Case of the Month: Penis

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2016, case 16, and is a squamous cell carcinoma, poorly differentiated.

Sections show a large tumor demonstrating squamous differentiation with exo- and endophytic components; however, not all slides contain every feature described below. In some areas, the tumor shows exophytic papillary projections composed of polygonal epithelial cells with dense eosinophilic cytoplasm, intercellular bridges, and large nuclei with prominent nucleoli. In other areas, the tumor is seen invading into the corpus spongiosum and corpus cavernosum as tumor nodules and is composed of epithelial cells with abundant cytoplasm and marked nuclear pleomorphism with occasional multinucleation. Areas with sarcomatoid/spindle cell morphology are also noted. Mitotic figures are easily found with occasional atypical forms. The tumor involves the urethral mucosa. Based on the clinical, gross, and microscopic evaluation, a diagnosis of squamous cell carcinoma, poorly differentiated is rendered.

Primary penile squamous cell carcinoma (P-SCC) is the most common type of penile cancer with a predilection for older adults. The highest incidence of P-SCC is in South America and Africa (2-4/100,000) and the lowest among Israeli Jews. P-SCCs usually involve the glans, coronal sulcus, and inner/mucosal surface of the foreskin, and presents as an exophytic or ulcerated lesion. Predisposing factors include phimosis, chronic inflammation, lichen sclerosus et atrophicus, ultraviolet irradiation, history of warts or condylomas, and lack of circumcision. Infection with high-risk types of human papillomavirus (HPV) also plays a major etiologic role. P-SCCs arising from glans are more likely to be HPV-related compared to those arising from the inner foreskin.

Several P-SCC variants have been described, including conventional (keratinizing), basaloid, warty, warty-basaloid, papillary, verrucous, sarcomatoid, mixed, adenosquamous, pseudoglandular, and pseudohyperplastic. The basaloid, warty, and warty-basaloid subtypes are usually associated with HPV infection while the others are mostly HPV negative. Penile in situ SCC may also be encountered and was historically termed “erythroplasia of Queyrat”. More recently, penile intraepithelial neoplasia (PeIN) terminology was introduced for penile in situ SCC, following similar terminology used at other genital sites. Two categories of PeIN are described, differentiated PeIN and undifferentiated PeIN. The differentiated PeIN is seen in association with conventional (keratinizing), pseudohyperplastic, and papillary P-SCC variants. HPV is usually not detected in differentiated PeIN similar to their associated invasive subtypes. Histologically, this type shows acanthosis with elongated rete and only minimal, basally located cytologic atypia. In the absence of an invasive component, this type of PeIN may be difficult to differentiate from reactive hyperplasia. Undifferentiated PeIN is subclassified in warty, basaloid, and mixed warty-basaloid and if an invasive component is seen is usually of the same type. Warty PeIN shows a papillary architecture with parakeratosis, koilocytosis, and cytologic atypia. Basaloid PeIN shows a flat epithelial surface with a monotonous population of basaloid cells. Undifferentiated PeIN is frequently HPV-associated.

More than half of all invasive P-SCCs are of the conventional (keratinizing) variant. The histology of this variant is similar to SCC in other sites and consists of nests, tongues, and sheets of squamous cells that tend to arise from the surface epidermis or squamous mucosa and extend into the dermis or lamina propria. Stromal invasion is usually represented by irregularly shaped islands of epithelial cells separated from the surface epidermis and surrounded by a desmoplastic stroma. The cells have dense eosinophilic cytoplasm and a variable degree of nuclear atypia and keratinization. SCCs are usually graded into "well," "moderately," and "poorly" differentiated categories, depending on the extent of atypia, keratinization, and resemblance with normal epidermis. Generally, a tumor is classified according to its least differentiated region. The basaloid variant of P-SCC is composed of small blue cells with high mitotic activity arranged in nests or nodules with peripheral palisading and central comedo-necrosis. This is an aggressive variant with a high metastatic rate and mortality. The warty variant is characterized by papillomatosis with an exo/endophytic growth pattern, parakeratosis, and koilocytosis. In the pure form, it has a significantly better prognosis compared to the basaloid variant. The mixed warty-basaloid variant is usually characterized by a warty appearance superficially, and basaloid histology deeper. Verrucous carcinoma (VC) is a distinct variant of well-differentiated P-SCC, which presents as a slow-growing warty tumor. VC is characterized by an exo-endophytic appearance with papillomatosis and bulbous epidermal down-growths. There is usually no koilocytosis and the keratinocytes have only low-grade atypia and low mitotic activity. Individual infiltrative foci of unequivocal stromal invasion, not connected to the overlying epidermis, are difficult to find; however, the bulbous epidermal processes in VC show a pushing margin, which is considered a form of invasion. In its pure form, this variant rarely metastasizes; however, it may recur. Carcinoma cunniculatum is a variant originally described on the foot, characterized by burrowing deep sinuses giving the clinical picture of intercommunicating branching tunnels and clefts that resemble the burrows in a "rabbit warren" (from the Latin cuniculatus meaning in the form of a channel or tube). It is a low-grade carcinoma considered by some to be a version of VC. The papillary variant of P-SCC has an exophytic profile and complex irregular papillae, shows low-grade histology, and lacks koilocytes. This variant is reminiscent of VC. In contrast to VC, papillary carcinoma shows a jagged, irregular interface with the underlying stroma. The sarcomatoid variant is characterized by a spindle/epithelioid cell morphology and pleomorphism. Heterologous differentiation can be seen. This variant has been associated with radiation therapy and, similar to sarcomatoid carcinomas at other sites, has a poor prognosis. The pseudoglandular variant is an aggressive subtype characterized by acantholysis mimicking an adenocarcinoma. Adenosquamous carcinoma is a rare tumor showing a combination of squamous areas and true glandular foci. It is thought to arise from metaplastic or heterotopic mucinous glands and originates usually centrally in the glans. The pseudohyperplastic variant involves the foreskin of elderly patients. Differentiation of this subtype from pseudoepitheliomatous hyperplasia is challenging, especially on small biopsies, and is based on identifying invasion with surrounding reactive stroma. Finally, the mixed variant of P-SCC shows a combination of the above variants, usually conventional SCC and another subtype.

