Diseases of the Penis, Urethra, and Scrotum

Glans Penis

The glans is composed of the following layers: stratified nonkeratinizing squamous mucosa, lamina propria, corpus spongiosum, tunica albuginea, and corpora cavernosa. Most epithelial neoplasms of the penis originate from the glans mucosa. The lamina propria is a loose connective tissue layer, 1 to 3 mm thick, that separates the mucosa from the corpus spongiosum. The corpus spongiosum is the main component of the glans and is composed of specialized erectile tissues with numerous anastomosing venous sinuses of varying caliber that have multiple peripheral nerves between them ( Fig. 9-2 ). The glans corpus spongiosum is about 8 to 10 mm thick, and the transition from the lamina propria is frequently abrupt, which is an important feature to recognize for the purposes of staging invasive carcinoma ( Table 9-1 ). The tunica albuginea is a very dense, fibrous, and elastic membrane that separates the spongiosum from underlying corpora cavernosa and constitutes an important barrier to the spread of cancer.

Foreskin

The foreskin is a double membrane that encases the glans. Microscopically, it has five histologic layers: (1) the innermost mucosal epithelium, similar to the glans; (2) the 2-mm to 3-mm thick lamina propria; (3) the 6-mm to 10-mm thick dartos muscle composed of a double layer of smooth muscle fibers situated within the loose connective tissue; (4) the dermis; and (5) the epidermis, which is the outermost, thin, wrinkled squamous epithelium that contains scant adnexal structures.

Body

Microscopically, the body shows the following layers: (1) outer epidermis layer, similar to foreskin; (2) dermis; (3) dartos muscle; (4) adipose tissue; (5) Buck fascia, with numerous vessels and nerves; (6) tunica albuginea; and (7) erectile tissue of the corpora cavernosa and spongiosum, the latter encasing the urethra. Both the corpora cavernosa and corpus spongiosum are covered by the tunica albuginea and encased in Buck fascia ( Fig. 9-3 ).

Clinical Features

Patients usually present with an exophytic, ulcerative, or fungated mass or occasionally present with flat erythematous and granular lesion ( Fig. 9-4 ). In patients with long phimotic foreskin, a submucosal mass may delay the clinical presentation, with metastasis as a presenting sign. Mean age at presentation is usually 60 years. Most penile squamous cell carcinomas originate in the squamous epithelium that lines one of three penile compartments: mucosa of glans (75% to 80%), mucosa of the foreskin (15%), and coronal sulcus (5%); and multicentric (2%). Only few arise in the skin of the foreskin and shaft. Adjacent precancerous lesions (see subsequent discussion) often can be seen as marble white thickening, leukoplakia or moist, erythematous lesion (see Fig. 9-4 ).

Pathologic Features

Gross Findings

Growth Patterns of Penile Squamous Cell Carcinoma

The gross characteristics depend on the overall growth pattern, which strongly correlates with prognosis. Three main growth patterns are recognized ( Fig 9-5 ):

• 1.

  Superficial spreading (seen in up to 40% of cases) is a flat white plaque-like or granular firm tumor that grows horizontally and usually shows a prominent intraepithelial component and invasion, chiefly superficial, of the anatomic layers of penis. More than one epithelial compartment (glans, sulcus, or foreskin) is frequently involved.

• 2.

  Vertical growth pattern (seen in up to 30% of cases), with a large ulcerated or fungating white-gray or hemorrhagic mass that spreads down deeply, is often of high grade and has a high rate of inguinal lymph node metastasis.

• 3.

  Verruciform growth pattern (seen in approximately 18% to 20% of cases) is composed of several histologic subtypes of well-differentiated papillary neoplasms, as discussed subsequently, with a low incidence of metastasis. The glans is the most commonly involved site, but the foreskin and coronal sulcus may be involved. Grossly, these are large, granular, white to gray, exophytic cauliflower-like neoplasms.

Mixture of the growth patterns can occur in about 10% to 15% of carcinomas.

Microscopic Findings

Histologic Subtypes

Histologically, most squamous cell carcinomas of the penis (about 70%) are similar to their counterparts in other organs; they show usual, nonpapillary type growth and range from good to moderate to poor differentiation. The remaining 30% have a predominant histologic appearance that is different and includes basaloid carcinoma, a spectrum of verruciform carcinomas (warty [condylomatous] carcinoma, verrucous carcinoma, carcinoma cuniculatum, and papillary carcinoma, not otherwise specified), and very rare pseudohyperplastic carcinoma. Clinical and histologic features of subtypes of squamous carcinoma are discussed in detail in the following section.

