- Email: [email protected]
Pathology of Penile Cancer
EURSUP-750; No. of Pages 6 EUROPEAN UROLOGY SUPPLEMENTS XXX (2017) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Pathology of Penile Cancer Eva Compe´rat a,b,* a
Department of Pathology, Hoˆpital Tenon, HUEP, Ap-HP, Paris, France; b UPMC Paris VI, Sorbonne Universities, Paris, France
Article info
Abstract
Keywords: Pathology Squamous cell carcinoma Human papilloma virus
The majority of malignant tumors of the penis are squamous cell carcinomas. The origin is mostly the inner lining of the mucosa of the glans, the coronal sulcus, and the foreskin. Other tumors, such as basal cell carcinoma, are very rare. Numerous different subtypes have been reported and have been integrated into the new World Health Organization 2016 classification. These subtypes have distinct features and outcomes, and it is important to make the difference from a pathological point of view. During the last 2 decades, major progress has been made and it has become obvious that human papilloma virus (HPV) infection plays a major role. Mostly the morphological aspects will lead the pathologist to classify the carcinoma into HPV-related and nonrelated carcinoma. Although polymerase chain reaction is the gold standard for HPV detection, immunohistochemistry is also useful. These tumors have to be staged according to the pTNM system; nevertheless, two different systems exist, and the pathologist should tell whether he/she uses the European (Union for International Cancer Control) or the American (American Joint Committee on Cancer) staging system. # 2017 Published by Elsevier B.V. on behalf of European Association of Urology. * Department of Pathology, Hoˆpital Tenon, HUEP, Ap-HP, Paris, France. E-mail address: [email protected].
1.
Epidemiology
Penile carcinoma affects most often patients in their 5th or 6th decade, but they can occur in younger and older age. Familial cases are rare. No racial predilection has been described. The highest incidence rates are observed in South America, Asia, and Africa; the incidence is relatively low in Europe and North America. Penile carcinoma accounts for 0.4–0.6% of malignancies [1]. The incidence has been slightly decreasing in some countries, but human papilloma virus (HPV)–related tumors increase in several countries such as the USA. Risk factors such as lack of neonatal circumcision, poor genital hygiene, phimosis, HPV infection, lichen sclerosus, and smoking are well known [2]. Obesity also seems to play a role [3,4].
It is crucial to have good knowledge of the very complex anatomy of the penis. In the distal penis, three different epithelial mucosa compartments exist: glans, coronal sulcus, and foreskin. Different anatomic levels in the glans are the lamina propria, corpus spongiosum, tunica albuginea, and corpus cavernosum. The foreskin has an inner mucosa and a surface skin, both different from a histological point of view. The anatomical levels from the mucosa to the skin are lamina propria, dartos, dermis, and epidermis. The penile fascia covers the shaft and inserts into the lamina propria of the coronal sulcus. The fossa navicularis corresponds to the distal penile urethra; its squamous lining is continuous with the perimeatal glans. The penile urethra is ventral, and surrounded by a lamina propria corpus spongiosum and a penile fascia.
http://dx.doi.org/10.1016/j.eursup.2017.08.005 1569-9056/# 2017 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Compe´rat E, Pathology of Penile Cancer. Eur Urol Suppl (2017), http://dx.doi.org/10.1016/ j.eursup.2017.08.005
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EUROPEAN UROLOGY SUPPLEMENTS XXX (2017) XXX–XXX
2.
Histopathology
It is important to distinguish precursor lesions from malignant tumors; premalignant lesions, similar to malignant lesions, can be divided into HPV-related and non–HPVrelated groups. 2.1.
Precursor lesions
2.1.1.
Penile intraepithelial neoplasms
In this setting, the basement membrane remains intact, but intraepithelial changes occur. A penile intraepithelial neoplasm (PeIN) is a recognized precursor of invasive squamous cell carcinoma (SCC). Like in case of invasive carcinomas, two subgroups can be distinguished: HPV-related and non–HPV-related PeIN. Mostly there exists a good correlation between the grade of PeIN and the differentiation of SCC. The same is true for warty/basaloid PeIN. Precursor lesions are mostly seen in patients between 40 and 70 yr of age. Their size can vary from small millimetric ones to widespread lesions. Differentiated PeINs are frequently seen with lichen sclerosus. It affects the foreskin; the warty–basaloid type affects the glans more frequently [5]. On gross examination, solitary white or pink maculae or plaques can be observed, borders can be sharp or irregular, and solitary or multifocal lesions are possible. The warty– basaloid PeIN has more velvet-like moist dark brown aspects. Under the microscope, differentiated PeIN looks like thickened skin; keratin pearl forming and parakeratosis are frequent. In simplex (differentiated) PeIN, atypia exists in the basal layer. The higher the atypia takes place in the epithelium, the higher is the risk of developing an invasive carcinoma. Grading PeIN is optional. It has to be underlined that lichen sclerosus is often associated with PeIN. The difference between a PeIN and a reactive condition can be very difficult to establish. Basaloid PeIN is characterized by the replacement of the whole thickness of the epithelial layer by small monotonous cells. Apoptosis and mitosis are common; these lesions are HPV positive [6]. Warty PeIN displays atypical parakeratosis. Cellular pleomorphism, koilocytes, and mitosis are usual. These lesions are also HPV positive. It is unknown to which percentage these lesions evolve toward an infiltrating carcinoma. Extramammary Paget disease can also be observed. This rare, slowly growing adenocarcinoma can affect the penile skin or surface, mostly scrotal perianal or perineal. Erosive plaques can be misdiagnosed as eczema and can be very large lesions including the pubic region. Under a microscope, an intraepithelial lesion can be observed; sometimes neoplastic cells contain melanin. When excised completely, prognosis is favorable. In case of dermal invasion, the prognosis becomes more severe [5]. 2.2.
