Paediatric Urology

22. RARE CONDITIONS IN CHILDHOOD

22.1. Urachal remnants

22.1.1. Introduction

The urachus is an embryonic structure arising as a result of the separation of the allantois from the ventral cloaca. The allantois appears on day 16 as a tiny, fingerlike outpouching from the caudal wall of the yolk sac, which is contiguous with the ventral cloaca at one end and the umbilicus at the other. The ventral portion of the cloaca develops into the bladder after cloacal division by the urogenital septum. Therefore, the bladder initially extends all the way to the umbilicus [1323]. With progressive foetal development, as the bladder descends towards the pelvis, the attachment between the umbilicus and the urachus becomes looser and the apical portion progressively narrows to a small, epithelialised, fibromuscular strand by the fourth or fifth month of gestation. The urachus then obliterates completely by birth, forming the median umbilical ligament [1324-1326]. The urachus varies from 3 to 10cm in length and from 8 to 10mm in diameter. It is a three-layered tubular structure, the innermost layer being lined with transitional epithelium, the middle layer composed of connective tissue, and the outermost muscular layer in continuity with the detrusor muscle [1327].

Urachal remnants (URs) originate from the failure of allantois obliteration, resulting in a urachal anomaly such as (1) urachal sinus, (2) urachal cyst, (3) vesicourachal diverticulum, or patent urachus [1324,1325,1328].

22.1.2. Epidemiology

The reported prevalence of URs is highly variable, possibly due to the use of different definitions of URs. For example, in a study with patients undergoing laparoscopy for inguinal hernia repair, all visible residual tissue was scored as a UR, and therefore a UR was visualised in 35.4% of patients, particularly in patients < 1 year (63.2%). All of these patients were asymptomatic [1329]. This supports a physiological regression of URs with age. In contrast, in a large study evaluating ultrasonographic exams in patients < 18 years old with specific attention focussed on diagnosing URs, the prevalence of URs was only 0.2% [1330]. The incidence rate in boys is slightly higher than in girls [1331,1332]. The subtypes of various URs reported in the literature is 10-48% for a patent urachus, 31-43% for a urachal cyst, 18-43% for a urachal sinus and 3-4% for a urachal diverticulum [1333,1334].

22.1.3. Symptoms

Most often, the UR is asymptomatic. The most common symptom of a urachal remnant is umbilical granulation, discharge and erythema in infants and abdominal pain in older children [1333]. A patent urachus can cause continuous or intermittent urine leakage from the umbilicus, causing umbilical granulation and erythema [1333]. A urachal cyst is usually diagnosed (1) incidentally, or (2) when it becomes infected causing abdominal pain and discharge of pus from the umbilicus or recurrent UTIs when it drains into the bladder. Other symptoms of infected urachal anomalies can vary from high fever and abdominal pain to urinary tract infections, LUTS and/or an abdominal mass [1334-1338]. A urachal diverticulum is often asymptomatic and is usually found incidentally during investigations for other problems. Urachal remnants can have associated or simultaneous anomalies. In one study, these anomalies were found in 17 of 46 children, of which VUR was the most common (six patients) [1339].

22.1.4. Diagnosis

When a UR is suspected, a careful history and physical examination should be performed. In many patients, the diagnosis can be confirmed by US [1340]. However, in a retrospective study investigating 56 patients, the diagnostic accuracy of ultrasound to diagnose a UR or omphalomesenteric remnant in patients with umbilical discharge was shown to be relatively low (sensitivity 71.1%, specificity 72.2%, positive predicting value [PPV] 76.2%, negative predicting value [NPV] 66.7%) [1341]. A MRI or CT scan may be necessary in a minority of children for more detailed imaging [1337]. In general, a VCUG is only indicated when the child also presents with UTI or when the US shows signs of upper tract abnormalities [1342].

22.1.5. Treatment

If a UR is symptomatic, the standard approach is the surgical removal of the remnant. However, in children less than six months old, even when they are symptomatic, a conservative approach with observation and/or antibiotics is possible, since there is a high chance of spontaneous resolution [1333,1335,1338,1343,1344]. In the event of active inflammation/infection, this should be treated first, and surgery should preferably be performed as an elective procedure. A Pfannenstiel, periumbilical or infraumbilical midline incision can be used for the open surgical approach [1336,1345]. Alternatively, a laparoscopic or robotic approach has been shown to be safe and effective [1344,1346-1348]. Complication rates can vary with age. In one study, it was shown that operative management of younger patients resulted in more reoperations, readmissions and longer length of stay [1349], while in another study, patients had fewer complications when surgery was performed at < 1 year of age [1350]. Given that a conservative approach can be effective, it should precede an eventual surgical resection.

