Department of Urology Case of the Month

Recurrent Penile Swelling in a Healthy Adolescent

EVALUATION AT NYU LANGONE HEALTH This 15 y.o. presented for evaluation of recurrent penile swelling. Three years ago, he had significant penile swelling attributed to insect bites. Keflex was administered with resolution of the swelling. One year ago, he re-developed penile swelling, which was treated with Keflex and steroids with eventual resolution. Allergy testing was positive for common allergens, including pollen and cats. Endocrinology evaluation revealed no etiology for the swelling, which reoccurred about 1 month before his visit to NYU Langone. He was given Amoxicillin, Keflex, a Medrol pack, and Atarax without resolution of the swelling. There was no discomfort or erythema associated with the swelling. No history of other abnormal areas of swelling, i.e., mouth or lips.

PMH and family history: Constipation, age 9 years; normal colonoscopy; no current GI symptoms; short stature treated with growth hormone therapy Dad: irritable bowel syndrome; Hashimoto’s disease Mom: Sjogren’s syndrome; Hashimoto’s disease

Pertinent findings on physical examination: Circumcised phallus; entire penile shaft edematous, non-pitting with chronic skin thickening/induration; dorsal skin foreshortening with saxophone- like shape to shaft and glans; glans normal; normal meatus; bilaterally descended testes normal on palpation; in supine, + left varicocele difficult to palpate due to upper half of scrotum involved with skin thickening/induration; no erythema (Figure 1)

Sonographic evaluation: A scrotal sonogram showed normal-appearing testes, bilaterally. The right testis has a volume of 12.6 cc and the left, 10.4 cc. A large left varicocele was present; no varicocele on the right in standing. Thick (1.2 cm) edematous scrotal wall (upper 1/3) extending to the penile shaft without hyperemia. No abscess or focal lesion.

The working diagnosis was lymphedema of the penile shaft. The left varicocele with the significant size discrepancy was discussed with the recommendation for delayed left varicocelectomy. The patient was advised to consult a pediatric dermatologist for examination and punch biopsy for a definitive diagnosis. Physical examination by the pediatric dermatologist confirmed the findings of penile edema and revealed no other areas of swelling or skin abnormalities. A presumptive diagnosis of cutaneous Crohn’s disease (CD) involving the penis was confirmed on penile shaft punch biopsy, which showed granulomatous inflammation.

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Figure 1. “Saxophone” Penis Pediatric Dermatology, Vol 33, Issue: 1, 14-15 ; 2016.

MANAGEMENT The patient was started on prednisone 60 mg QD with very minimal improvement. While tapering the prednisone, Tacrolimus 0.1% ointment BID (an immunosuppressant that is a topical calcineurin inhibitor that blocks T cells’ activation) was started pending approval for adalimumab (Humira®), a biologic medication. The prior pediatric GI was consulted. Since the inflammatory markers were WNL, and there were no GI symptoms, a colonoscopy was not performed. The Crohn’s IBDX prognostic panel and a fecal calprotectin level were WNL. (Calprotectin is a protein found in neutrophils that has strong antibacterial and antifungal properties. Calprotectin is activated when inflammation occurs and can be used as a diagnostic indicator. The concentration of calprotectin relates directly to the severity of the inflammation. Calprotectin assesses disease activity but also flares in both symptomatic and asymptomatic patients. Regular follow-up with pediatric GI is planned.

DISCUSSION This case represents the second patient I have managed in 30 years with cutaneous CD. The lessons learned from our very knowledgeable pediatric dermatologist, Dr. Vikash Oza, were instructive, and in the future, CD will be included in my differential of penile swelling. The first patient with this condition presented at 10 years of age with oral/facial swelling as well as chronic penile lymphedema for 2 years. He had been seen by a variety of specialists without a diagnosis. The patient was referred to Dr. Oza, who noted uniform swelling of the lips; upper gingival overgrowth; mild erythema of the cheeks and upper arms; uniform swelling of the penile shaft; and indurated, erythematous plaques in the perianal region. Dr. Oza made the presumptive diagnosis of cutaneous CD in a “split-second.” He has not developed CD 3 years later.

