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Verruciform and Condyloma-like Squamous Proliferations in the Anogenital Region.

Condyloma acuminatum frequently enters the differential diagnosis of anogenital papules or plaques, especially those with a verruciform silhouette. Classification of these lesions is often challenging owing to significant histopathologic overlap and sometimes controversial and confusing diagnostic criteria. Insufficient "crosstalk" between genitourinary, gynecologic, gastrointestinal, and general surgical pathologists and dermatopathologists further contributes to the practice gap in this area. This article reviews the clinicopathologic features and etiopathogenesis of condyloma acuminatum and its mimics, with an emphasis on their morphologic similarities and unique characteristics that help in their distinction. The clinical and pathologic features of all discussed entities are summarized in the Table.

CONDYLOMA ACUMINATUM

The incidence of condyloma acuminatum (genital wart) is highest among young adults, (1) but has declined since the introduction of human papillomavirus (HPV) vaccines. (2-4) The lesions typically arise in the genitalia, anus, and the surrounding area (pubis, groin, and medial thigh). Clinically, these are solitary or coalescent skin-colored papules with a papillomatous surface. Its giant variant (giant condyloma acuminatum of Buschke-Lowenstein) is discussed separately in the next section. Condyloma acuminatum is caused by HPV infection, with HPV types 6 and 11 being the most prevalent. (5) HPV 6 and 11 belong to the low-risk HPV group, which essentially has no risk for malignant progression. Cases associated with high-grade intraepithelial neoplasia and warty/basaloid squamous cell carcinoma (SCC) are coinfected with high-risk HPV types. (6-8)

The epithelium in condyloma acuminatum is acanthotic with variable degree of papillomatosis. Compared to the "spiky" papillae in verruca vulgaris (VV), the papillae in condyloma acuminatum have more rounded and undulating contours, with less robust hyperkeratosis (Figure 1, A). Collectively, these feature give rise to a "softer" appearance compared to VV. Koilocytes containing enlarged and irregular nuclei, perinuclear halos, and coarse keratohyalin granules may be found in the granular and upper spinous layers. These viral cytopathic changes serve as an important diagnostic hallmark (Figure 1, B). (9) Binucleated or multinucleated forms may be present. The rest of the keratinocytes lack cytologic atypia and mature orderly toward the surface.

A common diagnostic quandary is regarding anogenital seborrheic keratosis (SK)-like lesions without identifiable koilocytes (Figure 1, C). Multiple studies have demonstrated the presence of HPV, predominantly type 6, in up to 70% of anogenital SKs. (10-14) In contrast, HPV was rarely detected in extragenital SK and other non-HPV-mediated lesions on genital skin (such as fibroepithelial polyp, epidermolytic acanthoma, and chronic dermatitis). (12,13) These findings suggest that genital SK is at least similar or related to condyloma acuminatum. Indeed, Li and Ackerman (15) regarded HPV-harboring SK in the anogenital region as synonymous with condyloma acuminatum. As a general rule, anogenital SK-like lesions with an undulating appearance (Figure 1, C), with or without pseudohorn cysts, are probably best treated as condyloma acuminatum, as opposed to those with a flat base. (15)

Pirog et al (16,17) have found positive Ki-67 (MIB-1) immunostaining, defined as any cluster of at least 2 positive nuclei in the upper two-thirds of the epithelium, in all vulvar and anal condylomas examined, a finding that correlated well with positive HPV results by polymerase chain reaction (PCR) and DNA sequencing. Unlike lesions infected with high-risk HPV, which are diffusely and strongly positive for p16, condylomas display negative, focal, or patchy staining (Figure 1, D). (17,18) When necessary, testing for low-risk HPV (types 6 and 11) by PCR-DNA sequencing, in situ hybridization, or immunohistochemistry may also aid in diagnosis. (19)

GIANT CONDYLOMA ACUMINATUM (BUSCHKE-LOWENSTEIN TUMOR)

Giant condyloma acuminatum is a large, fungating, and locally destructive form of condyloma acuminatum. It is 3 times more common in men than women, with a predisposition for immunocompromised individuals. (20) Giant condyloma acuminatum often covers multiple anatomic structures owing to its large size, most frequently involving the penis and the anorectum. The scrotum, groin, and pubis may also be affected. (21-23) The tumor grows exophytically and endophytically, and the exophytic excrescences are often described as "cauliflower-like." Fistula formation between papillae is common. Given its papillomatous architecture and large size, many regarded giant condyloma acuminatum as a variant of verrucous carcinoma. However, this view has been challenged by the frequent detection of HPV in giant condylomas but rarely in verrucous carcinomas. (24,25) As in ordinary condyloma acuminatum, giant condylomas usually harbor HPV 6 and 11. (24) Recurrence rate is high, (21) and malignant transformation to invasive SCC has been reported in more than 50% of cases, most commonly in HIV-positive patients. (20,21) Not surprisingly, coinfection with high-risk HPV has been demonstrated in carcinoma ex giant condyloma acuminatum. (26)

The microscopic features of giant condyloma acuminatum are similar to those of its ordinary counterpart except for its large size and more florid excrescences. There is marked papillomatosis with usually mild hyperkeratosis (Figure 2, A). Aside from koilocytosis, cytologic atypia is absent (Figure 2, B). Mitotic activity is low and is confined to the lower third of the epithelium. The large tumor mass compresses but does not infiltrate normal structures. Reverse maturation and stromal invasion, when present, should raise concern for malignant transformation. (21,27) Immunohistochemical profile, including negative, focal, or patchy staining for p16, is the same as described in ordinary condyloma acuminatum. (24)

VERRUCOUS CARCINOMA

Verrucous carcinoma is a unique variant of well-differentiated SCC. As mentioned above, controversy exists regarding the relationship between verrucous carcinoma and giant condyloma acuminatum. While some authors believe that the 2 are either identical or closely related on a continuous spectrum, accumulating evidence suggests that these are distinct entities. Much of the confusion stems from the lack of consistent diagnostic criteria, leading to mixed data with controversial diagnoses reported in the literature. Multiple studies have shown that unlike giant condylomas, which consistently harbor HPV, anogenital verrucous carcinomas diagnosed on the basis of strict histopathologic criteria (see below) are predominantly negative for HPV. (24,25,28-30) These findings support distinct pathogenetic pathways in verrucous carcinoma and giant condyloma acuminatum, and that they should be considered separate entities. Similar to other HPV-negative SCCs of the anogenital tract, verrucous carcinoma is associated with chronic inflammatory conditions such as lichen sclerosus and lichen simplex chronicus, which play a key role in its pathogenesis. (29,31-33)

Clinically, verrucous carcinoma and giant condyloma acuminatum share many common features including large tumor size, verrucous surface, exophytic and endophytic growth, typically slow progression, and virtual lack of metastatic potential. (34,35) In addition to the anogenital area, verrucous carcinoma also occurs in the oral cavity, larynx, and extragenital skin. (34,36) The warty excrescences in verrucous carcinoma tend to be coarse and irregular, whereas those in giant condyloma acuminatum are finer and more regular. (25) Verrucous carcinoma is also more keratotic and firm than giant condyloma acuminatum, which has a more delicate and soft texture. (25)

