UrologySchool.com

ANDROLOGY: PEYRONIE'S DISEASE

Includes 2015 AUA and 2018 CUA Peyronie's Disease Guideline Notes

Background
Epidemiology
Pathophysiology
Penile anatomy and Peyronie's Disease
Natural history
Diagnosis and Evaluation
Management
- Non-surgical
- Surgical
Questions
Answers

Background

Definition of Peyronie’s disease (PD):
1. Acquired penile abnormality
2. Characterized by fibrosis of the tunica albuginea
3. Which MAY be accompanied by (4) Peyronie’s Disease Erectile Dysfunction:

Pain
Deformity
- Including curvature, indentation, hinge effect, and shortening
Erectile dysfunction
Distress

Epidemiology

Peak age of onset is early 50s, affects all races
Prevalence: 9% of men

Pathophysiology

PD is an inflammatory disorder of the tunica albuginea

Microvascular trauma to the penile shaft associated with penile buckling in the erect or semi-erect state secondary to sexual activity is thought to be the most common inciting event, though most men cannot recall a specific event
- Exact cause not known. Some injurious stimulus is necessary to trigger the cascade of events that leads to PD in the susceptible individual. This can be in the form of trauma in the erect or flaccid state. However, not all trauma is associated with PD.
Normal wound healing involves 3 phases:
1. An acute phase
2. A proliferative phase
3. A remodeling phase
  - In PD, the scar does not undergo normal remodeling and therefore the scar and deformity persist

Risk factors (9): IT DRAG A Crooked Wand
1. Infection
2. Trauma
3. Diabetes
4. Radical prostatectomy (prevalence 11-16%)
5. Increasing Age
6. Genetic predisposition
7. Autoimmune factors
8. Collagen disorders (Dupuytren contracture, fibrosis of plantar fascia (Ledderhose’s disease), tympanosclerosis)
9. Aberration of localized Wound healing
10. Others: hypertension, hyperlipidemia, smoking, heart disease
Hypogonadism is associated with more severe Peyronie's disease. Supplemental testosterone improved the efficacy of intralesional verapamil in patients with hypogonadism
PDE5 inhibitors are not associated with Peyronie's disease

Oxidative stress has a well-documented role in tissue fibrosis and has been studied in the pathogenesis of PD
Nitric oxide has anti-fibrotic effects
Myofibroblast activation is a key event in the development of fibrosis
TGF-β1 has been shown to be significantly associated with PD. TGF-β is a strong activator of myofibroblasts and is known to be a potent fibrotic growth factor by stimulating the deposition of ECM.
A variety of alterations may be present in a given patient so no treatment works uniformly for all patients

Penile Anatomy and Peyronie's Disease

See Penile Anatomy Chapter Notes
The outer longitudinal layer of the tunica albuginea is thinnest at the 3 and 9 o clock positions of the corpora. It is completely absent between the 5 and 7 o'clock positions.
- This may contribute to greater ease of dorsal buckling and explain why most PD patients exhibit dorsal curvature
  - 60-70% of plaques are located on the dorsal aspect of the penis and are usually associated with the septum
Penile deformity is caused by asymmetrical expansion of the corpora.
- When expansion is limited at one point along the circumference of the corpora by the inelastic scar of the Peyronie plaque, deviation to that side occurs
  - Note that in penile fracture, the penis deviates away from side of injury
  - A circumferential plaque may lead to an hourglass deformity

Natural history

PD is characterized by symptoms with a variable course, some of which may improve or resolve without treatment in some patients.
Plaque-related pain improves and/or resolves in the majority of patients with time even in the absence of treatment. Conversely, spontaneous resolution or significant improvement of penile deformity is rare

The natural history of Peyronie disease is complete pain resolution in ≈90% of men
Penile curvature improves in only 12-13% of men, worsens in ≈45%, and remains stable in ≈42%.

