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Biopsy Is Contraindicated in the Management of Penile Calciphylaxis
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Biopsy Is Contraindicated in the Management of Penile Calciphylaxis Cara B. Cimmino, MD and Raymond A. Costabile, MD Department of Urology, University of Virginia, Charlottesville, VA, USA DOI: 10.1111/jsm.12390
ABSTRACT
Introduction. Calciphylaxis, a rare obliterative small vessel vasculopathy associated with diabetes mellitus (DM), end-stage renal disease (ESRD), portends a poor prognosis. Because penile involvement is rare, agreement on appropriate diagnosis and management is unclear. Aim. To determine the role and effect of penile biopsy for diagnosis and management of penile calciphylaxis. Methods. Medical records of three penile calciphylaxis patients from our institution were evaluated. Data collected included age, history of DM, ESRD, and hemodialysis (HD) status, serum calcium (Ca), Ca × phosphorous product (C × P), parathyroid hormone (PTH), performance of biopsy, presence of non-penile cutaneous lesions, intervention, survival, and time from diagnosis to death. PubMed Search for relevant publications from 1995 to 2012 was performed to identify case reports of penile calciphylaxis that provided the same clinical data obtained from the 3 patients from our institution. Main Outcome Measures. Clinical evidence for outcomes in patients with penile calciphylaxis after biopsy of penile lesion compared to those without biopsy. Results. A total of sixteen patients were identified in the literature and in our institution with clinical data of interest. Overall, 10/16 (62.5%) patients identified with penile calciphylaxis had a penile biopsy, and 7/10 (70%) experienced disease progression, while only 3/10 (30%) stabilized. Mean time to death in this patient population was short, approximately 6.5 months, regardless of type of intervention. Conclusion. Based on the results of our study, we argue that conservative measures should be employed as first line therapy for penile calciphylaxis. More importantly, secondary to likely resultant progression of necrosis, penile biopsy is not only unnecessary for diagnosis of penile calciphylaxis, but is also harmful and contraindicated. Cimmino CB and Costabile RA. Biopsy is contraindicated in the management of penile calciphylaxis. J Sex Med 2014;11:2611–2617. Key Words. Penile Biopsy; Penile Calciphylaxis; Penile Calcific Uremic Arteriolopathy
Introduction
C
alcific uremic arteriolopathy, or calciphylaxis, is an obliterative small vessel vasculopathy characterized by medial calcification of small arteries and arterioles. This vascular calcification leads to luminal narrowing of the artery, resulting in cutaneous necrosis and ulceration. The distribution of these dermatologic lesions has been described as proximal (involving the face, trunk, genitalia, or buttocks), or distal (extremities) [1]. Patients with proximal calciphylaxis have a mortality rate of 63–80%, while those with distal © 2013 International Society for Sexual Medicine
lesions have a mortality rate of approximately 23% [2–4]. Because penile involvement is rare, agreement on its appropriate diagnosis and management is not clear. Diagnosis of penile calciphylaxis can be made on the basis of clinical history and physical examination, laboratory studies and imaging, demonstrating calcification of penile and pelvic arteries with Computerized tomography (CT) scan or radiographs. Some studies have reported the use of penile lesional biopsy to confirm the diagnosis and rule out other vascular, infectious, or malignant causes. After our experience with 3 recent patients, J Sex Med 2014;11:2611–2617
2612 and a review of reported cases in the literature, we would propose that diagnosis of penile calciphylaxis is best done with analysis of clinical parameters, and the risk of penile biopsy outweighs potential benefits. Case Histories
Over the past 5 years, three patients presented to our single institution, ultimately diagnosed with penile calciphylaxis. Given the low incidence of this disease, we were encouraged to report our findings.
Patient 1 A 62-year-old male with history of end stage renal disease (ESRD) secondary to diabetic nephropathy, on hemodialysis (HD) for 3 years prior to presentation, was referred to the Urology Department after a transfer of care between facilities for a 3 month history of painful, necrotic ulcers on the distal penis and scrotum. He was voiding per urethra without difficulty. On examination, the patient was circumcised with swelling of the penile shaft and scrotum. The glans was nodular and hard with several black necrotic lesions. Several small necrotic lesions were noted on the scrotal skin as well. Mild tenderness was noted on penile and scrotal exam. No evidence of erythema, crepitus or purulent drainage was noted. On presentation, his serum calcium (Ca) was 9.0 mg/dL, Calcium × Phosphate product (C × P) was 75.6 mg2/dL2, and parathyroid hormone (PTH) was not recorded. The patient’s Ca and phosphorous levels were tightly controlled by Nephrology via regular hemodialysis. The patient was managed with narcotic pain control, local wound care, and debridement of the penile and scrotal lesions as needed on an outpatient basis. A pain management consult was eventually called for assistance with the patient’s pain control regimen. One year after initial presentation, the patient underwent amputation of two right toes secondary to osteomyelitis. During the following year the patient required several hospitalizations for infected foot ulcers and osteomyelitis requiring surgical debridement and washout. He was followed regularly by Urology, during which time his penile and scrotal lesions remained stable, but did not resolve. He did not require biopsy or surgical intervention for his penile lesion. He ultimately expired 22 months after presentation secondary to complications from osteomyelitis and overwhelming sepsis. J Sex Med 2014;11:2611–2617
Cimmino and Costabile
Patient 2 A 38-year-old male with history of Type I insulindependent diabetes mellitus (DM), congestive heart failure (CHF), and ESRD on HD, who presented to the emergency room with complaints of a painful blister at the tip of his penis. He first noticed this lesion 2 weeks prior to presentation, however, the blister “popped” and developed into an open ulcer, which was tender to palpation. He initially presented to an outside facility where a biopsy of the lesion was performed. His pain increased after this intervention, as did the area of ulceration. He then transferred his care to our facility. At this point the patient complained of pain with voiding secondary to irritation of the lesion when contacted by urine, but denied difficulty emptying his bladder. He denied any fever, chills, nausea or vomiting. He denied any other concurrent lesions elsewhere on his body, however on exam it became apparent that he had two previous toe amputations and one current necrotic toe. Physical examination demonstrated a 1 cm ulceration on the lateral aspect of the glans penis, with an area of eschar. He was circumcised, but had some redundant foreskin which did not appear involved. The urethral meatus was patent and visible, though in close proximity to the edge of the lesion. Scrotal exam was normal. The patients laboratory studies revealed calcium level of 8.7 mg/dL, but a phosphorous, C × P product and PTH were not obtained. As there was no evidence of infection the patient was managed with wound care and pain control with Tramadol. He was seen one month later for persistent pain and was given narcotic pain medication, the eschar was carefully debrided at that time as well. Management continued with conservative wound care, pain control and debridement for the next six months. The wound stabilized, and improved somewhat, though it failed to completely resolve. The patient discontinued his Urology follow-up after approximately 3 months of care and was lost to follow-up. Patient 3 A 49-year-old male with history of DM, ESRD on HD, and peripheral vascular disease, admitted to the vascular surgery service for amputation of a gangrenous left fifth toe. On admission a small soft ulcer was noted on the tip of his penis. After 3 days this lesion became painful necrotic, and hard to the touch. The Urology service was notified to evaluate the lesion at this time. On exam the patient was
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Biopsy Recommendations for Penile Calciphylaxis circumcised with normal urethral meatus. A 2 cm lesion was noted on the left coronal margin of the glans penis which was black, firm, and raised. No erythema or purulent drainage was noted. The patient denied difficulty with voiding. His laboratory studies revealed a Ca of 7.4 mg/dL, C × P 71.0 mg2/dL2, and PTH of 799.8 pg/mL. The findings on initial consultation were consistent with penile calciphylaxis. The patient was managed with wound care, debridement of eschar, and pain control. No surgical intervention or biopsy was performed, and no antibiotics initiated secondary to a lack of evidence of infection. The patient was monitored closely in follow-up and was able to be managed with conservative interventions. He was readmitted approximately 3 month after initial presentation for amputation of two gangrenous toes and angioplasty of his right popliteal, internal iliac, and anterior tibial arteries for management of his peripheral vascular disease. He was lost to follow-up 5 months after his initial presentation.