22.1.6. Pathology of removed remnants

Removed specimens may show inflammation or a cystic structure [1335]. Patients presenting without symptoms are as likely to have epithelial elements in the UR as those presenting with symptoms [1337].

22.1.7. Urachal cancer

Urachal cancer has not been shown to occur in children. Urachal anomalies are thought to be associated with an increased risk of bladder adenocarcinoma in adults, and urachal adenocarcinoma has an estimated incidence of 0.18 per 100,000 individuals yearly [1351]. In a large database study, the most frequent tumour type was adenocarcinoma (65-82%) followed by urothelial carcinoma (UC) (11-21%) [1352]. Five-year survival was 54.8-64.4%. Urachal adenocarcinoma is very rare, especially when one considers that up to 62% of children under sixteen years of age may have a UR [1340,1353]. A study by Copp et al. found no association between the presence of UR symptoms and the presence or absence of epithelial tissue in pathology specimens, leading them to conclude that UR symptoms have poor predictive value for malignancy potential in these remnants [1332,1352]. Gleason et al. found that 5,721 URs would need to be excised to prevent a single case of urachal adenocarcinoma out of the nearly 65,000 patients reviewed [1351]. Assuming that epithelium is required in the development of urachal adenocarcinoma, the extrapolated number needed to treat (NNT) would be more than 8,000, as nearly 30% of urachal anomalies are void of an epithelial component. Fewer than 5% of urachal cancers have a nonepithelial origin such as sarcoma [1354]. At present, no long-term follow-up on untreated UR in children is available, and there is no evidence that urachal anomalies in children increase the likelihood of future malignancy [1333,1355].

22.1.8. Summary of evidence and recommendation for management of urachal remnants

22.2. Papillary tumours of the bladder in children and adolescents (Papillary urothelial neoplasm of low malignant potential)

22.2.1. Incidence

Papillary tumours of the bladder in children and adolescents are extremely rare and differ from papillary tumours in adults. A ‘grape-like’ papillary tumour in young children is more likely to represent rhabdomyosarcoma of the bladder, which is not the focus of this guideline. Papillary tumours in older children or adolescents will more likely be papillary urothelial neoplasms of low malignant potential (PUNLMP) [1356]. Children with risk factors such as previous bladder surgery and immunosuppressive medication can also develop a nephrogenic adenoma of the bladder, also presenting as a papillary tumour of the bladder.

22.2.2. Differences and similarities of papillary tumours of the bladder in children and adults

Sex
The overall the risk of a papillary tumour in the bladder in paediatric and young adult patients is approximately double in males compared to females [1357].

22.2.3. Risk factors

The majority of these patients have no identifiable risk factors [1358].

22.2.4. Presentation

The most common symptom at presentation is monosymptomatic haematuria. Other less-common symptoms include abdominal pain, storage LUTS including frequency, dysuria and at times obstructive symptoms [1357].

22.2.5. Investigations and treatment

Ultrasound of the genitourinary tract is the first investigation of choice. It is an excellent screening tool and can often accurately diagnose the nature and location of the lesion. In children and adolescents, a bladder US of the full bladder is more sensitive compared with adults due to reduced abdominal fat and thinner muscle layer [1359]. In the event of a need to differentiate the renal or bladder origin of the haematuria, a red blood cell morphology will reveal isomorphic blood cells, indicating a bladder origin. Urine cytology can be performed, however, it has very limited value, likely due to the low-grade nature of these tumours in children. If a bladder tumour is suspected on imaging, cystoscopy should be performed for simultaneous diagnosis and treatment, as well as transurethral resection of the tumour. In children, cystoscopy requires general anaesthesia [1360].

