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Histology of penile cancer

Punch biopsies, resected  tissue, or amputation specimens are the most common type of specimens from the penis.

Operation specimens are usually photo documented before  and after  a gross procedure. The pathology report should include tumor diameter, tumor thickness, and whether the following tissues are infiltrated: Lamina propria, corpus spongiosum, urethra, and preputium, and whether resection borders are free of tumor. Whole-organ microscopic sections are often used to better evaluate tumor extension and resection borders . Malignant tumors are classified according to WHO 2016.

Benign tumors

Apart from genital warts the benign tumors are rare. Genital warts (Condyloma Acuminata)  are very common and appear in 5-10% of sexually active younger people. The area is generally small (a few mm up to 2-3 cm) and localized on the glans, in the urethra, or on the preputium. They are caused by low risk HPV (Human Papilloma Virus) types (6 or 11), and transmitted through sexual activity. It has not been documented that they can develop into malignant tumors. Giant condyloma (Buschke-Lowenstein tumor) is very seldom and is also caused by HPV. They often exceed 5 cm and can be difficult to microscopically separate from well differentiated squamous cell carcinomas. Giant condyloma must be removed completely and can recur. Rare benign tumors also occur such as hemangioma, lymphangioma, and leiomyoma.

Image 1. Photomicrograph of condyloma. Click to enlarge. Magnification from image 1 showing the condyloma with koilocytes in upper epithelial layer. Click to enlarge.

Precursor lesions

The majority of penile carcinomas develop through a series of epithelial changes (percursor lesions) usually in the squamous epithelium of glans. What earlier was classified as dysplasias, carcinoma in situ and squamous epithelium hyperplasia, are now classified as Penil Intraepitelial Neoplasi (PeIN). PeIN is not graded.

There are two types of PeIN with different etiology. One is associated with HPV and is now called undifferentiated PeIn formerly called moderate/severe dysplasia and carcinoma in situ. Undifferentiated PeIN can be divided into a condylomatous and basaloid type but this has no clinical significance, both are associated with high-risk HPV infection (image 2a and 2b). Precursors that are not associated with HPV but often Lichen Sclerosus (formerly called atypical squamous epithelium hyperplasia) are now classified as differentiated PeIN. If doubts pathologists  may use immunohistochemistry and HPV analysis for correct classification of precursors.

Differentiated PeIN has minimal atypia (image 3) and is negative for p16 and positive for p53 basal and parabasal. Undifferentiated PeIN has rough atypia throughout the thickness of the epithelium (image 2a and 2b) and is throughout the epithelium thickness sharply positive for p16. Immunohistochemical examination for p16 is a surrogate marker for high-risk HPV infection and less expensive to perform than PCR.

Bowenoid papulosis, Erythroplasia Queyrat and Bowen's disease is clinical diagnoses where the light microscopic findings are identical with undifferentiated PeIN (image 2a and b). Bowenoid papulosis is caused by HPV and appears in younger sexually active men (16-35 years old) and usually regress spontaneously within one year without treatment. Erythroplasia de Queyrat and Bowen's disease appear in older men and is increasingly associated with cancer development. These lesions should be treated. What has previously been classified as light dysplasia and HPV changes are now classified as flat condyloma (image 4).

Lysmikroskopisk bilde av udifferensiert PeIN, kondylomatøs type Lysmikroskopisk bilde av udifferensiert PeIN, basaloid type Lysmikroskopisk bilde av differensiert PeIN

Image 2a. Photomicrograph of undifferentiated PeIN  condylomatous type. Click to enlarge

Image 2b. Photomicrograph of undifferentiated PeIN  basaloid type. Click to enlarge

Image 3. Photomicrograph of differentiated PeIN   Click to enlarge 

Image 4. Photomicrograph demonstrating a low-grade dysplasia with koilocytes in squamous cell epithelium. Click to enlarge.
Image 5. Photomicrograph demonstrating lichen sclerosis. Click to enlarge.