Malignant epithelial tumors
The most frequent entity is the SCC (Fig. 1). Most of them occur from the inner foreskin, inner lining of the glans, and
Fig. 1 – Squamous cell carcinoma NOS developing on the foreskin and glans, glansectomy. NOS = not otherwise specified.
coronal sulcus. Anatomy is important for the staging of penile carcinomas. Most penile carcinomas originate from the mucosa and not from the skin. According to pathological classification, penile squamous carcinomas are divided into two subgroups: non– HPV-and HPV-related SCCs [7] (see Table 1). The relationship between HPV and penile carcinoma was first recognized in 1995 [8]. Tumors with basal and/or warty morphology display HPV more frequently. On the contrary, it is rare in usual and low-grade variants of keratinizing SCC and constantly negative in differentiated PeIN [5]. SCC can occur in any part of the penis and can be multifocal. Little is known about its genetic features. Two pathways exist in the carcinogenesis; one is related to HPV, which occurs in about 30–50% of cases. The second, non–HPV-related pathway, can be divided into two subgroups: TP53 mutations and the other with chromosomic instability [7]. 2.2.1.
Non–HPV-related SCC
2.2.1.1. SCC usual type/not otherwise specified. These carcinomas
display the usual aspects of SCC with different degrees of differentiation and keratinization; this diagnosis can be proposed if all the other histological variants have been excluded. Most of the time these tumors have an exophytic gross appearance; endophytic ulcerated cases have also been described. The grading, like in many other tumors, is a very important prognostic factor. The three-tiered International Society of Urological Pathology/World Health Organization system should be used [7]. The admitted grades range from well to poorly differentiated with different nuclear polymorphisms, atypia, and keratinization (see Table 2). If well differentiated (grade 1), the aspect is the same as keratinizing tissue, they grow in large sheets and can have nested patterns, and the stroma reaction is limited. In moderately differentiated (grade 2) carcinomas, the nests become smaller and the tumor stroma is more abundant. In poorly differentiated (grade 3) tumors, keratinization can be difficult to find, growth is angular and irregular, and mitosis is frequent. As soon as a tumor displays anaplasia, it
Please cite this article in press as: Compe´rat E, Pathology of Penile Cancer. Eur Urol Suppl (2017), http://dx.doi.org/10.1016/ j.eursup.2017.08.005
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Table 1 – Different types of SCCs Non-HPV related
Prognosis
HPV related
SCC usual type/NOS Pseudohyperplastic carcinoma Pseudoglandular carcinoma Verrucous carcinoma Carcinoma cuniculatum Papillary carcinoma NOS Adenosquamous carcinoma Sarcomatoid carcinoma
30% DOD 0% >50% Good Good Good Good 75% DOD
Basaloid SCC Papillary basaloid carcinoma Warty carcinoma Warty–basaloid carcinoma Clear-cell carcinoma Lymphoepithelioma-like carcinoma
Prognosis >50% DOD Mortality low 30% DOD 20% Not known
DOD = dead of disease; HPV = human papilloma virus; NOS = not otherwise specified; SCC = squamous cell carcinoma.
Table 2 – Different grades Feature Cytological atypia Keratinization Intercellular bridges Mitotic activity Tumor margin
Grade 1
Grade 2
Grade 3
Sarcomatoid
Mild Usually abundant Prominent Rare Pushing, well defined
Moderate Less prominent Occasional Increase Ill defined, infiltrative
Anaplasia May be present Few Abundant Ill defined, infiltrative
Sarcomatoid Absent Absent Abundant Ill defined, infiltrative
association with other histological types is frequent. Gross aspects are flat or slightly elevated; multifocality is common. In histology, borders are sharp, cells are very well differentiated, and peritumoral stroma is absent or minimal. PeINs can be observed; their grade is 1. No vascular or perineural invasion or metastasis is reported.