22.2.6. Histology

All the lesions in the paediatric and adolescent age group are identified as papillary and over 85% are solitary [1359]. Papillary bladder tumours in patients younger than twenty years of age have low-grade non-invasive disease (WHO classification) [1361]. These findings allow pathologists to conclude that, in children and adolescents, a papillary bladder tumour can be classified as papillary urothelial neoplasm of low malignant potential (PUNLMP). Papillary urothelial neoplasm of low malignant potential has minimal or no cytological atypia and differs from low grade urothelial carcinoma (UC), which has cytologic atypia, hyperchromatic nuclei and scattered mitosis and is rare in children but should always be considered [1362,1363]. For optimal diagnosis and staging it is important that resection includes the detrusor. For resection technique and staging, see Chapter 22.1.

22.2.7. Additional treatment

Despite lacking evidence, adjuvant instillations have been used sporadically in cases of paediatric UC [1357,1358,1364].

22.2.8. Prognosis, recurrence and surveillance

Overall, the prognosis of papillary tumours of the bladder in children is good. The recurrence rate in children and adolescents varies from 8 to 15% [1356,1357,1359]. Mean time to recurrence can vary from 11 to 29 months depending on the study, with recurrences occurring up to 90 months from diagnosis, though 64% occur in the first year [1357]. In certain cases, recurrences can be aggressive [1359].

Follow-up strategies are based on the guidelines and protocols of papillary tumours of the bladder in adults. It is advised to follow-up children and adolescents with a history of a PUNLMP initially with a short interval of three to six months in the first year, and thereafter at least yearly, with urinalysis for haematuria and a US of the full bladder. In the event of sudden gross haematuria, the evaluation must be performed immediately. If the tumour was completely resected at primary surgery, standard follow-up cystoscopy is not necessary but should be performed in children or adolescents with any form of UC or suspected recurrence on bladder US [1359]. The exact duration of follow-up is unknown, but this Panel recommends follow-up for at least five years. Urine cytology has no place in follow-up. All cases should be managed in an MDT setting.

Inflammatory myofibroblastic tumours of the bladder (IMTB)
This type of tumour is rare, with nearly 200 cases reported in the literature [1365,1366]. Approximately 25% occur in children with a median age at diagnosis of 7.5 years and a median tumour size of 5.5cm. Boys and girls are equally affected [1367]. These tumours are usually benign, with only very few reported malignant cases [1368]. Treatment is mostly surgical with transurethral resection, but local resection or partial cystectomy may be required in selected cases [1367,1369]. Additionally, a conservative approach is reported [1370]. Histological examination is required to exclude other malignant tumours such as a rhabdomyosarcoma. In children, no recurrence has been reported so far. However, due to the malignant potential and few recurrences in adults, the same follow-up as for papillary bladder tumours is recommended.

Eosinophilic cystitis
Although well described in adults, the inflammatory condition eosinophilic cystitis is rare in the paediatric population, with fewer than 100 cases reported in the literature to date [1371]. Its aetiology remains unknown but is thought to be incited by immunoglobulin E-mediated attraction of eosinophils to the bladder wall, followed by mast cell degranulation. Eosinophilic cystitis has been linked to medications, specifically antibiotics such as penicillin, chemotherapeutic agents such as cyclophosphamide and mitomycin, and chronic bladder catheterisation [1372,1373]. In children, as opposed to adults, males are more frequently afflicted, with seven years being the mean age of presentation. However, the condition can be seen throughout childhood even in LUTS [1371,1374].

LUTS such as dysuria, frequency, urgency and incontinence are the most frequent and can mimic UTI [1375]. Other symptoms include haematuria, suprapubic tenderness and systemic symptoms. Obstructive manifestations due to mass formation in the bladder wall can result in ureteral obstruction leading to hydroureteronephrosis and suprapubic mass in infants in addition to voiding dysfunction [1371,1374,1376].

Although associated with allergy, only about a third of reported cases had a history of other allergic conditions, whereas half had significant eosinophilia or eosinophiluria. Diagnosis is often delayed as symptoms of eosinophilic cystitis (EC) mimic other more common conditions such as UTI and LUTS, and most patients will ultimately have undergone imaging studies such as ultrasound, VCUG, CT and MRI, which while not specially diagnostic for the condition, may show bladder wall thickening or even mass formation, with rhabdomyosarcoma constituting an important differential diagnosis. A high index of suspicion for the diagnosis should therefore be maintained when dealing with protracted urinary symptoms not responsive to conventional intervention. Definitive diagnosis can only be attained on tissue biopsy obtained by cystoscopy. Histologically, eosinophilic infiltration of lamina propria and muscularis are seen in acute phases with > 25 eosinophils per high power field considered to be significant [1371,1374,1376]. Management is not standardised. Removal of any possible allergens is the obvious first step and there are reports of self-limiting course of the disease. However, empirical treatment with corticosteroids, antibiotics, anticholinergics and antihistamines, in addition to cyclosporine A have been utilised and lead to resolution of symptoms in most cases. Partial cystectomy has been performed in circumscribed lesions that do not disappear spontaneously. No standard follow-up recommendations exist, however, surveillance is justified as recurrence has been reported in approximately a third of patients [1371,1374].