Characteristic histologic features of the usual well-differentiated to moderately differentiated squamous cell carcinomas include keratinizing nests of squamous cells with variable cytologic atypia surrounded by reactive fibrous stroma ( Fig. 9-6 ). Very well-differentiated and solid nonkeratinizing poorly differentiated carcinomas ( Fig. 9-7 ) are unusual. Invasion can be seen as individual cells, cords, or large cohesive sheets present in the lamina propria or corpus spongiosum (see Fig. 9-6 ). Superficially invasive tumors tend to be well differentiated, and deep tumors tend to be poorly differentiated. The adjacent squamous epithelium frequently shows changes that are known to be associated with squamous carcinoma that ranges from hyperplasia to PeIN and well-developed lichen sclerosus et atrophicus.

Differential Diagnosis

Pseudoepitheliomatous Hyperplasia

Superficially invasive, well-differentiated squamous cell carcinoma should be distinguished from pseudoepitheliomatous hyperplasia. In pseudoepitheliomatous hyperplasia, the acanthotic epithelium has long, slender, often angulated rete ridges that, when cut tangentially, appear as infiltrating nests in the stroma (see Fig. 9-8 ). The presence of detached nests from overlying epithelium, which show disorderly maturation, paradoxic differentiation characterized by keratinization, more eosinophilia, and nuclear atypia, favors diagnosis of carcinoma over hyperplasia (see Fig. 9-6 ). Desmoplasia may be seen in both conditions but is more pronounced and frequent in carcinomas. The presence of nests deep in the dartos or corpora favors the diagnosis of carcinoma. In 2004 Cubilla and colleagues described 10 cases of very well-differentiated nonverruciform squamous carcinoma of the penis that showed pseudohyperplastic features and posed similar diagnostic difficulty with pseudoepitheliomatous hyperplasia, particularly in superficial biopsies ( Fig. 9-9 ). Emphasis on the similar diagnostic features discussed should be helpful. Presence of adjacent PeIN or lichen sclerosus may also aid in the diagnosis.

Ancillary Studies

Prognosis and Treatment

Prognosis of squamous cell carcinoma largely depends on the stage of disease as determined with both local invasion and involvement of inguinal nodes (see Table 9-1 ). Pathologic factors related to prognosis of penile carcinomas are site of the primary tumor, histologic type, grade, depth of invasion, and vascular invasion. Of these pathologic parameters, histologic grade, depth of invasion, and vascular invasion have been most strongly correlated with final outcome. Tumors limited to the foreskin carry a better prognosis because of the frequent superficial invasive nature of the tumor. In one large series, inguinal lymph node metastasis was found in 82%, 42%, and 33% of pathologic types of vertical growth, superficial spreading, and multicentric carcinomas, respectively. Verrucous tumors without conventional or destructive invasion did not show metastasis. In another large series from 2000, Banon Perez and colleagues demonstrated that patients with pT1a tumor and good cell differentiation showed no metastastic adenopathy in long follow-up periods. The overall mortality rate for patients with superficially spreading carcinomas is 10% compared with 67% for patients with vertical growth pattern; therefore evaluation of the depth of invasion is important on all penile resection specimens. Measurement of depth of invasion should be performed from the basement membrane of the adjacent squamous epithelium to the deepest point of invasion. For large exophytic (verrucous) tumors, depth should be measured from the nonkeratinizing surface of the tumor to the deepest point of invasion. The threshold for penile metastasis is about 4-mm to 6-mm invasion into the corpus spongiosum.

In 2009 Chaux and associates have proposed a prognostic index system on a scale of 1 to 6 that combines numeric values for histologic grade (1 to 3) and anatomic level of invasion (1 to 3; lamina propria [LP], corpus spongiosum [CS], and corpora cavernosa [CC] invasion, respectively, for glans tumors and LP, dartos, and skin for the foreskin tumors). Indices of 1 to 3 are associated with no mortality, and high indices of 5 and 6 are associated with high metastatic rate and mortality rate. Inguinal metastases were observed in 64% to 83% of patients in high-risk groups, in 20% to 33% in intermediate groups, and in 0 to 8% in low-risk groups. Patients in high-risk groups could benefit from prophylactic bilateral groin dissection. In addition, patients in low-risk groups might be managed with surveillance alone. Finally, sentinel lymph node biopsy may be of benefit in intermediate-risk groups.