Active vs. Stable Disease

Active (acute) disease:

Characterized by dynamic and changing symptoms
Defining symptom: penile and/or glanular pain or discomfort with or without erection

Stable (chronic) disease:

Symptoms have been clinically quiescent or unchanged for ≥3 months
Pain with or without erection may be present but is less common
Additional symptoms include difficulty in maintaining erectile function and inability to sustain intercourse

The presence of penile pain, especially with erection, increases the likelihood of a penile septal scar, an atypical form of Peyronie disease, which may be characterized by symptoms including penile shortening, pain, and ED, even in the absence of deformity or palpable disease

Diagnosis and Evaluation

UrologySchool.com Summary:
- AUA:
  - Mandatory (1): history and physical exam
  - Recommended (1): detailed examination of erection (photograph or in-office ICI testing) prior to invasive intervention
- CUA:
  - Mandatory (1): history and physical exam
  - Recommended (1): detailed examination of erection (photograph or in-office ICI testing) prior to invasive intervention

History and Physical exam
- History
  - Symptoms: onset, duration, history of traumatic event if applicable, deformity and erectile changes over time, acquired vs. lifelong (to differentiate Peyronie disease vs. congenial penile curvature), and medical history inclusive of family presence of Peyronie disease, Dupuytren’s contracture, and other related conditions that may impact erectile and sexual function. Prior Peyronie disease and ED treatments should be documented.
  - Penile characteristics: extent of penile deformity, direction of curvature, presence of hourglass deformity, palpable plaque(s), interference with intercourse, penile pain with and without erection, shortening, and presence of hinging. Penile sensation, ejaculatory function, and length/girth concerns should be documented. Digital home photographic documentation may aid in objectively determining treatment effects, especially when non-surgical options are used
    - Pain, when present in the acute phase, can occur in the flaccid penis with palpation of the plaque, with erection, or during intercourse
    - Once the disease process is stable, most pain will resolve, but in some men the pain persists with a pulling sensation on the plaque when a strong erection occurs (torque pain)
  - Sexual function: erectile rigidity, ability to penetrate, ability to complete intercourse, and partner complaints and support should be documented. The use of the International Index of Erectile Function-5 (IIEF-5) or the Disease Questionnaire Peyronie’s (PDQ), which is a newer, 15-item, validated instrument specific to Peyronie disease may be of use.
  - Psychologic impact: Many men with PD experience emotional distress, depressive symptoms, and relationship difficulties. PD can have a profound negative impact on men’s QoL.
    - Based on bother/psychologic impact, consideration may be made for referral to a mental health professional with expertise in sexuality.
  - AUA Guidelines: “The recent onset of penile curvature and varying degrees of penile pain, without a palpable penile abnormality, in the non-erect state, may be considered diagnostic”
  - A diagnosis of ED or failed first- and second-line ED treatments warrants ruling out Peyronie disease
- Physical exam of the genitalia to assess for palpable abnormalities of the penis
  - Plaque(s) can be palpated or documented on ultrasound.
    - To assess the plaque, the penis should be examined on stretch. Palpation should be performed to identify the location, size, number and tenderness of the plaque.
      - The most common plaque location is on the dorsal mid-shaft
      - The location of the plaque may be useful to record, but the measurement of size of the plaque with any modality, including imaging, has been found to be inaccurate
  - Measurement of stretched penile length from the penopubic skin junction to the coronal sulcus or the tip is recommended to establish baseline penile length prior to any intervention as penile length loss is a primary concern and contributor to distress for Peyronie disease patients

Penis with ventral curvature

Source: Wikipedia

Laboratory

Routine laboratory testing is not recommended; however, targeted bloodwork may be obtained in response to specific findings on history or physical examination (for example, signs/symptoms of hypogonadism)

Imaging

Options
- Ultrasound
  - Benefits (4):
    1. Identification and measurement of calcification during initial surveillance in the flaccid state
      - Calcification may occur early after the onset of the scarring process, not necessarily only in chronic/mature disease.
      - Men with extensive calcification are less likely to benefit from non-surgical treatment
    2. Identification of corporeal fibrosis
    3. Assessment of penile vascular flow parameters after intracavernosal injection of vasoactive agent
    4. Observation of the erectile response to the vasoactive injection compared to the patient’s sexually induced erection; best opportunity to objectively assess deformity (curvature, girth irregularities, hinge effect)
  - CUA: colour duplex ultrasonography may be offered, but may not be readily available; combination of ultrasound with intracavernosal injection may also identify arterial insufficiency or veno-occlusive dysfunction, influencing choice of Peyronie disease management

