Predictive histopathological factors of nodal metastasis in penile cancer

Campos, Marcos Adriano Garcia; Teixeira Júnior, Antonio Augusto Lima; Calixto, José de Ribamar Rodrigues; Larges, Joyce Santos; Pinho, Jaqueline Diniz; Silva, Gyl Eanes Barros

doi:10.1590/S1677-5538.IBJU.2022.0640

INTRODUCTION

Penile cancer (PC) is a neoplasm with variable incidence depending on geographic location, with higher prevalence in underdeveloped countries when compared with developed countries (¹). Moreover, the poorest regions of Brazil have the highest incidence of PC, according to the literature (²–⁴). Because PC mainly affects a socially disadvantaged population from underdeveloped countries, knowledge of its pathology, clinical management, and treatment is still limited. However, it has been revealed that the presence and extent of inguinal lymph node metastasis are the most important prognostic factors of PC (⁵–⁷).

PC often metastasizes first to the superficial inguinal lymph nodes, then extends to the deeper nodes, and, finally, to the iliac lymph nodes (⁸). Enlarged lymph nodes >1.5cm in diameter, pathological stage T2 and above, low-to-middle differentiation, and lymphatic vascular infiltration were independent predictive factors that worsened the prognosis of patients with PC (⁹). Lymphadenectomy can interrupt this process and acts as a curative treatment for PC, avoiding radical procedures that may further impact quality of life and sexual function (¹⁰). Moreover, recent studies have revealed better survival outcomes in patients with microscopic metastases who undergo prophylactic inguinal lymphadenectomy (IL) compared with those whose physical examination initially showed no metastasis to the lymph nodes but who later had recurrent disease (¹¹–¹⁵). Clinical and radiological assessments are insufficient to detect early lymph node metastasis. Therefore, prophylactic lymphadenectomy is a viable procedure for selected patients at high risk of metastasis, although, IL has a high rate of short- and long-term complications. Accordingly, several histological factors have been explored with regard to their potential to reliably predict the occurrence of metastasis in inguinal lymph nodes.

This study aimed to provide pathologists, oncologists, and urologists with a review of the main histopathological parameters that should be considered when deciding to perform lymphadenectomy, along with observations from the region with the highest incidence of PC worldwide (²).

Histological type

Squamous cell carcinoma (SCC) constitutes 95% of PCs. The remaining 5% are classified as sarcoma (leiomyosarcoma, Kaposi's sarcoma, angiosarcoma, rhabdomyosarcoma, epithelioid sarcoma, and Ewing's sarcoma, melanoma, adenocarcinoma, or sebaceous carcinoma) (¹⁶). Although there is less evidence to support the use of lymphadenectomy in these other neoplasms, aggressive approaches should be considered in appropriate patients. Furthermore, it is important to consider tumor stage and nodal status when predicting the outcome of patients with non-SCC neoplasms (¹⁷).

In cases of penile melanoma, sentinel lymph node evaluation is similar to the established protocol for melanoma in other sites (¹⁸). Penile sebaceous carcinoma has a strong tendency to metastasize to regional lymph nodes; thus, it is usually treated with wide local excision and regional lymphadenectomy. Regional lymphadenectomy is performed only if clinically significant nodes are found. In a previous study, three of five patients with sebaceous carcinoma presented with bilateral palpable inguinal lymph nodes and underwent IL. In two of these three patients, a biopsy revealed nodal metastasis (¹⁹).

Histological subtype

Penile SCC is classified into several subtypes that demonstrate varying rates of inguinal lymph node involvement and survival. The most recent World Health Organization classification divided SCC into two categories: human papillomavirus (HPV)-associated and non-HPV-associated SCC (²⁰). Unlike in SCC of the head and neck, the presence of HPV in penile SCC does not necessarily dictate prognosis or therapeutic approach. Thus, classifying tumors as HPV+ or HPV- may not be as useful as grouping them into histological subtypes of low risk or high risk for developing lymph node metastasis.

The frequency of SCC subtypes varies according to geographic location. In northeastern Brazil, HPV was detected in approximately 89.1% of pe-nile SCC cases (²¹), a rate higher than that observed in other regions, which have a prevalence of 1.3–72.9%. In our previous study, we showed many HPV-associated subtypes, differing from other regions, characterized by a large predominance of the usual variant (HPV−) (²²).