Two different pathways are thought to be involved in P-SCC oncogenesis and they are associated with different tumor phenotypes. One is driven by HPV genomic integration and involves the disruption of RB/p16 and p21/p53 pathways similar to cervical carcinomas. The exact pathogenesis of P-SCC not associated with HPV is less clear. Proposed theories include signaling through HER/ PTEN/Akt pathway or chronic inflammation.

Most P-SCCs are aggressive tumors with a 30-80% rate of metastatic disease. Prognosis is influenced by the site of the tumor (tumors of the foreskin have a better prognosis), pattern of growth (superficial versus vertical), tumor size, histological type, tumor grade, depth of invasion (> 4-6 mm indicates a high potential for metastasis), and vascular invasion.

Differential diagnosis of P-SCC includes lesions of condyloma accuminatum, keratoacanthoma, and reactive pseudoepitheliomatous hyperplasia (PEH).

Condyloma acuminatum (genital warts) are polypoid lesions caused by HPV infection, usually of a low-risk type. They are often multiple and may involve the entire genital area including penis, scrotum, and perineum. Microscopic examination shows parakeratosis, papillomatosis, and koilocytosis. In contrast to P-SCC, condylomas show no cytologic atypia or stromal invasion.

PEH is a reactive epidermal response caused by a variety of factors including an underlying tumor (such as granular cell tumor), infection (such as fungal), or repetitive mechanical trauma (scratching). PEH is characterized by epidermal hyperplasia with irregular and sharp epidermal projections. In contrast to SCC, PEH usually shows a less complex architecture and the tumor cells demonstrate only reactive cytologic atypia with large but regular nuclei with vesicular chromatin and prominent nucleoli. Nuclear pleomorphism, hyperchromasia, and frank stromal invasion are not seen. Stromal desmoplasia is more common in SCC but may also be present in PEH. At times, however, distinguishing PEH from SCC is difficult and interpretation must take into account the clinical picture.

Keratoacanthoma (KA) is a keratinocytic tumor presenting with a nodule containing a central keratin-filled crater. KAs are usually seen on sun-exposed skin exposed surfaces of the body; however, KAs may rarely involve genital areas, including the penis. KAs are characterized by rapid growth (over 1-2 weeks) and spontaneous involution over the course of several months. Histology shows an exo-endophytic crateriform squamous lesion composed of bland keratinocytes with abundant cytoplasm that may resemble a well-differentiated SCC. Current case can be distinguished from KA by its slow growth, lack of crateriform architecture, deeper invasion, and high-grade atypia.

1. Which of the following variants of penile squamous cell carcinoma is commonly associated with HPV?
   1. Basaloid type
   2. Conventional type
   3. Papillary type
   4. Sarcomatoid type
   5. Verrucous type
2. Which of the following are histologic features of keratoacanthoma?
   1. Epithelioid and spindle cells with sarcomatoid features
   2. High-grade cytologic atypia
   3. Low-grade atypia with crateriform architecture and keratin plug
   4. Low-grade atypia with verrucous architecture and pushing deep border
3. Which of the following statements best describes the biologic behavior of penile squamous cell carcinoma?
   1. Metastatic disease is exceptionally rare.
   2. Incidence of metastatic disease is 0.5%.
   3. Incidence of metastatic disease is 2-3%.
   4. Incidence of metastatic disease is 3-16%.
   5. Incidence of metastatic disease is 30-80%.

1. Clayman GL, Lee JJ, Holsinger FC, et al. Mortality risk from squamous cell skin cancer. J Clin Oncol. 2005;23(4):759-765.
2. Cubilla AL, Dilner J, Schelhammer PF, Horenblas S. Malignant epithelial tumours. In: Eble J et al. WHO Pathology and genetics of tumours of the urinary system and male genital organs. Lyon, FR: IARC Press; 2004:281-291
3. Downes MR. Review of in situ and invasive penile squamous cell carcinoma and associated non-peoplastic dermatological conditions. J Clin Pathol 2015;68(5):333-340.
4. del Pino M, Bleeker MC, Quint WG, Snijders PJ, Meijer CJ, Steenbergen RD. Comprehensive analysis of human papillomavirus prevalence and the potential role of low-risk types in verrucous carcinoma. Mod Pathol. 2012;25(10):1354-1363.
5. Kubik MJ, Rhatigan RM. Carcinoma cuniculatum: not a verrucous carcinoma. J Cutan Pathol. 2012; 39(12):1083-1087.
6. 6. McKee PH, Calonje E, Granter SR. eds. Pathology of the Skin. 4th ed. Philadelphia, PA: Elsevier Saunders; 2012.

2016
Aleodor A. Andea, MD, MBA
Surgical Pathology Committee
University of Michigan
Ann Arbor, MI

1. Basaloid type (a)
2. Low-grade atypia with crateriform architecture and keratin plug (c)
3. Incidence of metastatic disease is 30-80%. (e)