Nephrogenic adenoma
Nephrogenic adenomas (NA) in children are rare benign lesions that usually occur in the setting of previous surgery or chronic irritation of the urinary tract [1377]. These benign proliferative lesions are most commonly found in the bladder. There is a significant predominance of girls compared to boys (5:1). The exact pathogenesis is unknown. It is proposed to be a metaplastic process of native urothelium in response to chronic injury. Recent evidence suggests that these cells can be derived from renal tubular cells that shed, migrate, reimplant and proliferate within urothelial mucosa [1378]. Although they are known to occur concurrently with bladder cancer, there are no de novo cases of bladder cancer diagnosed after nephrogenic adenoma. Previous history of bladder surgery such as bladder augmentation or presence of chronic inflammation or irritation is important [1379]. Lesions tend to develop at sites prone to chronic catheterisation injury. Other risk factors include trauma, immunosuppression and radiation. They present with haematuria and storage LUTS with a papillary/polypoid mass on cystoscopy. The recurrence rate is as high as 80% over four years [1377]. The final diagnosis is established by cystoscopy and histopathological review of biopsy specimen. Treatment is excision either by transurethral resection (which often requires reresections), open excision or partial cystectomy. Again, no standard follow-up recommendations exist. However, regular follow-up with cystoscopy has been advocated, particularly for patients with augmented bladders, because recurrence seems particularly high in this subgroup [1379].

22.2.9. Summary of evidence and recommendations for papillary tumours of the bladder in children

22.3. Penile rare conditions

Paediatric lesions of the penis are uncommon, but an important part of the paediatric urological practice. The most common of these lesions are cystic penile lesions followed by vascular malformations and neurogenic lesions [1380]. Soft tissue tumours of the male external genitalia are uncommon but have been described in the paediatric age group and can be malignant [1381].

22.3.1. Cystic lesions

Epidermal inclusion cysts
Epidermal inclusion cysts are the most common genital cystic lesion and can occur anywhere on the body in both men and women. In the penis, these types of cysts occur most commonly over the penile shaft, varying from 0.1 to 1cm in diameter. The epithelium of these cysts is lined and filled with keratin. It is a painless swelling and can present in the age group with a history of circumcision. Treatment by total surgical excision is mainly indicated for cosmetic or symptomatic (e.g. infection) reasons and should be performed without rupturing the cyst to avoid recurrence [1382].

Mucoid cyst of the penis
Mucoid cysts are synonymous with parameatal cyst or genitoperineal cyst of median raphe. Mucoid cysts are midline developmental cysts arising from ectopic urethral mucosa filled with mucoid material. These types of cysts present starting at birth but are usually detected during adolescence or later. These cysts are usually asymptomatic, developing over the penile ventral surface around the glans and require surgical removal for either cosmetic, functional or symptomatic reasons [1383].

Median raphe cysts
These types of cysts arise from incomplete closure of the genital fold during embryogenesis; they are commonly diagnosed in the first decade of life but can present later as they tend to be asymptomatic [1384]. They are either unilocular or multilocular fluid containing cysts, with a mean size of 0.8cm, but cysts larger than 2cm have also been reported [1385]. Cysts are centred in dermis, with no connection to urethra or epidermis. Histopathologically, there are four types: urethral (urothelium-like epithelium, account for 55% cases), as well as epidermoid, glandular and mixed. Epidermoid cysts may be congenital or acquired. Acquired penile epidermoid cysts (PECs) occur by traumatic implantation of the epidermal components into the dermis, usually as a result of surgical procedures such as circumcision and hypospadias repair [1386].