Methods
Three recent patients with diagnoses of penile calciphylaxis from our institution were identified. The medical records of these men were examined and clinical and epidemiologic information was identified. Data pertaining to medical history were collected, including age, medical history of DM, ESRD and HD requirement. Laboratory data collected included serum Ca, C × P product, and PTH level. Management decisions were recorded including whether a penile biopsy had been
Table 1
obtained, as well as additional intervention. Clinical parameters noted included the presence or absence of non-penile cutaneous lesions at the time of diagnosis, as well as the location and characterization of the penile lesion itself. Outcomes including survival data, and time from diagnosis to death were recorded. A literature search from 1995 to 2012 was performed to identify case reports of penile calciphylaxis. Key words included penile calciphylaxis and penile calcific uremic arteriolopathy. Those studies included were those that provided the same clinical data obtained from the 3 patients from our institution.
Results
Three patients from our institution and 13 case reports from the literature were identified and reviewed for a total of 16 patients. The average age at diagnosis was 55.9 years old. Clinical attributes of these patients can be found in Table 1. Of the 16 cases of penile calciphylaxis evaluated, all patients had a past medical history significant for ESRD with HD requirement, and all but one patient (93.8%) carried a diagnosis of DM. Half of the patients (8/16) reported additional necrotic lesions present at sites other than the penis. Table 1 also illustrates the laboratory data obtained from these patients. Interestingly, of the 12 patients (75%), who had reported Ca values, only 1 patient had a slightly elevated level of 10.4 mg/dL (nml 8.5–10.2 mg/dL), while the rest were within normal limits. However, 80% (8/10) of those with reported C × P products and
Clinical attributes of men with penile calciphylaxis
Case #
Other site(s) of necrosis
DM
ESRD and dialysis
Calcium
C×P product
PTH
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Yes No Yes Yes Yes No Yes No No Yes No Yes No Yes No No
Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
7.4 8.7 9 ? 9.8 8.9 ? 8 ? ? 10.4 8.5 10.2 7.9 8.4 8.9
71.0 ? 75.6 ? 50.9 44.5 ? 64.8 ? ? 87 ? 105 75.8 62.1 67
799.8 ? ? 33 ? 1,462 816 516 30.8 48 430 121 82 379 38 1,280
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Table 2
Outcome of penile biopsy in men with penile calciphylaxis
Case #
Age
Biopsy
Intervention/outcome
1 2 3 4 5 6 7
49 38 62 72 41 72 59
No Yes No No Yes Yes Yes
8
64
Yes
9 10
66 38
No Yes
11 12
60 65
No Yes
13
58
Yes
14
59
No
15
35
Yes
16
56
Yes
Debridement Debridement Debridement Debridement Total penectomy, progression of disease, sepsis Circumcision Glans autoamputated, progression of disease, partial penectomy Debridement, progression of disease, total penectomy Partial penectomy, death from MI Circumcision, progression of disease, partial penectomy Partial penectomy Partial penectomy, progression of disease, total penectomy Debridement, progression of disease, resection of glans Glans autoamputated, progression of disease, partial penectomy Partial penectom, progression of disease, total penectomy Circumcision, progression of disease, partial penectomy, progression, total penectomy
Time (diagnosis to death)
Source
Alive at 5 months Alive at 3 months, LTF Death, 22 months Unknown, LTF Death, 9 months Death, 9 months Unknown, LTF
UVA series UVA series UVA series Bappa et al.; 2011 [5] Ohta et al.; 2007 [6] O’Neill et al.; 2012 [7] O’Neill et al.; 2012 [7]
Unknown, LTF
O’Neill et al.; 2012 [7]
Death, 4 weeks Alive at print
Prematilleke et al.; 2012 [8] Prematilleke et al.; 2012 [8]
Death, 5 weeks Unknown, LTF
Jacobsohn et al.; 2002 [9] Sorensen et al.; 2007 [10]
Alive at print
Sandhu et al.; 2012 [11]
Death, 3 months
Karpman et al.; 2003 [12]
Death, 2 months
Woods et al.; 2006 [13]
Unknown, LTF
Wood et al., 1997 [14]
Notes: LTF = Lost to follow-up
69.2% (9/13) with identifiable PTH levels had elevated values of >55 mg∧2/dL∧2, and >55 pg/mL respectively. Management and outcome data are presented in Table 2. The majority, 7/16 (43.7%), were managed aggressively with partial or total penectomy as the initial intervention. Following this, the second most common initial intervention was debridement in 6/16 (37.5%), while the least frequent initial management was biopsy and circumcision in only 3/16 (18.8%). Of those managed conservatively with debridement alone, 2/6 (33.3%) progressed. One required further intervention of a subsequent glans resection, while the other required total penectomy with perineal urethrostomy for progression. Patients managed with circumcision or dorsal slit as the initial intervention demonstrated a two-thirds rate of progression to subsequent partial or total penectomy. Of the 43.7% managed aggressively with initial partial or total penectomy, 5/7 (71.4%) progressed to require further resection or death, 1/7 (14.3%) stabilized, and the last patient died of a perioperative MI before his clinical course could be fully realized. Table 2 additionally includes data regarding outcomes, interventions, and disease course. In this cohort, 10/16 (62.5%) underwent biopsy as part of their initial treatment, while 6/16 (37.5%) J Sex Med 2014;11:2611–2617
did not. Of those biopsied 7/10 (70%) progressed and 3/10 (30%) stabilized. In the 6/16 (37.5%) patients who did not undergo penile biopsy, 3/6 (50%) stabilized, 2/6 (33.3%) progressed, and 1/6 (16.7%) died prior to documentation of progression. In the group managed aggressively with partial or total penectomy at presentation, 4/7 (57.1%) had an initial biopsy, and all but one (85.7%) progressed further after initial treatment. Of the 3/7 (42.9%) of this group that did not undergo biopsy, two progressed despite intervention and ultimately died, and one died perioperatively from MI. In the circumcision/ dorsal slit group, the two circumcision patients had biopsy performed prior to their circumcision with resultant progression of one patient, and stabilization of the other. The one patient who initially underwent a dorsal slit did not have a biopsy, but did progress. In the final group of patients who underwent debridement as initial intervention, 3/6 (50%) underwent biopsy prior to debridement. One progressed to a total penectomy, one to glans resection, and one stabilized after debridement. Of the 3/6 (50%) who had debridement only with no biopsy, none progressed. At the time of print, the survival data was only identified for 11/16 (68.8%) of the reported patients, as the remainder were lost to follow-up. The majority, 7/11 (63.6%) died, while the
