Differential Diagnosis of Verruciform Tumors

The term "verruciform tumors" refers to all penile tumors presenting a predominantly exophytic pattern of growth. As a group, verruciform tumors are characterized by a well-differentiated morphology, low metastatic rate, and better survival compared with the usual SCC variant. Verruciform tumors include warty, papillary, and verrucous carcinoma. Rare tumors, such as carcinoma cuniculatum and giant condyloma (Bushke-Lowenstein tumor) also belong to this category. The hallmark of all these is the presence of papillomatosis. Differences among subtypes are established evaluating the architecture of papillae, extension of fibrovascular cores, morphology of tumor base, degree of differentiation, and presence of koilocytic changes (Table 3.2). Additional immunohistochemical and molecular techniques may help in difficult cases.

Fig. 3.8 Warty (condylomatous) carcinoma. (a) Papillae harboring conspicuous fibrovascular cores. There are nuclear atypias, koilocytosis, and parakeratosis. (b) Tumor front is jagged and irregular and stromal reaction is evident. Note koilocytotic changes in superficial papillae as well as in deeper tumor nests

Fig. 3.8 Warty (condylomatous) carcinoma. (a) Papillae harboring conspicuous fibrovascular cores. There are nuclear atypias, koilocytosis, and parakeratosis. (b) Tumor front is jagged and irregular and stromal reaction is evident. Note koilocytotic changes in superficial papillae as well as in deeper tumor nests

Warty carcinomas represent 7-10% of all penile cancers and 34-35% of all verruciform tumors and are characterized by papillae with prominent fibrovascular cores, a spiky surface with evident parakeratosis, and conspicuous koilocytosis (Fig. 3.8a).9,10,49 Tumor base is irregular and jagged and stromal reaction is common (Fig. 3.8b). The presence of koilocytes is not limited to papillae and they are also easily found in infil-trative tumor nests. Warty carcinoma frequently invades penile erectile tissues, either corpus spongiosum or cavernosum. Tumors limited to the lamina propria are uncommon. Most tumors are moderately differentiated (grade 2) although areas of highgrade can be found in up to one-quarter of the cases. Inguinal nodal metastases are present in about one-third of all patients but the mortality rate is low, ranging from 0% to 9%. Papillary, not otherwise specified (NOS) carcinomas account for 5-15% of all penile carcinomas and 27-53% of all verruciform tumors and are similar to warty carcinomas except that papillae are architecturally more complex with round, spiky, or blunt tips (Fig. 3.9a).9,10,50 Parakeratosis is a common finding but is not as prominent as in warty carcinomas. Acanthosis ranges from mild to moderate and koilocytes are absent. Fibrovascular cores are irregular and their presence is not constant in most of the papillae. Tumors are usually low-grade but in rare occasions areas of poorly differentiated cells can be found. As in warty carcinomas, these foci of anaplastic cells do not predominate, representing only about 5% of the tumor mass. Tumor base is jagged and irregular, stromal reaction ranges from moderate to intense, and invasive tumor nests usually retain the same degree of differentiation of papillae (Fig. 3.9b).

Verrucous carcinoma, which represents 3-8% of all penile SCC and 12-38% of all verruciform tumors, is quite different compared to the aforementioned tumors. Papillae are characterized by marked acanthosis, fibrovascular cores are very inconspicuous or absent, and intraepithelial keratin plugs are frequently found (Fig. 3.10a).9,10 Koilocytes are absent and parakeratosis ranges from mild to prominent. Tumor base is broad and pushing and stromal reaction is moderate to severe (Fig. 3.10b). Occasionally finger-like invaginations from the main mass are observed

Fig. 3.9 Papillary, NOS carcinoma. (a) Papillae show irregular fibrovascular cores, with moderate acanthosis and parakeratosis. Koilocytotic changes are absent. (b) Tumor base is irregular and jagged and stromal reaction is intense. Neoplastic cells retain the morphological features of those located in papillae

Fig. 3.9 Papillary, NOS carcinoma. (a) Papillae show irregular fibrovascular cores, with moderate acanthosis and parakeratosis. Koilocytotic changes are absent. (b) Tumor base is irregular and jagged and stromal reaction is intense. Neoplastic cells retain the morphological features of those located in papillae