Median raphe cysts can be treated conservatively and can resolve spontaneously or persist. Cyst aspiration is associated with high risk of recurrence and surgical excision is the treatment of choice. Although most penile cysts are asymptomatic, these types of cysts may become infected, resulting in pain and tenderness. They can also present with ulceration, rupture and urinary obstruction if they are close to the urethral meatus. This, along with cosmetic issues, leads most caregivers and patients to opt for surgical excision.

Smegmal cysts or smegmal pearls
Smegmal cysts can be a differential for aforementioned cysts. Smegmal cysts are a benign collection of smegma in the subpreputial space in uncircumcised boys with anticipated spontaneous resolution [1387].

Dermoid cysts
Dermoid cysts are congenital, asymptomatic, firm, solitary, subcutaneous cystic lesions occurring commonly in the region of the corona involving the foreskin. Histopathologically, these types of cysts contain sweat and sebaceous glands, with elements of hair and squamous epithelium. Pilosebaceous cysts have been described on the glans. These cysts are benign and usually diagnosed after excision.

22.3.2. Vascular malformations

A broad classification of penile vascular lesions into haemangiomas and vascular malformations was proposed by Ramos in 1999 [1388]. Haemangiomas develop rapidly at birth and involute slowly. Venous malformations are usually present at birth and slowly progress [1389]. Haemangiomas also include pyogenic granulomas, which are benign outgrowths of cutaneous capillary vessels formed usually from chronic irritation [1380]. The growth cycle of infantile haemangiomas is divided into early and late proliferative stages, followed by a slow involution phase, completing growth by the age of nine months [1390]. Propranolol (oral or topical) is currently first-line treatment for infantile haemangiomas. The exact mechanism of action is unknown but can include inhibition of angiogenesis and vasoconstriction, among others. The dose is in the range of 1.5-2.5mg/kg, which must be continued for 12 to 18 months and then tapered through active or passive weaning to reduce risk of rebound growth [1390]. Other factors leading to rebound growth after propranolol treatment include deep haemangiomas, which occur in approximately 38% of patients despite propranolol therapy, requiring local therapy such as topical timolol, pulsed dye laser or intralesional steroids. After twelve months, the median improvement with treatment is reported as 81% (range 70-90%), based on VAS scores of serial patient photographs.

Vascular malformations are congenital lesions of capillary, lymphatic and venous (or slow-flow) or arterial/arteriovenous (fast-flow) origin that enlarge slowly as the patient grows. These malformations include glomus tumours, which are primarily congenital arteriovenous shunts that develop from thermoregulatory glomus bodies (fast-flow vascular malformations). Glomus tumours of the penis can arise on the glans penis, corpora of the penis and as periurethral masses, sometimes accompanied by glomus tumours of fingers and feet [1391]. These are usually asymptomatic at presentation or may have symptoms such as priapism, palpitation and perineal pain. Glomus tumours are benign despite exhibiting high-grade nuclear polymorphism. Vascular malformations are usually benign and managed conservatively. Treatment options include LASER, sclerotherapy [1389] or surgical excision [1392].

In the treatment of children’s penile venous malformations, relatively conservative and mild sclerosing agents, such as polidocanol, pingyangmycin or bleomycin, are recommended [1389]. However, glomus tumours specifically need surgical treatment and follow-up due to the risk of recurrence from incomplete excision [1393].

22.3.3. Neurogenic lesions

Penile neurofibroma (PNF) is an extremely rare lesion arising from perineural and Schwann cells and usually occurs with evidence of systemic neurofibromatosis or Von Recklinghausen syndrome [1394]. Neurogenic lesions are successfully treated with complete excision [1380]. It should be noted that penile schwannomas in children may differ from those in adults, as they may grow faster and be bound up with genetic syndromes or certain specific tumours that affect intelligence [1395].

Rare cases of malignant schwannomas on the penis, presumably secondary to malignant transformation of benign neurofibromas, have been reported in boys with a strong family history of neurofibromatosis. This type of malignant degeneration of neurofibromatosis reportedly occurs in 5-16% of children [1394]. Therefore, these patients require long-term follow-up due to risk of recurrence, new tumour formation and malignant transformation.

22.3.4. Soft tissue tumours of penis

Mesenchymal tumours are rare in the external genitalia, and they require excision to differentiate between benign and malignant neoplasms. Histopathological characterisation is essential to ensure that malignant tumours receive radical treatment with adjuvant therapy or close follow-up [1381].