Biopsy Recommendations for Penile Calciphylaxis remaining 36.4% were alive at the time of print. Of those 7 patients managed more aggressively with partial or total penectomy as initial intervention, 5 (71.4%) subsequently died, and 2 (28.6%) had unknown outcomes. The 3 patients managed initially with circumcision had divided outcomes with 1 dead, 1 alive, and 1 with unknown outcome. Finally, the debridement group reported 3 (50%) alive, 1 (16.7%) dead and 2 (33.3%) unknown. Overall, 10/16 (62.5%) patients underwent penile biopsy as part of their management (Table 2). Of those biopsied 7/10 (70%) progressed and 3/10 (30%) stabilized. In those patients who were not biopsied and only underwent debridement, none progressed. Of the seven patients who progressed to death at the time of print, 3/7 (42.9%) had a penile biopsy at some point during their care, while 4/7 (57.3%) did not. Of the 10 (62.5%) patients in our cohort not lost to follow-up 70% were deceased at the time of print, with a mean time to death of 6.5 months (Table 2). Excluding one patient who survived for 22 months, the mean time to death was 4 months. Discussion
Our rationale for the avoidance of lesional biopsy for the diagnosis of penile calciphylaxis is threefold. Firstly, we would argue that the diagnosis of penile calciphylaxis can be made from the history, physical exam findings, and laboratory values. Should further evidence be required, non-invasive imaging with CT scan or plain film has been reported to demonstrate visible calcification of the pelvic and perineal vasculature. Second, the development of penile calciphylaxis tends to be a late clinical manifestation of ESRD, with a high rate of mortality over a relatively rapid period of time. Finally, there is evidence in the literature to support that biopsy, and aggressive surgical intervention, of these poorly vascularized lesions frequently leads to poor wound healing, infection risk, and progression of disease [6,15]. As a result of these statistics, we would argue for the least invasive and disfiguring intervention possible. Addressing our first point, certain clinical findings are characteristic of patients with calciphylaxis. Calciphylaxis has been reported in up to 1–4% of patients with ESRD and HD requirement, and portends a poor prognosis and life expectancy [4,16,17]. Additionally, DM and obesity are associated with increased risk of calciphylaxis. In a study of 33 patients with penile calciphylaxis, 66% demonstrated additional gan-
2615 grenous sites, other than the penis at the time of presentation, and 76% had diabetes mellitus [12]. Supporting this data, all of the patients evaluated in this study reported a history of ESRD requiring HD, and 93.8% possessed a diagnosis of DM. Fifty percent of our patients had dermatologic lesions in additional regions aside from the penis. Laboratory values that have been associated with calciphylaxis include low serum albumin, elevated PTH, Ca, phosphate, and elevated C × P product [18,19]. Patients on HD are prone to develop high serum phosphate, which acts to promote calcification and differentiation of vascular smooth muscle into osteoblasts [20]. The elevation of serum phosphate promotes secondary hyperparathyroidism by decreasing serum Ca and inhibiting vitamin D activation. Elevation of PTH, in turn, causes release of Ca and phosphate from the bone, which elevates the serum C × P product. The C × P product is reportedly elevated in 80% of patient’s diagnosed with calciphylaxis [21]. When this product is higher than 70, the risk of ectopic vascular calcification is promoted [22]. When present, the elevation of PTH levels and C × P product, can help distinguish calciphylaxis from other diseases with dermatologic manifestations, such as scleroderma, without requiring biopsy of the lesion. While only one of our patients had an elevated serum Ca level, the majority with this reported data had elevation in C × P product (80%) and/or PTH (69.2%). As previously mentioned, biopsy has been utilized in the past to distinguish the dermatologic stigmata of calciphylaxis from other vascular, infectious, or malignant lesions. The lesions of calciphylaxis can be clinically differentiated from other dermatologic lesions including those from vascular calcification leading to arterial insufficiency and peripheral atherosclerotic gangrene without the utilization of biopsy [23]. These vascular deposits develop gradually over time, and are not associated with rapid tissue necrosis at multiple synchronous sites, as opposed to those associated with calciphylaxis [19,23]. Additionally, these two entities can be clinical distinguished by the typical absence of pain with distal gangrenous lesions due to vascular disease, whereas pain is often a presenting characteristic of calciphylaxis. All of the 16 patients reviewed here had painful, penile lesions at the time of diagnosis. The presence of peripheral pulses may also suggest a diagnosis of calciphylaxis as opposed to arterial insufficiency. Further characterizing these separate etiologies of gangrenous lesions is the observation J Sex Med 2014;11:2611–2617