Molecular markers have also been studied as prognostic factors. p53 appears to be an independent risk factor for nodal metastasis, progression of disease, and survival. Recently, tissue-associated eosinophilia has also been suggested to predict improved survival in patients with penile cancer.

Penile carcinomas show a fairly predictable dissemination pattern, initially to superficial lymph nodes and then to deep groin and pelvic nodes and lastly to retroperitoneal nodes. The first metastatic site is usually a superficial inguinal lymph node located in the groin upper inner quadrant (sentinel node). This pattern of metastasis is present in about 70% of cases. Skip pattern of metastasis is rare. Systemic blood borne metastasis occurs late and usually to liver, heart, lungs, and bone.

Surgery is the preferred treatment option. Partial penile resection is the treatment of choice for superficially invasive primary lesions. Deeply invasive tumors necessitate total penectomy with inguinal node dissection. Radiotherapy provides no demonstrable benefits. Patient follow-up is fundamental to detect recurrence or metastatic adenopathy during the postoperative period.

Clinical Features

Only a few cases are reported in the literature. It primarily affects males in their 8th decade.

Clinically, it presents as nonverruciform hyperkeratotic tumor that affects the foreskin. The tumor is often multicentric. Other concurrent tumor patterns may be verrucous carcinoma. Slowly growing lesions usually arise within the background of lichen sclerosus et atrophicus.

Pathologic Features

Differential Diagnosis

Pseudoepitheliomatous hyperplasia is the principal differential diagnosis, particularly in the superficial biopsy specimens (see Fig. 9-8 ). Pseudoepitheliomatous hyperplasia is limited to subepithelial connective tissue. Infiltration of dartos or corpus spongiosum is not seen in hyperplasia. Downward proliferation is more organized with elongated rete ridges. Keratinization (keratin pearls) is less frequent. Well-developed lichen sclerosus is also usually not present with hyperplasia but is common in pseudohyperplastic carcinoma.

Clinical Features

Patients usually present with a large (average size, 3 cm) cauliflower-like mass ( Fig. 9-10 ) of relatively long duration (average, 56 months). Most of the masses involve the glans and coronal sulcus with frequent involvement of preputial skin.

Pathologic Features

Microscopic Findings

Microscopically, verrucous carcinoma is a very well-differentiated squamous cell carcinoma with an exophytic papillary growth pattern, acanthosis, and hyperkeratosis. The papillations usually do not contain any fibrovascular cores. Cross sections of the tip of the papillae show a central keratin plug with neoplastic cells at the periphery. Characteristically, the tumor shows a pattern of broad-based bulbous infiltration into underlying stroma ( Fig. 9-11 , A ). Deeper infiltration into corpora cavernosa is unusual. Cytologic atypia is minimal, and mitoses are rare and usually confined to the deeper portion of the tumor. A dense inflammatory cell infiltrate may be present at the interface between tumor and stroma and occasionally may obscure it. Koilocytic change is absent or minimal ( Fig. 9-11 , B ). Extensive sampling of the tumor is essential because up to 5% of verrucous carcinomas may have foci of conventional squamous cell carcinoma (hybrid tumor).

Differential Diagnosis

Verrucous carcinomas should be distinguished from other verruciform neoplasms. The morphologic features helpful in separating them are summarized in Table 9-4 and illustrated in Figure 9-12 . Verrucous carcinomas lack HPV-related cellular changes characteristically seen in giant condyloma and warty carcinoma. Papillary carcinoma, NOS type, exhibits more cytologic atypia than verrucous carcinoma and has an irregular invasive front. In a superficial biopsy, distinction of verrucous carcinoma from squamous cell hyperplasia of papillary or verrucous type may be impossible. Wider excision is necessary in such situations to assess the tumor and stroma interaction.

Prognosis and Treatment

Pure verrucous carcinomas have an aggressive behavior locally but not biologically and do not metastatize. However, one third of verrucous carcinomas recur, usually because of insufficient surgery or because of multicentricity. Verrucous carcinomas that contain a component of conventional squamous carcinoma (hybrid tumor) may metastatize. Preferred treatment is surgery. Wide surgical excision, usually necessitating partial penectomy, is the treatment of choice. Anaplastic transformation of penile verrucous carcinoma has also been reported after radiotherapy.