Fig. 2 – SCC invading deeply into the penis, infiltration of the inner foreskin and surrounding tissue. SCC = squamous cell carcinoma.
becomes grade 3. Grades should be assigned according to the high power field with the highest atypia. A particular feature is the heterogeneity in these tumors. SCCs have a tendency to invade deeply into the penile tissue deeply (Fig. 2), two-thirds of patients present inguinal metastasis, and the mortality is about 30%. The grade, as mentioned above, is the most important predictor of clinical behavior. Vascular invasion accounts for a third of cases; local and regional recurrences are linked to insufficient surgery. Between 28% and 39% of the patients develop inguinal lymph node metastases; the 10-yr mortality rate is 78% [9,10]. Several risk nomograms exist; extranodal spread is a factor of bad outcome and is considered immediately as N3, even if a single lymph node is concerned, independently of the lymph node size. The number of positive lymph nodes is an important prognosticator. 2.2.1.2. Pseudohyperplastic carcinoma. This tumor is an extremely differentiated SCC, mostly associated with lichen sclerosis, and occurs on the foreskin of older patients. An
2.2.1.3. Pseudoglandular carcinoma. This variant is aggressive with acantholysis and pseudoglandular spaces. Patients are younger, around 50 yr of age, with a distal, irregular, firm, whitish, ulcerated mass. Histologically, honeycomb aspects are common, which are filled with necrotic debris. Most of these cases are poorly differentiated and high-grade tumors. Lymph node metastases occur in more than two-thirds and the mortality rate is high [11]. 2.2.1.4. Verrucous carcinoma. Like in other organs, this tumor is extremely well differentiated with papillomatous aspects; the tumor base is broad and the tumor has borders pushing into the stroma (Fig. 3). This carcinoma has a slow evolution and is seen in older patients. It is frequently associated with lichen sclerosus. This carcinoma accounts for 2–3% of penile cancers. Grossly, the aspect is exophytic, papillomatous is white to gray, and the interface between tumor and stroma is sharply delineated [12]. This well-differentiated carcinoma shows hyperkeratosis, acanthosis, and papillomatous aspects. The tumor does not directly invade the lamina propria, but pushes the borders into deeper tissue (Fig. 4), making the diagnosis of invasion, especially on small biopsies, very difficult. In case of clarified cells, they should not be mistaken for koilocytes, as these carcinomas are HPV negative. The tumor can be focally invasive, but normally remains superficially invasive. In case of mixed features the case should be reported as a mixed case; most frequent is an association with SCC not
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Histologically, we see well-differentiated hyperkeratotic lesions. Atypia is minimal and HPV negative. These tumors can recur, but mortality and metastasis are rare [15]. 2.2.1.7. Adenosquamous carcinoma. These carcinomas are SCCs with mucinous features; they are also called mucoepidermoid carcinomas. Only few cases exist; recurrence and lymph node metastasis is seen in up to 50%, but mortality remains low [16].
Fig. 3 – Verrucous carcinoma developing on the surface of the glans, with a broad base.
Fig. 4 – Verrucous carcinoma pushing borders into deeper tissue.
otherwise specified (NOS), which should be called verrucous hybrid carcinoma. Their prognosis is good; the slowly growing tumor recur in a third of cases, mostly because of underestimation in histology as a benign neoplasm or because of insufficient surgery [13]. 2.2.1.5. Carcinoma cuniculatum. This entity is a variant of the verrucous carcinoma and a low-grade carcinoma. Men between the age of 70 and 80 yr are mostly concerned; different anatomic parts can be affected, but most frequently the lesions grow from the glans into the deeper layers to the erectile corpora. The tumor is whitish and grey, and deep invaginations are common. Histologically, the lesions are close to the verrucous carcinoma and well differentiated; no koilocytes are seen. No vascular or perineural invasion has been reported. The invasion is with broad pushing borders; no metastasis can be found [14]. 2.2.1.6. Papillary carcinoma NOS. This type of carcinoma is papillomatous and verruciform, and are seen without koilocytes. This tumor accounts for about 5–8% of penile carcinomas and is usually associated with lichen sclerosus. The size can be very small, but huge lesions have been reported. The tumor has a cauliflower-like, whitish aspect that is badly limited.
2.2.1.8. Sarcomatoid SCC. This entity is aggressive; focal squamous differentiation is seen. The spindle cell component should be present in at least 30%. Predilection is for the glans; this carcinoma occurs in 1–4% [9]. It is important to identify tumor localization; otherwise, it may be impossible to differentiate it from a sarcoma affecting the penile shaft and corpora cavernosa can be impossible. These masses are slowly growing and frequently ulcerated; recurrence and regional or systemic metastases are possible. Sarcomatoid transformation of an SCC NOS after radiation therapy has been described. Necrosis and hemorrhage are frequent. The histological aspects join atypia, mitosis, pleomorphism, and sarcomatoid aspects, similar to those in other sarcomas. These carcinomas are the most aggressive neoplasms of the penis. Bad prognostic factors, such as high-grade lesions, deep invasion, and perineural invasion, are present. In 80%, local recurrence exists with inguinal metastases, mortality is high (up to 75%), and most patients die within a year [17]. 2.2.1.9. Mixed SCC. Mixed carcinomas contain at least two variants of SCCs. Patients are older, mostly in their 7th decade. Tumors are located on the glans and present as a white, exophytic, grayish mass replacing the distal penis, invading deeply the erectile tissue. Most frequent is the combination of warty and basaloid carcinomas. Adenosquamous tumors also belong to this group. It is possible to have HPV- and non–HPV-related features in the same tumors. Low-grade tumors are most frequent in about 75%; vascular and perineural invasion is seen in about 25%. Recurrence has been reported in 20% and regional lymph nodes in 9%, but mortality is rare (<5%) [17]. 2.2.2.
