An overview of benign and premalignant lesions of the foreskin

Open AccessPublished:August 07, 2019DOI:https://doi.org/10.1016/j.mpdhp.2019.07.002

      Abstract

      The foreskin is a common surgical specimen encountered by the practising histopathologist. Therapeutic circumcisions are performed to treat both benign and neoplastic foreskin lesions. Penile intraepithelial neoplasia (PeIN) is the precursor lesion of penile squamous cell carcinoma (SCC). The World Health Organisation (WHO) classifies PeIN into two subtypes based on the association with Human Papillomavirus (HPV); these include differentiated and undifferentiated PeIN. These subtypes of PeIN can be differentiated by specific cytological and architectural characteristics. This review article will discuss these histological characteristics and highlight potential difficulties that may arise in diagnosing PeIN. Furthermore, it will also consider common benign and preneoplastic foreskin lesions that may be encountered when reporting the foreskin specimen.

      Keywords

      Introduction

      Penile cancer is an uncommon genitourinary malignancy with an incidence rate that increases with age.
      • Montes Cardona C.E.
      • Garcia-Perdomo H.A.
      Incidence of penile cancer worldwide: systematic review and meta-analysis.
      In England the age-standardised incidence rate for penile cancer is 1.3 per 100,000 males. The age-specific rate is approximately 1 per 100,000 males aged 40–49 years with a rise to above 8 per 100,000 males aged 80 years and over.
      The vast majority of invasive neoplasms of the penis are squamous cell carcinoma (SCC). Other primary malignancies include but are not limited to basal cell carcinoma, extra-mammary Paget's disease, melanoma, lymphoma and various mesenchymal tumours. Metastases to the penis are extremely rare and usually arise from the genitourinary and gastrointestinal tracts.
      Risk factors for penile SCC have been heavily scrutinised. Of mention in particular is the benefit attributed to neonatal circumcision, the risk associated with pathological phimosis, the rather debated carcinogenic effects of smegma and the close association with lichen sclerosus (LS).
      • Douglawi A.
      • Masterson T.A.
      Updates on the epidemiology and risk factors for penile cancer.
      Furthermore, the association of human papillomavirus (HPV) with certain penile neoplastic diseases is well known. One of the earliest systematic review articles on HPV prevalence by Backes et al. found that HPV infection was present in 48% of penile SCC.
      • Backes D.M.
      • Kurman R.J.
      • Pimenta J.M.
      • Smith J.S.
      Systematic review of human papillomavirus prevalence in invasive penile cancer.
      Other review articles have reported HPV incidence rates of 14%–100%.
      • Anic G.M.
      • Giuliano A.R.
      Genital HPV infection and related lesions in men.
      Penile intraepithelial neoplasia (PeIN) is the precursor lesion of penile SCC. By definition, it is dysplastic squamous epithelium with an intact basement membrane with reports quoting a transformation rate of 10–30%.
      • Kristiansen S.
      • Svensson A.
      • Drevin L.
      • Forslund O.
      • Torbrand C.
      • Bjartling C.
      Risk factors for penile intraepithelial neoplasia: a population-based register study in Sweden, 2000–2012.
      It has a tendency to affect the foreskin and glans with other anatomical sites such as the coronal sulcus less commonly affected.
      • Morton C.
      • Birnie A.
      • Eedy D.
      British Association of Dermatologists' guidelines for the management of squamous cell carcinoma in situ (Bowen's disease) 2014.
      Like its malignant counterpart, certain variants are closely linked to HPV infection.
      The foreskin is the most frequent penile specimen received by histopathology departments in the United Kingdom. Box 1 presents the most common reasons for completing a therapeutic circumcision. This article will discuss the macroscopic assessment and cut up of the foreskin. It will also provide an overview of common benign and premalignant lesions that are encountered in routine practise with emphasis on the current classification and histological diagnosis of PeIN. Although reference will be made to invasive penile malignancy, it is beyond the scope of this article to explore this area in significant detail.
      Indications for therapeutic circumcision
      Pathological phimosis (a non-retractable foreskin due to chronic inflammation and scarring closely associated with lichen sclerosus).
      Severe balanoposthitis (acutely inflamed foreskin and glans).
      Recurrent paraphimosis (the inability to return the foreskin to the normal anatomical position).
      Congenital urological abnormalities.
      Traumatic foreskin injury.
      Persistent or recurrent urological infections.
      Treatment of a pre-malignant or malignant condition confined to the foreskin.