Histopathologically, verrucous carcinoma is a well-demarcated verrucous squamous proliferation with bulbous rete ridges that push, rather than infiltrate, into the underlying stroma (Figure 3, A). Compact hyperkeratosis often fills the spaces between the verrucous projections (Figure 3, A). (24,25,37) Fibrovascular cores tend to be thin and inconspicuous relative to the hypertrophic epithelium. These features impart a "firm" and "rigid" appearance at low magnification, which contrasts with the "soft" appearance of giant condyloma acuminatum. Keratinocytes in the spinous layer are markedly enlarged with abundant eosinophilic cytoplasm and minimal nuclear atypia (Figure 3, B). (25,28) Scattered dyskeratotic cells are common. (24) An important diagnostic criterion is the absence of koilocytes, which distinguishes it from giant condyloma acuminatum. Mitoses are rare and confined to the basal layer. (25) A band of lymphocytic infiltrate is usually found at the base of the tumor (Figure 3, A).

Immunohistochemistry for p16 does not distinguish verrucous carcinoma from giant condyloma acuminatum, as both display negative or focal staining. (30) Nuclear p53 staining is commonly present but mostly confined to the basal and suprabasal layers. Likewise, Ki-67 positivity is mainly observed in the basal layer. (28) Absence of HPV may be confirmed by PCR-DNA sequencing, in situ hybridization, or immunohistochemistry. (24,25,28,30)

WARTY/WARTY-BASALOID HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESION AND SQUAMOUS CELL CARCINOMA

Infection by high-risk HPV, most commonly HPV 16 and less commonly HPV 18, 31, 33, 45, 51, 52, and 59 amongst others, causes undifferentiated intraepithelial neoplasia (-IN) of the vulva, vagina, penis, scrotum, and anus. (38-42) These HPV-related squamous intraepithelial lesions may be subclassified into warty, basaloid, and warty-basaloid types by histopathologic features. To facilitate unified nomenclature across subspecialties, the Lower Anogenital Squamous Terminology (LAST) work group has recommended a 2-tier system for all HPV-associated noninvasive squamous lesions of the lower anogenital tract: low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL). (43) It is optional to further classify LSIL and HSIL as "-IN 1" and "-IN 2 or 3," respectively, according to the specific sites. (43) Although HSIL is synonymous with "SCC in situ" and "Bowen disease," the latter terminologies are best avoided in pathology reporting for the purpose of consistency. Clinically, warty and warty-basaloid HSIL and invasive SCC may mimic condyloma acuminatum when discrete papillomatous papules or plaques are present. (44)

On histopathology, warty HSIL and SCC mimic condyloma acuminatum by their verruciform architecture, conspicuous fibrovascular cores, and koilocytosis (Figure 4, A). Parakeratosis is usually more abundant than in condyloma acuminatum. (37) The key distinguishing feature is the presence of cytologic atypia in that the keratinocytes in the lower epithelium are enlarged and pleomorphic (Figure 4, B). The upper keratinocytes acquire a moderate to abundant amount of cytoplasm as they mature toward the surface, (45,46) where koilocytosis is readily appreciated (Figure 4, B). In contrast, basaloid HSIL is characterized by a flat surface and minimal maturation from the basal layer to the granular layer. While the basaloid subtype rarely mimics condyloma acuminatum, it shares overlapping features with the warty-basaloid subtype, which has a condyloma-like, verruciform silhouette (Figure 4, C). (37) The epithelium is basaloid due to a high nuclear to cytoplasmic ratio and nuclear hyperchromasia (Figure 4, C; inset). Occasional koilocytes may be found in the upper layers. (37) Mitoses and apoptoses are frequent and found at all levels of the epithelium (Figure 4, C; inset). (46) When invasion occurs in the basaloid and warty-basaloid subtypes, the invasive nests often take on a basaloid appearance without keratinization. Occasionally, keratinizing SCC may occur. (37,38)

As a surrogate marker for high-risk HPV infection, p16 immunohistochemical stain serves as a helpful tool to distinguish warty, basaloid, and warty-basaloid squamous neoplasms from condyloma acuminatum and HPV-independent (differentiated) squamous neoplasms. Staining in the former is strong and diffuse, and in both cytoplasmic and nuclear compartments (Figure 4, D). This is in contrast with the negative or patchy staining in condyloma acuminatum and differentiated squamous lesions. (33,46-50) Ki-67 proliferation index is typically high, with staining observed at all levels of the epithelium. (49,50) Unlike differentiated squamous lesions, p53 staining in warty, basaloid, and warty-basaloid squamous neoplasms is either negative or patchy. (46,49)

PAPILLARY SQUAMOUS CELL CARCINOMA

HPV-independent (differentiated) squamous neoplasms seldom cause diagnostic confusion with condyloma acuminatum, with the exception of papillary SCC. The latter refers to well-differentiated SCC with a papillary architecture. This tumor type is rarely described in the anogenital region. The most comprehensive study reported 35 cases of penile papillary SCC, most of which occurred on the glans with or without involvement of the coronal sulcus and foreskin. (51) The tumors form white-grey, irregular masses with serrated surfaces.

Microscopically, the squamous papillae are of variable lengths and shapes, lined by irregular well-differentiated squamous epithelium with overlying hyperkeratosis (Figure 5, A). Compared to condyloma acuminatum, the fibrovascular cores in papillary SCC are more irregular, and the tumor base is ragged (owing to stromal invasion) as opposed to round. (37,51) It also differs from condyloma acuminatum and warty/warty-basaloid squamous neoplasms by the absence of koilocytes (Figure 5, B). Conspicuous fibrovascular cores and an infiltrative, rather than broad pushing, tumor base further distinguish papillary SCC from verrucous carcinoma. Differentiated intraepithelial neoplasia and lichen sclerosus may be found in the adjacent epithelium. (37,51)

BOWENOID PAPULOSIS

Bowenoid papulosis is another HPV-associated disease affecting the squamous epithelium. Patients typically present with multiple red-brown or violaceous papules on penile or vulvar skin, although any anogenital sites may be affected. The papules have a median diameter of 0.7 cm according to one study and may be flat-topped or slightly verruciform, commonly mistaken for condyloma acuminatum on clinical examination. (52-54) Most patients are young adults in the third and fourth decades of life. (53,54) Similar to HSIL, bowenoid papulosis is associated with high-risk HPV, particularly HPV 16. (53,55) However, as progression to invasive SCC is exceptional, treatment options often include simple excision as well as local destructive modalities such as imiquimod and photodynamic therapy, although recurrence is common. (53,56-60) A small percentage of cases may regress spontaneously. (53) A DNA ploidy study showed an intermediate "malignancy grade" between that of Bowen disease and SK, suggesting it to be a low-grade SCC in situ. (61) Patients with bowenoid papulosis are at increased risk of developing external anogenital SCC and cervical neoplasia, and therefore warrant clinical surveillance on a regular basis. (62,63)