Given the importance of the SCC histological subtype, it is vital that adequate tissue representation is used in macroscopy for the correct subclassification of these tumors. This is especially true for regions of high incidence, where patients seek medical assistance at a very advanced stage, with an average of almost 2 years after the first signs of the disease and large tumors measuring approximately 4.5 cm (³). In these cases, more than one pattern is often observed macro and microscopically, and each of them may have different degrees of differentiation and a different prognostic profile, considering the high frequency of mixed subtypes in our cases, particularly in advanced tumors. Given these peculiarities regarding morphological criteria, we recommend that the same professional should conduct all diagnostic steps, from macroscopy to microscopy. In the next section, we group the subtypes based on the risk of developing lymph node metastasis.

Low-risk group

In this section, we group the PC subtypes according to the risk of developing lymph node metastasis. Verruciform neoplasms constitute one class of PC that is at low risk of metastasis, regardless of the presence or absence of HPV. The prototype of this exophytic pattern is verrucous carcinoma, an HPV− in-situ neoplasm that is rarely invasive. Therefore, in-situ tumors and verrucous SCC are not recommended for IL, even when there is clinical suspicion of nodal involvement. In fact, there are no reports of metastasis in patients with these tumors. Usually, antibiotic treatment is initiated for enlarged nodules, and the nodule is excised if enlargement persists (²³). Other subtypes of verruciform carcinoma that are not associated with HPV and exhibit low rates of lymph node metastasis include pseudohyperplastic, papillary, and cuniculatum SCC.

Condylomatous carcinoma is a form of verruciform carcinoma that is associated with HPV and demonstrates a low rate of inguinal metastasis of approximately 17% (²⁴). Nevertheless, more advanced tumors with a higher level of infiltration are more likely to lead to lymph node metastasis. In our country, where the neoplasm is diagnosed after 2 years of disease progression, the lesions are large, often forming part of a mixed-pattern neoplasm, especially with the usual type. In these cases, the patient faces a less favorable prognosis, usually with a more aggressive carcinoma component.

High-risk group

We classified tumors as high-risk if they demonstrate a risk of lymph node metastasis at a diagnosis rate of > 50%. Like low-risk tumors, there are representatives of both HPV+ and HPV− tumors in this category. Non-HPV-associated subtypes include the usual (pattern solid), pseudoglandular and sarcomatoid, showing a risk of nodal involvement above 85% (²⁵).

Among the subtypes associated with HPV are basaloid, clear cell, and mixed forms of SCC such as warty-basaloid. The risk of lymph node metastasis in these subtypes ranges from 50% to 66% in basaloid SCC to 100% in clear cell SCC (²⁶). Other HPV+ forms of PC, such as lymphoepithelioma-like and medullary cancer, are high-grade neoplasms rich in inflammatory cells, but their prognosis has not yet been established.

Hybrid, warty-basaloid, and papillary-basaloid carcinomas should be further evaluated according to the percentage of the highest risk component. Thus, the tissues of the lesions should be accurately represented and observed to detect different subtypes. At our institution, lesions are well represented, with those smaller than 3.0 cm being fully represented, and the larger lesions being prepared with at least 30 blocks of paraffin.

Histological grade

Tumor histological grade is the most important prognostic factor in PC patients with clinically negative lymph nodes that do not undergo regional lymphadenectomy (²⁷). The National Comprehensive Cancer Network (NCCN) and the European Association of Urology (EAU) have published guidelines on the management of PC based on the histological grade and staging of the primary tumor (pTNM, AJCC). In epithelial tumors, it is generally more difficult to define the histological grade of squamous carcinomas than in adenocarcinomas. Moreover, classification criteria vary according to the institution, resulting in high interobserver variability in the grading of PC (²⁸). Additionally, it is important to note that knowledge of SCC in other sites does not necessarily apply to SCC of the penis.

The morphological features commonly used to assess SCC grade are keratinization; cell atypia/anaplasia calculated by the nucleus to cytoplasm ratio; thickness of the cell membrane; nuclear pleo-morphism and chromatin pattern; pattern of tumor growth and expansion in nests, cords, solid blocks, and detached cells; and presence of nucleolus, mitotic activity, intercellular bridges, and tumor edge (²⁹). Tumor grading is classified as follows: G1: well--differentiated, tumors with minimal changes and morphological proximity to a normal or hyperplastic epithelium, and atypia in the most basal layer; G2: moderately differentiated, tumors with alterations between G1 and G3; and G3: poorly differentiated, tumors with any percentage of cell anaplasia (⁸). This classification system demonstrates the importance of accurate sampling to detect small areas of undifferentiated cells.