      The pathologist's approach to the foreskin specimen

       Foreskin anatomy

      The foreskin provides an anatomical covering to the glans of the penis, the corona and the urethral meatus. It consists of five distinct layers. The outer epidermal layer comprises keratinising stratified squamous epithelium with basal melanocytes and scattered Langerhans cells. The underlying dermis consists of connective tissue, blood vessels and nerve bundles and is rich in elastic fibres. There are Meissner corpuscles within the dermal papillae and Pacinian corpuscles in the deeper dermis. Scattered sebaceous glands and hair follicles are rarely encountered. Beneath the dermis, there is a delicate subcutaneous layer of Dartos muscle, a thin sheath of smooth muscle that surrounds the penis. The Dartos muscle extends proximally, loosely adherent to Buck's fascia, to become continuous with Dartos proper of the scrotum. The fourth layer of the foreskin is the vascular-rich lamina propria. The most inner layer directly in contact with the glans is the inner squamous mucosal layer. This is a continuation of the mucosa of the glans and corona and extends distally to converge with the epidermis. Within this layer, neoplastic lesions of the foreskin develop.

       The surgical specimen

      A clinically benign foreskin is frequently encountered at cut up. This will typically be in a non-orientated state and as such, representative full-thickness sections of any visible lesion can be taken. A circumcision may also be performed for lesions suspicious of malignancy, or where a diagnosis of PeIN or superficial invasive SCC localised to the foreskin has been made on biopsy. This specimen should be submitted by the surgeon pinned to a board and orientated as shown in Figure 1. The surgeon has cut along the dorsal surface of the foreskin to create a dorsal slit. The foreskin has then been cut circumferentially along the coronal/corporal margins and detached from the shaft at the frenulum. When the specimen is pinned, the epidermis of the foreskin and inner squamous mucosal layer are stretched apart such that a rectangular piece of tissue is formed with the frenulum innermost and the left and right dorsal slits outermost. The “true” surgical margins are the circumferential shaft and coronal margins (the longitudinal edges of the rectangle). Differential inking is applied to these margins (Figure 2) and the specimen is sliced from one dorsal slit to the other, perpendicular to the shaft/coronal margins. The whole lesion should be embedded but it is often easier to embed the entire specimen.
      Figure 1
      Figure 1An orientated foreskin with long suture marking the left coronal margin. The dorsal slits are not considered “true” surgical margins.
      Figure 2
      Figure 2(Underside of ): Differential ink is applied to the coronal and shaft margins. The specimen is then sliced perpendicular to these margins.

      Benign and pre-neoplastic lesions of the foreskin

       Penile lichen sclerosus

      This condition was first described by Stuhmer in 1928 and termed balanitis xerotica obliterans, referring to the Greek xeros meaning ‘dry’ and obliterare meaning ‘to efface’.
      • Clouston D.
      • Hall A.
      • Lawrentschuk N.
      Penile lichen sclerosus (balanitis xerotica obliterans).
      • Stühmer A.
      Balanitis xerotic obliterans (post-operationem) und ihre Beziehungen zur “Kraurosis glandis et praeputii penis”.
      Penile or male genital lichen sclerosus is used synonymously but is now the favoured term. It is a chronic progressive inflammatory condition characterised by a lymphocytic response with a bimodal distribution affecting young boys and middle-aged men. Clinically, it presents as a scaly white atrophic patch or plaque on the glans or foreskin that may become significantly sclerosed causing phimosis and stricturing of the urethral meatus. The aetiology of LS is not entirely understood but is most probably multifactorial. Exposure to urine has been proposed with higher incidences described in patients with post-micturition dribbling and microincontinence.
      • Bunker C.B.
      • Shim T.N.
      Male genital licen sclerosus.
      Furthermore, LS is invariably a condition affecting uncircumcised males suggesting that a high moisture environment or the accumulation of cellular debris may play a role. A Koebner phenomenon has also been implicated, with lesions tending to develop at sites of previous trauma.
      • Clouston D.
      • Hall A.
      • Lawrentschuk N.
      Penile lichen sclerosus (balanitis xerotica obliterans).
      • Bunker C.B.
      • Shim T.N.
      Male genital licen sclerosus.
      The true incidence of penile LS is not known. However, Kizer et al. reported a prevalence of 0.07% in a population of over 153,000 patients.
      • Kizer W.S.
      • Prarie T.
      • Morey A.F.
      Balanitis xerotica obliterans: epidemiological distribution in an equal access healthcare system.
      Numerous studies have reported an association between LS and invasive penile SCC.
      • Barbagli G.
      • Palminteri E.
      • Mirri F.
      • Guazzoni G.
      • Turini D.
      • Lazzeri M.
      Penile carcinoma in patients with genital lichen sclerosus: a multicenter survey.
      • Nasca M.R.
      • Innocenzi D.
      • Micali G.
      Penile cancer among patients with genital lichen sclerosus.
      • Perceau G.
      • Derancourt C.
      • Clavel C.
      • et al.
      Lichen sclerosus is frequently present in penile squamous cell carcinomas but is not always associated with oncogenic human papillomavirus.
      Furthermore, PeIN is also frequently encountered in the same specimen suggesting that this precancerous lesion may provide the link between LS and invasive SCC. As such, LS is now considered an important risk factor for the development of certain subtypes of PeIN and invasive SCC.
      Histologically, early LS may show a mild or pronounced band-like CD8 and CD57 positive lymphocytic infiltrate often accompanied by a lymphocytic vasculitis, basal cell vacuolar degeneration and pigment incontinence.
      • Dalal V.
      • Kaur M.
      • Rai C.B.
      • Singh A.
      • Ramesh V.
      Histopathological spectrum of lichen sclerosus et atrophicus.
      As the lesion progresses, subepidermal oedema develops and there is a loss of elastic fibres within the upper dermis. This gradually becomes replaced by dense fibrosis to create the classic appearance of subepidermal hyalinisation with loss of dermal structures (Figure 3). Ectatic vessels may be encountered and are a particular feature in lesions previously treated with topical steroids.
      • Dalal V.
      • Kaur M.
      • Rai C.B.
      • Singh A.
      • Ramesh V.
      Histopathological spectrum of lichen sclerosus et atrophicus.
      Gradually, the epidermis becomes more atrophic with flattening of rete ridges and hyperkeratosis. In later stage disease the band-like lymphocytic infiltrate is less pronounced. A Periodic acid-Schiff (PAS) stain can be used to highlight a thickened basement membrane and elastic-Van Gieson stain will show loss of upper dermal elastic fibres.
      Figure 3
      Figure 3Penile lichen sclerosus. There is thinning of the epidermis with hyperkeratosis and dense subepidermal hyalinisation. There is a band-like lymphocytic infiltrate deep within the dermis.