Clinical Feaures

It affects the glans of older men (mean age, 77 years) with extension to the coronal sulcus or foreskin. Carcinoma cuniculatum is not related to HPV infection.

Pathologic Features

Gross Findings

Grossly, it presents with large, papillomatous tumors with “cobblestone” appearance. On the surface, the tumors can resemble other penile verruciform lesions, but on cut surface, irregular narrow sinus tracts extend down to deep anatomic structures ( Fig. 9-13 ).

Microscopic Findings

Carcinoma cuniculatum resembles verruciform carcinoma. The distinguishing feature is the growth pattern, with irregular and narrow sinus tracts that extend deep beneath the surface to adjacent anatomic structures. These sinus tracts can be contiguous with deep, dilated keratin-filled cysts ( Fig. 9-14 ). Some cases may have high histologic grade or microscopically infiltrative borders. There is lack of koilocytic atypia.

Differential Diagnosis

Carcinoma cuniculatum similar to verrucous carcinomas lacks HPV-related cellular changes characteristically seen in giant condyloma and warty carcinoma. Compared with verrucous carcinoma, carcinoma cuniculatum has deep invaginations and forms interanastomosing channels and pseudocystic structures lined by well-differentiated squamous cell carcinoma. Papillary carcinoma, NOS type, exhibits more cytologic atypia than carcinoma cuniculatum and has an irregular invasive front. In a superficial biopsy, distinction from other verruciform tumors may be impossible. Wider excision is

necessary in such situations to assess the tumor and stroma interaction.

Prognosis and Treatment

Carcinoma cuniculatum, despite its deep invasion, has not been associated with lymph node metastasis. The growth pattern reflects its deep extension into underlying tissue and necessity for wide resection.

Clinical Features

These are relatively slow-growing lesions that are frequently present for several years before pathologic diagnosis. Average age at presentation is 61 years. The most common site is the glans, but multiple sites can be involved. Inguinal lymphadenopathy is infrequent.

Pathologic Features

Microscopic Findings

Microscopically, warty carcinoma shows hyperparakeratotic arborizing papillomatous growth. The papillae are long with complex undulating appearance and have central fibrovascular core, and the tips are variably rounded or tapered. Koilocytic atypia in the neoplastic cells is conspicuous and the definitional feature. Intraepithelial abscesses may be prominent, especially in the basal areas. Tumors may infiltrate deeply, and the interface of tumor with stroma is usually irregular ( Fig. 9-15 , A and B ).

Differential Diagnosis

Warty carcinomas should be distinguished from other verruciform neoplasms, which are summarized in Table 9-4 and Figure 9-12 . Giant condyloma may be histologically similar, but pleomorphism is less marked and, most importantly, the base of the tumor is broad with pushing margins rather than the irregular infiltrative appearance seen with warty carcinomas. Verrucous and papillary carcinomas do not show HPV-related changes.

Prognosis and Treatment

Some have metastasized to regional lymph nodes, usually associated with deeply invasive tumors. In one reported large series, two of 11 warty carcinoma showed metastasis to the inguinal nodes.

Clinical Features

Papillary carcinoma, NOS type, is the most common of all the verruciform cancers; it accounts for approximately 15% of penile cancers. The average age at the time of presentation is 60 years. The most common sites of involvement are the glans and foreskin. Patients often present with a large cauliflower-like mass.

Pathologic Features

Microscopic Findings

Histologically, well-differentiated to moderately differentiated hyperkeratotic lesions with irregular, complex papillae, with or without fibrovascular cores, are typical. Cytologic atypia is usually obvious, which differentiates it from verrucous carcinoma. The key feature is the absence of HPV-associated cytologic changes, which, if present, put the tumor in the category of a warty carcinoma. The base of the lesion is characteristically jagged, with irregular nests infiltrating into deeper soft tissues. Irregular wide areas of keratinization referred to as keratin lakes are frequently present between adjacent papillae, sometimes reaching to the tip ( Fig. 9-16 , A and B ).