Lichen Sclerosus (Balanitis Xerotica Obliterans) (Fig. 6) is a degenerative condition also appearing in the vulva of older women. It is also a relatively common condition in older men, affecting the preputium and glans sometimes causing phimosis. Light microscopy does not reveal any atypia in the squamous epithelium, however, these findings are associated with squamous cell carcinoma, and is observed relatively frequently in the mucosa in patients with differentiated PeIN and cornified squamous cell carcinoma (usual type), verrucous carcinoma and papillary carcinoma.

Malignant tumors

Image 6. Photomicrograph showing a well differentiated squamous cell carcinoma. Click to enlarge.

Most of the penile squamous cells originate from the glans or preputium, but they  may also originate from transitional epithelium in urethra.( urothelial carcinomas), supporting tissue (sarcomas) or lymphoid tissue (lymphomas). Metastasis to the penis occurs very rarely.

More than 95% of penile squamous cells originate from the glans, preputium, or sulcus coronarius. On the skin of the penis shaft,  the same type of tumors that are common in skin may be developed. (These tumors are not included here). There are several subtypes of squamous cell carcinomas of varying etiology and prognosis (28,29), it is therefore important that pathologists subclassify properly so the patient receives the correct prognosis and treatment. Up to 50% of penile carsinomas are caused by HPV. Other risk factors include poor hygiene, phimosis, smoking, chronic inflammation, Lichen Sclerosus, immunosuppression and PUVA treatment.

Variants of squamous cell carcinomas not caused by HPV

Usual type (45-65%) are associated with differentiated PeIN, Lichen Sclerosus and phimosis (Image 6). According to WHO, these types are graded as high (grade 1), intermediate (grade 2) and poorly differentiated (grade 3) based on grade of nuclear atypia and keratinization. At the time of diagnosis, most of these tumors are grade 2.

Verrucous carcinoma (2-3%) occurs in older men. When performing a clinical examination, verrucous carcinoma, Giant cell condyloma, papillary carcinoma and condylomatous carcinoma are difficult to tell apart. Punch biopsies are therefore not suitable for the correct diagnosis;  the complete tumor must be removed to find the correct diagnosis.  It occurs more often in combination with usual type (hybrid verrucous carcinoma), the prognosis is then worse. The pure form (Image 9) has very little nuclear atypia papillary growth pattern with broad invasion front (not infiltrative) and has a very good prognosis. Metastases are not described, but local recurrence is a problem if the tumor and differentiated PeIN are not being removed with free resection margins.

Papillary carcinomas (5-10%) occurs in older men. This is also tumors with little nuclear atypia but with infiltrative basis and papillary growth pattern without koilocytosis. Infiltration of blood vessels and perineural infiltration may occur, but metastases are rare and the prognosis is good. Local recurrence may occur if tumor and differentiated PeIN are not removed with free resection margins.

Cuniculatum, pseudoglandular carcinoma, pseudohyperplastic carcinoma, adenosquamous carcinoma and sarcomatoid carcinoma are rare variants of squamous cell carcinoma that is not associated with HPV. Sarcomatoid carcinoma is a highly aggressive tumor which immunohistochemistry may be needed to exclude sarcoma.

Variants of squamous cell carcinomas associated with HPV

Basaloid carcinoma (10%) occurs in younger men and if sufficient number of sections of tumor are taken, there will always be  undifferentiated PeIN side of invasive tumor (Image 7 and 2b). This is a ulcero infiltrative with necrosis, large nuclear atypia and many mitosis. Keratinization is missing or very limited and without maturation. At the time of diagnosis more than half of the patients have  lymph node metastases. The tumor is not graded; this is an aggressive tumor with high mortality.

Condylomatous carcinoma (Image 8) is a more slowly growing verrucous tumor with moderate nuclear atypia and koilocytosis. Not invasive variant occurs, on the side by the tumorundifferentiated PeIN is observed. (Image 2a). This type is graded, they are often grade 1-2. Intermediate prognosis with relatively low mortality.

Plateepitelkarsinom av kondylomatøs type
Image 7. Photomicrograph showing basaloid carcinoma. Click to enlarge.
Image 8. Squamous cell carcinoma of condylomatous type. Click to enlarge.
Image 9. Photomicrograph showing verrucous squamous cell carcinoma. Click to enlarge.

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