The risk of nodal involvement, as well as tumor invasiveness and aggressiveness increase with histological grade. Specifically, nodal metastasis is found in approximately 8%, 50%, 60% of G1, G2 and G3 tumors respectively (³⁰, ³¹).

Tumor location and measurement

The glans is the most frequent site of involvement in PC, followed by the foreskin. Tumors of the foreskin have a better prognosis than those of the glans because they are of a lower grade and are more superficial, thus demonstrating less potential for nodal metastasis.

Although tumor size is not a good predictive factor for penile SCC, tumors 2–4 cm in size are more likely to be associated with nodal metastasis, in contrast to tumors smaller than 2 cm or larger than 4 cm. This is due to tumors with superficial dissemination (verruciforms) that reach large proportions (³², ³³).

It is important to determine advanced loco--regional disease to define its management. Primary radical inguinal surgical debulking alone for these cases is unlikely to promote long-term survival and is related to a high incidence of complications (³⁴)

Presence of koilocytosis/HPV

Koilocytosis is a morphological parameter indicative of the presence of HPV that should be included in the histopathological report. Through polymerase chain reaction, HPV has been identified as an important prognostic biomarker for penile neoplasia because of its tumorigenic pathway in SCC and its occurrence in tumor tissues (³⁵). At least two Brazilian studies have identified an association between koilocytosis and a low incidence of lymph node metastasis (³⁶, ³⁷). However, further research is warranted for confirmation.

Perineural invasion

Perineural invasion is characterized by infiltration of the clear space surrounding the nerve bundle under the epineurium and should not be confused with the nerve trapped within the tumor mass. The role of perineural invasion in PC is controversial. Some researchers have declared the presence of perineural invasion to be associated with a high risk of inguinal lymph node metastasis in PC patients (³⁰, ³⁸). Others, including studies from Brazil, have found different results (³⁶, ³⁸–⁴⁰). In 2009, the EAU guidelines identified perineural invasion as an important prognostic factor in lymph node metastasis (⁴¹), although the same recognition was not given to the 2014 EAU, 2017 NCCN, or the eighth edition of the AJCC TNM staging guidelines.

Lesion depth/tumor thickness

The depth of invasion and tumor thickness are often confused, and although they represent different measurements, they have equivalent significance. The depth of invasion is measured from the intact basement membrane of the tumor edge to the deepest tumor cell. Tumor thickness, in turn, is measured from the top of the neoplasm to the deepest tumor cell. In exophytic and keratinizing lesions, tumor thickness is measured from the surface, excluding the keratin layer; in ulcerated lesions, tumor thickness is measured from the surface of the ulcer (³, ⁶, ³²).

The mean thickness of neoplasia-free penile tissue to the lamina propria is 3 mm (T1), to the corpus spongiosum is 5 mm (T2), and to the corpus cavernosum is 10 mm (T3). In the foreskin, the thickness from the skin to the mucosa is approximately 10 mm (³⁰).

Studies have shown a correlation between tumor thickness and lymph node metastasis index. Additionally, higher tumor infiltration and histological grade are correlated with a greater likelihood of lymph node metastasis. Thus, tumors with a thickness of <5 mm have a minimal risk of metastasis, those with a thickness of 5–10 mm have an intermediate risk of metastasis, and those with a thickness of >10 mm have a high risk of metastasis (approximately 80–86%). Nevertheless, due to anatomical variation in thickness, we believe TNM staging classification (based on anatomical structure) to be more efficient in assessing of depth of invasion than the measurement in millimeters (¹¹).

Growth pattern and invasion front

Neoplasm growth patterns can be horizontal or vertical and correspond to the form of tumor spread and the relationship with the host tissue. Some studies have determined the vertical growth pattern to be associated with a more unfavorable prognosis compared to the horizontal growth pattern (⁴², ⁴³). Moreover, the horizontal growth pattern is typically found in exophytic verruciform tumors.

Recently, researchers have turned their attention to the assessment of the so-called “invasion front” (⁴⁴). Translocation of neoplastic cells is a well-known feature at the invasion front of malignant tumors. The change in the phenotypic pattern of invasion with the absence of epithelial biomarkers and the presence of mesenchymal biomarkers may be associated with invasion and lymph node involvement (⁴⁵, ⁴⁶). Unlike in colorectal and head and neck tumors, no studies have yet assessed tumor budding in PC. Thus, future study of this topic is warranted.