2616 of clinical improvement seen in patients with calciphylaxis and elevated PTH after parathyroidectomy, while this intervention has no bearing on the course of vascular calcification with subsequent arterial insufficiency [14]. Similarly clinical history and physical exam can distinguish calciphylaxis from other infectious, inflammatory, or malignant causes for penile ulceration. A medical history including ESRD requiring HD, DM, obesity and/or a history of additional ischemic lesions, would increase the likelihood of calciphylaxis. An infectious or sexually transmitted lesion would clinically demonstrate other systemic and local signs and symptoms. Locally the wound would typically be warm, erythematous, painful, and possibly express exudate. Systemically, the patient would usually demonstrate leukocytosis, fevers, chills, and other outward signs. Wound and blood cultures could also be positive for bacterial organisms. Lesions caused by a systemic inflammatory or rheumatologic disease such as sarcoidosis, would likely be accompanied by a prior medical history consistent with these disease states. The lesions of malignancy tend to be distinct from those of penile calciphylaxis. The second factor supporting our recommendation to avoid biopsy and aggressive intervention, is the high mortality rate and short progression time to death reported in patients with penile calciphylaxis. A mortality rate of 64–69%, with a mean time to death of 2.5–6 months has been reported [12,24]. Though the majority of the seven patients in our study who died did not undergo biopsy, the average time to death between these two groups was longer for the group that was not biopsied. Additionally the average time to death was short regardless of the group, indicating a poor prognosis regardless of intervention. In our study, of the 10 (62.5%) patients in our cohort not lost to follow-up, 70% were deceased at the time of print, with a mean time to death of 6.5 months (Table 2). Excluding one patient who survived for 22 months, the mean time to death was 4 months. Our data supports the findings of poor prognosis and life expectancy in this patient population. Finally, we argue that more aggressive intervention, may lead to progression of the penile lesion. As seen in the literature, biopsy has repeatedly been followed by post-operative progression of the sampled lesion, requiring further, more invasive interventions [15]. One theory behind the rapid development and progression of these skin ulcers after biopsy and surgical intervention is that the J Sex Med 2014;11:2611–2617
Cimmino and Costabile surgical stress leads to increased activation of the sympathetic nervous system, promoting circulatory dysfunction, and rapid progression of the necrosis [6]. Though the pathophysiology is poorly understood, the literature demonstrates progression after insult, and corroborates the superiority of conservative treatment, unless patients had severe pain or in cases where administration of antimicrobial agents was difficult [25]. As seen in our cohort, 7/10 (70%) of patients who underwent biopsy ultimately progressed. Moreover, of the 3/16 (18.8%) patients who avoided biopsy and were managed with debridement only, all stabilized without further progression. Given the data regarding the high mortality, high risk of progression with intervention, and short duration of life portended by this diagnosis, it stands to reason that increasing comfort, and minimizing invasive procedures in this patient population is the appropriate management. The authors recognize that calciphylaxis is a rare disease, and involvement of the male genitalia is even less common. As a result, the number of patients available for evaluation is exceedingly low, making a more robust study with sophisticated statistical analysis challenging to provide. By evaluating the cases reports in the literature, as well as those patients from our own recent clinical experience we hoped to establish a pattern of response to interventions in this rare condition. Though these patients are not frequently encountered, mismanagement with biopsy or aggressive surgical intervention can lead to deterioration of the condition, and a marked worsening of quality of life for the patient. Through this review, the authors hope to raise awareness of this disease process in an attempt to guide treatment, and avoid unnecessary procedures when penile calciphylaxis is encountered by the consulting Urologist. Conclusion
Calciphylaxis is an uncommon, but devastating manifestation of ESRD. Due to the abundant blood supply to the penis, penile necrosis secondary to disorders of circulation are even more rare leading to uncertainty regarding diagnosis and management. Based on the results of our study, we argue that conservative measures such as careful wound debridement and aggressive management of electrolyte abnormalities should be employed as first line therapy for penile calciphylaxis. More aggressive measures such as partial or total
Biopsy Recommendations for Penile Calciphylaxis penectomy should be reserved for progressive infection or intractable pain. More importantly we argue that, secondary to the likely resultant progression of necrosis, penile biopsy is not only unnecessary for diagnosis of penile calciphylaxis, but is also harmful and contraindicated. Corresponding Author: Cara B. Cimmino, MD, Piedmont Urology Specialists, 275 Collier Rd, Suite 400, Atlanta, GA 30309, USA. Tel: 404-605-4848; Fax: 404-351-5517; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Statement of Authorship
Category 1 (a) Conception and Design Cara B. Cimmino; Raymond A. Costabile (b) Acquisition of Data Cara B. Cimmino (c) Analysis and Interpretation of Data Cara B. Cimmino
Category 2 (a) Drafting the Article Cara B. Cimmino (b) Revising It for Intellectual Content Cara B. Cimmino; Raymond A. Costabile
Category 3 (a) Final Approval of the Completed Article Cara B. Cimmino; Raymond A. Costabile References 1 Guvel S, Yaycioglu O, Kilinc F, Torun D, Kayaselcuk F, Ozkardes H. Penile necrosis in end-stage renal disease. J Androl 2004;25:25–9. 2 Mohammed IA, Sekar V, Bubtana AJ, Mitra S, Hutchinson AJ. Proximal calciphylaxis treated with calcimimetic “Cincacalcet”. Nephrol Dial Transplant 2008;23:387–9. 3 Llach F. The evolving clinical features of calciphylaxis. Kidney Int Suppl 2003;85:S122–4. 4 Rogers NM, Coates PTH. Calcific uraemic arteriolopathy: An update. Curr Opin Nephrol Hypertens 2008;17:629–34. 5 Bappa A, Fayaz H, Mustafa A, Abdullah A. Penile gangrene due to calcific uremic areteriopathy. Ann Afr Med 2011;10: 181–4.