I think about how many swollen penises I have seen over the years and attributed the swelling to an allergic reaction due to; possibly an insect bite or contact dermatitis. Being unfamiliar with cutaneous CD years ago, I would not have recognized this cutaneous marker in a child or adolescent, which would aid in their timely diagnosis and management of CD since approximately 30% of individuals with CD present in childhood.

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HISTORICAL NOTES AND INTRODUCTION In 1932, Dr. Burrill B. Crohn and his colleagues reported on a subacute or chronic necrotizing inflammation of the terminal ileum, termed regional ileitis. Later, it was found that this disorder could involve any area of the GI tract. It was soon recognized that up to 44% of patients with CD have a cutaneous manifestation at some point in their disease course, making the skin the most common site of extra-intestinal involvement. In 1965, the first description of non-caseating or non-necrotizing granulomas at sites noncontiguous to the GI tract was reported by Parks et al., and 5 years later, Mountain coined the term MCD—metastatic Crohn’s disease. In children, the skin findings more frequently precede the GI symptoms by months to years. Skin lesions often complicate CD.

The GI tract and skin lesions have been divided into 3 broad categories based on pathologic mechanism. (Table 1)

1. CD-specific manifestations: oral CD, fissures and fistulas, and MCD; mechanism identical to that of the GI tract; majority of lesions with the exception of MCD, which is rare but critical to recognize since it often precedes the diagnosis of GI CD.

2. Reactive: erythema nodosum and oral aphthae are most common; mechanism distinct from GI tract; development may be related to cross-antigenicity between the skin and GI tract.

3. Associated: vitiligo, palmar erythema, clubbing, hidradenitis suppurativa; no well-defined Tablemechanism 1 Cutaneous Manifestations of Metastatic Crohn's Disease

Table 1. Cutaneous Manifestations of Metastatic Crohn’s Disease (Pediatric Dermatology, Volume: 35, Issue: 5, 566-574)

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Pathogenesis of MCD In a susceptible host, CD is thought to develop genetic predisposition, environmental factors, epithelial barrier dysfunction, and abnormal immune responses to pathogenic and commensal bacteria. Although there are several theories on the pathogenesis of MCD, the exact etiology remains unknown. MCD lesions are thought to be related to a granulomatous response to unidentified antigens from the GI tract. The antigens are deposited into the skin leading to a perivascular inflammatory response. Another theory invokes a granulomatous vasculitis as seen in type IV hypersensitivity via sensitized T lymphocytes reacting to circulating antigens, causing granulomatous injury to the vessel wall and inflammation.

Epidemiology As many as 30% of patients present with CD at < 20 years, and ~2% are diagnosed at < 10 years. Cutaneous CD occurs in almost half of patients who ultimately develop CD. Cutaneous CD affects males and females of all ages equally (mean age of presentation ~9 years for both sexes). At least 7-24% of children have MCD, but this lower occurrence rate is thought to be an underestimation of reporting or diagnosis.

Clinical Presentation MCD can occur before, concurrently, or after GI symptoms manifest. About 86% of pediatric MCD occur in patients with no known intestinal CD, but in those patients, intestinal disease was diagnosed within 6 years of the MCD diagnosis. Another study reported children with MCD diagnosed with intestinal CD 9 months to 14 years of age with a mean age of onset of pediatric CD being 10-14 years. There has been no correlation between MCD and GI disease, but cutaneous findings tend to be associated more frequently with colonic vs. ileal involvement. Genital swelling is the most common presentation of MCD. This can involve edema; erythema; fissures; and ulceration of the vulva, penis, and scrotum, as well as lymphedema; skin tags; and condyloma-like growths. About 2/3 of children had genital involvement at presentation, while only 1/2 of adults have affected genital sites; 82% of the children had had GI symptoms at presentation. Extra-genital MCD may involve the extremities, trunk, breast, and intertriginous zones.

Diagnosis Management MCD is a rare cutaneous manifestation of CD and is often difficult to recognize since it appears similar to other dermatoses, both granulomatous and non-granulomatous, as listed in Table 2. Diagnosis starts with a detailed history and physical examination. Once the possibility of MCD or other cutaneous manifestations of CD have been entertained, a referral to dermatology for a thorough skin examination and biopsy is warranted for definitive diagnosis.