       Differential diagnosis

      In early LS, the findings of a band-like lymphocytic infiltrate may mimic lichen planus (LP). However, the infiltrate in LP tends to be denser and obscures the dermoepidermal junction. Furthermore, epidermal atrophy of LS contrasts with the saw-tooth appearance seen in LP. LP may also show wedge-shaped hypergranulosis and an accumulation of eosinophilic, hyalinised globules known as Civatte bodies within the epidermis. Civatte bodies are formed by apoptotic keratinocytes. They are PAS positive and demonstrate various immunoreactant deposits, most commonly IgM. Other useful distinguishing features include loss of superficial dermal elastic fibres and basement membrane thickening in LS. Difficulty may also arise in differentiating severely hyalinised LS from localised morphoea. Both will show homogenised collagen bundles but in morphoea these tend to be located within the deep dermis and subcutaneous tissue.
      • Dalal V.
      • Kaur M.
      • Rai C.B.
      • Singh A.
      • Ramesh V.
      Histopathological spectrum of lichen sclerosus et atrophicus.

       Plasma cell balanitis

      Plasma cell balanitis (PCB), also known as balanitis circumscripta plasmacellularis, was first described by Zoon, a Dutch dermatologist in 1952 and is now commonly referred to as Zoon's balanitis.
      • Zoon J.
      Balanoposthite chronique circonscrite benign a plasmocytes (contra erythroplasie de Queyrat).
      This uncommon dermatosis typically affects uncircumcised middle-aged to elderly men. It presents as a well-defined, erythematous plaque with purpuric spots creating a “cayenne pepper” appearance on the glans and inner foreskin.
      • Buechner S.
      Common skin disorders of the penis.
      Its appearance can sometimes resemble erythroplasia of Queyrat (in situ SCC of the glans). Although there have been case reports of the simultaneous involvement of PCB with in situ and invasive SCC, PCB is a benign entity.
      The pathogenesis of PCB remains unclear. As the condition is strongly associated with uncircumcised males, a high moisture environment with entrapment of cellular debris producing a plasma cell-rich inflammatory response is the widely accepted theory. An IgE class antibody mediated hypersensitivity reaction has also been postulated by Nishimura et al.
      • Nishimura M.
      • Matsuda T.
      • Muto M.
      • Hori Y.
      Balanitis of Zoon.
      Histological changes affecting the epidermis include acanthosis, spongiosis, ulceration and parakeratosis. Later changes include epidermal atrophy, subepidermal cleft formation and effacement of the rete.
      • Pastar Z.
      • Rados J.
      • Lipozencić J.
      • Skerlev M.
      • Loncarić D.
      Zoon plasma cell balanitis: an overview and role of histopathology.
      So called “lozenge keratinocytes” are also a recognised feature referring to the parallel arrangement of diamond-shaped keratinocytes within the epidermis. The dermis shows a dense lichenoid inflammatory infiltrate rich in plasma cells as well as lymphocytes, eosinophils and neutrophils (Figure 4). Prominent dilated blood vessels, red blood cell extravasation, haemosiderin deposition and haemosiderophages are also noted. A degree of fibrosis may also be seen within the superficial dermis.
      • Pastar Z.
      • Rados J.
      • Lipozencić J.
      • Skerlev M.
      • Loncarić D.
      Zoon plasma cell balanitis: an overview and role of histopathology.
      The main difficulty encountered in formulating the diagnosis is when only scattered plasma cells are seen. In such a scenario, LP and a balanoposthitis secondary to bacteria or candida need to be excluded. Furthermore, reactive cytological atypia may be present mimicking differentiated PeIN. In this situation, the entire specimen should be examined to exclude dysplasia. Clinical correlation and discussion at MDT is also recommended.
      Figure 4
      Figure 4Plasma cell balanitis. There is epidermal atrophy, spongiosis and effacement of rete ridges. Within the dermis there is a dense infiltrate of plasma cells, ectatic vessels and pigment incontinence.