HPV-related SCC
2.2.2.1. Basaloid SCC. About 5–10% account for this aggressive
and solid type of carcinoma. The origin is most frequently the glans or the foreskin. Metastasis is seen in about 50% of cases. The carcinomas present as flat ulcerated masses, which are deeply invasive and sometimes necrotic. The tumor consists of closely packed small basophilic cells; mitosis is frequent with central keratinization. Another aspect is ‘‘starry sky’’–like features; sometimes they display features close to neuroendocrine tumors. Hyalinization of the stroma is frequent. These HPV-related
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carcinomas are p16 positive. As they are of high grade, and frequently massively invasive with lymphovascular and perineural invasion, lymph node metastasis is seen in >50% [9]. Local recurrence is high; mortality is high and depends on the extension at time of treatment. 2.2.2.2. Papillary basaloid carcinoma. These exo/endophytic car-
cinomas resemble urothelial carcinomas. They are rare and affect the glans; hyperparakeratosis and kondylomatous features are frequent. Like other HPV-related carcinomas, they are p16 positive. In case of doubt of an urothelial origin, urinary-related immunostains are helpful [9]. 2.2.2.3. Warty carcinoma. These exophytic carcinomas look like condylomas and account for 5–10% of the penile carcinomas. They have a macronodular cauliflower-like appearance; the papillae have a dark fibrovascular core that the tumor surrounds with a whitish aspect. Endophytic growth may be present. The histological aspect shows pleomorphic koilocytes, hyper- and parakeratosis, nuclear pleomorphism, and cellular clarification. Individual cell necrosis is observed. HPV is positive in these carcinomas. These carcinomas, invading the corpus cavernosum and the dartos, usually do not display intravascular or perineural invasion. Nodal metastasis is seen in <20%. The mortality rate is low [18,19]. 2.2.2.4. Warty–basaloid carcinoma. This HPV-related SCC shows both warty and basaloid features. Normally, these carcinomas present as voluminous masses growing from the glans and foreskin. From a histological point of view, these tumors are mixed with a papillomatous warty-like surface and a solid basaloid invasive component; p16 is strongly expressed. Invasion into deeper structures is frequent, the grade is mostly high, and vascular and perineural invasions are frequent. They are more aggressive than their warty counterpart. Around 50% will develop lymph node metastasis; 30% will die of disease [20]. 2.2.2.5. Clear-cell carcinoma. The clear-cell SCC is aggressive and HPV related, and occurs as a large mass of the glans and foreskin. The tumor develops in sheets; necrosis is frequent. Staining of the clear cells is positive for p16. These tumors are highly aggressive; vascular and perineural invasion is frequent. The tumor-related mortality is around 20%. Distant metastasis is frequent [21]. 2.2.2.6. Lymphoepithelioma-like carcinoma. This carcinoma is
poorly differentiated, resembling the lymphoepitheliomalike carcinoma of the nasopharynx. It occurs in men around the 6th decade of life; the tumor growth starts most of the time at the glans and extends to the foreskin. The tumors are more or less circumscribed; sheets with lymphocytic or plasmacytic cells mixed with tumor cells are common, and p63 and p16 positive. Prognosis is adverse; only few cases have been described [22].
5
Table 3 – TNM classification of carcinomas of the penis Stage pT pTx pT0 pTis pTa pT1 pT1a
Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ
Tumor invades subepithelial connective tissue Tumor invades subepithelial connective tissue without lymphovascular invasion and is not poorly differentiated or undifferentiated (T1G1–2) Tumor invades subepithelial connective tissue with pT1b lymphovascular invasion or is poorly differentiated or undifferentiated (T1G3–4) Tumor invades corpus spongiosum/corpora cavernosa pT2 Tumor invades urethra pT3 Tumor invades other adjacent structures pT4 pN (regional lymph nodes) No regional lymph node metastasis pN0 Regional lymph nodes cannot be assessed pNx Intranodal metastasis in a single inguinal lymph node pN1 pN2 Metastasis in multiple or bilateral inguinal lymph nodes Metastasis in pelvic lymph node(s), unilateral or bilateral pN3 or extranodal extension of regional lymph node metastasis pM No distant metastasis pM0 pM1 Distant metastasis TNM = tumor, node, metastasis.
Other histological forms of penile carcinoma
3.
Other rare carcinomas such as carcinomas with medullary features or desmoplastic variants have been described. Neuroendocrine and Merkel cell carcinomas are exceedingly rare. Skin tumors such as melanoma also exist. Mesenchymal tumors, such as leiomyomas, and also sarcomas and even Kaposi sarcomas have been described [7]. All tumors should be staged according to the pTNM system (see Table 3). Conflicts of interest The author has nothing to disclose.