Table 2. Differential Diagnosis of Metastatic Crohn’s Disease (BioMed Research International 2017 p 3)

Granulomatous Disorders Nongranulomatous Disorders

Cutaneous sarcoidosis Hidradenitis suppurative Tuberculosis Pyoderma gangrenosum Syphilis Impetigo Mycobacterial infections Erythema nodosum Actinomycosis Factitial dermatitis from factitial injection of foreign substances Deep fungal infections Schistosomiasis Lymphogranuloma venereum Chronic lymphedema resulting from obstruction Erysipelas Granuloma inguinale Chronic cellulitis Foreign body reaction

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The histology of the MCD is similar to the dominant histology of the CD bowel lesions, as previously mentioned. (Figure 2) On biopsy of genital lesions, the finding of sterile, non-caseating granulomas with foreign body or Langerhans giant cells, epithelioid histocytes, lymphocytic infiltrate, and plasma cells, similar to CD or granulomatous lymphangitis, are seen on histological examination. The inflammatory infiltrate can surround dermal blood vessels and is termed “granulomatous perivasculitis.”

Figure 2. Pathology of Metastatic Crohn’s Disease-9 Metastatic Crohn’s disease. A, Microscopic examination demonstrates noncaseating granuloma formation with brisk lymphocytic infiltration involving the papillary and mid dermis. B, Higher magnification highlights a well-formed granuloma consisting of epithelioid histiocytes and lymphocytes. Some histiocytes are angiocentric. (A and B, Hematoxylin-eosin stain; original magnifications: A, ×20; B, ×40.) J Am Acad Dermatol, Vol 71, Issue 4, 2014, 807,

The finding of granulomas makes it difficult to differentiate from sarcoidosis. Epidermal ulceration, eosinophilic infiltrate, and marked dermal edema are useful in determining the diagnosis. Since the infectious granulomatous disorders listed in Table 3 can show similar pathologic features, additional studies are performed, including periodic acid-Schiff tissue cultures and acid-fast bacilli testing.

Management Despite MCD causing significant morbidity, treatment has not been standardized in the past. In 2014, The American Academy of Dermatology published MCD treatment guidelines. (Table 3) Current management approach should initially follow an algorithm but remain individualized according to disease severity and clinical response. Topical treatments, both steroidal and nonsteroidal, have been used. Systemic forms of glucocorticosteroids have been the mainstay of therapy. Sulfasalazine, both topical and oral, has been promising in the healing of MCD lesions. Metronidazole has been efficacious in cases when steroid therapy was unsuccessful. In addition, antibiotics and immunosuppressive drugs have been used, including methotrexate, azathioprine, and cyclosporine. Biologic therapy using adalimumab from living cells and belongs to a class of medications known as tumor necrosis factor (TNF-alpha) inhibitors has been observed to reduce the inflammation associated with CD.

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Table 3. Therapeutic Approach to Metastatic Crohn’s Disease Table 3

Surgery When MCD remains refractory to these various medical interventions, surgical excision and debridement may be indicated. Excision of GI segments have not been effective for the prevention of or the treatment of MCD since the skin and GI lesions often have different clinical courses and severity.

CONCLUSION Cutaneous CD occurs in about 50% of individuals with CD, and MCD is a rare subset of the cutaneous manifestations of CD. Since the genitalia are the more common site of MCD, urologists, both pediatric and adult, need to be aware of this entity due to its non-specific clinical presentation, which is similar to other inflammatory skin disorders that are more common to our specialty. It is important to recognize this rare dermatosis since it can serve as a marker of significant risk for the development of Crohn’s disease that needs to be monitored by gastroenterologists.