       Condyloma acuminatum

      Condylomas are warty, exophytic, squamoproliferative sexually transmitted lesions. They may affect any part of the anogenital region and are commonly found on the foreskin and shaft. They present as single or multiple papules or plaques that are soft and friable. Condylomas are considered a benign lesion and in 90% of cases, are associated with HPV subtypes 6 and 11. However, co-infection with high risk oncogenic subtypes, particularly HPV 16 can occur increasing the risk of invasive SCC.
      • Anic G.M.
      • Giuliano A.R.
      Genital HPV infection and related lesions in men.
      The histological diagnosis is normally relatively straightforward particularly with immunohistochemistry confirming low risk HPV infection. The classic appearance is of an arborescent, papillomatous squamous proliferation with fibrovascular cores (Figure 5). The architecture is reticulated and the deep margin is rounded and smooth. There may be hyperkeratosis and intraepidermal keratin cysts. Epidermal maturation is an essential feature. The presence of koilocytes (single, binucleate or multinucleated cells with irregular, wrinkled nuclei and a perinuclear halo) within the granular cell layer helps formulate the diagnosis. However, they may be absent. Other features that may be seen include scattered ectatic vessels, a lymphocytic infiltrate and epidermal spongiosis.
      Figure 5
      Figure 5Condyloma Acuminatum. This is a hyperkeratotic squamoproliferative lesion with koilocytosis. The dermoepidermal interface is smooth and round and there is no evidence of dysplasia.

       Buschke-Löwenstein tumour

      A Buschke-Löwenstein tumour, also known as giant condyloma, is a variant of the condyloma. These cauliflower-like tumours present as large bulbous exophytic masses with a cobblestone surface that can affect any part of the anogenital region including the foreskin. Microscopically, they resemble a condyloma with a typical papillomatous growth pattern, well-defined broad deep margins, fibrovascular cores and koilocytosis. Surface ulceration and abscess formation are common features. Unlike a condyloma, they may penetrate into deep tissues causing significant local destruction. Furthermore, malignant transformation can rarely occur. As such, they are treated like a low-grade invasive SCC and radically excised. The differential diagnosis includes warty and verrucous carcinoma. The presence of low risk HPV and morphologically benign lesional cells would favour giant condyloma over a warty carcinoma. Warty carcinomas tend to show pleomorphic koilocytes distributed throughout the entire epithelium rather than confined to the granular cell layer. Warty carcinomas also show a jagged tumour/stromal interface.
      • Chaux A.
      • Cubilla A.L.
      Advances in the pathology of penile carcinomas.
      Koilocytosis and fibrovascular cores are not seen in verrucous carcinoma.

       Penile traumatic neuroma

      Clinically, the differential diagnosis for single or multiple penile papules is broad and includes condyloma acuminatum, pearly penile papules, Bowenoid papulosis and sebaceous gland hyperplasia.
      • Park H.J.
      • Kim T.N.
      • Baek S.R.
      • Lee K.M.
      • Choi K.U.
      • Park N.C.
      Penile traumatic neuroma: a late complication of penile dorsal neurotomy to treat premature ejaculation.
      Rarely, a traumatic neuroma may also present as a papular penile lesion.
      Traumatic neuromas are benign and develop as a consequence of trauma to a nerve. The normal reparative process of the damaged nerve is disrupted leading to a disorganised exuberant proliferation of axons and nerve sheath cells.
      • Cardoso T.A.
      • dos Santos K.R.
      • Franzotti A.M.
      • Avelar J.C.
      • Tebcherani A.J.
      • Pegas J.R.
      Traumatic neuroma of the penis after circumcision - case report.
      When found on the penis they are commonly associated with unintended nerve injury during circumcision but may occur following any form of trauma. Histologically, these non-neoplastic lesions show a disorganised proliferation of nerve fascicles, Schwann cells and fibroblasts normally encased within a collagenous or myxoid stroma (Figure 6) with varying degrees of background chronic inflammation.
      Figure 6
      Figure 6Penile traumatic neuroma. Multiple scattered nerve bundles are seen surrounded by a collagenous myxoid stroma.