Source: Wikipedia

MRI is an excellent imaging modality for penile pathology, including Peyronie disease, but its routine use in clinical practice is not supported
CT and plain radiography do not have a role

Other
- Detailed examination of erection prior to any invasive intervention (e.g., intralesional treatments or surgery)
  - Prior to invasive therapy, obtain accurate assessment of erect penile length, degree of curvature, hourglass deformities, and rigidity of erection
    - This can be done with digital photographs or examination after penile injection of vasoactive agents (gold standard)
      - The ICI test enables assessment of penile deformity, plaque(s), and pain in the erect state.
        
        When the ICI test is combined with duplex ultrasound, additional measurements of plaque size and/or density can be made, calcified and non-calcified plaques can be differentiated, and information on the vascular integrity of the penis can be obtained.
      - AUA prefers in-office intracavernosal injection (ICI) test with or without duplex Doppler ultrasound but describes that home photography of the erect penis with the use of a protractor during an erection in the office may be sufficient to document deformity from some cases.
      - CUA describes both as options but describes the use of ICI as the most reliable method and that penile injection remains the gold standard, especially in patients reporting complex deformity (hourglass or bidirectional curvature) or ED

Differential diagnosis of Peyronie's Disease (4):
1. Congenital penile curvature
2. Thrombosed or torn dorsal penile vein
3. Penile fracture
4. Penile cancer (rarely)

Management

See 2015 AUA and 2018 CUA Guideline Notes

Only clinicians with expertise in Peyronie’s disease should treat affected patients
Discuss with the patient a care plan, which is consistent with patient symptom status, current health, and treatment goals.
Conservative
- Patients without pain or difficulty in accomplishing penetrative sex may only require reassurance
Intervention
- Non-surgical (4) options:
  1. Penile traction
  2. Oral medication
  3. Intralesional injection
  4. ESWT
- UrologySchool.com Summary of non-surgical interventions for Peyronie's Disease
  - AUA:
    - Recommended:
      - Active phase: NSAIDs for pain
      - Stable phase: penile traction, intralesional treatment with modelling
    - Conditional: extracorporeal shockwave therapy for pain
      - Recommendation is Conditional because the broader PD literature indicates that pain is the PD symptom that is most likely to resolve over time without intervention, the patient burden involved in obtaining ESWT treatment to treat pain may be substantial, and other treatments may be equally effective at alleviating pain. Further, ESWT is associated with frequent adverse events
  - CUA (mostly similar to AUA, except CUA lists some oral medications that may be considered while these are not supported by AUA):
    - Recommended:
      - Active phase: NSAIDs for pain
      - Stable phase: penile traction, intralesional treatment with modelling (first-line: collagenase; second-line: verapamil or interferon where cost or concern related to adverse events limits use of collagenase; AUA does not use similar hierarchy of preferred treatments)
    - May be considered:
      - Oral medication (alone or as a part of multimodal care) (different than AUA):
        
        Can Consider Peyronie's Pills (4)
        
        Colchicine
        
        Co-enzyme Q10
        
        Potassium paraaminobenzoate
        
        Pentoxifylline
      - Extracorporeal shockwave therapy for pain
  1. Penile traction
    - First-line non-invasive, non-surgical treatment modality
    - No RCT to date
    - Associated with (4):
      1. Reduced curvature
      2. Increased stretched penile length
      3. Increased erect girth
      4. Correction of hinge effect
      - Benefit maintained at 6 months of completion of therapy
    - Critical that patient wears device for ≥3 hours per day to get satisfactory results
  2. Oral medication
  3. Intralesional injection
    1. Clostridial collagenase (Xiaflex)
      - Produced by the bacterium C. histolyticum
      - Selectively degrades collagen types I and III in connective tissues
      - Associated with:
        
