Carcinoma of the penis pathophysiology

Editor(s)-in-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753; Swathi Venkatesan, M.B.B.S.[2]

On gross pathology, the glans and the foreskin are the most common locations to find scaly patches, nodules, palpable painless lump, erythematous, ulceration, concurrent phimosis may conceal the lesion, surface of the lesion may be exophytic, flat, or ulcerated, chronic penile rash or subtle burning sensation and swollen inguinal lymph nodes as characteristic findings of carcinoma of penis. On microscopic histopathological analysis, keratinization and intercellular bridges are characteristic findings of carcinoma of the penis.

• Penile cancers traditionally begin as small lesions, most commonly on the glans or prepuce ^[1]
• About 95% of penile cancers develop from flat, scale-like cells called squamous cells. squamous cell carcinoma (SCC) can develop anywhere on the penis, but most develop on the foreskin (in uncircumcised men) or the glans. This type of cancer is typically slow growing. When found early, it is often curable
• Penile cancer arises from precursor lesions, which generally progress from low-grade to high-grade lesions

Grossly noted growth patterns include:

1. Superficial spreading: tumors are limited to lamina propria or superficial corpus spongiosum.
   1. Usually extend horizontally through multiple anatomical compartments
2. Vertical growth: tumors invade deep anatomical levels, surface is non-verruciform and frequently ulcerated
3. Verruciform: tumors are exophytic and papillomatous with a cauliflower-like aspect.
   1. May be limited to surface (verrucous) or invade deep anatomical levels (cuniculatum)
4. Mixed patterns: observed in 10 – 15% of all cases

On microscopic histopathological analysis, characteristic findings of carcinoma of the penis include:

• keratinization
• intercellular bridges
• Most histologic subtypes resemble those in vulva, anus or buccal mucosa
• 48 – 65% are squamous cell carcinoma
• Verruciform tumors are verrucous, warty, papillary or cuniculatum carcinomas
• Basaloid and sarcomatoid carcinomas usually have a vertical growth pattern

• Penile malignant lesions and tumors, can be divided into HPV-related and non–HPV-related groups^[2]
• For HPV related penile cancers this sequence is as follows:^[3]

• Squamous hyperplasia
• Low-grade penile intraepithelial neoplasia (PIN)
• High-grade PIN (carcinoma in situ—Bowen’s disease, erythroplasia of Queyrat and bowenoid papulosis (BP))
• Invasive carcinoma of the penis

• Non-HPV related penile squamous cell cancers include:

• SCC usual type/Not Otherwise Specified (NOS)
• Pseudohyperplastic carcinoma
• Pseudoglandular carcinoma
• Verrucous carcinoma
• Carcinoma cuniculatum
• Papillary carcinoma NOS
• Adenosquamous carcinoma
• Sarcomatoid carcinoma

• Tumors with basal and/or warty morphology display HPV more frequently

Grading:

• Grade 1: well differentiated cells, almost undistinguishable from normal squamous cells except for the presence of minimal basal / parabasal cell atypia
• Grade 2: all tumors not fitting into criteria for grade 1 or 3
• Grade 3: any anaplastic cells

HPV-related Penile Carcinoma

• Basaloid SCC
  • Occurs most frequently the glans or the foreskin ^{[4] [5]}
  • Flat ulcerated masses, which are deeply invasive and sometimes necrotic
  • Metastasis is seen in about 50% of cases; lymph nodes most common
  • Closely packed small basophilic cells; mitosis is frequent with central keratinization
  • “Starry sky” like features; displays close features to neuroendocrine tumors
  • p16 positive
  • Hyalinization of the stroma is frequent
  • Local recurrence is high; mortality is high, depends on the extension at time of treatment

• Papillary basaloid carcinoma
  • Rare and affect the glans
  • Hyperparakeratosis and kondylomatous features are frequent ^[6]
  • p16 positive
  • Resemble urothelial carcinomas

• Warty carcinoma
  • Look like condylomas
  • Account for 5–10% of the penile carcinomas
  • Macronodular cauliflower-like appearance
  • Papillae have a dark fibrovascular core that the tumor surrounds with a whitish aspect
  • Pleomorphic koilocytes, hyper and parakeratosis, nuclear pleomorphism, and cellular clarification
  • Individual cell necrosis
  • Carcinomas invading corpus cavernosum and dartos, usually do not display intravascular or perineural invasion
  • Nodal metastasis is seen in <20%
  • The mortality rate is low

• Warty–basaloid carcinoma
  • Shows both warty and basaloid features
  • Present as voluminous masses growing from the glans and foreskin
  • Histologically, these tumors are mixed with a papillomatous warty-like surface and a solid basaloid invasive component
  • p16 is strongly expressed
  • Invasion into deeper structures is frequent, vascular and perineural invasions are frequent
  • More aggressive than their warty counterpart
  • Around 50% will develop lymph node metastasis; 30% will die of disease

