Penile intraepithelial neoplasia (PeIN) is considered intraepithelial lesion of invasive squamous cell carcinoma (synonyms: Erythroplasia of Queyrat, Bowen disease, squamous cell carcinoma in situ, squamous intraepithelial lesion (SIL)) (Table 5.5).

PeIN may present as uni- or multifocal, flat to slightly elevated hyperkeratotic, sharp, or ill-defined borders or even papillary lesions. Clinically seen as moist, white, erythematous, dark brown or black macules, papules, or plaques.

Real incidence is unknown, but most are associated with invasive squamous cell carcinoma, differentiated PeIN (65 %) and undifferentiated PeIN (35 %). Most cases present in fifth and sixth decades.

Differentiated or simplex PeIN is unrelated to HPV. Lichen sclerosus may be implicated in pathogenesis of differentiated PeIN. Frequently affects foreskin.

Warty, warty/basaloid, and basaloid (undifferentiated) PeIN are HPV-related, with frequent HPV16 genotype. Usually affects glans, perimeatal region. Usually not associated with lichen sclerosus. Patients may have history of condyloma or genital warts (Figs. 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 and 5.10).

HPV-related multifocal papular condition typically seen in anogenital region in young adults. May be pruritic, painful or asymptomatic. Usually transmitted via sexual contact. Related to high-risk HPV, especially HPV 16. Other HPV types have also been implicated.

Lesions are often small, brown, or red-colored and exhibit histologic spectrum of changes from dysplasia to in situ carcinoma. Usually affect skin of shaft and surface may be verruciform. May also affect epithelium of glans, coronal sulcus or foreskin. Spontaneous regression has been reported, but minority of lesions evolves to invasive squamous cell carcinoma.

Proliferation of atypical basaloid cells that may be scattered throughout epidermis, often with preserved maturation. Koilocytic-like changes are also seen.

Atypia ranges from scattered atypical cells of low-grade dysplasia to full thickness atypia of the squamous epithelium. Most lesions are indistinguishable from squamous cell carcinoma in situ. Variable increased pigmentation of basal layer.

Differential diagnosis with squamous cell carcinoma in situ requires clinical correlation.

Most common epithelial change associated with penile cancer. Almost all keratinizing squamous cell carcinoma have associated squamous hyperplasia. There is thickening of mucosal squamous epithelium without cytologic atypia. It seems to be a reactive condition rather than specific entity. May be associated with reactive inflammatory conditions.

Clinically, it may be difficult to distinguish from PeIN. Micaceous balanitis and penile horn are clinically florid forms of squamous hyperplasia with prominent hyperkeratosis. Usually found in continuity or slightly distant from in situ or invasive carcinoma. Maybe precursor lesion of HPV-unrelated squamous cell carcinoma.

The differential diagnosis of squamous hyperplasia from differentiated PeIN or from extremely low-grade invasive neoplasms (e.g., pseudohyperplastic and verrucous carcinomas) may be particularly difficult.

Whitish areas with irregular borders with acanthosis with orthokeratotic and minimal to absent parakeratosis with normal epithelial maturation. Chronic inflammation may be present. There is absence of cytologic atypia, koilocytosis, and intraepithelial keratin pearls. Frequently associated with differentiated PeIN and with lichen sclerosus in some cases. Usually found in association with usual, papillary, and verrucous squamous cell carcinoma (HPV-unrelated variants). Rarely present adjacent to condylomatous (warty) or basaloid squamous cell carcinoma.

Flat is the most common subtype. There is non-atypical acanthosis, hyperkeratosis with orthokeratosis, and linear interface between basal layer and stroma.

Mixed form is the second most common type. There is presence of mixed areas of flat and papillary squamous hyperplasia.

Pseudoepitheliomatous hyperplasia is an uncommon pattern. There is acanthosis, downward elongated proliferation of rete ridges that appear detached from epithelium. Regular epithelial nests with peripheral palisading and stromal reaction are not prominent. Some cases are associated to papillary squamous hyperplasia.

Papillary, represents minority of cases with serrated appearance on low-power view and jagged interface with underlying stroma. There is non-atypical acanthosis with short hyperkeratotic papillae.

Verrucous pattern presents adjacent to verrucous carcinoma with marked acanthosis with no atypia, hyperkeratosis with hypergranulosis, and slight papillomatosis.