        Decrease in deviation angle
        
        Reduction in plaque size
        
        Does NOT treat pain or ED
      - Appropriate in patients with (2)
        
        Curvature >30° and <90°
        
        Intact erectile function (with or without the use of medications)
      - Potential adverse effects: penile bruising, pain, swelling, hematoma, and corporal rupture
        
        Corporal rupture, while extremely rare, will often necessitate surgical repair
      - Should be combined with penile modeling by the physician and patient
      - Discontinued in Europe and Canada in 2020 due to cost and poor market uptake§
    2. Calcium channel blocker
      1. Verapamil
        
        Affects fibroblast function on several levels, including cell proliferation, ECM protein synthesis and secretion, and collagen degradation
        
        Evidence for the use of intralesional verapamil is weak
        
        Poor candidates include those with:
        
        Extensive calcification
        
        Curvature >90°
        
        Ventral curvature (difficult to adequately infiltrate the plaque)
        
        Predictors of success include:
        
        Younger age (age < 40)
        
        Curvature >30°
        
        Potential adverse effects: penile hematoma, pain, dizziness, and nausea
      2. Nicardipine
        
        Demonstrated significant reduction in pain, improvement in IIEF-5 score, and reduction of plaque size when compared to placebo
    3. Interferon alfa-2b
      - Modest improvement compared to placebo
      - Used to reduce curvature, plaque size, pain, and improve some vascular outcomes
      - Can be used in patients with curvature > 30° and without calcified plaque
        
        The magnitude of treatment effect beyond placebo is modest
      - Significant cost and side effects, including: sinusitis, flu-like symptoms of arthralgia, fevers, and chills, and local effects including penile hematoma, swelling, and pain; rarely used in Canada
  4. Extracorporeal shockwave therapy
  - Combination therapy of daily pentoxifylline and L-arginine, biweekly verapamil injections, and daily traction, provides the best opportunity for deformity improvement.
  - Not effective
    - Topical agents
      - No topically applied agent (e.g. verapamil gel) has been shown to be effective in the treatment of PD
    - Transdermal drug delivery with verapamil or dexamethosone using electromotive technology
      - Was proposed to be superior to oral or injection therapy because it bypasses hepatic metabolism and minimizes the pain of inject. This approach has limited evidence of benefit
    - Vacuum therapy
      - Safe but unlikely to be of benefit due to short-term duration of stretching forces
    - Radiation
      - Should be avoided because of potential risk of malignant change and increase in the risk of ED in aging patients

Surgical management

Indications for surgical intervention in Peyronie’s disease (4):

Stable disease (defined by AUA as disease that is ≥ 1 year from onset and ≥3-6 months of stable deformity)

CUA considers stable disease after 6-12 months after disease onset and ≥3-6 months of stable deformity

The surgical literature focuses almost entirely on patients with stable disease; outcomes for patients with active disease are not known.

Although pain is associated with acute phase, surgery may be considered even in the presence of pain if persistent penile pain during erection is related to penile deformity.

Deformity that compromises sexual intercourse

Failure of non-surgical therapy

It is not incorrect to bypass medical management and proceed straight to surgery; however, the patient must clearly be aware and have consented to the potential treatment side-effects of surgery.

Desire for most rapid and reliable result

Pre-operative counselling (4):

Persistent or recurrent curvature

Goal is to make penis “functionally straight” (penetration not compromised, usually corresponding to residual curvature < 20º) vs. completely straight (comparing to pre-PD anatomy))

Reduction of penile erect length

Result is more likely shorter with plication than with grafting

Diminished rigidity

≥5% in all studies—grafting more than plication

≥30% if suboptimal pre-operative rigidity—dependent on pre-operative erectile quality

Decreased sexual sensation

Typically resolves in 1-6 months

Rarely compromises orgasm or ejaculation

Surgical approach

Depends on erectile function and severity of deformity

Options (3):

Capable of erection (with or without adjunct therapy (oral medications, vacuum pump therapy, or intracavernosal injection) and lack of deformity precluding intercourse