Nomograms

Several nomograms have been created to predict lymph node metastasis (²⁹, ⁴⁷, ⁴⁸). However, the diverging importance of each individual histological parameter results in poor performance of the combination of these parameters in nomograms. Another challenge of using these nomograms is the lack of independent external verification and validation. Nomograms applied by different groups to the same population did not obtain the same results (⁴⁹, ⁵⁰).

Ki67, p53, and p16

Ki67, p53, and p16 have been evaluated as potential biomarkers of prognosis and lymph node metastasis in PC (⁵¹). Although p53 demonstrated the best predictive ability among the three biomarkers, it was not shown to be better than that of other predictive factors, such as tumor stage, and there are no consistent results concerning its use in the ma nagement of PC (⁵²). Moreover, Brazilian studies have found good results with the evaluation of p53 (⁵³, ⁵⁴). Furthermore, a strong association between high Ki67 expression and lymph node metastasis in PC has been reported (⁵⁵, ⁵⁶). Other studies have confirmed this association (⁵⁷, ⁵⁸). Although the absence of p16 may be associated with poor survival, most studies did not find an association between p16 and lymph node metastasis (²¹, ⁵⁹, ⁶⁰).

Figure 1
Pathological features associated with low risk (A, B, C, D) and high risk (F, G, H, Y, Z) lymph node metastases.

Immunohistochemical biomarkers require further investigation as they are simple to employ and are widely used. Moreover, in Brazil, the use of immunohistochemical biomarkers is funded by the public health system. Finally, it is noteworthy that the three biomarkers listed above can be assessed in any basic pathology laboratory. Our group will soon present the results of a study using these biomarkers.

CONCLUSIONS

No definitive predictive biomarker of inguinal lymph node metastasis has yet been established. There are many challenges to achieving this goal: the disease is most prevalent in regions with low socioeconomic conditions, there is difficulty in standardizing the criteria for inguinal lymph node metastasis, there is difficulty in accessing radiological exams and medical monitoring of patients, there is varying prevalence of HPV and histological subtypes according to geographic location, there is interobserver variation, and there is the need for extensive tissue sampling in advanced tumors. However, several studies and international guidelines demonstrate that the strongest predictors of inguinal lymph node metastasis are the stage of the primary tumor, the histological grade, and the presence of angiolymphatic invasion.

FUNDING

This research was funded by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES), grant number 001.

ACKNOWLEDGMENTS

Hospital Universitário da Universidade Federal do Marananhão, Brasil e Fundação de Pesquisa e Desenvolvimento Científico e Tecnológico do Maranhão (FAPEMA).