      Penile intraepithelial neoplasia

       Classification

      Penile intraepithelial neoplasia (PeIN) is the precursor lesion of invasive squamous cell carcinoma and now replaces previously used terminology including Erythroplasia of Queyrat, squamous cell carcinoma in-situ, Bowen's disease and Bowenoid papulosis. Unlike other organ sites this is not graded on the degree of dysplasia. In 2016, the World Health Organisation (WHO) reclassified PeIN to incorporate two separate pathways of penile carcinogenesis based on the relationship with HPV.
      • Moch H.
      • Humphrey P.A.
      • Ulbright T.M.
      • Reuter V.
      WHO classification of tumours of the urinary system and male genital organs.
      This classification also applies to invasive penile SCC (Table 1). Both categories of PeIN show distinct morphological characteristics. Undifferentiated PeIN encompasses basaloid and warty subtypes. These subtypes show pronounced atypical features and can be distinguished with relative ease from background benign squamous epithelium. Differentiated PeIN displays only subtle cellular and architectural atypia making identification difficult. In general, differentiated PeIN is associated with non-HPV related well-differentiated carcinoma such as usual-type and verrucous SCC whilst undifferentiated PeIN is more commonly seen with warty and basaloid invasive subtypes.
      Table 12016 WHO Classification of PeIN and invasive penile SCC
      HPV-relatedNon-HPV-related
      PeIN – (Undifferentiated)PeIN – Differentiated
      Warty
      Basaloid
      Warty-basaloid
      SCC – Warty carcinomaSCC – Usual-type
      Basaloid carcinomaVerrucous (incl. carcinoma cuniculatum)
      Warty-basaloid carcinomaPapillary carcinoma
      Clear cell carcinomaPseudohyperplastic carcinoma
      Pseudoglandular carcinoma
      Adenosquamous carcinoma
      Sarcomatoid carcinoma
      Mixed carcinoma

       Differentiated PeIN

      The mean age of PeIN diagnosis is 64 years.
      • Chaux A.
      • Velazquez E.F.
      • Amin A.
      • et al.
      Distribution and characterization of subtypes of penile intraepithelial neoplasia and their association with invasive carcinomas: a pathological study of 139 lesions in 121 patients.
      Differentiated PeIN tends to develop in slightly older, uncircumcised men with a history of longstanding lichen sclerosus and preferentially affects the inner foreskin. Macroscopically, differentiated and undifferentiated PeIN cannot be accurately distinguished from one another. Both present as solitary or multiple, white or pink and sometimes pigmented macules or plaques. The borders of the lesion can be well-demarcated and smooth or irregular and poorly-defined.
      • Chaux A.
      • Cubilla A.L.
      Advances in the pathology of penile carcinomas.
      • Velazquez E.F.
      • Chaux A.
      • Cubilla A.L.
      Histologic classification of penile intraepithelial neoplasia.
      Differentiated PeIN is characterised by epithelial hyperplasia, hyperkeratosis and parakeratosis. There is elongation and anastomosis of rete ridges creating a reticulated epithelial architecture. Keratin pearls and prominent intercellular bridges are commonly seen. On low power, there is an impression of surface maturation and hypergranulosis with hyperchromatic, atypical cells confined to the basal and parabasal layers. However, higher power demonstrates scattered, full-thickness yet subtle atypical keratinocytes with abundant eosinophilic cytoplasm, vesicular nuclei and occasional prominent nucleoli (Figure 7). Lichen sclerosus may be present within the background. Features that should prompt one to consider an alternative diagnosis include a basaloid morphology, marked full-thickness pleomorphism, koilocytosis and a papillomatous lesional surface. p16 and HPV immunohistochemistry are invariably negative.
      Figure 7
      Figure 7Differentiated PeIN. The squamous epithelium is thickened with dysplasia predominantly confined to the basal layer. Occasional atypical cells and scattered mitotic figures are observed towards the surface. Maturation is maintained.