Source of funding None.
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Please cite this article in press as: Compe´rat E, Pathology of Penile Cancer. Eur Urol Suppl (2017), http://dx.doi.org/10.1016/ j.eursup.2017.08.005
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Pathology of Penile Cancer Eva Compe´rat a,b,* a
Department of Pathology, Hoˆpital Tenon, HUEP, Ap-HP, Paris, France; b UPMC Paris VI, Sorbonne Universities, Paris, France
Article info
Abstract
Keywords: Pathology Squamous cell carcinoma Human papilloma virus
The majority of malignant tumors of the penis are squamous cell carcinomas. The origin is mostly the inner lining of the mucosa of the glans, the coronal sulcus, and the foreskin. Other tumors, such as basal cell carcinoma, are very rare. Numerous different subtypes have been reported and have been integrated into the new World Health Organization 2016 classification. These subtypes have distinct features and outcomes, and it is important to make the difference from a pathological point of view. During the last 2 decades, major progress has been made and it has become obvious that human papilloma virus (HPV) infection plays a major role. Mostly the morphological aspects will lead the pathologist to classify the carcinoma into HPV-related and nonrelated carcinoma. Although polymerase chain reaction is the gold standard for HPV detection, immunohistochemistry is also useful. These tumors have to be staged according to the pTNM system; nevertheless, two different systems exist, and the pathologist should tell whether he/she uses the European (Union for International Cancer Control) or the American (American Joint Committee on Cancer) staging system. # 2017 Published by Elsevier B.V. on behalf of European Association of Urology. * Department of Pathology, Hoˆpital Tenon, HUEP, Ap-HP, Paris, France. E-mail address: [email protected].
1.
Epidemiology
Penile carcinoma affects most often patients in their 5th or 6th decade, but they can occur in younger and older age. Familial cases are rare. No racial predilection has been described. The highest incidence rates are observed in South America, Asia, and Africa; the incidence is relatively low in Europe and North America. Penile carcinoma accounts for 0.4–0.6% of malignancies [1]. The incidence has been slightly decreasing in some countries, but human papilloma virus (HPV)–related tumors increase in several countries such as the USA. Risk factors such as lack of neonatal circumcision, poor genital hygiene, phimosis, HPV infection, lichen sclerosus, and smoking are well known [2]. Obesity also seems to play a role [3,4].
It is crucial to have good knowledge of the very complex anatomy of the penis. In the distal penis, three different epithelial mucosa compartments exist: glans, coronal sulcus, and foreskin. Different anatomic levels in the glans are the lamina propria, corpus spongiosum, tunica albuginea, and corpus cavernosum. The foreskin has an inner mucosa and a surface skin, both different from a histological point of view. The anatomical levels from the mucosa to the skin are lamina propria, dartos, dermis, and epidermis. The penile fascia covers the shaft and inserts into the lamina propria of the coronal sulcus. The fossa navicularis corresponds to the distal penile urethra; its squamous lining is continuous with the perimeatal glans. The penile urethra is ventral, and surrounded by a lamina propria corpus spongiosum and a penile fascia.
http://dx.doi.org/10.1016/j.eursup.2017.08.005 1569-9056/# 2017 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Compe´rat E, Pathology of Penile Cancer. Eur Urol Suppl (2017), http://dx.doi.org/10.1016/ j.eursup.2017.08.005
EURSUP-750; No. of Pages 6 2
EUROPEAN UROLOGY SUPPLEMENTS XXX (2017) XXX–XXX
2.
Histopathology
It is important to distinguish precursor lesions from malignant tumors; premalignant lesions, similar to malignant lesions, can be divided into HPV-related and non–HPVrelated groups. 2.1.
Precursor lesions
2.1.1.
Penile intraepithelial neoplasms
In this setting, the basement membrane remains intact, but intraepithelial changes occur. A penile intraepithelial neoplasm (PeIN) is a recognized precursor of invasive squamous cell carcinoma (SCC). Like in case of invasive carcinomas, two subgroups can be distinguished: HPV-related and non–HPV-related PeIN. Mostly there exists a good correlation between the grade of PeIN and the differentiation of SCC. The same is true for warty/basaloid PeIN. Precursor lesions are mostly seen in patients between 40 and 70 yr of age. Their size can vary from small millimetric ones to widespread lesions. Differentiated PeINs are frequently seen with lichen sclerosus. It affects the foreskin; the warty–basaloid type affects the glans more frequently [5]. On gross examination, solitary white or pink maculae or plaques can be observed, borders can be sharp or irregular, and solitary or multifocal lesions are possible. The warty– basaloid PeIN has more velvet-like moist dark brown aspects. Under the microscope, differentiated PeIN looks like thickened skin; keratin pearl forming and parakeratosis are frequent. In simplex (differentiated) PeIN, atypia exists in the basal layer. The higher the atypia takes place in the epithelium, the higher is the risk of developing an invasive carcinoma. Grading PeIN is optional. It has to be underlined that lichen sclerosus is often associated with PeIN. The difference between a PeIN and a reactive condition can be very difficult to establish. Basaloid PeIN is characterized by the replacement of the whole thickness of the epithelial layer by small monotonous cells. Apoptosis and mitosis are common; these lesions are HPV positive [6]. Warty PeIN displays atypical parakeratosis. Cellular pleomorphism, koilocytes, and mitosis are usual. These lesions are also HPV positive. It is unknown to which percentage these lesions evolve toward an infiltrating carcinoma. Extramammary Paget disease can also be observed. This rare, slowly growing adenocarcinoma can affect the penile skin or surface, mostly scrotal perianal or perineal. Erosive plaques can be misdiagnosed as eczema and can be very large lesions including the pubic region. Under a microscope, an intraepithelial lesion can be observed; sometimes neoplastic cells contain melanin. When excised completely, prognosis is favorable. In case of dermal invasion, the prognosis becomes more severe [5]. 2.2.