The histopathologic features of bowenoid papulosis overlap significantly with those of basaloid HSIL (Bowen disease). (52) The lesions are acanthotic and may appear psoriasiform or slightly verruciform (Figure 6, A). The keratinocytes are crowded and display high nuclear to cytoplasmic ratio and impaired maturation toward the surface (Figure 6, A; inset). (54) Scattered apoptotic cells and mitotic figures are present at all levels of the epithelium. (60) Some cells in the granular layer may resemble koilocytes. Pigmented lesions consist of melanophages in the underlying stroma. In a series of 108 cases, it was concluded that a background of maturing keratinocytes and sparing of the follicular epithelium could distinguish bowenoid papulosis from basaloid HSIL. (53) Another morphometric analysis showed significantly larger and more irregular nuclei in basaloid HSIL compared to bowenoid papulosis. (64) In practice, however, the histopathologic differences are often subtle, and definitive diagnosis relies heavily on stringent clinical correlation: Presence of multiple small pigmented papules in a young adult, as opposed to a solitary, slowly progressive plaque or erythematous patch in an older patient, would support a diagnosis of bowenoid papulosis over basaloid HSIL. (53,60)

High-risk HPV in bowenoid papulosis can be detected by in situ hybridization or PCR-DNA sequencing. (65-67) Expression of both p16 and human telomerase reverse transcriptase (hTERT) by immunohistochemistry is associated with high-risk HPV infection and has been demonstrated in bowenoid papulosis. (67) Diffuse p16 expression is especially helpful in differentiating occasional cases of bowenoid papulosis with more orderly maturation, subtle cytologic atypia, and koilocyte-like cells from condyloma acuminatum (Figure 6, B). (18)

VERRUCA VULGARIS

Although VV (common wart) usually occurs on extragenital skin, it can occasionally arise in the anogenital area and may result in diagnostic confusion with condyloma acuminatum. Both condyloma acuminatum and VV are caused by low-risk HPV. However, in contrast with condyloma acuminatum, which is typically caused by HPV types 6 and 11, VV is most commonly induced by HPV 2, followed by HPV 1, 4, 65, 27, and others. (68,69) Distinction of VV and condyloma acuminatum has important clinical implication especially in the pediatric population, as condyloma acuminatum would raise suspicion for sexual abuse, whereas VV is nonsexually transmitted. Approximately 40% of warts in the genital area of young girls are VV (positive for HPV 2) while the rest are condylomas (positive for HPV 6 or 11). (70) The clinical morphologies of VV and condyloma acuminatum are similar in that both are exophytic and verrucous papules, but VV tends to be more hyperkeratotic than condyloma acuminatum.

Histopathologically, VV is characterized by marked verruciform acanthosis and hyperkeratosis. The elongated rete ridges tend to converge toward the center of the lesion ("in-toeing") (Figure 7, A). The papillae have pointed tips and fibrovascular cores housing capillaries near the surface (Figure 7, B), which are prone to thrombosis and infarction. These papillae are surmounted by columns of parakeratosis ("church spire" parakeratosis), whereas the "valleys" between the papillae show hypergranulosis (Figure 7, B). Koilocytosis may be subtle but often can be appreciated in a background of hypergranulosis. The constellation of marked hyperkeratosis, "spiky" papillae, and convergence of elongated rete ridges allows for distinction of VV from condyloma acuminatum.

When necessary, diagnosis of VV can be confirmed by HPV genotyping. Demonstration of HPV 2 or other nongenital HPV types in the absence of HPV 6 or 11, either by in situ hybridization or by PCR-DNA sequencing, would support a diagnosis of VV and exclude condyloma acumi natum. (68-72)

EPIDERMOLYTIC ACANTHOMA

Epidermolytic acanthoma can present as solitary or multiple (disseminated) lesions on the trunk, extremities, or genitalia. The disseminated form most frequently affects genital skin, particularly the scrotum and the vulva. (73-75) The lesions are skin-colored or whitish papules with a smooth or verruciform surface, frequently confused with condyloma acuminatum clinically. (74,76) Multiple reports have confirmed the absence of HPV in epidermolytic acanthomas, (73,76,77) although 1 reported case of scrotal epidermolytic acanthoma tested positive for HPV 16 when using a highly sensitive HPV DNA chip. (78) It is possible that HPV was an incidental finding, rather than a pathogenic agent, in this isolated case.

The histopathologic features of epidermolytic acanthoma frequently raise suspicion for condyloma acuminatum or VV to the untrained eye. The lesion is acanthotic and hyperkeratotic with variable degree of papillomatosis and/ or invagination (Figure 8, A). (76,79) The histopathologic pattern is that of epidermolytic hyperkeratosis (EHK), in which the keratinocytes in the granular and spinous layers display cytoplasmic vacuolation, reticular degeneration, coarse keratohyalin granules, and perinuclear eosinophilic inclusions (Figure 8, B). (73,76,79) Despite superficial resemblance to koilocytosis, these unique characteristics of EHK effectively exclude condyloma acuminatum and VV.

Although a diagnostic hallmark of epidermolytic acanthoma, the EHK pattern is not specific for this diagnosis, as it may also be seen in epidermolytic ichthyosis, (80) epidermolytic epidermal nevus, (81,82) or as an incidental finding. (83,84) These conditions are histologically indistinguishable, and clinical correlation is the key to correct diagnosis. Unlike epidermolytic ichthyosis, which is caused by germline mutation in KRT1 or KRT10, somatic mutations in these genes have not been found in epidermolytic acanthomas. (85,86) Interestingly, however, reduced expression of cytokeratin (CK) 1 and CK10 has been demonstrated by immunohistochemistry. (85,87) While the exact cause of epidermolytic acanthoma remains unclear, it has been hypothesized that repetitive trauma (scratching) or other stimuli may trigger local disruption of CK1 and CK10 protein synthesis and formation of epidermolytic acanthoma. (85)

VERRUCIFORM XANTHOMA

Verruciform xanthoma is a benign proliferation most commonly occurring in the oral cavity. Extraoral lesions are rare and usually arise on the vulva, penis, scrotum, and extremities. (88) Most patients present with a solitary lesion, although coexistence of multiple lesions can occur. Verruciform xanthomas are well-demarcated, yellowishorange papules or plaques with verruciform surfaces ranging from 0.2 to 2 cm in diameter. (89) Not surprisingly, the clinical morphology often raises concern for condyloma acuminatum or verrucous carcinoma. (89,90) In a study of 10 vulvar verruciform xanthomas, all were associated with vulvar inflammatory or neoplastic conditions including lichen sclerosus, lichen planus, Paget disease, and radiodermatitis. (89) Although HPV has been proposed in the past as the etiologic agent, multiple studies have failed to confirm a causal relationship. (91-93) Based on its benign nature and association with various diseases, it is now widely believed that verruciform xanthoma represents a mucocutaneous reaction to localized trauma and chronic inflammation. (94)