       Undifferentiated PeIN

      Undifferentiated PeIN includes warty, basaloid and warty-basaloid subtypes. The terms ‘severe dysplasia’ and ‘carcinoma in situ’ were previously used for this category of non-invasive neoplasm. Undifferentiated PeIN preferentially affects the glans of slightly younger men although it may occur in other sites including the inner foreskin which is the most frequently affected area in patients presenting with any non-invasive lesion.
      • Velazquez E.F.
      • Chaux A.
      • Cubilla A.L.
      Histologic classification of penile intraepithelial neoplasia.
      Undifferentiated PeIN accounts for approximately 25% of precancerous lesions.
      • Chaux A.
      • Cubilla A.L.
      Advances in the pathology of penile carcinomas.
      Basaloid PeIN is normally well-defined from background benign squamous epithelium. The lesion is typically flat and there can be abrupt parakeratosis. The epithelium is entirely replaced by a monotonous population of small to intermediate-sized basophilic cells with oval to round hyperchromatic nuclei and a raised nuclear to cytoplasmic ratio (Figure 8). Koilocytes, although infrequent, may be found within the parakeratotic surface.
      • Chaux A.
      • Cubilla A.L.
      Advances in the pathology of penile carcinomas.
      Mitoses and apoptotic bodies are readily identified and marked pleomorphism may be encountered. Rarely, occasional lesional cells may have a spindled or polyhedral morphology. Basaloid PeIN is strongly associated with HPV infection, in particular HPV genotype 16.
      Figure 8
      Figure 8Basaloid PeIN. The epithelium is entirely replaced by a monotonous basophilic proliferation of cells with frequent mitoses. Squamous maturation is not discernible.
      Warty PeIN is characterised by an undulating, spiky or papillary surface with epithelial hyperplasia and marked parakeratosis. There is prominent full-thickness cellular pleomorphism, dyskeratosis and atypical koilocytosis (Figure 9a). Unlike basaloid PeIN, some epithelial surface maturation is normally retained. Warty PeIN tends to be positive for p16 (Figure 9b) and multiple HPV genotypes.
      Figure 9
      Figure 9(a) Warty PeIN. The epithelial surface is undulating and there is pronounced hyperkeratosis and dyskeratosis. There is full-thickness epithelial dysplasia with scattered koiloctyes identified by the irregular, hyperchromatic nuclei and perinuclear halo. (b) p16 immunohistochemistry performed on the same specimen showing strong, diffuse, full-thickness positivity.
      Warty-basaloid PeIN shows a mixture of cellular and architectural features. The surface is normally undulating and spiking. The upper portion of the lesion may show surface maturation and large atypical cells with occasional scattered koilocytes. However, the lower half of the epithelium is replaced by a small, monomorphic population of basaloid cells. High grade HPV infection and p16 positivity is normally found.

       Diagnostic challenges of PeIN

      As discussed previously, differentiated PeIN can sometimes be difficult to distinguish from benign squamous hyperplasia. Identification of basal cell atypia, abnormal squamous maturation and parakeratosis are highly suggestive of PeIN. Immunohistochemistry may also prove useful. p16 is expectedly negative in differentiated PeIN and benign squamous hyperplasia. Patchy or diffuse Ki67 and p53 positivity in lesional cells above the basal cell layer would favour differentiated PeIN over squamous hyperplasia.
      • Chaux A.
      • Pfannl R.
      • Rodríguez I.M.
      • et al.
      Distinctive immunohistochemical profile of penile intraepithelial lesions: a study of 74 cases.
      Squamous hyperplasia is typically negative for p53 but may show scattered Ki67 positive basal cells. A diagnosis of undifferentiated PeIN can normally be made on morphology. However, diffuse full-thickness p16 and Ki67 positivity would support this diagnosis (Table 2).
      Table 2Immunohistochemistry: benign squamous hyperplasia, differentiated PeIN and undifferentiated PeIN
      p16p53Ki67
      Squamous Hyperplasianegativenegativescattered basal cell positivity
      Differentiated PeINnegativepositivepositive cells above basal layer
      Undifferentiated PeINfull-thickness positivitypositive/negativefull-thickness positivity
      Basaloid PeIN may be confused with an in-situ urothelial carcinoma that has developed in the distal urethra and has spread to the urethral meatus. In this extremely uncommon situation, a negative p16 and positive GATA3, CK7 and uroplakin-III or thrombomodulin would favour meatal involvement by neoplastic urothelium.
      • Alvarado-Cabrero I.
      • Sanchez D.F.
      • Piedras D.
      • et al.
      The variable morphological spectrum of penile baseloid carcinomas: differential diagnosis, prognostic factors and outcome report in 27 cases classified as classic and mixed variants.

       Bowenoid papulosis

      Bowenoid papulosis is a clinical term used to describe multiple papular lesions that develop on the anogenital region. On the penis, these lesions typically affect the shaft and foreskin. They are associated with HPV infection, particularly genotype 16 and are more commonly encountered in immunosuppressed patients.
      • Nayak S.U.
      • Shenoi S.D.
      • Bhat S.T.
      • Shivamurthy A.
      Bowenoid papulosis.
      Histologically, these lesions show hyperplastic squamous epithelium with varying degrees of cytological atypia, ranging from focally scattered atypical cells to full-thickness proliferation of poorly differentiated cells resembling basaloid PeIN. Dyskeratotic cells, mitotic figures and koilocytosis are normally present. The clinical course of these lesions can be very different from undifferentiated PeIN with most cases regressing spontaneously. However, rarely these lesions may develop into invasive SCC.
      • Marcucci C.
      • Sabban E.C.
      • Friedman P.
      • Peralta R.
      • Calb I.
      • Cabo H.
      Dermoscopic findings in bowenoid papulosis: report of two cases.
      Most cases are indistinguishable from undifferentiated PeIN. Therefore, it is recommended that they are diagnosed as warty/basaloid undifferentiated PeIN and discussed at the urological MDT meeting.