Presentation is usually of a painless penile mass that is nontender and rubbery upon examination. Ultrasound may be useful in characterising the lesion but is not diagnostic. The ultrasound can exclude urethral invasion if it is close to the urethra [1381]. Once an excision biopsy is performed, if aggressive malignant components are found, a further wider resection may be required.

Fibrosarcoma is a rare, non-rhabdomyosarcoma soft tissue tumour that arises from fibrous tissue. The infantile form of fibrosarcoma is rare and those occurring on the penis are even rarer in the paediatric age group. Surgical intervention has a favourable prognosis in the paediatric age group, with long-term survival of 90% in sporadic cases [1396]. Myofibroma is a benign congenital lesion that occurs either as a solitary lesion or as a part of myofibromatosis with multiple soft tissue tumours. Excision is necessary for histological diagnosis [1381].

Primary penile teratomas are an extremely rare subtype of congenital germ cell tumours, and they tend to be asymptomatic and are subdermal on US with no blood flow on Doppler [1397]. These teratomas require aggressive treatment with surgical resection due to their unpredictable behaviour and unresponsiveness to chemotherapy. Mature teratomas are benign, but immature teratoma, or even mixed teratomas with immature components, can turn malignant and have the potential to metastasise and recur.

22.3.5. Penile lymphedema

Lymphedema in adults is usually secondary to malignancy or infectious disease affecting lymphatic drainage. In the paediatric age group, however, lymphedema is usually primary and generally very rare, affecting 1.2 per 100,000 persons under the age of 20 years [1398]. Of these, only a very small fraction relates to the genital region. Regardless of underlying aetiology, inefficient lymphatic drainage leads to accumulation of subcutaneous lymph, which causes tissue swelling and inflammation. This in turn stimulates adipose deposition and fibrosis, further exacerbating enlargement. With time, the oedematous tissue becomes vulnerable to infection, chronic cutaneous changes and disfigurement [1399]. Additionally, when occurring in the genital region, urological complications may ensue, such as phimosis, haematuria, bleeding, bladder outlet obstruction, pain, dysuria, lymphorrhea and severe psychological distress due to resultant deformity [1400,1401].

In the largest cohort of male genital oedema in the paediatric age group, 92% of cases were primary. Of these, only 25% had a discernible familial or syndromic association, such as Noonan syndrome, lymphedema-distichiasis or Milroy disease [1400]. Secondary genital lymphedema in children has been reported after inguinal surgery and noncaseating granulomatous lymphangitis as seen with metastatic Crohn’s disease [1400-1402]. Average age of onset was reported to be from 4.5 to ± 6.3 years, with 61% of cases presenting in infancy, 13% in childhood and the remaining 26% in adolescence. Oedema is usually penoscrotal in 72% of cases, isolated scrotal in 24% and very rarely confined exclusively to the penis in 4%. Moreover, concomitant lower limb oedema is the rule in two-thirds of cases [1400].

There is no general consensus on diagnostic workup of these patients. History and physical examination (including family history) is usually sufficient. However, lymphoscintigraphy can be used as a confirmatory test, more so for limb than genital oedema, where results can be difficult to interpret [1400]. Ultrasonography is nonspecific but has been advocated by some to exclude secondary lymphedema by examining the patency of iliac and caval vessels [1403]. Magnetic resonance imaging is useful to exclude other differential diagnoses, such as other venous or lymphatic anomalies [1400].

Conservative treatment is the accepted first-line treatment. The mainstay is compression therapy to maintain and prevent further swelling. This can be achieved by compression stockings and undergarments. Additionally, close observation and protection of the skin to prevent excoriations and infection is essential [1400,1403]. Compression therapy is, however, less effective on genital oedema than it is on limb oedema, particularly in growing children. When conservative management fails, and particularly in symptomatic cases, or in patients with functional impairment, surgical debulking may be necessary. This can either take the form of circumcision in cases in which the foreskin is affected or excision of affected skin and subcutaneous tissues with restructuring and contouring for optimal cosmetic outcome. Complete skin excision and grafting may also be required [1400-1403]. Surgical management can be challenging and must be restricted to patients with significant symptoms. Complications include recurrences, continuous lymphatic leakage, haematoma, infection and poor cosmetic outcome [1398,1403,1404].