Fig. 3.10 Verrucous carcinoma. (a) Broadly based highly differentiated acanthotic tumor with a sharp delimitation of tumor and stroma. There is minimal basal atypia. (b) Tumor base is broad and pushing with well-defined boundaries. Stromal reaction is readily evident

but the interface between the tumor base and stroma is regular and remains well-defined. In verrucous carcinoma neoplastic cells are extremely well-differentiated whilst warty and papillary carcinomas range from well to moderately differentiated, with a minority of the cases in the poorly differentiated category. Verrucous carcinomas usually invade up to the lamina propria or corpus spongiosum and extension beyond these areas is infrequent while warty and papillary tend to infiltrate deeper into penile tissues and with an irregular tumor front. Verrucous carcinoma should be distinguished not only from other verruciform tumors but also from other variants with verrucous features such as mixed usual-verrucous (hybrid) carcinoma.9 In hybrid verrucous carcinoma typical areas of verrucous carcinoma coexist with foci of an otherwise usual low or high-grade SCC (Fig. 3.11).9,11 Distinction is clinically important since pure verrucous carcinomas and verrucous carcinomas with minimal

Fig. 3.12 Rare verruciform tumors. (a) Carcinoma cuniculatum. Well-differentiated tumor nests forming cysts (leftfield) and sinus-like (rightfield) structures. (b) Giant condyloma with fibrovas-cular cores and conspicuous koilocytosis but no evident cytological atypias. Tumor growth shows a broad and pushing front

Fig. 3.12 Rare verruciform tumors. (a) Carcinoma cuniculatum. Well-differentiated tumor nests forming cysts (leftfield) and sinus-like (rightfield) structures. (b) Giant condyloma with fibrovas-cular cores and conspicuous koilocytosis but no evident cytological atypias. Tumor growth shows a broad and pushing front

(<2 mm) stromal invasion (microinvasive verrucous carcinomas) are not associated with nodal metastasis and prognosis is excellent, despite the large size these tumors can reach.9 However, in hybrid verrucous carcinoma metastatic and recurrence rates are higher and prognosis approaches that of a usual SCC.51-53 Generous sampling is advised in order to rule out the presence of usual SCC foci.

Although rare, carcinoma cuniculatum and giant condyloma should also be considered in the differential diagnosis of verruciform tumors. Carcinoma cuniculatum is similar to a verrucous carcinoma at the surface but is characterized by extensive infiltration of deep erectile tissues, usually up to the corpora cavernosa, with the formation of sinus-and cyst-like tracts (Fig. 3.12a).12 Fistulization to foreskin or the penile shaft is not unusual. Neoplastic cells are extremely well differentiated and retain this morphology throughout the tumor, even in the deepest infiltrative nests. Despite the deep erectile tissue invasion the prognosis is excellent and similar to a pure verrucous carcinoma.

Giant condyloma is characterized by papillomatosis, acanthosis, prominent fibrovascular cores and a broad and pushing tumor base (Fig. 3.12b). Koilocytes are easily found but nuclear atypia is minimal and limited to the basal layers. Deep penetration can be observed but morphology remains bland. The presence of a regular tumor front of invasion and lack of nuclear atypia permits the distinction between giant condyloma and warty carcinoma. Prominent fibrovascular cores and conspicuous koilocytosis aid in the differential diagnosis with verrucous carcinoma. Finally, as stated above, in papillary carcinomas the tumor base is jagged and irregular and koilocytes are absent. Malignant change in a giant condyloma is not a rare event and should be ruled out. In most cases malignant foci correspond to usual SCC and should be evaluated using the same approach for conventional penile carcinomas. Generous sampling is imperative for proper evaluation of this and other verruciform tumors.

Some verruciform tumors are complex, showing more than one histological pattern and are difficult to classify. In this context, identification and genotyping of HPV can be helpful.46-48,54 Verrucous and papillary carcinomas are usually negative for HPV while in warty carcinomas and giant condylomas HPV is found in the majority of cases. High-risk HPV, mainly genotypes 16 and 18, are found in the former while in the latter low-risk genotypes, mainly HPV-6 and HPV-11, predominate. Patterns of p16™K4a expression can also be useful. Warty carcinomas tend to be p16I NK4a positive while giant condylomas and papillary and verrucous carcinomas are consistently negative. Notwithstanding this, there will be some rare cases in which the distinction between a papillary, warty, or verrucous carcinoma will not be possible on morphological or molecular grounds, especially in limited biopsies and small lesions. In these cases the diagnosis of "verruciform tumor, not otherwise specified" would be appropriate. Histological grading is particularly useful in these situations since it seems that it has a greater impact on prognosis than tumor depth or thickness.55,56

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