients managed surgically, time to death data were available in 24 cases, with an average time to death of 4 months. No statistically significant difference was found between the mean time to death in conservative versus surgical groups (p=0.67). While some authors of case series promote early penectomy in low-operative risk patients to avoid progression to wet gangrene,³³ others have demonstrated a higher morbidity and mortality rate,³⁴ and the survival benefit remains unproven. Of those treated surgically, early surgery was performed in 11 patients, with a mean time to death of 6.1 months, in the 5 cases with available data. Of the 30 patients who were managed with expectant surgery, 19 reports contained time to death data, with a mean time to death of 3.5 months. No statistically significant difference was found between the mean time to death in early and expectant surgically managed groups (p=0.54). Although surgical intervention has not been proven to decrease mortality in these patients, it may play a role in improving quality of life by limiting further ischaemia and decreasing pain.³³

Similarly, the role of parathyroidectomy is also controversial in the literature. Parathyroid hormone levels were reported in 44/81 (54%) patients with an average parathyroid hormone level of 461.8 pg/mL. There were a total of 11/81 (14%) patients with penile calciphylaxis who underwent a parathyroidectomy, and 1 case where parathyroidectomy had already been performed 3 years prior.³⁵ Of these 11 cases, 5 had mortality data available, with a mean time to death of 7.4 months. There were 30 patients with a documented elevated parathyroid hormone level (PTH) who did not undergo parathyroidectomy. Of these 30 patients, 17 had mortality data available, with a mean time to death of 3.6 months. However, there was no statistically significant difference in the mean time to death between these two cohorts of patients with elevated PTH levels (p=0.06). This conclusion was different from that made by Karpman et al, in their retrospective review of 34 patients with penile calciphylaxis in 2003, who underwent parathyroidectomy, which suggested reduced mortality in those who underwent parathyroidectomy.⁷ The difference between these two reviews may be because the study by Karpman et al included patients without a documented parathyroid hormone level.

Despite the success reported with intravenous sodium thiosulfate in retrospective case series,^{36 37} the lack of randomised controlled trials and prospective studies precludes its standardised use. Similarly, evidence for phosphate binders, bisphosphonates, calcitriol analogues and calcimimetics have been shown anecdotally to have varying success.^38–42 Two cases of penile calciphylaxis were treated with hyperbaric oxygen treatment, with improvement of extragenital wounds, but not penile lesions. Both of these patients died within a month from the start of the treatment.^{2 35 43} Although the feasibility of revascularisation has been demonstrated by several recent case reports,^{44 45} most patients will not be candidates for revascularisation because of their extremely poor prognosis.

Ultimately, there continues to be a poor prognosis associated with penile calciphylaxis. We found a 3-month mortality rate of 38% and an overall reported all-cause mortality rate of 58%. The mean time to death was 3.6 months, which is comparable to the rates reported by Karpman et al in 2003. We found documented progression to wet gangrene in 31/76 (41%) of reported cases, excluding 5 cases where this information was not available. Data regarding the cause of death were present in 43/81 (53%) of cases. Sepsis was the leading cause of death, as documented in 41% of cases, and was predominately related to extragenital gangrene 2/49 (4%) as opposed to genital gangrene. Non-sepsis-related cause of death was documented as myocardial infarction in 8/49 (16%), cerebrovascular accident in 2/49 (4%), respiratory failure in 3/49 (6%), renal failure in 2/49 (4%), multiorgan failure in 3/49 (6%), palliation in 2/49 (4%) and undetermined in 3/49 (6%). The importance of a multidisciplinary team approach, involving urologists, reconstructive surgeons, nephrologists, perioperative physicians and pathologists, has been highlighted by the clinical challenges in our reported case as well as the poor overall health outcomes associated with similar cases in the literature.

Learning points.

• Penile calciphylaxis is a rare manifestation of an already uncommon systemic condition that is associated with high morbidity and mortality.

• The diagnosis of calciphylaxis must be made clinically, given the unreliable biochemical features and risk of progression to gangrene associated with biopsy.

• A multidisciplinary team approach is essential, given the poor prognosis and lack of evidence for management options.

• Patients and families should be counselled extensively about the systemic nature of calciphylaxis.