Plication

Plaque incision, partial excision, or excision, with grafting

Refractory erectile dysfunction or severe deformity

Prosthesis

Men who are considering penile straightening procedures without a penile prosthesis should be carefully evaluated for the quality of their pre-operative erections

CUA Guidelines recommend pre-operative evaluation with combination of colour duplex ultrasonography with intracavernosal injection (CDU-ICI) to delineate both disease extent and intact erectile function; however, CDU-ICI may not be required in cases where normal rigidity is present and digital photographs at full erection delineate disease extent

Plication may have less risk of new ED compared with grafting procedures. However, grafting more likely to restore penile length compared to plication.

Post-operative rehabilitation period (e.g. traction) is designed to improve postoperative healing and outcomes by (4):

Preventing shortening

Encourage straight wound healing

Preserve vascular integrity

Encourage partner participation.

Tunical plication (tunical shortening procedures)

Aims to shorten the longer (or convex) side of the tunica albuginea to match the length to the shorter side

Recommended for (3):

Simple curvature <70°

Minimal/absent hourglass or hinge effects

Adequate penile length; those in whom the anticipated loss of length would be < 20% of total erect length

Advantages (4):

Shorter surgical time

Good cosmetic outcomes

Minimal effect on rigidity

Simple and safe surgery

Effective straightening

Disadvantages (2):

Penile shortening

Predictors of shortening include direction and degree of curvature

Ventral curvature >60° has greatest potential for loss of penile length

Failure to correct an hourglass or hinge

Complications (7):

Persistent pain

Persistence or recurrence of penile curvature (>30º, ≈10%)

Penile hematoma (≈5%)

Urethral injury (≈1%)

Palpable suture knots

Loss of penile length by default, but tend to preserve potency

Types of plication surgery (3):

Nesbit: excision of an elliptical segment of the tunica on the contralateral side of the curvature

Yachia: full-thickness vertical incision is made on the vertical shaft tunica, which is then closed transversely to shorten the ventral aspect and correct the curvature

16-dot

Imbrication procedures are used to avoid making a full-thickness tunical incision and fold the tunica to correct curvature

No head-to-head studies of the primary types of plication surgery

During a dorsal penile plication, the deep dorsal vein is occasionally ligated, dissected, and excised and the plication sutures are then placed in the venous bed.

Plaque incision or partial excision and grafting (tunical lengthening procedures)

Aims to lengthen the shorter (or concave) side of the tunica albuginea to match the length of the longer side

Grafting follows incision, partial excision, or excision of plaque

Recommended for:

More complex curves >70° (CUA suggests >60°)

Large plaques

Hourglass or complex deformities

Concern or functional compromise attributable to further length loss with plication approaches

Ventral deformity does not do well with grafting procedures

Grafting does not ensure length preservation, but offers the advantage of decreasing risk of irreversible erectile tissue damage

Grafting associated with increased risk of reduced rigidity compared to plication

Must have strong pre-operative erections for grafting (either with plaque incision and grafting (PIG) or partial plaque excision and grafting (PEG)) and no evidence of venous insufficiency on duplex ultrasound

Graft material

Two most commonly used grafts are Tutoplast (processed human and bovine pericardium), and porcine small intestinal submucosa grafts

Multiple autologous grafts have been used historically, including fat, dermis, tunica vaginalis, dura mater, temporalis fascia, saphenous vein, crura or albuginea, and buccal mucosa. These have fallen out of favor because of a need for extended surgery to harvest the graft as well as a second surgical site, which has its own potential complications of healing, scarring, and possible lymphedema

Synthetic grafts, including polyester and polytetrafluoroethylene, should not be used due to increased risks of infection, secondary graft inflammation causing tissue fibrosis, graft contractures, and possibility of allergic reactions

Penile prosthesis for men with Peyronie Disease

Gold standard treatment for PD requiring surgery occurring concurrently with refractory ED

Indications (2):

Severe deformity refractory to non-surgical management or failed plication/grafting

Profound penile instability (buckling or hinge).