REFERENCES

¹ Montes Cardona CE, García-Perdomo HA. Incidence of penile cancer worldwide: systematic review and meta-analysis. Rev Panam Salud Publica. 2017;41:e117.
² Coelho RWP, Pinho JD, Moreno JS, Garbis DVEO, do Nascimento AMT, Larges JS, et al. Penile cancer in Maranhão, Northeast Brazil: the highest incidence globally? BMC Urol. 2018;18:50.
³ Vieira CB, Feitoza L, Pinho J, Teixeira-Júnior A, Lages J, Calixto J, et al. Profile of patients with penile cancer in the region with the highest worldwide incidence. Sci Rep. 2020;10:2965.
⁴ Favorito LA, Nardi AC, Ronalsa M, Zequi SC, Sampaio FJ, Glina S. Epidemiologic study on penile cancer in Brazil. Int Braz J Urol. 2008;34:587-91; discussion 591-3.
⁵ Azevedo RA, Roxo AC, Alvares SHB, Baptista DP, Favorito LA. Use of flaps in inguinal lymphadenectomy in metastatic penile cancer. Int Braz J Urol. 2021;47:1108-19.
⁶ Ficarra V, Akduman B, Bouchot O, Palou J, Tobias-Machado M. Prognostic factors in penile cancer. Urology. 2010;76(2 Suppl 1):S66-73.
⁷ Srinivas V, Morse MJ, Herr HW, Sogani PC, Whitmore WF Jr. Penile cancer: relation of extent of nodal metastasis to survival. J Urol. 1987;137:880-2.
⁸ Chaux A, Caballero C, Soares F, Guimarães GC, Cunha IW, Reuter V, et al. The prognostic index: a useful pathologic guide for prediction of nodal metastases and survival in penile squamous cell carcinoma. Am J Surg Pathol. 2009;33:1049-57.
⁹ Jia Y, Zhao H, Hao Y, Zhu J, Li Y, Wang Y. Analysis of the related risk factors of inguinal lymph node metastasis in patients with penile cancer: A cross-sectional study. Int Braz J Urol. 2022;48:303-13.
¹⁰ Barros R, Favorito LA, Nahar B, Almeida R Jr, Ramasamy R. Changes in male sexuality after urologic cancer: a narrative review. Int Braz J Urol. 2023;49:175-83.
¹¹ McDougal WS. Carcinoma of the penis: improved survival by early regional lymphadenectomy based on the histological grade and depth of invasion of the primary lesion. J Urol. 1995;154:1364-6.
¹² Leone A, Diorio GJ, Pettaway C, Master V, Spiess PE. Contemporary management of patients with penile cancer and lymph node metastasis. Nat Rev Urol. 2017;14:335-47.
¹³ Kroon BK, Horenblas S, Lont AP, Tanis PJ, Gallee MP, Nieweg OE. Patients with penile carcinoma benefit from immediate resection of clinically occult lymph node metastases. J Urol. 2005;173:816-9.
¹⁴ Djajadiningrat RS, van Werkhoven E, Horenblas S. Prophylactic pelvic lymph node dissection in patients with penile cancer. J Urol. 2015;193:1976-80.
¹⁵ Graafland NM, Lam W, Leijte JA, Yap T, Gallee MP, Corbishley C, et al. Prognostic factors for occult inguinal lymph node involvement in penile carcinoma and assessment of the high-risk EAU subgroup: a two-institution analysis of 342 clinically node-negative patients. Eur Urol. 2010;58:742-7.
¹⁶ Moses KA, Sfakianos JP, Winer A, Bernstein M, Russo P, Dalbagni G. Non-squamous cell carcinoma of the penis: single-center, 15-year experience. World J Urol. 2014;32:1347-53.
¹⁷ Bhambhvani HP, Greenberg DR, Parham MJ, Eisenberg ML. A population-level analysis of nonsquamous penile cancer: The importance of histology. Urol Oncol. 2021;39:136.e1-136.e10.
¹⁸ Leiter U, Stadler R, Mauch C, Hohenberger W, Brockmeyer N, Berking C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2016;17:757-67.
¹⁹ Ornellas AA, Frota R, Lopes da Silva LF, Dauster B, Quirino R, de Santos Schwindt AB, et al. Sebaceous carcinoma of the penis. Urol Int. 2009;82:477-80.
²⁰ Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours. Eur Urol. 2016;70:93-105.
²¹ Martins VA, Pinho JD, Teixeira Júnior AAL, Nogueira LR, Silva FF, Maulen VE, et al. P16INK4a expression in patients with penile cancer. PLoS One. 2018;13:e0205350.
²² Kidd LC, Chaing S, Chipollini J, Giuliano AR, Spiess PE, Sharma P. Relationship between human papillomavirus and penile cancer-implications for prevention and treatment. Transl Androl Urol. 2017;6:791-802.
²³ Sánchez-Ortiz RF, Pettaway CA. The role of lymphadenectomy in penile cancer. Urol Oncol. 2004;22:236-44; discussion 244-5.