• Clear-cell carcinoma
  • Aggressive
  • Occurs as a large mass of the glans and foreskin
  • Tumor develops in sheets
  • Necrosis is frequent
  • Staining of the clear cells is positive for p16
  • Vascular and perineural invasion is frequent
  • Tumor-related mortality is around 20%

• Lymphoepithelioma-like carcinoma
  • Poorly differentiated
  • Tumor growth starts most of the time at the glans and extends to the foreskin
  • More or less circumscribed; sheets with lymphocytic or plasmacytic cells mixed with tumor cells are common
  • p63 and p16 positive
  • Prognosis is adverse; only few cases have been described

Non-HPV related Penile Carcinoma

• SCC usual type/not otherwise specified
  • Exophytic gross appearance
  • Endophytic ulcerated cases
  • A tendency to invade deeply into the penile tissue deeply
  • Two-thirds of patients present inguinal metastasis, and the mortality is about 30%
  • The number of positive lymph nodes is an important prognosticator

• Pseudohyperplastic carcinoma
  • Tumor is an extremely differentiated SCC
  • Mostly associated with lichen sclerosis, and occurs on the foreskin of older patients
  • An association with other histological types is frequent
  • Gross aspects are flat or slightly elevated; multifocality is common
  • Sharp borders, cells are very well differentiated, and peritumoral stroma is absent or minimal
  • No vascular or perineural invasion or metastasis

• Pseudoglandular carcinoma
  • This variant is aggressive with acantholysis and pseudoglandular spaces
  • Patients are younger, around 50 yr of age
  • Distal, irregular, firm, whitish, ulcerated mass
  • Histologically, honeycomb aspects present
  • Filled with necrotic debris.
  • Poorly differentiated and high-grade tumors
  • Lymph node metastases occur in more than two-thirds and the mortality rate is high

• Verrucous carcinoma
  • Accounts for 2-3% of all penile carcinomas
  • Extremely well differentiated with papillomatous aspects;
  • Tumor base is broad and the tumor has borders pushing into the stroma
  • Has a slow evolution and is seen in older patients
  • Frequently associated with lichen sclerosus
  • Grossly, the aspect is exophytic, papillomatous is white to gray, and the interface between tumor and stroma is sharply delineated
  • Shows hyperkeratosis, acanthosis, and papillomatous aspects
  • Tumor does not directly invade the lamina propria, but pushes the borders into deeper tissue, known as invasion
  • Prognosis is good
  • Slowly growing tumor recur in a third of cases, mostly because of underestimation in histology as a benign neoplasm or because of insufficient surgery

• Carcinoma cuniculatum
  • A variant of the verrucous carcinoma and a low-grade carcinoma
  • Men between the age of 70 and 80 yr
  • Most frequently the lesions grow from the glans into the deeper layers to the erectile corpora
  • Tumor is whitish and grey, and deep invaginations are common
  • Histologically well differentiated; no koilocytes are seen
  • No vascular or perineural invasion
  • The invasion is with broad pushing borders; no metastasis can be found

• Papillary carcinoma NOS
  • carcinoma is papillomatous and verruciform
  • No koilocytes
  • Tumor accounts for about 5–8% of penile carcinomas and is usually associated with lichen sclerosus
  • Tumor has a cauliflower-like, whitish aspect that is badly limited
  • Histologically, we see well-differentiated hyperkeratotic lesions
  • Tumors can recur, but mortality and metastasis are rare

• Adenosquamous carcinoma
  • SCCs with mucinous features
  • Also called mucoepidermoid carcinomas
  • Recurrence and lymph node metastasis is seen in up to 50%, but mortality remains low
  • Rare

• Sarcomatoid SCC
  • The most aggressive neoplasm of penis
  • Focal squamous differentiation is seen
  • Spindle cell component should be present in at least 30%
  • Masses are slowly growing and frequently ulcerated
  • Recurrence and regional or systemic metastases are possible
  • Necrosis and hemorrhage are frequent.
  • Atypia, mitosis, pleomorphism, and sarcomatoid aspects
  • In 80%, local recurrence exists with inguinal metastases
  • Mortality is high (up to 75%), and most patients die within a year

• Mixed SCC
  • Contain at least two variants of SCCs
  • Patients are older, mostly in their 7th decade
  • Located on the glans
  • Present as a white, exophytic, grayish mass replacing the distal penis, invading deeply the erectile tissue
  • Most frequent is the combination of warty and basaloid carcinomas
  • Possible to have HPV– and non–HPV-related features in the same tumors
  • Mortality is rare (<5%)
  • Less aggressive

• On microscopic histopathological analysis, keratinization and intercellular bridges are characteristic findings of carcinoma of the penis.^[7]

• Grading is a way of classifying penile cancer cells based on their appearance and behaviour when viewed under a microscope.^[8]

• The grade of penile cancer is based on the degree of differentiation of cells and their rate of growth.

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