Histopathologic examination confirms an exophytic papillomatous lesion. A diagnostic clue at low magnification is the presence of compact parakeratosis with an orange hue or peach color completely filling the spaces between the papillary projections (Figure 9, A and B). (89) Neutrophils are often found in the parakeratotic stratum corneum (Figure 9, B). These features should prompt a closer inspection for xanthomatous (foam) cells, which are confined to the dermal papillae (Figure 9, C). The deeper dermis is remarkable for an inflammatory infiltrate and ectatic vessels. It is hypothesized that the inciting event (trauma or other cutaneous disorder) causes keratinocytic degeneration and release of cellular lipids and chemokines, which then lead to a foam cell response, chemotaxis of neutrophils, and stimulation of epidermal proliferation. (93,95) The absence of cytologic atypia or koilocytosis in verruciform xanthoma speaks against condyloma acuminatum, and the presence of xanthomatous cells excludes verrucous carcinoma.

CONCLUSIONS

Besides condyloma acuminatum, a number of cutaneous and mucosal lesions in the anogenital region share a similar verruciform architecture and/or clinical presentation, often representing a common source of diagnostic confusion. Amongst these are relatively rare entities such as bowenoid papulosis, epidermolytic acanthoma, and verruciform xanthoma, which are underrecognized by surgical pathologists. Giant condyloma acuminatum and verrucous carcinoma used to be considered synonymous, but accumulating evidence supports that these are distinct entities with different pathogenetic pathways. Familiarization with the clinicopathologic characteristics and HPV status of various anogenital lesions described in this review should allow for more accurate classification and appropriate management of these conditions.

References

(1.) Patel H, Wagner M, Singhal P, Kothari S. Systematic review of the incidence and prevalence of genital warts. BMC Infect Dis. 2013;13:39.

(2.) Bauer HM, Wright G, ChowJ. Evidence of human papillomavirus vaccine effectiveness in reducing genital warts: an analysis of California public family planning administrative claims data, 2007-2010. Am J Public Health. 2012; 102(5):833-835.

(3.) Guerra FM, Rosella LC, Dunn S, Wilson SE, Chen C, Deeks SL. Early impact of Ontario's human papillomavirus (HPV) vaccination program on anogenital warts (AGWs): a population-based assessment. Vaccine. 2016;34(39):4678-4683.

(4.) Canvin M, Sinka K, Hughes G, Mesher D. Decline in genital warts diagnoses among young women and young men since the introduction of the bivalent HPV (16/18) vaccination programme in England: an ecological analysis. Sex Transm Infect. 2017;93(2):125-128.

(5.) Cong X, Sun R, Zhang X, Wang Y, Wang L, Yu Y. Correlation of human papillomavirus types with clinical features of patients with condyloma acuminatum in China. Int J Dermatol. 2016;55(7):775-780.

(6.) Maniar KP, Ronnett BM, Vang R, Yemelyanova A. Coexisting high-grade vulvar intraepithelial neoplasia (VIN) and condyloma acuminatum: independent lesions due to different HPV types occurring in immunocompromised patients. Am J Surg Pathol. 2013;37(1):53-60.

(7.) Erman-Vlahovic M, Vlahovic J, Mrcela M, Hrgovic Z. Coexistence of condylomata acuminata with warty squamous cell carcinoma and squamous cell carcinoma. Med Arch. 2017;71(1):72-75.

(8.) Fernandez-Nestosa MJ, Guimera N, Sanchez DF, et al. Human papillomavirus (HPV) genotypes in condylomas, intraepithelial neoplasia, and invasive carcinoma of the penis using laser capture microdissection (LCM)-PCR: a study of 191 lesions in 43 patients. Am J Surg Pathol. 2017;41(6):820-832.

(9.) Nuovo GJ, O'Connell M, Blanco JS, Levine RU, Silverstein SJ. Correlation of histology and human papillomavirus DNA detection in condyloma acuminatum and condyloma-like vulvar lesions. Am J Surg Pathol. 1989;13(8):700-706.

(10.) Leonardi CL, Zhu WY, Kinsey WH, Penneys NS. Seborrheic keratoses from the genital region may contain human papillomavirus DNA. Arch Dermatol. 1991;127(8):1203-1206.

(11.) Zhu WY, Leonardi C, Penneys NS. Detection of human papillomavirus DNA in seborrheic keratosis by polymerase chain reaction. J Dermatol Sci. 1992; 4(3):166-171.

(12.) Bai H, Cviko A, Granter S, Yuan L, Betensky RA, Crum CP. Immunophenotypic and viral (human papillomavirus) correlates of vulvar seborrheic keratosis. Hum Pathol. 2003;34(6):559-564.

(13.) Tardlo JC, Bancalari E, Moreno A, Martin-Fragueiro LM. Genital seborrheic keratoses are human papillomavirus-related lesions: a linear array genotyping test study. APMIS. 2012;120(6):477-483.

(14.) Reutter JC, Geisinger KR, LaudadioJ. Vulvar seborrheic keratosis: is there a relationship to human papillomavirus? J Low Genit Tract Dis. 2014;18(2):190-194.

(15.) Li J, Ackerman AB. "Seborrheic keratoses" that contain human papillomavirus are condylomata acuminata. Am J Dermatopathol. 1994;16(4):398-405.

(16.) Pirog EC, Chen YT, Isacson C. MIB-1 immunostaining is a beneficial adjunct test for accurate diagnosis of vulvar condyloma acuminatum. Am J Surg Pathol. 2000;24(10):1393-1399.

(17.) Pirog EC, Quint KD, Yantiss RK. P16/CDKN2A and Ki-67 enhance the detection of anal intraepithelial neoplasia and condyloma and correlate with human papillomavirus detection by polymerase chain reaction. Am J Surg Pathol. 2010;34(10):1449-1455.

(18.) Kazlouskaya V, Shustef E, Allam SH, Lal K, Elston D. Expression of p16 protein in lesional and perilesional condyloma acuminata and bowenoid papulosis: clinical significance and diagnostic implications. JAm Acad Dermatol. 2013;69(3):444-449.

(19.) Wititsuwannakul J, Klump VR Jr, McNiff JM, Ko CJ. Detecting HPV in cutaneous lesions using anti-HPV antibody immunohistochemistry. Am J

Dermatopathol. 2013;35(3):327-331.

(20.) Trombetta LJ, Place RJ. Giant condyloma acuminatum of the anorectum: trends in epidemiology and management: report of a case and review of the literature. Dis Colon Rectum. 2001;44(12):1878-1886.