Malignant epithelial tumors
The most frequent entity is the SCC (Fig. 1). Most of them occur from the inner foreskin, inner lining of the glans, and
Fig. 1 – Squamous cell carcinoma NOS developing on the foreskin and glans, glansectomy. NOS = not otherwise specified.
coronal sulcus. Anatomy is important for the staging of penile carcinomas. Most penile carcinomas originate from the mucosa and not from the skin. According to pathological classification, penile squamous carcinomas are divided into two subgroups: non– HPV-and HPV-related SCCs [7] (see Table 1). The relationship between HPV and penile carcinoma was first recognized in 1995 [8]. Tumors with basal and/or warty morphology display HPV more frequently. On the contrary, it is rare in usual and low-grade variants of keratinizing SCC and constantly negative in differentiated PeIN [5]. SCC can occur in any part of the penis and can be multifocal. Little is known about its genetic features. Two pathways exist in the carcinogenesis; one is related to HPV, which occurs in about 30–50% of cases. The second, non–HPV-related pathway, can be divided into two subgroups: TP53 mutations and the other with chromosomic instability [7]. 2.2.1.
Non–HPV-related SCC
2.2.1.1. SCC usual type/not otherwise specified. These carcinomas
display the usual aspects of SCC with different degrees of differentiation and keratinization; this diagnosis can be proposed if all the other histological variants have been excluded. Most of the time these tumors have an exophytic gross appearance; endophytic ulcerated cases have also been described. The grading, like in many other tumors, is a very important prognostic factor. The three-tiered International Society of Urological Pathology/World Health Organization system should be used [7]. The admitted grades range from well to poorly differentiated with different nuclear polymorphisms, atypia, and keratinization (see Table 2). If well differentiated (grade 1), the aspect is the same as keratinizing tissue, they grow in large sheets and can have nested patterns, and the stroma reaction is limited. In moderately differentiated (grade 2) carcinomas, the nests become smaller and the tumor stroma is more abundant. In poorly differentiated (grade 3) tumors, keratinization can be difficult to find, growth is angular and irregular, and mitosis is frequent. As soon as a tumor displays anaplasia, it
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Table 1 – Different types of SCCs Non-HPV related
Prognosis
HPV related
SCC usual type/NOS Pseudohyperplastic carcinoma Pseudoglandular carcinoma Verrucous carcinoma Carcinoma cuniculatum Papillary carcinoma NOS Adenosquamous carcinoma Sarcomatoid carcinoma
30% DOD 0% >50% Good Good Good Good 75% DOD
Basaloid SCC Papillary basaloid carcinoma Warty carcinoma Warty–basaloid carcinoma Clear-cell carcinoma Lymphoepithelioma-like carcinoma
Prognosis >50% DOD Mortality low 30% DOD 20% Not known
DOD = dead of disease; HPV = human papilloma virus; NOS = not otherwise specified; SCC = squamous cell carcinoma.
Table 2 – Different grades Feature Cytological atypia Keratinization Intercellular bridges Mitotic activity Tumor margin
Grade 1
Grade 2
Grade 3
Sarcomatoid
Mild Usually abundant Prominent Rare Pushing, well defined
Moderate Less prominent Occasional Increase Ill defined, infiltrative
Anaplasia May be present Few Abundant Ill defined, infiltrative
Sarcomatoid Absent Absent Abundant Ill defined, infiltrative
association with other histological types is frequent. Gross aspects are flat or slightly elevated; multifocality is common. In histology, borders are sharp, cells are very well differentiated, and peritumoral stroma is absent or minimal. PeINs can be observed; their grade is 1. No vascular or perineural invasion or metastasis is reported.