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REFERENCES 1. Kumaran, M, Gupta, Somesh, Ajith, C, Kalra, Navin, Sethi, Sunil, Kumar, Bhushan, et al. (2006). Saxophone penis revisited. Int J STD AIDS. 2006 Jan;17(1):65-66. 2. Drew J.B. Kurtzman, Trevor Jones, Fangru Lian, Lisan S. Peng. Metastatic Crohn’s disease: A review and approach to therapy. J Am Acad Dermatol. 2014 Oct;71(4):804-13. 3. Aberumand B, Howard J, Howard J. Metastatic Crohn’s Disease: An Approach to an Uncommon but Important Cutaneous Disorder. Biomed Res Int. 2017;2017:8192150. 4. Schneider SL, Foster K, Patel D, Shwayder T. Cutaneous manifestations of metastatic Crohn’s disease. Pediatr Dermatol. 2018 Sep;35(5):566-574.

ELLEN SHAPIRO, MD Ellen Shapiro, MD, is professor of urology at the NYU Grossman School of Medicine. She has been director of Pediatric Urology at NYU School of Medicine, now NYU Grossman School of Medicine, since 1993. Dr. Shapiro brings more than 30 years of expertise in all areas of pediatric urology, including treatment and management of congenital anomalies of the kidneys and urinary tract (e.g., ureteropelvic junction obstruction, vesicoureteral reflux, and ureterocele/ectopic ureter), hypospadias, undescended testes, hernias, varicocele and kidney stones as well as complex reconstruction for neurogenic bladder and bladder exstrophy. Dr. Shapiro completed her urology residency at the Johns Hopkins Hospital and a fellowship in pediatric urology at the Children’s Hospital of Michigan. Dr. Shapiro has served on the executive committee of the American Academy of Pediatrics Section on Urology and has been chair of the section’s Pediatric Urology Workforce Study. She has served as a member of the Examination Committee of the American Board of Urology and the Vesicoureteral Reflux Guidelines Committee of the American Urological Association. In addition, Dr. Shapiro has been on the NYU Grossman School of Medicine Faculty Promotion and Tenure Committee and is currently a member of the executive committee of the Admissions Committee.

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Department of Urology

Our renowned urologic specialists have pioneered numerous advances in the surgical and pharmacological treatment of urologic disease. For questions and/or patient referrals, please contact us by phone or by e-mail.

Faculty Specialty Phone Number/Email

Kidney stones, Kidney Cancer, Ureteral Stricture, UPJ obstruction, Endourology, Robotic Renal Surgery, 646-825-6387 James Borin, MD Partial Nephrectomy, Ablation of Renal Tumors, PCNL [email protected]

Female Pelvic Medicine and Reconstructive Surgery, Pelvic Organ Prolapse-Vaginal and Robotic 646-754-2404 Benjamin Brucker, MD Surgery, Voiding Dysfunction, Male and Female Incontinence, Benign Prostate Surgery, Neurourology [email protected]

Female Sexual Dysfunction, Male Sexual Dysfunction, General Urology, Benign Disease Prostate, 646-825-6318 Seth Cohen, MD Post-Prostatectomy Incontinence, Erectile Dysfunction, Hypogonadism [email protected]

Robotic and Minimally Invasive Urology, BPH and Prostatic Diseases, Male and Female Voiding 718-630-8600 Frederick Gulmi, MD* Dysfunction, Kidney Stone Disease, Lasers in Urologic Surgery, and Male Sexual Dysfunction [email protected]

Urologic Oncology, Open, Laparoscopic, or Robot-Assisted Approaches to Surgery, Surgical 646-825-6325 Mohit Gupta, MD† Management of Genitourinary Malignancies including Kidney, Bladder, Prostate, Adrenal, Penile, [email protected] and Testis Cancers

Urologic Oncology (Open and Robotic) – for Kidney Cancer (Partial and Complex Radical), Urothelial 646-744-1503 William Huang, MD Cancers (Bladder and Upper Tract), Prostate and Testicular Cancer [email protected]

Pediatric Urology including Hydronephrosis, Hypospadias, Varicoceles, Undescended Testicles, 212-263-6420 Grace Hyun, MD Hernias, Vesicoureteral Reflux, Urinary Obstruction, Kidney Stones, Minimally Invasive Procedures, [email protected] Congenital Anomalies