²⁴ Guimarães GC, Cunha IW, Soares FA, Lopes A, Torres J, Chaux A, et al. Penile squamous cell carcinoma clinicopathological features, nodal metastasis and outcome in 333 cases. J Urol. 2009;182:528-34; discussion 534.
²⁵ Velazquez EF, Melamed J, Barreto JE, Aguero F, Cubilla AL. Sarcomatoid carcinoma of the penis: a clinicopathologic study of 15 cases. Am J Surg Pathol. 2005;29:1152-8.
²⁶ Sanchez DF, Rodriguez IM, Piris A, Cañete S, Lezcano C, Velazquez EF, et al. Clear Cell Carcinoma of the Penis: An HPV-related Variant of Squamous Cell Carcinoma: A Report of 3 Cases. Am J Surg Pathol. 2016;40:917-22.
²⁷ Aita GA, Zequi SC, Costa WH, Guimarães GC, Soares FA, Giuliangelis TS. Tumor histologic grade is the most important prognostic factor in patients with penile cancer and clinically negative lymph nodes not submitted to regional lymphadenectomy. Int Braz J Urol. 2016;42:1136-43.
²⁸ Kakies Ch, Lopez-Beltran A, Comperat E, Erbersdobler A, Grobholz R, Hakenberg OW, et al. Reproducibility of histopathologic tumor grading in penile cancer--results of a European project. Virchows Arch. 2014;464:453-61.
²⁹ Solsona E, Iborra I, Rubio J, Casanova JL, Ricós JV, Calabuig C. Prospective validation of the association of local tumor stage and grade as a predictive factor for occult lymph node micrometastasis in patients with penile carcinoma and clinically negative inguinal lymph nodes. J Urol. 2001;165:1506-9.
³⁰ Velazquez EF, Ayala G, Liu H, Chaux A, Zanotti M, Torres J, et al. Histologic grade and perineural invasion are more important than tumor thickness as predictor of nodal metastasis in penile squamous cell carcinoma invading 5 to 10 mm. Am J Surg Pathol. 2008;32:974-9.
³¹ Ficarra V, Martignoni G, Maffei N, Cerruto MA, Novara G, Cavalleri S, et al. Predictive pathological factors of lymph nodes involvement in the squamous cell carcinoma of the penis. Int Urol Nephrol. 2002;34:245-50.
³² Cubilla AL. The role of pathologic prognostic factors in squamous cell carcinoma of the penis. World J Urol. 2009;27:169-77.
³³ Caballero C, Barreto J, Riveros M, Cubilla, AL. Carcinoma epidermoide de glande peneano: parâmetros patológicos predictores de metastasis ganglionar inguinal. Patol Spain .1991; 24: 1137–41.
³⁴ Koifman L, Hampl D, Ginsberg M, Castro RB, Koifman N, Ornellas P, et al. The role of primary inguinal surgical debulking for locally advanced penile cancer followed by reconstruction with myocutaneous flap. Int Braz J Urol. 2021;47:1162-75.
³⁵ Djajadiningrat RS, Jordanova ES, Kroon BK, van Werkhoven E, de Jong J, Pronk DT, et al. Human papillomavirus prevalence in invasive penile cancer and association with clinical outcome. J Urol. 2015;193:526-31.
³⁶ Nascimento ADMTD, Pinho JD, Júnior AALT, Larges JS, Soares FM, Calixto JRR, et al. Angiolymphatic invasion and absence of koilocytosis predict lymph node metastasis in penile cancer patients and might justify prophylactic lymphadenectomy. Medicine (Baltimore). 2020;99:e19128.
³⁷ de Paula AA, Netto JC, Freitas R Jr, de Paula LP, Mota ED, Alencar RC. Penile carcinoma: the role of koilocytosis in groin metastasis and the association with disease specific survival. J Urol. 2007;177:1339-43; discussion 1343.
³⁸ Mentrikoski MJ, Stelow EB, Culp S, Frierson HF Jr, Cathro HP. Histologic and immunohistochemical assessment of penile carcinomas in a North American population. Am J Surg Pathol. 2014;38:1340-8.
³⁹ Mannweiler S, Sygulla S, Tsybrovskyy O, Razmara Y, Pummer K, Regauer S. Clear-cell differentiation and lymphatic invasion, but not the revised TNM classification, predict lymph node metastases in pT1 penile cancer: a clinicopathologic study of 76 patients from a low incidence area. Urol Oncol. 2013;31:1378-85.
⁴⁰ Ornellas AA, Nóbrega BL, Wei Kin Chin E, Wisnescky A, da Silva PC, de Santos Schwindt AB. Prognostic factors in invasive squamous cell carcinoma of the penis: analysis of 196 patients treated at the Brazilian National Cancer Institute. J Urol. 2008;180:1354-9.