Fig. 2 – SCC invading deeply into the penis, infiltration of the inner foreskin and surrounding tissue. SCC = squamous cell carcinoma.
becomes grade 3. Grades should be assigned according to the high power field with the highest atypia. A particular feature is the heterogeneity in these tumors. SCCs have a tendency to invade deeply into the penile tissue deeply (Fig. 2), two-thirds of patients present inguinal metastasis, and the mortality is about 30%. The grade, as mentioned above, is the most important predictor of clinical behavior. Vascular invasion accounts for a third of cases; local and regional recurrences are linked to insufficient surgery. Between 28% and 39% of the patients develop inguinal lymph node metastases; the 10-yr mortality rate is 78% [9,10]. Several risk nomograms exist; extranodal spread is a factor of bad outcome and is considered immediately as N3, even if a single lymph node is concerned, independently of the lymph node size. The number of positive lymph nodes is an important prognosticator. 2.2.1.2. Pseudohyperplastic carcinoma. This tumor is an extremely differentiated SCC, mostly associated with lichen sclerosis, and occurs on the foreskin of older patients. An
2.2.1.3. Pseudoglandular carcinoma. This variant is aggressive with acantholysis and pseudoglandular spaces. Patients are younger, around 50 yr of age, with a distal, irregular, firm, whitish, ulcerated mass. Histologically, honeycomb aspects are common, which are filled with necrotic debris. Most of these cases are poorly differentiated and high-grade tumors. Lymph node metastases occur in more than two-thirds and the mortality rate is high [11]. 2.2.1.4. Verrucous carcinoma. Like in other organs, this tumor is extremely well differentiated with papillomatous aspects; the tumor base is broad and the tumor has borders pushing into the stroma (Fig. 3). This carcinoma has a slow evolution and is seen in older patients. It is frequently associated with lichen sclerosus. This carcinoma accounts for 2–3% of penile cancers. Grossly, the aspect is exophytic, papillomatous is white to gray, and the interface between tumor and stroma is sharply delineated [12]. This well-differentiated carcinoma shows hyperkeratosis, acanthosis, and papillomatous aspects. The tumor does not directly invade the lamina propria, but pushes the borders into deeper tissue (Fig. 4), making the diagnosis of invasion, especially on small biopsies, very difficult. In case of clarified cells, they should not be mistaken for koilocytes, as these carcinomas are HPV negative. The tumor can be focally invasive, but normally remains superficially invasive. In case of mixed features the case should be reported as a mixed case; most frequent is an association with SCC not
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Histologically, we see well-differentiated hyperkeratotic lesions. Atypia is minimal and HPV negative. These tumors can recur, but mortality and metastasis are rare [15]. 2.2.1.7. Adenosquamous carcinoma. These carcinomas are SCCs with mucinous features; they are also called mucoepidermoid carcinomas. Only few cases exist; recurrence and lymph node metastasis is seen in up to 50%, but mortality remains low [16].
Fig. 3 – Verrucous carcinoma developing on the surface of the glans, with a broad base.
Fig. 4 – Verrucous carcinoma pushing borders into deeper tissue.
otherwise specified (NOS), which should be called verrucous hybrid carcinoma. Their prognosis is good; the slowly growing tumor recur in a third of cases, mostly because of underestimation in histology as a benign neoplasm or because of insufficient surgery [13]. 2.2.1.5. Carcinoma cuniculatum. This entity is a variant of the verrucous carcinoma and a low-grade carcinoma. Men between the age of 70 and 80 yr are mostly concerned; different anatomic parts can be affected, but most frequently the lesions grow from the glans into the deeper layers to the erectile corpora. The tumor is whitish and grey, and deep invaginations are common. Histologically, the lesions are close to the verrucous carcinoma and well differentiated; no koilocytes are seen. No vascular or perineural invasion has been reported. The invasion is with broad pushing borders; no metastasis can be found [14]. 2.2.1.6. Papillary carcinoma NOS. This type of carcinoma is papillomatous and verruciform, and are seen without koilocytes. This tumor accounts for about 5–8% of penile carcinomas and is usually associated with lichen sclerosus. The size can be very small, but huge lesions have been reported. The tumor has a cauliflower-like, whitish aspect that is badly limited.
2.2.1.8. Sarcomatoid SCC. This entity is aggressive; focal squamous differentiation is seen. The spindle cell component should be present in at least 30%. Predilection is for the glans; this carcinoma occurs in 1–4% [9]. It is important to identify tumor localization; otherwise, it may be impossible to differentiate it from a sarcoma affecting the penile shaft and corpora cavernosa can be impossible. These masses are slowly growing and frequently ulcerated; recurrence and regional or systemic metastases are possible. Sarcomatoid transformation of an SCC NOS after radiation therapy has been described. Necrosis and hemorrhage are frequent. The histological aspects join atypia, mitosis, pleomorphism, and sarcomatoid aspects, similar to those in other sarcomas. These carcinomas are the most aggressive neoplasms of the penis. Bad prognostic factors, such as high-grade lesions, deep invasion, and perineural invasion, are present. In 80%, local recurrence exists with inguinal metastases, mortality is high (up to 75%), and most patients die within a year [17]. 2.2.1.9. Mixed SCC. Mixed carcinomas contain at least two variants of SCCs. Patients are older, mostly in their 7th decade. Tumors are located on the glans and present as a white, exophytic, grayish mass replacing the distal penis, invading deeply the erectile tissue. Most frequent is the combination of warty and basaloid carcinomas. Adenosquamous tumors also belong to this group. It is possible to have HPV- and non–HPV-related features in the same tumors. Low-grade tumors are most frequent in about 75%; vascular and perineural invasion is seen in about 25%. Recurrence has been reported in 20% and regional lymph nodes in 9%, but mortality is rare (<5%) [17]. 2.2.2.