(21.) Chu QD, Vezeridis MP, Libbey NP, Wanebo HJ. Giant condyloma acuminatum (Buschke-Lowenstein tumor) of the anorectal and perianal regions: analysis of 42 cases. Dis Colon Rectum. 1994;37(9):950-957.

(22.) Nain PS, Sidhu S, Garg B. Giant condyloma acuminata of the inguinal region. Indian J Surg. 2015;77(suppl 2):729-730.

(23.) Ogrodnik J, Gulati S, Hodge J, Koonce C. Giant condyloma acuminatum of the scrotum, bilateral groins, and suprapubic region: a treatment and reconstruction challenge. Am Surg. 2015;81(5):E215-E217.

(24.) 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.

(25.) Zidar N, Langner C, Odar K, et al. Anal verrucous carcinoma is not related to infection with human papillomaviruses and should be distinguished from giant condyloma (Buschke-Lowenstein tumour). Histopathology. 2017;70(6):938-945.

(26.) Diani M, Boneschi V, Ramoni S, Gadda F, Del Gobbo A, Cusini M. Rapidly invasive Buschke-Lowenstein tumor associated with human papillomavirus types 6 and 52. Sex Transm Dis. 2015;42(10):547-548.

(27.) Bambao C, Nofech-Mozes S, Shier M. Giant condyloma versus verrucous carcinoma: a case report. J Low Genit Tract Dis. 2010;14(3):230-233.

(28.) Gualco M, Bonin S, Foglia G, et al. Morphologic and biologic studies on ten cases of verrucous carcinoma of the vulva supporting the theory of a discrete clinico-pathologic entity. Int J Gynecol Cancer. 2003;13(3):317-324.

(29.) Nascimento AF, Granter SR, Cviko A, Yuan L, Hecht JL, Crum CP. Vulvar acanthosis with altered differentiation: a precursor to verrucous carcinoma? Am J Surg Pathol. 2004;28(5):638-643.

(30.) Stankiewicz E, Kudahetti SC, Prowse DM, et al. HPV infection and immunochemical detection of cell-cycle markers in verrucous carcinoma of the penis. Mod Pathol. 2009;22(9):1160-1168.

(31.) Klima M, Kurtis B, Jordan PH Jr. Verrucous carcinoma of skin. J Cutan Pathol. 1980;7(2):88-98.

(32.) Bain L, Geronemus R. The association of lichen planus of the penis with squamous cell carcinoma in situ and with verrucous squamous carcinoma. J Dermatol Surg Oncol. 1989;15(4):413-417.

(33.) de Koning MN, Quint WG, Pirog EC. Prevalence of mucosal and cutaneous human papillomaviruses in different histologic subtypes of vulvar carcinoma. Mod Pathol. 2008;21(3):334-344.

(34.) Schwartz RA. Verrucous carcinoma of the skin and mucosa. J Am Acad Dermatol. 1995;32(1):1-21.

(35.) Chuanyu S, Ke X, Jie Z, Guowei X, Zujun F, Qiang D. Surgical treatment for 11 cases of penile verrucous carcinoma. Ann Dermatol. 2011;23(suppl 3):S346-S349.

(36.) Kraus FT, Perezmesa C. Verrucous carcinoma: clinical and pathologic study of 105 cases involving oral cavity, larynx and genitalia. Cancer. 1966;19(1):26-38.

(37.) Chaux A, Cubilla AL. Diagnostic problems in precancerous lesions and invasive carcinomas of the penis. Semin Diagn Pathol. 2012;29(2):72-82.

(38.) Fuste V, del Pino M, Perez A, etal. Primary squamous cell carcinoma of the vagina: human papillomavirus detection, p16(INK4A) overexpression and clinicopathological correlations. Histopathology. 2010;57(6):907-916.

(39.) de Sanjose S, Alemany L, Ordi J, et al. Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva. Eur J Cancer. 2013;49(16):3450-3461.

(40.) Matoso A, Fabre V, Quddus MR, et al. Prevalence and distribution of 15 high-risk human papillomavirus types in squamous cell carcinoma of the scrotum. Hum Pathol. 2016;53:130-136.

(41.) Velazquez EF, Chaux A, Cubilla AL. Histologic classification of penile intraepithelial neoplasia. Semin Diagn Pathol. 2012;29(2):96-102.

(42.) Bornstein J, Bogliatto F, Haefner HK, et al. The 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) terminology of vulvar squamous intraepithelial lesions. Obstet Gynecol. 2016;127(2):264-268.

(43.) Darragh TM, Colgan TJ, Cox JT, et al. The Lower Anogenital Squamous Terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med. 2012;136(10):1266-1297.

(44.) Chaux A, Velazquez EF, Amin A, et al. Distribution and characterization of subtypes of penile intraepithelial neoplasia and their association with invasive carcinomas: a pathological study of 139 lesions in 121 patients. Hum Pathol. 2012;43(7):1020-1027.

(45.) Cubilla AL, Velazques EF, Reuter VE, Oliva E, Mihm MC Jr, Young RH. Warty (condylomatous) squamous cell carcinoma of the penis: a report of 11 cases and proposed classification of 'verruciform' penile tumors. Am J Surg Pathol. 2000;24(4):505-512.

(46.) Dong F, Kojiro S, Borger DR, Growdon WB, Oliva E. Squamous cell carcinoma of the vulva: a subclassification of 97 cases by clinicopathologic, immunohistochemical, and molecular features (p16, p53, and EGFR). Am J Surg Pathol. 2015;39(8):1045-1053.

(47.) Santos M, Landolfi S, Olivella A, et al. p16 overexpression identifies HPVpositive vulvar squamous cell carcinomas. Am J Surg Pathol. 2006;30(11):1347-1356.

(48.) Chaux A, Pfannl R, Lloveras B, et al. Distinctive association of p16INK4a overexpression with penile intraepithelial neoplasia depicting warty and/or basaloid features: a study of 141 cases evaluating a new nomenclature. Am J Surg Pathol. 2010;34(3):385-392.

(49.) Chaux A, Pfannl R, Rodriguez IM, etal. Distinctive immunohistochemical profile of penile intraepithelial lesions: a study of 74 cases. Am J Surg Pathol. 2011;35(4):553-562.

(50.) Cotter MB, Kelly ME, O'Connell PR, et al. Anal intraepithelial neoplasia: a single centre 19 year review. Colorectal Dis. 2014;16(10):777-782.

(51.) Chaux A, Soares F, Rodriguez I, etal. Papillary squamous cell carcinoma, not otherwise specified (NOS) of the penis: clinicopathologic features, differential diagnosis, and outcome of 35 cases. Am J Surg Pathol. 2010;34(2):223-230.

(52.) Wade TR, Kopf AW, Ackerman AB. Bowenoid papulosis of the penis. Cancer. 1978;42(4):1890-1903.

(53.) Patterson JW, Kao GF, Graham JH, Helwig EB. Bowenoid papulosis: a clinicopathologic study with ultrastructural observations. Cancer. 1986;57(4): 823-836.