Differential Diagnosis

Papillary carcinomas should be distinguished from other verruciform neoplasms, which are summarized in the Table 9-4 and Figure 9-12 . Warty carcinomas and giant condylomas have distinctive HPV-related cellular changes in most cells. Verrucous carcinomas do not demonstrate cytologic atypia and also do not demonstrate irregular stromal infiltration. Papillary carcinoma also should be distinguished from typical squamous cell carcinoma, in which papillary features and a high degree of differentiation are not prominent.

Prognosis and Treatment

Despite the fact that deep invasion can occur, regional lymph node metastasis is usually rare. The 5-year survival rate is approximately 90%. Surgery is the treatment of choice.

Clinical Features

Most commonly it arises in the glans in the perimeatal region. The median age at presentation is usually 52 years. Patients present with a flat, ulcerated, firm, and deeply infiltrative mass. More than half of the patients present with enlarged inguinal lymph node as a result of metastatic disease.

Pathologic Features

Microscopic Findings

Microscopically, it is composed of crowded nests of basaloid tumor cells, often associated with comedo-type necrosis ( Fig. 9-17 , A ). The cells are small with scant cytoplasm and oval to round, hyperchromatic nuclei and inconspicuous nucleoli. Mitotic rate is usually brisk. Palisading at the periphery of the nests and abrupt central keratinization are occasionally seen ( Fig. 9-17 , B ). The cells tend to infiltrate deeply into corpora cavernosa. A striking starry-sky appearance may be noted as a result of a high amount of apoptotic cells. Perineural and angiolymphatic invasions are frequent. Atypical basal cell hyperplasia and basaloid carcinoma in situ (undifferentiated PeIN) are frequently associated lesions. Basaloid carcinoma may coexist with conventional squamous cell carcinoma and infrequently with warty carcinoma.

Ancillary Studies

In situ hybridization studies show that most cases are positive for high-risk HPV 16 and 18. Basaloid carcinomas are positive for cytokeratins.

Differential Diagnosis

Prognosis and Treatment

In comparison with usual squamous cell carcinoma, basaloid carcinoma tends to have higher histologic grade, a deeper invasion of the penile anatomic layers, and higher mortality. It is one of the aggressive variants of squamous cell carcinoma with a high rate of inguinal lymph node metastasis and a mortality rate of 59% at 5 years.

Clinical Features

Patients present with a large ulcerated or exophytic mass that is usually situated on the glans but that may also occur on the mucosal side of the foreskin. It accounts for approximately 1% to 3% of penile carcinomas. The average patient age is 60 years.

Pathologic Features

Differential Diagnosis

The usual differential is from sarcoma or malignant melanoma. Tumors with focal presence of in situ carcinoma or differentiated carcinoma favor the diagnosis of sarcomatoid carcinoma. Diagnosis can be made in absence of typical squamous cell carcinoma if there is a history of pure squamous cell carcinoma at that site that was not treated with radiation. Pure spindle cell tumors without such history may pose a diagnostic problem, and additional immunohistochemical stains and electron microscopy may be useful to rule out sarcoma and melanoma. Sometimes squamous cell carcinoma may have pseudoangiomatoid areas, which may raise the possibility of angiosarcoma.

Ancillary Studies

Prognosis and Treatment

Sarcomatoid carcinomas are associated with a high rate of regional lymph node metastasis and carry a bad prognosis. Recurrence is common, with a mortality rate of 60%.

Clinical Features

Patients with PeIN lesions are typically in the middle to later years of life, with a peak frequency in the 6th decade. These lesions occur, on average, at a later age than cases of bowenoid papulosis, which presents at a younger age. These lesions may present as solitary but are more frequently associated with adjacent invasive squamous cell carcinoma (see Fig. 9-4 ). Differentiated lesions predominate (68%), followed by warty-basaloid (14%), basaloid (11%), and warty (7%) subtypes. Differentiated lesions are preferentially located in foreskin, whereas warty and basaloid subtypes are more prevalent in the glans. The former lesions are preferentially seen in association with keratinizing variants of squamous carcinoma, whereas the latter subtypes are found mostly in conjunction with invasive warty, basaloid, and warty-basaloid carcinomas. Lichen sclerosus et atrophicus is commonly associated with differentiated (simplex) PeIN but is absent in undifferentiated PeIN lesions.

The lesions typically present as an irregular, moist, and erythematous area or as scaly plaques ( Fig. 9-19 ). Low-grade lesions may not be clinically apparent or may present as white patches of leukoplakia.