2617 6 Ohta A, Ohomori S, Mizukami T, Obi R, Tanaka Y. Penile necrosis by calciphylaxis in a diabetic patient with chronic renal failure. Intern Med 2007;64:985–90. 7 O’Neill B, Southwick AW. Three cases of penile calciphylaxis: Diagnosis, treatment strategies, and the role of sodium thiosulfate. Urology 2012;80:5–8. 8 Prematilleke I, Espinosa O, Henderson J, Altmann P, Roberts I. Penile calciphylaxis: An unusual cause of penile necrosis. Histopathology 2012;61:749–50. 9 Jacobsohn HA, Jenkins PG, Jacobsohn KM. Penile calciphylaxis. Urology 2002;60:344. 10 Sorensen MD, Long LO, Wessells H, Kuan JK. Monckeberg’s calciphylaxis with necrosis of the glans penis: A case presentation. Hemodial Int 2007;11:300–2. 11 Sandhu G, Gini MB, Ranade A, Djebali D, Smith S. Penile calciphylaxis: A life-threatening condition successfully treated with sodium thiosulfate. Am J Ther 2012;19:e66–8. 12 Karpman E, Das S, Kunrock EA. Penile calciphylaxis: Analysis of risk factors and mortality. J Urol 2003;169:2206–9. 13 Woods M, Pattee SF, Levine N. Penile calciphylaxis. J Am Acad Dermatol 2006;54:736. 14 Wood JC, Monga M, Hellstrom WJG. Penile calciphylaxis. Urology 1997;50:622–4. 15 Latus J, Kimmel M, Ott G, Ting E, Alscher MD, Braun N. Early stages of calciphylaxis: Are skin biopsies the answer? Case Rep Dermatol 2011;3:201–5. 16 Angelis M, Wong LL, Myers SA, Wong LM. Calciphylaxis in patients on hemodialysis: A prevalence study. Surgery 1997;122:1083–9. 17 Fine A, Zacharias J. Calciphyaxis: Rare but fatal. Kidney Int 2002;61:2210–7. 18 Bargman JM. Caciphylaxis, calcinosis, and calcergy-separate but not equal. J Rheumatol 1995;22:5–7. 19 Ivker RA, Woosley J, Briggaman RA. Calciphylaxis in three patients with end stage renal disease. Arch Dermatol 1995;31:63–8. 20 Jono S, McKee MD, Murray CE, Shioi A, Nishizawa Y, Mori K, Morii H, Giachelli CM. Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 2000;87:e10–7. 21 Bour J, Steinhardt G. Penile necrosis in patients with diabetes mellitus and end-stage renal disease. J Urol 1984;132:560–2. 22 Hafner J, Keusch G, Wahl C, Sauter B, Hurlimann A, von Weizsacker F, Krayenbuhl M, Biedermann K, Brunner U, Helfenstein U. Uremic small artery disease with medial calcification and intimal hypertrophy (so-called calciphylaxis): A complication of chronic renal failure and benefit from parathyroidectomy. J Am Acad Dermatol 1995;33:954–62. 23 Kent RB, Lyerly RT III. Systemic calciphylaxis. South Med J 1994;87:278–81. 24 Halachmi S, Storch S. Penile gangrene secondary to severe vascular calcification. Isr Med Assoc J 2006;8:888–9. 25 Stein M, Anderson C, Ricciardi R, Chamberlin JW, Lerner SE, Glicklich D. Penile gangrene associated with chronic renal failure: Report of 7 cases and review of the literature. J Urol 1994;152:2014–6.
J Sex Med 2014;11:2611–2617
Biopsy Is Contraindicated in the Management of Penile Calciphylaxis Cara B. Cimmino, MD and Raymond A. Costabile, MD Department of Urology, University of Virginia, Charlottesville, VA, USA DOI: 10.1111/jsm.12390
ABSTRACT
Introduction. Calciphylaxis, a rare obliterative small vessel vasculopathy associated with diabetes mellitus (DM), end-stage renal disease (ESRD), portends a poor prognosis. Because penile involvement is rare, agreement on appropriate diagnosis and management is unclear. Aim. To determine the role and effect of penile biopsy for diagnosis and management of penile calciphylaxis. Methods. Medical records of three penile calciphylaxis patients from our institution were evaluated. Data collected included age, history of DM, ESRD, and hemodialysis (HD) status, serum calcium (Ca), Ca × phosphorous product (C × P), parathyroid hormone (PTH), performance of biopsy, presence of non-penile cutaneous lesions, intervention, survival, and time from diagnosis to death. PubMed Search for relevant publications from 1995 to 2012 was performed to identify case reports of penile calciphylaxis that provided the same clinical data obtained from the 3 patients from our institution. Main Outcome Measures. Clinical evidence for outcomes in patients with penile calciphylaxis after biopsy of penile lesion compared to those without biopsy. Results. A total of sixteen patients were identified in the literature and in our institution with clinical data of interest. Overall, 10/16 (62.5%) patients identified with penile calciphylaxis had a penile biopsy, and 7/10 (70%) experienced disease progression, while only 3/10 (30%) stabilized. Mean time to death in this patient population was short, approximately 6.5 months, regardless of type of intervention. Conclusion. Based on the results of our study, we argue that conservative measures should be employed as first line therapy for penile calciphylaxis. More importantly, secondary to likely resultant progression of necrosis, penile biopsy is not only unnecessary for diagnosis of penile calciphylaxis, but is also harmful and contraindicated. Cimmino CB and Costabile RA. Biopsy is contraindicated in the management of penile calciphylaxis. J Sex Med 2014;11:2611–2617. Key Words. Penile Biopsy; Penile Calciphylaxis; Penile Calcific Uremic Arteriolopathy
Introduction
C
alcific uremic arteriolopathy, or calciphylaxis, is an obliterative small vessel vasculopathy characterized by medial calcification of small arteries and arterioles. This vascular calcification leads to luminal narrowing of the artery, resulting in cutaneous necrosis and ulceration. The distribution of these dermatologic lesions has been described as proximal (involving the face, trunk, genitalia, or buttocks), or distal (extremities) [1]. Patients with proximal calciphylaxis have a mortality rate of 63–80%, while those with distal © 2013 International Society for Sexual Medicine
lesions have a mortality rate of approximately 23% [2–4]. Because penile involvement is rare, agreement on its appropriate diagnosis and management is not clear. Diagnosis of penile calciphylaxis can be made on the basis of clinical history and physical examination, laboratory studies and imaging, demonstrating calcification of penile and pelvic arteries with Computerized tomography (CT) scan or radiographs. Some studies have reported the use of penile lesional biopsy to confirm the diagnosis and rule out other vascular, infectious, or malignant causes. After our experience with 3 recent patients, J Sex Med 2014;11:2611–2617
2612 and a review of reported cases in the literature, we would propose that diagnosis of penile calciphylaxis is best done with analysis of clinical parameters, and the risk of penile biopsy outweighs potential benefits. Case Histories
Over the past 5 years, three patients presented to our single institution, ultimately diagnosed with penile calciphylaxis. Given the low incidence of this disease, we were encouraged to report our findings.