      Early invasive squamous cell carcinoma

      When PeIN of either type becomes hyperplastic, the diagnosis of early invasive squamous cell carcinoma should be considered. Often this can be highly subjective. In foreskin specimens, this is clinically less important than in glans biopsies, as removal of the foreskin and monitoring is normally the surgical management for early invasion. In low grade invasive squamous cell carcinoma of the foreskin, the background can show transition from squamous hyperplasia to a complex squamoproliferative lesion to overt invasion.
      • Oertell J.
      • Caballero C.
      • Iglesias M.
      • et al.
      Differentiated precursor lesions and low-grade variants of squamous cell carcinomas are frequent findings in foreskins of patients from a region of high penile cancer incidence.
      This suggests that these complex hyperplastic proliferations may be precursor lesions requiring clinical follow up even when no definite invasion is identified. In undifferentiated PeIN with hyperplasia, there may be paradoxical keratinisation referring to hypermature, keratinising small buds at the base of the lesion (Figure 10). This feature is highly suggestive of early invasion.

       Practice points

      • PeIN now replaces previously used outdated terminology referring to the precursor lesion of invasive SCC of the penis. It is not graded.
      • PeIN has two subtypes: differentiated (non-HPV related) and undifferentiated (HPV related)
      • LS is an important risk factor for the development of differentiated PeIN. Differentiated PeIN may show only subtle atypia which is predominantly confined to the basal layer. Immunohistochemistry can be used to help distinguish between differentiated PeIN and reactive benign squamous epithelium.
      • Bowenoid papulosis is a clinical term which refers to an HPV-associated squamoproliferative penile lesion with a very different clinical course to PeIN. Histological examination alone cannot accurately distinguish this entity from undifferentiated PeIN.
      Figure 10
      Figure 10This foreskin specimen shows features of undifferentiated PeIN including prominent hyperkeratosis, epithelial hyperplasia, full-thickness dysplasia and koilocytosis. At the base of the lesion there is a nest of hypermature squamous epithelium with keratinisation, a feature highly suggestive of early invasion.