Differential diagnosis of squamous hyperplasia includes differentiated PeIN that shows aberrant keratinization with cytologic basal atypia.

Warty/basaloid PeIN with cytologic atypia with loss of squamous maturation and monotonous population of small cells with scant cytoplasm throughout epithelium in basaloid PeIN. Detection of HPV in high proportion of cases and immunohistochemical overexpression of p16 is the rule.

Pseudohyperplastic squamous cell carcinoma simulating pseudoepitheliomatous hyperplasia in which there is prominent stromal reaction and mass forming clinically.

Verruciform xanthoma, an exophytic lesion with acanthosis, hyperkeratosis, and “xanthoma” cells (foamy histocytes) in lamina propria.

Warty, papillary, and verrucous carcinomas show evidence of destructive stromal invasion. Diagnosis may be difficult in small biopsies (Figs. 5.11, 5.12, 5.13 and 5.14).

Affect inner aspect of foreskin, glans, and perimeatal region, and may be focally hyperkeratotic. About 9 % of patients will develop penile squamous cell carcinoma, usual type.

Well-established lesions appear as white-gray, atrophic, and geographic with frequent erosion or ulceration. Early lesions appear as pink macules that become papules. It is a chronic process of unknown pathogenesis that tends to be broad and multifocal, and affect epithelium and superficial dermis/lamina propria.

Typical case shows interface vacuolar or lichenoid dermatitis with thickened papillary dermis/lamina propria with band-like hyalinization (sclerosis). Scattered melanophages may be sen in superficial dermis and occasionally there is prominent edema of papillary dermis/lamina propria. Dermal-epidermal clefting or blisters may form secondary to marked basal cell vacuolar alteration.

In well-established lesions, a band-like lymphoid infiltrate underneath band of sclerosis. Early lesions show more superficial lymphoid infiltrate underneath epithelium without well-formed sclerotic band, but late lesions are sclerotic with minimal inflammation.

Rare cases of chronic lichen sclerosus may be associated with atypical foci in epithelium raising concern of epithelial dysplasia.

Lichen Planus enters differential diagnosis, shows a wedge-shaped hypergranulosis and band-like lymphoid infiltrate obscuring dermal-epidermal junction. Hyalinized band in superficial dermis/lamina propria is absent (Fig. 5.14).

Rare nonverruciform low-grade squamous cell carcinoma preferentially affecting foreskin in elderly patients (eighth decade) strongly associated with lichen sclerosus et atrophicus. Most unrelated to HPV infection. It is often multicentric. Other concurrent tumor pattern may be verrucous carcinoma. Minority of cases may recur showing higher grade areas.

Nonverruciform tumors usually affecting foreskin that may be hyperkeratotic flat or slightly elevated, often multicentric, on a background of lichen sclerosus. Mean size is 2 cm.

Extremely well-differentiated tumor that May be confined to subepithelial connective tissue or infiltrate dartos in foreskin. There is downward proliferation of keratinizing nests of squamous cells. Keratin-pearl formation within infiltrating nests. Occasional individual cell keratinization and mild atypia of basal cells. Lack of kolocytosis. Uneven or jagged infiltrative borders. Asymmetrical infiltrative nests surrounded by reactive fibrous stroma with mild inflammation. Adjacent epithelium may show differentiated PeIN.

Differential diagnosis may include pseudoepitheliomatous hyperplasia. Infiltration of dartos or corpus spongiosum is not seen in hyperplasia. Downward proliferation is more organized with elongated rete ridges. Keratin pearl formation is less frequent and inflammation is more prominent.

Slow-growing verruciform tumor usually affecting glans, but also, coronal sulcus, and/or foreskin. It is related to HPV infection (most frequent HPV16). Shares some gross and microscopic characteristics with condyloma but has definitive malignant potential. May represent up to 10 % of penis carcinomas and is more frequent in patients in their 50s.

It is placed as an intermediate aggressiveness between that of low risk verrucous or papillary carcinomas and high risk squamous cell carcinoma, usual type. It may present with inguinal nodal metastasis. Level of invasion and higher histologic grade are important prognostic factors.

Rare verruciform, cauliflower-like tumor, with exo- to endophytic growth and papillomatous surface on cut sections. Usually affects at least two anatomical compartments (glans, coronal sulcus, and foreskin). Variable deep borders, pushing and/or jagged, usually penetrate into corpora spongiosum and or cavernosa.