Patient 1 A 62-year-old male with history of end stage renal disease (ESRD) secondary to diabetic nephropathy, on hemodialysis (HD) for 3 years prior to presentation, was referred to the Urology Department after a transfer of care between facilities for a 3 month history of painful, necrotic ulcers on the distal penis and scrotum. He was voiding per urethra without difficulty. On examination, the patient was circumcised with swelling of the penile shaft and scrotum. The glans was nodular and hard with several black necrotic lesions. Several small necrotic lesions were noted on the scrotal skin as well. Mild tenderness was noted on penile and scrotal exam. No evidence of erythema, crepitus or purulent drainage was noted. On presentation, his serum calcium (Ca) was 9.0 mg/dL, Calcium × Phosphate product (C × P) was 75.6 mg2/dL2, and parathyroid hormone (PTH) was not recorded. The patient’s Ca and phosphorous levels were tightly controlled by Nephrology via regular hemodialysis. The patient was managed with narcotic pain control, local wound care, and debridement of the penile and scrotal lesions as needed on an outpatient basis. A pain management consult was eventually called for assistance with the patient’s pain control regimen. One year after initial presentation, the patient underwent amputation of two right toes secondary to osteomyelitis. During the following year the patient required several hospitalizations for infected foot ulcers and osteomyelitis requiring surgical debridement and washout. He was followed regularly by Urology, during which time his penile and scrotal lesions remained stable, but did not resolve. He did not require biopsy or surgical intervention for his penile lesion. He ultimately expired 22 months after presentation secondary to complications from osteomyelitis and overwhelming sepsis. J Sex Med 2014;11:2611–2617
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Patient 2 A 38-year-old male with history of Type I insulindependent diabetes mellitus (DM), congestive heart failure (CHF), and ESRD on HD, who presented to the emergency room with complaints of a painful blister at the tip of his penis. He first noticed this lesion 2 weeks prior to presentation, however, the blister “popped” and developed into an open ulcer, which was tender to palpation. He initially presented to an outside facility where a biopsy of the lesion was performed. His pain increased after this intervention, as did the area of ulceration. He then transferred his care to our facility. At this point the patient complained of pain with voiding secondary to irritation of the lesion when contacted by urine, but denied difficulty emptying his bladder. He denied any fever, chills, nausea or vomiting. He denied any other concurrent lesions elsewhere on his body, however on exam it became apparent that he had two previous toe amputations and one current necrotic toe. Physical examination demonstrated a 1 cm ulceration on the lateral aspect of the glans penis, with an area of eschar. He was circumcised, but had some redundant foreskin which did not appear involved. The urethral meatus was patent and visible, though in close proximity to the edge of the lesion. Scrotal exam was normal. The patients laboratory studies revealed calcium level of 8.7 mg/dL, but a phosphorous, C × P product and PTH were not obtained. As there was no evidence of infection the patient was managed with wound care and pain control with Tramadol. He was seen one month later for persistent pain and was given narcotic pain medication, the eschar was carefully debrided at that time as well. Management continued with conservative wound care, pain control and debridement for the next six months. The wound stabilized, and improved somewhat, though it failed to completely resolve. The patient discontinued his Urology follow-up after approximately 3 months of care and was lost to follow-up. Patient 3 A 49-year-old male with history of DM, ESRD on HD, and peripheral vascular disease, admitted to the vascular surgery service for amputation of a gangrenous left fifth toe. On admission a small soft ulcer was noted on the tip of his penis. After 3 days this lesion became painful necrotic, and hard to the touch. The Urology service was notified to evaluate the lesion at this time. On exam the patient was
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Biopsy Recommendations for Penile Calciphylaxis circumcised with normal urethral meatus. A 2 cm lesion was noted on the left coronal margin of the glans penis which was black, firm, and raised. No erythema or purulent drainage was noted. The patient denied difficulty with voiding. His laboratory studies revealed a Ca of 7.4 mg/dL, C × P 71.0 mg2/dL2, and PTH of 799.8 pg/mL. The findings on initial consultation were consistent with penile calciphylaxis. The patient was managed with wound care, debridement of eschar, and pain control. No surgical intervention or biopsy was performed, and no antibiotics initiated secondary to a lack of evidence of infection. The patient was monitored closely in follow-up and was able to be managed with conservative interventions. He was readmitted approximately 3 month after initial presentation for amputation of two gangrenous toes and angioplasty of his right popliteal, internal iliac, and anterior tibial arteries for management of his peripheral vascular disease. He was lost to follow-up 5 months after his initial presentation.
Methods
Three recent patients with diagnoses of penile calciphylaxis from our institution were identified. The medical records of these men were examined and clinical and epidemiologic information was identified. Data pertaining to medical history were collected, including age, medical history of DM, ESRD and HD requirement. Laboratory data collected included serum Ca, C × P product, and PTH level. Management decisions were recorded including whether a penile biopsy had been
Table 1
obtained, as well as additional intervention. Clinical parameters noted included the presence or absence of non-penile cutaneous lesions at the time of diagnosis, as well as the location and characterization of the penile lesion itself. Outcomes including survival data, and time from diagnosis to death were recorded. A literature search from 1995 to 2012 was performed to identify case reports of penile calciphylaxis. Key words included penile calciphylaxis and penile calcific uremic arteriolopathy. Those studies included were those that provided the same clinical data obtained from the 3 patients from our institution.
Results
Three patients from our institution and 13 case reports from the literature were identified and reviewed for a total of 16 patients. The average age at diagnosis was 55.9 years old. Clinical attributes of these patients can be found in Table 1. Of the 16 cases of penile calciphylaxis evaluated, all patients had a past medical history significant for ESRD with HD requirement, and all but one patient (93.8%) carried a diagnosis of DM. Half of the patients (8/16) reported additional necrotic lesions present at sites other than the penis. Table 1 also illustrates the laboratory data obtained from these patients. Interestingly, of the 12 patients (75%), who had reported Ca values, only 1 patient had a slightly elevated level of 10.4 mg/dL (nml 8.5–10.2 mg/dL), while the rest were within normal limits. However, 80% (8/10) of those with reported C × P products and
Clinical attributes of men with penile calciphylaxis
Case #
Other site(s) of necrosis
DM
ESRD and dialysis
Calcium
C×P product
PTH
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Yes No Yes Yes Yes No Yes No No Yes No Yes No Yes No No
Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
7.4 8.7 9 ? 9.8 8.9 ? 8 ? ? 10.4 8.5 10.2 7.9 8.4 8.9
71.0 ? 75.6 ? 50.9 44.5 ? 64.8 ? ? 87 ? 105 75.8 62.1 67
799.8 ? ? 33 ? 1,462 816 516 30.8 48 430 121 82 379 38 1,280
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Table 2
Outcome of penile biopsy in men with penile calciphylaxis