If significant (> 30°) deformity persists after insertion of the penile prosthesis, additional straightening maneuvers including manual modeling and incising the tunica albuginea with or without grafting may be necessary

The most common adverse event occurring after manual modeling during placement of a penile prosthesis is urethral injury

Inflatable penile prosthesis is the preferred surgical implant.

See Surgery for Erectile Dysfunction Chapter Notes

Most common postoperative complaint with prosthesis is length loss

Complications may include prosthesis infection, persistent penile shortening or curvature, diminished sensitivity, and mechanical device failure or difficulties.

Questions

List risk factors associated with Peyronie’s disease
In the absence of treatment, what proportion of patients with Peyronie’s disease will have improvement, no change, or worsening of their disease?
What is the recommended work-up of a patient with suspected Peyronie’s disease?
What are signs and symptoms associated with Peyronie’s disease?
What is the differential diagnosis of Peyronie’s Disease?
Use of which oral medication is supported in the treatment of Peyronie’s disease? Which ones are not recommended? Which ones may be considered?
What are the recommended intralesional treatments of Peyronie’s disease? Which are not currently recommended?
What are potential adverse events related to the use of intralesional collagenase?
Which Peyronie’s disease defects may not be suitable for intralesional collagenase?
What is the role of extracorporeal shockwave lithotripsy in the management of Peyronie’s disease? Penile traction? Radiotherapy?
What are the indications for surgery of Peyronie’s disease?
What are potential risks of surgical intervention for Peyronie’s disease?
What are the surgical options to treat Peyronie’s disease? Which approach is suitable for a patient with intact erectile function and an hourglass deformity?
What are different techniques of performing tunical plication?

Answers

List risk factors associated with Peyronie’s disease

Infection
Trauma
Diabetes
Radical prostatectomy
Autoimmune
Genetic
Collagen disorders (Dupuytren’s, plantar fasciitis, tympanosclerosis)
Aberrant wound healing

In the absence of treatment, what proportion of patients with Peyronie’s disease will have improvement, no change, or worsening of their disease?
What is the recommended work-up of a patient with suspected Peyronie’s disease?
- History, physical exam, detailed examination of erect penis
What are signs and symptoms associated with Peyronie’s disease?
What is the differential diagnosis of Peyronie’s Disease?
Use of which oral medication is supported in the treatment of Peyronie’s disease? Which ones are not recommended? Which ones may be considered?
- Supported: NSAIDs for pain
- May be considered: potassium para-aminobenzoate, colchicine, co-enzyme Q10, and/or pentoxifylline
- Not recommended: vitamin E, tamoxifen, procarbazine, Vitamin E/L-carnitine
What are the recommended intralesional treatments of Peyronie’s disease? Which are not currently recommended?
- Recommended: collagenase, interferon alpha, and verapamil
- Not currently recommended: corticosteroids, botox, PRP
What are potential adverse events related to the use of intralesional collagenase?

Penile hematoma
Pain
Swelling
Corporal rupture

Which Peyronie’s disease defects may not be suitable for intralesional collagenase?
What is the role of extracorporeal shockwave lithotripsy in the management of Peyronie’s disease? Penile traction? Radiotherapy?
What are the indications for surgery of Peyronie’s disease?

Stable disease (defined as disease that is ≥ 1 year from onset and ≥6 months of stable deformity)
Deformity that compromises sexual intercourse
Failure of conservative therapy
Desire for most rapid and reliable result

What are potential risks of surgical intervention for Peyronie’s disease?

Persistent or recurrent curvature
Loss of penile length
Loss of penile sensation
Reduced erectile rigidity

What are the surgical options to treat Peyronie’s disease? Which approach is suitable for a patient with intact erectile function and an hourglass deformity?
What are different techniques of performing tunical plication?

References

Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, vol 1, chap 31
Nehra, Ajay, et al."Peyronie’s disease: AUA guideline." The Journal of urology 194.3 (2015): 745-753.
Bella, Anthony J., et al."2018 Canadian Urological Association guideline for Peyronie’s disease and congenital penile curvature." Canadian Urological Association Journal 12.5 (2018): E197.