HPV-related SCC
2.2.2.1. Basaloid SCC. About 5–10% account for this aggressive
and solid type of carcinoma. The origin is most frequently the glans or the foreskin. Metastasis is seen in about 50% of cases. The carcinomas present as flat ulcerated masses, which are deeply invasive and sometimes necrotic. The tumor consists of closely packed small basophilic cells; mitosis is frequent with central keratinization. Another aspect is ‘‘starry sky’’–like features; sometimes they display features close to neuroendocrine tumors. Hyalinization of the stroma is frequent. These HPV-related
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carcinomas are p16 positive. As they are of high grade, and frequently massively invasive with lymphovascular and perineural invasion, lymph node metastasis is seen in >50% [9]. Local recurrence is high; mortality is high and depends on the extension at time of treatment. 2.2.2.2. Papillary basaloid carcinoma. These exo/endophytic car-
cinomas resemble urothelial carcinomas. They are rare and affect the glans; hyperparakeratosis and kondylomatous features are frequent. Like other HPV-related carcinomas, they are p16 positive. In case of doubt of an urothelial origin, urinary-related immunostains are helpful [9]. 2.2.2.3. Warty carcinoma. These exophytic carcinomas look like condylomas and account for 5–10% of the penile carcinomas. They have a macronodular cauliflower-like appearance; the papillae have a dark fibrovascular core that the tumor surrounds with a whitish aspect. Endophytic growth may be present. The histological aspect shows pleomorphic koilocytes, hyper- and parakeratosis, nuclear pleomorphism, and cellular clarification. Individual cell necrosis is observed. HPV is positive in these carcinomas. These carcinomas, invading the corpus cavernosum and the dartos, usually do not display intravascular or perineural invasion. Nodal metastasis is seen in <20%. The mortality rate is low [18,19]. 2.2.2.4. Warty–basaloid carcinoma. This HPV-related SCC shows both warty and basaloid features. Normally, these carcinomas present as voluminous masses growing from the glans and foreskin. From a histological point of view, these tumors are mixed with a papillomatous warty-like surface and a solid basaloid invasive component; p16 is strongly expressed. Invasion into deeper structures is frequent, the grade is mostly high, and vascular and perineural invasions are frequent. They are more aggressive than their warty counterpart. Around 50% will develop lymph node metastasis; 30% will die of disease [20]. 2.2.2.5. Clear-cell carcinoma. The clear-cell SCC is aggressive and HPV related, and occurs as a large mass of the glans and foreskin. The tumor develops in sheets; necrosis is frequent. Staining of the clear cells is positive for p16. These tumors are highly aggressive; vascular and perineural invasion is frequent. The tumor-related mortality is around 20%. Distant metastasis is frequent [21]. 2.2.2.6. Lymphoepithelioma-like carcinoma. This carcinoma is
poorly differentiated, resembling the lymphoepitheliomalike carcinoma of the nasopharynx. It occurs in men around the 6th decade of life; the tumor growth starts most of the time at the glans and extends to the foreskin. The tumors are more or less circumscribed; sheets with lymphocytic or plasmacytic cells mixed with tumor cells are common, and p63 and p16 positive. Prognosis is adverse; only few cases have been described [22].
5
Table 3 – TNM classification of carcinomas of the penis Stage pT pTx pT0 pTis pTa pT1 pT1a
Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ
Tumor invades subepithelial connective tissue Tumor invades subepithelial connective tissue without lymphovascular invasion and is not poorly differentiated or undifferentiated (T1G1–2) Tumor invades subepithelial connective tissue with pT1b lymphovascular invasion or is poorly differentiated or undifferentiated (T1G3–4) Tumor invades corpus spongiosum/corpora cavernosa pT2 Tumor invades urethra pT3 Tumor invades other adjacent structures pT4 pN (regional lymph nodes) No regional lymph node metastasis pN0 Regional lymph nodes cannot be assessed pNx Intranodal metastasis in a single inguinal lymph node pN1 pN2 Metastasis in multiple or bilateral inguinal lymph nodes Metastasis in pelvic lymph node(s), unilateral or bilateral pN3 or extranodal extension of regional lymph node metastasis pM No distant metastasis pM0 pM1 Distant metastasis TNM = tumor, node, metastasis.
Other histological forms of penile carcinoma
3.
Other rare carcinomas such as carcinomas with medullary features or desmoplastic variants have been described. Neuroendocrine and Merkel cell carcinomas are exceedingly rare. Skin tumors such as melanoma also exist. Mesenchymal tumors, such as leiomyomas, and also sarcomas and even Kaposi sarcomas have been described [7]. All tumors should be staged according to the pTNM system (see Table 3). Conflicts of interest The author has nothing to disclose.
Source of funding None.
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