Case #
Age
Biopsy
Intervention/outcome
1 2 3 4 5 6 7
49 38 62 72 41 72 59
No Yes No No Yes Yes Yes
8
64
Yes
9 10
66 38
No Yes
11 12
60 65
No Yes
13
58
Yes
14
59
No
15
35
Yes
16
56
Yes
Debridement Debridement Debridement Debridement Total penectomy, progression of disease, sepsis Circumcision Glans autoamputated, progression of disease, partial penectomy Debridement, progression of disease, total penectomy Partial penectomy, death from MI Circumcision, progression of disease, partial penectomy Partial penectomy Partial penectomy, progression of disease, total penectomy Debridement, progression of disease, resection of glans Glans autoamputated, progression of disease, partial penectomy Partial penectom, progression of disease, total penectomy Circumcision, progression of disease, partial penectomy, progression, total penectomy
Time (diagnosis to death)
Source
Alive at 5 months Alive at 3 months, LTF Death, 22 months Unknown, LTF Death, 9 months Death, 9 months Unknown, LTF
UVA series UVA series UVA series Bappa et al.; 2011 [5] Ohta et al.; 2007 [6] O’Neill et al.; 2012 [7] O’Neill et al.; 2012 [7]
Unknown, LTF
O’Neill et al.; 2012 [7]
Death, 4 weeks Alive at print
Prematilleke et al.; 2012 [8] Prematilleke et al.; 2012 [8]
Death, 5 weeks Unknown, LTF
Jacobsohn et al.; 2002 [9] Sorensen et al.; 2007 [10]
Alive at print
Sandhu et al.; 2012 [11]
Death, 3 months
Karpman et al.; 2003 [12]
Death, 2 months
Woods et al.; 2006 [13]
Unknown, LTF
Wood et al., 1997 [14]
Notes: LTF = Lost to follow-up
69.2% (9/13) with identifiable PTH levels had elevated values of >55 mg∧2/dL∧2, and >55 pg/mL respectively. Management and outcome data are presented in Table 2. The majority, 7/16 (43.7%), were managed aggressively with partial or total penectomy as the initial intervention. Following this, the second most common initial intervention was debridement in 6/16 (37.5%), while the least frequent initial management was biopsy and circumcision in only 3/16 (18.8%). Of those managed conservatively with debridement alone, 2/6 (33.3%) progressed. One required further intervention of a subsequent glans resection, while the other required total penectomy with perineal urethrostomy for progression. Patients managed with circumcision or dorsal slit as the initial intervention demonstrated a two-thirds rate of progression to subsequent partial or total penectomy. Of the 43.7% managed aggressively with initial partial or total penectomy, 5/7 (71.4%) progressed to require further resection or death, 1/7 (14.3%) stabilized, and the last patient died of a perioperative MI before his clinical course could be fully realized. Table 2 additionally includes data regarding outcomes, interventions, and disease course. In this cohort, 10/16 (62.5%) underwent biopsy as part of their initial treatment, while 6/16 (37.5%) J Sex Med 2014;11:2611–2617
did not. Of those biopsied 7/10 (70%) progressed and 3/10 (30%) stabilized. In the 6/16 (37.5%) patients who did not undergo penile biopsy, 3/6 (50%) stabilized, 2/6 (33.3%) progressed, and 1/6 (16.7%) died prior to documentation of progression. In the group managed aggressively with partial or total penectomy at presentation, 4/7 (57.1%) had an initial biopsy, and all but one (85.7%) progressed further after initial treatment. Of the 3/7 (42.9%) of this group that did not undergo biopsy, two progressed despite intervention and ultimately died, and one died perioperatively from MI. In the circumcision/ dorsal slit group, the two circumcision patients had biopsy performed prior to their circumcision with resultant progression of one patient, and stabilization of the other. The one patient who initially underwent a dorsal slit did not have a biopsy, but did progress. In the final group of patients who underwent debridement as initial intervention, 3/6 (50%) underwent biopsy prior to debridement. One progressed to a total penectomy, one to glans resection, and one stabilized after debridement. Of the 3/6 (50%) who had debridement only with no biopsy, none progressed. At the time of print, the survival data was only identified for 11/16 (68.8%) of the reported patients, as the remainder were lost to follow-up. The majority, 7/11 (63.6%) died, while the
Biopsy Recommendations for Penile Calciphylaxis remaining 36.4% were alive at the time of print. Of those 7 patients managed more aggressively with partial or total penectomy as initial intervention, 5 (71.4%) subsequently died, and 2 (28.6%) had unknown outcomes. The 3 patients managed initially with circumcision had divided outcomes with 1 dead, 1 alive, and 1 with unknown outcome. Finally, the debridement group reported 3 (50%) alive, 1 (16.7%) dead and 2 (33.3%) unknown. Overall, 10/16 (62.5%) patients underwent penile biopsy as part of their management (Table 2). Of those biopsied 7/10 (70%) progressed and 3/10 (30%) stabilized. In those patients who were not biopsied and only underwent debridement, none progressed. Of the seven patients who progressed to death at the time of print, 3/7 (42.9%) had a penile biopsy at some point during their care, while 4/7 (57.3%) did not. Of the 10 (62.5%) patients in our cohort not lost to follow-up 70% were deceased at the time of print, with a mean time to death of 6.5 months (Table 2). Excluding one patient who survived for 22 months, the mean time to death was 4 months. Discussion
Our rationale for the avoidance of lesional biopsy for the diagnosis of penile calciphylaxis is threefold. Firstly, we would argue that the diagnosis of penile calciphylaxis can be made from the history, physical exam findings, and laboratory values. Should further evidence be required, non-invasive imaging with CT scan or plain film has been reported to demonstrate visible calcification of the pelvic and perineal vasculature. Second, the development of penile calciphylaxis tends to be a late clinical manifestation of ESRD, with a high rate of mortality over a relatively rapid period of time. Finally, there is evidence in the literature to support that biopsy, and aggressive surgical intervention, of these poorly vascularized lesions frequently leads to poor wound healing, infection risk, and progression of disease [6,15]. As a result of these statistics, we would argue for the least invasive and disfiguring intervention possible. Addressing our first point, certain clinical findings are characteristic of patients with calciphylaxis. Calciphylaxis has been reported in up to 1–4% of patients with ESRD and HD requirement, and portends a poor prognosis and life expectancy [4,16,17]. Additionally, DM and obesity are associated with increased risk of calciphylaxis. In a study of 33 patients with penile calciphylaxis, 66% demonstrated additional gan-
2615 grenous sites, other than the penis at the time of presentation, and 76% had diabetes mellitus [12]. Supporting this data, all of the patients evaluated in this study reported a history of ESRD requiring HD, and 93.8% possessed a diagnosis of DM. Fifty percent of our patients had dermatologic lesions in additional regions aside from the penis. Laboratory values that have been associated with calciphylaxis include low serum albumin, elevated PTH, Ca, phosphate, and elevated C × P product [18,19]. Patients on HD are prone to develop high serum phosphate, which acts to promote calcification and differentiation of vascular smooth muscle into osteoblasts [20]. The elevation of serum phosphate promotes secondary hyperparathyroidism by decreasing serum Ca and inhibiting vitamin D activation. Elevation of PTH, in turn, causes release of Ca and phosphate from the bone, which elevates the serum C × P product. The C × P product is reportedly elevated in 80% of patient’s diagnosed with calciphylaxis [21]. When this product is higher than 70, the risk of ectopic vascular calcification is promoted [22]. When present, the elevation of PTH levels and C × P product, can help distinguish calciphylaxis from other diseases with dermatologic manifestations, such as scleroderma, without