(54.) Gimeno E, Vilata JJ, Sanchez JL, Lloret A, Fortea JM. Bowenoid papulosis: clinical and histological study of eight cases. Genitourin Med. 1987;63(2):109-113.

(55.) Gross G, Hagedorn M, Ikenberg H, etal. Bowenoid papulosis: presence of human papillomavirus (HPV) structural antigens and of HPV 16-related DNA sequences. Arch Dermatol. 1985;121(7):858-863.

(56.) Richter ON, Petrow W, Wardelmann E, Dorn C, Kupka M, Ulrich U. Bowenoid papulosis of the vulva-immunotherapeutical approach with topical imiquimod. Arch Gynecol Obstet. 2003;268(4):333-336.

(57.) Yang CH, Lee JC, Chen CH, Hui CY, Hong HS, Kuo HW. Photodynamic therapy for bowenoid papulosis using a novel incoherent light-emitting diode device. Br J Dermatol. 2003;149(6):1297-1299.

(58.) Ricart JM, Cordoba J, Hernandez M, Esplugues I. Extensive genital bowenoid papulosis responding to imiquimod. J Eur Acad Dermatol Venereol. 2007;21(1):113-115.

(59.) Wu YH, Qiao JJ, Bai J, Fang H. Aminolevulinic acid photodynamic therapy for bowenoid papulosis. Indian J Dermatol Venereol Leprol. 2015;81(2):219-220.

(60.) Schwartz RA, Janniger CK. Bowenoid papulosis. J Am Acad Dermatol. 1991;24(2 pt 1):261-264.

(61.) Bocking A, Chatelain R, Salterberg A, Hagedorn M, Gross G. Bowenoid papulosis: classification as a low-grade in situ carcinoma of the epidermis on the basis of histomorphologic and DNA ploidy studies. Anal Quant Cytol Histol. 1989;11(6):419-425.

(62.) Obalek S, Jablonska S, Beaudenon S, Walczak L, Orth G. Bowenoid papulosis of the male and female genitalia: risk of cervical neoplasia. J Am Acad Dermatol. 1986;14(3):433-444.

(63.) Park KC, Kim KH, Youn SW, et al. Heterogeneity of human papillomavirus DNA in a patient with Bowenoid papulosis that progressed to squamous cell carcinoma. Br J Dermatol. 1998;139(6):1087-1091.

(64.) Yu DS, Kim G, Song HJ, Oh CH. Morphometric assessment of nuclei in Bowen's disease and bowenoid papulosis. Skin Res Technol. 2004;10(1):67-70.

(65.) Pala S, Poleva I, Vocatura A. The presence of HPV types 6/11, 16/18, 31/33/ 51 in Bowenoid papulosis demonstrated by DNA in situ hybridization. Int J STD AIDS. 2000;11(12):823-824.

(66.) Hama N, Ohtsuka T, Yamazaki S. Detection of mucosal human papilloma virus DNA in bowenoid papulosis, Bowen's disease and squamous cell carcinoma of the skin. J Dermatol. 2006;33(5):331-337.

(67.) Liu H, Urabe K, Moroi Y, et al. Expression of p16 and hTERT protein is associated with the presence of high-risk human papillomavirus in Bowenoid papulosis. J Cutan Pathol. 2006;33(8):551-558.

(68.) Hagiwara K, Uezato H, Arakaki H, et al. A genotype distribution of human papillomaviruses detected by polymerase chain reaction and direct sequencing analysis in a large sample of common warts in Japan. J Med Virol. 2005;77(1): 107-112.

(69.) Lei YJ, Gao C, An R, et al. Development of a multiplex PCR method for detecting and typing human papillomaviruses in verrucae vulgaris. J Virol Methods. 2008;147(1):72-77.

(70.) Aguilera-Barrantes I, Magro C, Nuovo GJ. Verruca vulgaris of the vulva in children and adults: a nonvenereal type of vulvar wart. Am J Surg Pathol. 2007; 31(4):529-535.

(71.) Nuovo GJ, Lastarria DA, Smith S, Lerner J, Comite SL, Eliezri YD. Human papillomavirus segregation patterns in genital and nongenital warts in prepubertal children and adults. Am J Clin Pathol. 1991;95(4):467-474.

(72.) Lee HS, Lee JH, Choo JY, Byun HJ, Jun JH, Lee JY. Immunohistochemistry and polymerase chain reaction for detection human papilloma virus in warts: a comparative study. Ann Dermatol. 2016;28(4):479-485.

(73.) Kukreja T, Krunic A. Multiple epidermolytic acanthomas must not be confused with genital human papillomavirus infection. Acta Derm Venereol. 2009;89(2):169-171.

(74.) Bogale SR, Chan CS, McIntire H, Hsu S. Epidermolytic acanthoma of the scrotum: a rare mimicker of condyloma acuminatum. Dermatol Online J. 2011; 17(1):6.

(75.) Hijazi MM, Succaria F, Ghosn S. Multiple localized epidermolytic acanthomas of the vulva associated with vulvar pruritus: a case report. Am J Dermatopathol. 2015;37(4):e49-e52.

(76.) Lee TJ, Wu YH. Multiple epidermolytic acanthomas mimicking condyloma: a retrospective study of 8 cases. Int J Dermatol. 2018;57(1):28-33.

(77.) Leonardi C, Zhu W, Kinsey W, Penneys NS. Epidermolytic acanthoma does not contain human papillomavirus DNA. J Cutan Pathol. 1991;18(2):103-105.

(78.) Jung JM, Lee SH, Won CH, et al. A case of multiple epidermolytic acanthoma of the scrotum: is the human papillomavirus a culprit? Ann Dermatol. 2015;27(5):633-634.

(79.) Abbas O, Wieland CN, Goldberg LJ. Solitary epidermolytic acanthoma: a clinical and histopathological study. J Eur Acad Dermatol Venereol. 2011;25(2): 175-180.

(80.) Vahlquist A, Fischer J, Torma H. Inherited nonsyndromic ichthyoses: an update on pathophysiology, diagnosis and treatment. Am J Clin Dermatol. 2018; 19(1):51-66.

(81.) Su WP. Histopathologic varieties of epidermal nevus: a study of 160 cases. Am J Dermatopathol. 1982;4(2):161-170.

(82.) Sarifakioglu E, Yenidunya S. Linear epidermolytic verrucous epidermal nevus of the male genitalia. Pediatr Dermatol. 2007;24(4):447-448.

(83.) Conlin PA, Rapini RP. Epidermolytic hyperkeratosis associated with melanocytic nevi: a report of 53 cases. Am J Dermatopathol. 2002;24(1):23-25.

(84.) Gaertner EM. Incidental cutaneous reaction patterns: epidermolytic hyperkeratosis, acantholytic dyskeratosis, and hailey-hailey-like acantholysis: a potential marker of premalignant skin change. J Skin Cancer. 2011;2011:645743.