      References

        • Montes Cardona C.E.
        • Garcia-Perdomo H.A.
        Incidence of penile cancer worldwide: systematic review and meta-analysis.
        Rev Panam Salud Públic. 2017; 41: 1-10
      1. Public Health England: national cancer registration and analysis service. Penile cancer report: malignant and in-situ tumours. National Cancer Registration and Analysis Service, 2013
        • Douglawi A.
        • Masterson T.A.
        Updates on the epidemiology and risk factors for penile cancer.
        Transl Androl Urol. 2017; 6: 785-790
        • Backes D.M.
        • Kurman R.J.
        • Pimenta J.M.
        • Smith J.S.
        Systematic review of human papillomavirus prevalence in invasive penile cancer.
        Cancer Causes Control. 2009; 20: 449-457https://doi.org/10.1007/s10552-008-9276-9
        • Anic G.M.
        • Giuliano A.R.
        Genital HPV infection and related lesions in men.
        Prev Med. 2011; 53: S36-S41
        • Kristiansen S.
        • Svensson A.
        • Drevin L.
        • Forslund O.
        • Torbrand C.
        • Bjartling C.
        Risk factors for penile intraepithelial neoplasia: a population-based register study in Sweden, 2000–2012.
        Acta Derm Venereol. 2018; https://doi.org/10.2340/00015555-3083
        • Morton C.
        • Birnie A.
        • Eedy D.
        British Association of Dermatologists' guidelines for the management of squamous cell carcinoma in situ (Bowen's disease) 2014.
        Br J Dermatol. 2014; 170: 245-260https://doi.org/10.1111/bjd.12766
        • Clouston D.
        • Hall A.
        • Lawrentschuk N.
        Penile lichen sclerosus (balanitis xerotica obliterans).
        BJU Int. 2011; 108 (2011): 14-19https://doi.org/10.1111/j.1464-410X.2011.10699.x
        • Stühmer A.
        Balanitis xerotic obliterans (post-operationem) und ihre Beziehungen zur “Kraurosis glandis et praeputii penis”.
        Arch F Dermat u Syph. 1928; 156: 613-623
        • Bunker C.B.
        • Shim T.N.
        Male genital licen sclerosus.
        Indian J Dermatol. 2015; 60: 111-117
        • Kizer W.S.
        • Prarie T.
        • Morey A.F.
        Balanitis xerotica obliterans: epidemiological distribution in an equal access healthcare system.
        South Med J. 2003; 96: 9-11
        • Barbagli G.
        • Palminteri E.
        • Mirri F.
        • Guazzoni G.
        • Turini D.
        • Lazzeri M.
        Penile carcinoma in patients with genital lichen sclerosus: a multicenter survey.
        J Urol. 2006; 175: 1359-1363
        • Nasca M.R.
        • Innocenzi D.
        • Micali G.
        Penile cancer among patients with genital lichen sclerosus.
        J Am Acad Dermatol. 1999; 41: 911-914
        • Perceau G.
        • Derancourt C.
        • Clavel C.
        • et al.
        Lichen sclerosus is frequently present in penile squamous cell carcinomas but is not always associated with oncogenic human papillomavirus.
        Br J Dermatol. 2003; 148: 934-938
        • Dalal V.
        • Kaur M.
        • Rai C.B.
        • Singh A.
        • Ramesh V.
        Histopathological spectrum of lichen sclerosus et atrophicus.
        Indian J Dermatopathol Diagn Dermatol. 2017; 4: 8-13
        • Zoon J.
        Balanoposthite chronique circonscrite benign a plasmocytes (contra erythroplasie de Queyrat).
        Dermatologica. 1952; 105: 1-7
        • Buechner S.
        Common skin disorders of the penis.
        BJU Int. 2002; 90: 498-506https://doi.org/10.1046/j.1464-410X.2002.02962.x
        • Nishimura M.
        • Matsuda T.
        • Muto M.
        • Hori Y.
        Balanitis of Zoon.
        Int J Dermatol. 1990; 29: 421-423https://doi.org/10.1111/j.1365-4362.1990.tb03826.x
        • Pastar Z.
        • Rados J.
        • Lipozencić J.
        • Skerlev M.
        • Loncarić D.
        Zoon plasma cell balanitis: an overview and role of histopathology.
        Acta Dermatovenerol Croat. 2004; 12: 268-273
        • Chaux A.
        • Cubilla A.L.
        Advances in the pathology of penile carcinomas.
        Hum Pathol. 2012; 43: 771-789
        • Park H.J.
        • Kim T.N.
        • Baek S.R.
        • Lee K.M.
        • Choi K.U.
        • Park N.C.
        Penile traumatic neuroma: a late complication of penile dorsal neurotomy to treat premature ejaculation.
        Sex Med. 2016; 4: e221-e224
        • Cardoso T.A.
        • dos Santos K.R.
        • Franzotti A.M.
        • Avelar J.C.
        • Tebcherani A.J.
        • Pegas J.R.
        Traumatic neuroma of the penis after circumcision - case report.
        Bras Dermatol. 2015; 90: 397-399
        • Moch H.
        • Humphrey P.A.
        • Ulbright T.M.
        • Reuter V.
        WHO classification of tumours of the urinary system and male genital organs.
        International Agency for Research on Cancer, Lyon, France2016
        • Chaux A.
        • Velazquez E.F.
        • Amin A.
        • et al.
        Distribution and characterization of subtypes of penile intraepithelial neoplasia and their association with invasive carcinomas: a pathological study of 139 lesions in 121 patients.
        Hum Pathol. 2012; 43: 1020-1027
        • Velazquez E.F.
        • Chaux A.
        • Cubilla A.L.
        Histologic classification of penile intraepithelial neoplasia.
        Semin Diagn Pathol. 2012; 9: 96-102
        • Chaux A.
        • Pfannl R.
        • Rodríguez I.M.
        • et al.
        Distinctive immunohistochemical profile of penile intraepithelial lesions: a study of 74 cases.
        Am J Surg Pathol. 2011; 35: 553-562
        • Alvarado-Cabrero I.
        • Sanchez D.F.
        • Piedras D.
        • et al.
        The variable morphological spectrum of penile baseloid carcinomas: differential diagnosis, prognostic factors and outcome report in 27 cases classified as classic and mixed variants.
        Appl Cancer Res. 2017; 37https://doi.org/10.1186/s41241-017-0010-3
        • Nayak S.U.
        • Shenoi S.D.
        • Bhat S.T.
        • Shivamurthy A.
        Bowenoid papulosis.
        Indian J Sex Transm Dis. 2015; 36: 223-225
        • Marcucci C.
        • Sabban E.C.
        • Friedman P.
        • Peralta R.
        • Calb I.
        • Cabo H.
        Dermoscopic findings in bowenoid papulosis: report of two cases.
        Dermatol Pract Concept. 2014; 4: 61-63https://doi.org/10.5826/dpc.0404a11
        • Oertell J.
        • Caballero C.
        • Iglesias M.
        • et al.
        Differentiated precursor lesions and low-grade variants of squamous cell carcinomas are frequent findings in foreskins of patients from a region of high penile cancer incidence.
        Histopathology. 2011; 58: 925-933