requiring biopsy of the lesion. While only one of our patients had an elevated serum Ca level, the majority with this reported data had elevation in C × P product (80%) and/or PTH (69.2%). As previously mentioned, biopsy has been utilized in the past to distinguish the dermatologic stigmata of calciphylaxis from other vascular, infectious, or malignant lesions. The lesions of calciphylaxis can be clinically differentiated from other dermatologic lesions including those from vascular calcification leading to arterial insufficiency and peripheral atherosclerotic gangrene without the utilization of biopsy [23]. These vascular deposits develop gradually over time, and are not associated with rapid tissue necrosis at multiple synchronous sites, as opposed to those associated with calciphylaxis [19,23]. Additionally, these two entities can be clinical distinguished by the typical absence of pain with distal gangrenous lesions due to vascular disease, whereas pain is often a presenting characteristic of calciphylaxis. All of the 16 patients reviewed here had painful, penile lesions at the time of diagnosis. The presence of peripheral pulses may also suggest a diagnosis of calciphylaxis as opposed to arterial insufficiency. Further characterizing these separate etiologies of gangrenous lesions is the observation J Sex Med 2014;11:2611–2617
2616 of clinical improvement seen in patients with calciphylaxis and elevated PTH after parathyroidectomy, while this intervention has no bearing on the course of vascular calcification with subsequent arterial insufficiency [14]. Similarly clinical history and physical exam can distinguish calciphylaxis from other infectious, inflammatory, or malignant causes for penile ulceration. A medical history including ESRD requiring HD, DM, obesity and/or a history of additional ischemic lesions, would increase the likelihood of calciphylaxis. An infectious or sexually transmitted lesion would clinically demonstrate other systemic and local signs and symptoms. Locally the wound would typically be warm, erythematous, painful, and possibly express exudate. Systemically, the patient would usually demonstrate leukocytosis, fevers, chills, and other outward signs. Wound and blood cultures could also be positive for bacterial organisms. Lesions caused by a systemic inflammatory or rheumatologic disease such as sarcoidosis, would likely be accompanied by a prior medical history consistent with these disease states. The lesions of malignancy tend to be distinct from those of penile calciphylaxis. The second factor supporting our recommendation to avoid biopsy and aggressive intervention, is the high mortality rate and short progression time to death reported in patients with penile calciphylaxis. A mortality rate of 64–69%, with a mean time to death of 2.5–6 months has been reported [12,24]. Though the majority of the seven patients in our study who died did not undergo biopsy, the average time to death between these two groups was longer for the group that was not biopsied. Additionally the average time to death was short regardless of the group, indicating a poor prognosis regardless of intervention. In our study, of the 10 (62.5%) patients in our cohort not lost to follow-up, 70% were deceased at the time of print, with a mean time to death of 6.5 months (Table 2). Excluding one patient who survived for 22 months, the mean time to death was 4 months. Our data supports the findings of poor prognosis and life expectancy in this patient population. Finally, we argue that more aggressive intervention, may lead to progression of the penile lesion. As seen in the literature, biopsy has repeatedly been followed by post-operative progression of the sampled lesion, requiring further, more invasive interventions [15]. One theory behind the rapid development and progression of these skin ulcers after biopsy and surgical intervention is that the J Sex Med 2014;11:2611–2617
Cimmino and Costabile surgical stress leads to increased activation of the sympathetic nervous system, promoting circulatory dysfunction, and rapid progression of the necrosis [6]. Though the pathophysiology is poorly understood, the literature demonstrates progression after insult, and corroborates the superiority of conservative treatment, unless patients had severe pain or in cases where administration of antimicrobial agents was difficult [25]. As seen in our cohort, 7/10 (70%) of patients who underwent biopsy ultimately progressed. Moreover, of the 3/16 (18.8%) patients who avoided biopsy and were managed with debridement only, all stabilized without further progression. Given the data regarding the high mortality, high risk of progression with intervention, and short duration of life portended by this diagnosis, it stands to reason that increasing comfort, and minimizing invasive procedures in this patient population is the appropriate management. The authors recognize that calciphylaxis is a rare disease, and involvement of the male genitalia is even less common. As a result, the number of patients available for evaluation is exceedingly low, making a more robust study with sophisticated statistical analysis challenging to provide. By evaluating the cases reports in the literature, as well as those patients from our own recent clinical experience we hoped to establish a pattern of response to interventions in this rare condition. Though these patients are not frequently encountered, mismanagement with biopsy or aggressive surgical intervention can lead to deterioration of the condition, and a marked worsening of quality of life for the patient. Through this review, the authors hope to raise awareness of this disease process in an attempt to guide treatment, and avoid unnecessary procedures when penile calciphylaxis is encountered by the consulting Urologist. Conclusion
Calciphylaxis is an uncommon, but devastating manifestation of ESRD. Due to the abundant blood supply to the penis, penile necrosis secondary to disorders of circulation are even more rare leading to uncertainty regarding diagnosis and management. Based on the results of our study, we argue that conservative measures such as careful wound debridement and aggressive management of electrolyte abnormalities should be employed as first line therapy for penile calciphylaxis. More aggressive measures such as partial or total
Biopsy Recommendations for Penile Calciphylaxis penectomy should be reserved for progressive infection or intractable pain. More importantly we argue that, secondary to the likely resultant progression of necrosis, penile biopsy is not only unnecessary for diagnosis of penile calciphylaxis, but is also harmful and contraindicated. Corresponding Author: Cara B. Cimmino, MD, Piedmont Urology Specialists, 275 Collier Rd, Suite 400, Atlanta, GA 30309, USA. Tel: 404-605-4848; Fax: 404-351-5517; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Statement of Authorship
Category 1 (a) Conception and Design Cara B. Cimmino; Raymond A. Costabile (b) Acquisition of Data Cara B. Cimmino (c) Analysis and Interpretation of Data Cara B. Cimmino
Category 2 (a) Drafting the Article Cara B. Cimmino (b) Revising It for Intellectual Content Cara B. Cimmino; Raymond A. Costabile
Category 3 (a) Final Approval of the Completed Article Cara B. Cimmino; Raymond A. Costabile References 1 Guvel S, Yaycioglu O, Kilinc F, Torun D, Kayaselcuk F, Ozkardes H. Penile necrosis in end-stage renal disease. J Androl 2004;25:25–9. 2 Mohammed IA, Sekar V, Bubtana AJ, Mitra S, Hutchinson AJ. Proximal calciphylaxis treated with calcimimetic “Cincacalcet”. Nephrol Dial Transplant 2008;23:387–9. 3 Llach F. The evolving clinical features of calciphylaxis. Kidney Int Suppl 2003;85:S122–4. 4 Rogers NM, Coates PTH. Calcific uraemic arteriolopathy: An update. Curr Opin Nephrol Hypertens 2008;17:629–34. 5 Bappa A, Fayaz H, Mustafa A, Abdullah A. Penile gangrene due to calcific uremic areteriopathy. Ann Afr Med 2011;10: 181–4.
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