646-825-6322 Christopher Kelly, MD Male and Female Voiding Dysfunction, Neurourology, Incontinence, Pelvic Pain, Benign Prostate Disease [email protected]

Prostate Cancer: Elevated PSA, 3D MRI/Ultrasound Co-registration Prostate Biopsy, Focal (Ablation) 646-825-6327 Herbert Lepor, MD of Prostate Cancer, Open Radical Retropubic Prostatectomy [email protected]

718-261-9100 Stacy Loeb, MD, MSc** Urologic Oncology, Prostate Cancer, Benign Prostatic Disease, Men’s Health, General Urology [email protected]

Benign Prostatic Hyperplasia, Erectile Dysfunction, Urinary Tract Infection, Elevated Prostate-specific 718-376-1004 Danil Makarov, MD, MHS*** Antigen, Testicular Cancer, Bladder Cancer, Prostate Cancer [email protected]

Urethral Strictures, Robotic and Open Reconstructive Surgery for Ureteral Obstruction/Stricture, Fistulas, 646-754-2419 Nnenaya Mmonu, MD, MS Bladder Neck Obstruction, Penile Prosthesis, Post Prostatectomy and Radiation Urinary Incontinence [email protected]

Male Infertility, Vasectomy Reversal, Varicocele, Post-Prostatectomy, Erectile Dysfunction, 646-825-6348 Bobby Najari, MD Male Sexual Health, Hypogonadism, Oncofertility [email protected]

Female Pelvic Medicine and Reconstructive Surgery, Voiding Dysfunction, Neurourology, Incontinence, 646-825-6311 Nirit Rosenblum, MD Female Sexual Dysfunction, Pelvic Organ Prolapse and Robotic Surgery [email protected]

Pediatric Urology including: Urinary Tract Obstruction (ureteropelvic junction obstruction), 646-825-6326 Ellen Shapiro, MD Vesicoureteral Reflux, Hypospadias, Undescended Testis, Hernia, Varicocele, and Complex [email protected] Genitourinary Reconstruction.

Kidney stones, PCNL, Kidney Cancer, UPJ obstruction, Endourology, Robotic Renal Surgery, 718-630-8600 Mark Silva, MD* Ablation of Renal Tumors [email protected]

Muscle-Invasive Bladder Cancer, Non-Invasive Bladder Cancer, Radical Cystectomy, 646-825-6327 Gary D. Steinberg, MD Urinary Tract Reconstruction After Bladder Removal Surgery [email protected]

Female Pelvic Medicine and Reconstructive Surgery, Pelvic Organ Prolapse, Incontinence in Women, 646-825-6324 Lauren Stewart, MD Female Voiding Dysfunction [email protected]

Urologic Oncology – Prostate Cancer (MRI-Guided Biopsy, Robotic Prostatectomy, Focal Therapy, 646-825-6321 Samir Taneja, MD Surveillance), Kidney Cancer (Robotic Partial Nephrectomy, Complex Open Surgery), Urothelial Cancers [email protected]

Urologic Oncology – Prostate Cancer, MRI-Guided Biopsy, Kidney and Prostate Cancer Surgery, 646-754-2470 James Wysock, MD, MS Robotic Urological Cancer Surgery, Prostate Cancer Image-guided Focal Therapy (Ablation, HIFU), [email protected] and Testicular Cancer

Robotic and Open Reconstructive Surgery for Ureteral Obstruction, Fistulas, Urinary Diversions, 646-754-2419 Lee Zhao, MD Urethral Strictures, Peyronie’s Disease, Penile Prosthesis, and Transgender Surgery [email protected]

Kidney Stone Disease, Upper Tract Urothelial Carcinoma, Ureteral Stricture Disease, and BPH/Benign 646-754-2434 Philip Zhao, MD Prostate Disease [email protected]

*at NYU Langone Hospital – Brooklyn ** NYU Langone Ambulatory Care Rego Park ***NYU Langone Levit Medical †222 East 41st street; NYU Langone Ambulatory Care Bay Ridge, and NYU Langone Levit Medical

nyulangone.org 222 East 41st Street New DCYork, 2/9/2021 NY 10017

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