(85.) Adachi T, Tanese K, Ouchi T, Igawa S, Nakano H, Ishiko A. Case of isolated epidermolytic acanthoma: Genetic and immunohistochemical analysis. J Dermatol. 2016;43(8):974-975.

(86.) Egozi-Reinman E, Avitan-Hersh E, Barzilai A, Indelman M, Bergman R. Epidermolytic acanthoma of the genitalia does not show mutations in KRT1 or KRT10. Am J Dermatopathol. 2016;38(2):164-165.

(87.) Cohen PR, Ulmer R, Theriault A, Leigh IM, Duvic M. Epidermolytic acanthomas: clinical characteristics and immunohistochemical features. Am J Dermatopathol. 1997;19(3):232-241.

(88.) Stiff KM, Cohen PR. Vegas (verruciform genital-associated) xanthoma: a comprehensive literature review. Dermatol Ther (Heidelb). 2017;7(1):65-79.

(89.) FiteC, Plantier F, Dupin N, Avril MF, Moyal-Barracco M. Vulvar verruciform xanthoma: ten cases associated with lichen sclerosus, lichen planus, or other conditions. Arch Dermatol. 2011;147(9):1087-1092.

(90.) De Rose AF, Tosi M, Mantica G, Piol N, Toncini C, Terrone C. Verruciform xanthoma of the penis: a rare benign lesion that simulates carcinoma. Arch Ital UrolAndrol. 2016;88(4):284-285.

(91.) Helm KF, Hopfl RM, Kreider JW, Lookingbill DP. Verruciform xanthoma in an immunocompromised patient: a case report and immunohistochemical study. J Cutan Pathol. 1993;20(1):84-86.

(92.) Iamaroon A, Vickers RA. Characterization of verruciform xanthoma by in situ hybridization and immunohistochemistry. J Oral Pathol Med. 1996;25(7): 395-400.

(93.) Mohsin SK, Lee MW, Amin MB, et al. Cutaneous verruciform xanthoma: a report of five cases investigating the etiology and nature of xanthomatous cells. Am J Surg Pathol. 1998;22(4):479-487.

(94.) Cumberland L, Dana A, Resh B, Fitzpatrick J, Goldenberg G. Verruciform xanthoma in the setting of cutaneous trauma and chronic inflammation: report of a patient and a brief review of the literature. J Cutan Pathol. 2010;37(8):895-900.

(95.) Zegarelli DJ, Aegarelli-Schmidt EC, Zegarelli EV. Verruciform xanthoma: a clinical, light microscopic, and electron microscopic study of two cases. Oral Surg Oral Med Oral Pathol. 1974;38(5):725-734.

May P. Chan, MD

Accepted for publication May 1, 2018.

Published online September 11, 201 8.

From the Department of Pathology, University of Michigan Health System, Ann Arbor.

The author has no relevant financial interest in the products or companies described in this article.

Corresponding author: May P. Chan, MD, Department of Pathology, University of Michigan Health System, Medical Science 1 Bldg M3261, 1301 Catherine Rd, Ann Arbor, MI 48109-0602 (email: mpchan@med.umich.edu).

Caption: Figure 1. Condyloma acuminatum. A, A typical papillomatous papule with only mild hyperkeratosis. The papillae have mostly rounded tips and prominent fibrovascular cores. B, Koilocytes containing enlarged, irregular, and hyperchromatic nuclei, perinuclear halos, and coarse keratohyalin granules are found in the granular and upper spinous layers. The rest of the keratinocytes appear normal. C, An anogenital seborrheic keratosis with an undulating base and numerous pseudohorn cysts without evidence of koilocytosis. Similar lesions frequently harbor human papillomavirus and should at least raise suspicion for a seborrheic keratosis-like condyloma acuminatum. D, Patchy p16 immunostaining in a condyloma acuminatum (hematoxylin-eosin, original magnifications X40 [A], X400 [B], and X100 [C]; original magnification X100 [D]).

Caption: Figure 2. Giant condyloma acuminatum. A, Portion of a large, mostly exophytic, and papillomatous lesion with a "cauliflower-like" silhouette. The papillae contain prominent fibrovascular cores and lack significant hyperkeratosis, imparting a relatively "soft" appearance. The tumor base is round and noninfiltrative. B, Koilocytes are readily found in the upper epidermis, while the remaining keratinocytes are cytologically uniform and bland (hematoxylin-eosin, original magnifications X10 [A] and X200 [B]).

Caption: Figure 3. Verrucous carcinoma. A, An exophytic and endophytic verrucous squamous proliferation with a bulbous, pushing base. Conspicuous parakeratosis fills many gaps between the verrucous projections, giving rise to a "firm" and "rigid" appearance. Fibrovascular cores are thin and inconspicuous relative to the hypertrophic epithelium. A lymphocytic band is present at the tumor base. B, Large spinous keratinocytes contain abundant eosinophilic cytoplasm and bland nuclei. There are occasional dyskeratotic cells, while koilocytes are absent (hematoxylin-eosin, original magnifications X10 [A] and X400 [B]).

Caption: Figure 4. Warty and warty-basaloid high-grade squamous intraepithelial lesion (HSIL) and squamous cell carcinoma. A, A warty squamous cell carcinoma shows an irregular verruciform architecture with conspicuous fibrovascular cores. B, Koilocytosis and cytologic atypia are readily appreciated in this warty squamous cell carcinoma. Angulated tumor nests infiltrate the underlying stroma. C, Warty-basaloid HSIL is characterized by a verruciform architecture and basaloid epithelium with full-thickness atypia. The basaloid tumor cells display high nuclear to cytoplasmic ratio and frequent mitoses at all levels of the epithelium (inset). D, There is strong and diffuse p16 immunostaining within the lesion (hematoxylin-eosin, original magnifications X20 [A], X200 [B], X40 [C], and X200 [C, inset]; original magnification X100 [D]).

Caption: Figure 5. Papillary squamous cell carcinoma. A, The papillae are of variable lengths and shapes, covered by irregular well-differentiated squamous epithelium. The ragged tumor base is indicative of stromal invasion. B, Fibrovascular cores are present. There is no evidence of koilocytosis (hematoxylin-eosin, original magnifications X20 [A] and X200 [B]).

Caption: Figure 6. Bowenoid papulosis. A, This lesion shows flat acanthosis with full-thickness basaloid atypia. The tumor cells display high nuclear to cytoplasmic ratio and frequent mitoses (inset). B, The lesion is diffusely positive for p16 (hematoxylin-eosin, original magnifications X40 [A] and X200 [A, inset]; original magnification X100 [B]).

Caption: Figure 7. Verruca vulgaris. A, A small verrucous papule with marked hyperkeratosis. Note the convergence of elongated rete ridges at the base. B, Many of the papillae have pointed tips surmounted by "church spire" parakeratosis. Hypergranulosis is accentuated in the "valleys" between papillae. A few koilocytes are present in the granular layer (hematoxylin-eosin, original magnifications X20 [A] and X200 [B]).

Caption: Figure 8. Epidermolytic acanthoma. A, This lesion demonstrates verruciform acanthosis and marked hyperkeratosis. B, Higher magnification reveals features of epidermolytic hyperkeratosis: cytoplasmic vacuolation, coarse keratohyalin granules, and perinuclear eosinophilic inclusions in the spinous and granular layers (hematoxylin-eosin, original magnifications X40 [A] and X400 [B]).

Caption: Figure 9. Verruciform xanthoma. A, A papillomatous lesion with parakeratosis completely filling the spaces between the papillary projections. The epithelium remains relatively thin. B, Parakeratosis is compact with a characteristic orange hue or peach color. A few neutrophils are typically present. The keratinocytes are bland and without koilocytic change. C, A defining feature is the presence of xanthomatous (foam) cells in the dermal papillae (hematoxylin-eosin, original magnifications X40 [A], X200 [B], and X400 [C]).
Summary of the Clinical and Histopathologic Features of Condyloma
Acuminatum and Condyloma-like Squamous Proliferations in the
Anogenital Region

                           Condyloma
                           Acuminatum (a)        (Giant Condyloma
                            Acuminatum (b)

Peak age group             Third decade          Third to fifth
                                                 decade
Common anogenital site(s)  Any site              Penis and anorectum
Size                       Small papule          3-13 cm
Configuration of papillae  Rounded tips          Rounded tips
Fibrovascular cores        Prominent             Prominent
Hyperkeratosis             Usually mild          Variable but
                                                 usually mild
Base of tumor              Undulating, round     Round, pushing
Koilocytosis               Present (except in    Present
                           SK-like lesions)
Cytologic atypia (other thaAbsent                Absent
Mitoses                    Few, confined to      Few, confined to
                           lower third of        lower third of
                           epithelium            epithelium
Other characteristic findinN/A                   N/A
Association with HPV       Low-risk HPV, most    Low-risk HPV, most
                           commonly types 6      commonly types 6
                           and 11                and 11
Staining for p16           Negative, focal,      Negative, focal,
                           or patchy             or patchy

                           Verrucous
                           Carcinoma (c)         Warty/Warty-Basaloid
                                                 HSIL and SCC (d)

Peak age group             Seventh decade        Fifth to sixth
                                                 decade (HSIL);
                                                 seventh decade (SCC)
Common anogenital site(s)  Glans penis, vulva,   Glans penis, vulva
Size                       anus 1.5-5 cm         2-12 cm
Configuration of papillae  Broad, hypertrophic   Variable
Fibrovascular cores        Thin and              Prominent
                           inconspicuous
Hyperkeratosis             Marked, often         Usually prominent
                           filling spaces
                           between verrucous
                           projections
Base of tumor              Bulbous, pushing      Round in
Koilocytosis                                     intraepithelial
                                                 neoplasia;
                                                 infiltrative in SCC
Cytologic atypia (other thaAbsent                Present (warty >
                                                 warty-basaloid)
                           Minimal               Prominent
Mitoses                    Rare, confined        Frequent (warty-
                           to basal layer        basaloid > warty),
                                                 at all levels of
                                                 epithelium
Other characteristic findinScattered             Full-thickness
                           dyskeratotic          atypia in warty-
                           cells; lymphocytic    basaloid type
                           band at base
Association with HPV       No                    High-risk HPV, most
                                                 commonly type 16

Staining for p16           Negative, focal,      Diffusely positive
                           or patchy

Abbreviations: HPV, human papillomavirus; HSIL, high-grade squamous
intraepithelial lesion;N/A, not applicable; SCC, squamous cell
carcinoma; SK, seborrheic keratosis.

(a) Relevant references for condyloma acuminatum: 1, 5, 8, 9,
13, 17, 18.

(b) Relevant references for giant condyloma acuminatum: 20, 21,
23, 25.

(c) Relevant references for verrucous carcinoma: 24, 25, 28,
30, 36.

(d) Relevant references for warty/warty-basaloid HSIL and SCC:
39, 41, 43-47, 49.

(e) Relevant reference for papillary SCC: 50.

(f) Relevant references for bowenoid papulosis: 52-55, 60-63.

(g) Relevant references for verruca vulgaris: 64-67.

(h) Relevant references for epidermolytic acanthoma:
68, 69, 71, 72, 82.

(i) Relevant references for verruciform xanthoma:
83, 84, 87, 89, 90.

                                    Extended

Papillary SCC (e)        Bowenoid Papulosis
                           (f)                   Verruca Vulgaris (g)

Sixth to seventh decade  Third to fourth         Children
                         decade
Glans penis              Penis, vulva            Any site
5.6 cm (mean)            0.7 cm (mean)           Small papule
Irregular, variable      True papillae usually   Slender with
shapes and lengths                               pointed tips
Variable                 Inconspicuous or
                         Absent                  Prominent,
                                                 containing dilated
                                                 capillaries
Variable                 Present                 Columns of
                                                 parakeratosis over
                                                 tips of papillae
                                                 ("church spires")
Ragged and infiltrative  Flat or round           Convergence of long,
                                                 pointed rete ridges
Absent                   May be present          Present but may
                                                 be subtle
Present                  Usually prominent       Absent
Variable                 Frequent, at all        Rare
                         levels of
                         epithelium
N/A                      Coexistence of          Hypergranulosis
                         multiple papules;       accentuated in
                         stromal                 valleys between
                         melanophages may        papillae
                         be present
No                       High-risk HPV,          Low-risk HPV, most
                         most commonly           commonly type 2
                         type 16

Negative, focal,         Diffusely positive      Negative, focal,
or patchy                                        or patchy

                           Epidermolytic
                           Acanthoma (h)         Verruciform
                                                 Xanthoma (i)

Sixth to seventh decade  Fifth to seventh        Sixth to seventh
                         decade                  decade
Glans penis              Scrotum, vulva          Scrotum, penis,
5.6 cm (mean)            Small papule            vulva 0.2-2 cm
Irregular, variable      Variable                Variable
shapes and lengths
Variable                 Variable                Filled with
                                                 xanthomatous cells

Variable                 Prominent               Compact
                                                 parakeratosis with
                                                 orange hue and
                                                 neutrophils filling
Ragged and infiltrative                          spaces between
                                                 papillary
                                                 projections
                         Flat or round           Regular,
                                                 noninfiltrative
Absent                   Absent                  Absent

Present                  Absent                  Absent
Variable                 Rare                    Rare

N/A                      Cytoplasmic vacuolation Ectatic vessels and
                         coarse keratohyalin     chronic
                         granules, perinuclear   inflammation in
                         eosinophilic inclusions underlying stroma

No                       No                      No

Negative, focal,         Negative                Negative
or patchy
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Date:Jul 1, 2019
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