⁴¹ Pizzocaro G, Algaba F, Horenblas S, Solsona E, Tana S, Van Der Poel H, et al. EAU penile cancer guidelines 2009. Eur Urol. 2010;57:1002-12.
⁴² Aita G, da Costa WH, de Cassio Zequi S, da Cunha IW, Soares F, Guimaraes GC, et al. Pattern of invasion is the most important prognostic factor in patients with penile cancer submitted to lymph node dissection and pathological absence of lymph node metastasis. BJU Int. 2015;116:584-9.
⁴³ Hu J, Cui Y, Liu P, Zhou X, Ren W, Chen J, et al. Predictors of inguinal lymph node metastasis in penile cancer patients: a meta-analysis of retrospective studies. Cancer Manag Res. 2019;11:6425-41.
⁴⁴ Guimarães GC, Lopes A, Campos RS, Zequi Sde C, Leal ML, Carvalho AL, et al. Front pattern of invasion in squamous cell carcinoma of the penis: new prognostic factor for predicting risk of lymph node metastases. Urology. 2006;68:148-53.
⁴⁵ da Cunha IW, Souza MJ, da Costa WH, Amâncio AM, Fonseca FP, Zequi Sde C, et al. Epithelial-mesenchymal transition (EMT) phenotype at invasion front of squamous cell carcinoma of the penis influences oncological outcomes. Urol Oncol. 2016;34:433.e19-26.
⁴⁶ Mohamed H, Haglund C, Jouhi L, Atula T, Hagström J, Mäkitie A. Expression and Role of E-Cadherin, β-Catenin, and Vimentin in Human Papillomavirus-Positive and Human Papillomavirus-Negative Oropharyngeal Squamous Cell Carcinoma. J Histochem Cytochem. 2020;68:595-606.
⁴⁷ Maiche AG, Pyrhönen S, Karkinen M. Histological grading of squamous cell carcinoma of the penis: a new scoring system. Br J Urol. 1991;67:522-6.
⁴⁸ Zhou X, Zhong Y, Song L, Wang Y, Wang Y, Zhang Q, et al. Nomograms to predict the presence and extent of inguinal lymph node metastasis in penile cancer patients with clinically positive lymph nodes. Transl Androl Urol. 2020;9:621-8.
⁴⁹ Li J, Wang B, Zheng SS, Zhou FJ, Yang JA, Yuan DZ, et al. [Independent external verification of the nomograms for predicting lymph node metastasis in penile cancer]. Zhonghua Nan Ke Xue. 2018;24:399-403. Chinese.
⁵⁰ Maciel CVM, Machado RD, Morini MA, Mattos PAL, Dos Reis R, Dos Reis RB, et al. External validation of nomogram to predict inguinal lymph node metastasis in patients with penile cancer and clinically negative lymph nodes. Int Braz J Urol. 2019;45:671-8.
⁵¹ Zargar-Shoshtari K, Spiess PE, Berglund AE, Sharma P, Powsang JM, Giuliano A, et al. Clinical Significance of p53 and p16(ink4a) Status in a Contemporary North American Penile Carcinoma Cohort. Clin Genitourin Cancer. 2016;14:346-51.
⁵² Gunia S, Kakies C, Erbersdobler A, Hakenberg OW, Koch S, May M. Expression of p53, p21 and cyclin D1 in penile cancer: p53 predicts poor prognosis. J Clin Pathol. 2012;65:232-6.
⁵³ Martins AC, Faria SM, Cologna AJ, Suaid HJ, Tucci S Jr. Immunoexpression of p53 protein and proliferating cell nuclear antigen in penile carcinoma. J Urol. 2002;167:89-92; discussion 92-3.
⁵⁴ Lopes A, Bezerra AL, Pinto CA, Serrano SV, de MellO CA, Villa LL. p53 as a new prognostic factor for lymph node metastasis in penile carcinoma: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. J Urol. 2002;168:81-6.
⁵⁵ Protzel C, Knoedel J, Zimmermann U, Woenckhaus C, Poetsch M, Giebel J. Expression of proliferation marker Ki67 correlates to occurrence of metastasis and prognosis, histological subtypes and HPV DNA detection in penile carcinomas. Histol Histopathol. 2007;22:1197-204.
⁵⁶ Zhu Y, Zhou XY, Yao XD, Dai B, Ye DW. The prognostic significance of p53, Ki-67, epithelial cadherin and matrix metalloproteinase-9 in penile squamous cell carcinoma treated with surgery. BJU Int. 2007;100:204-8.
⁵⁷ Berdjis N, Meye A, Nippgen J, Dittert D, Hakenberg O, Baretton GB, et al. Expression of Ki-67 in squamous cell carcinoma of the penis. BJU Int. 2005;96:146-8.
⁵⁸ Stankiewicz E, Ng M, Cuzick J, Mesher D, Watkin N, Lam W, et al. The prognostic value of Ki-67 expression in penile squamous cell carcinoma. J Clin Pathol. 2012;65:534-7.
⁵⁹ Steinestel J, Al Ghazal A, Arndt A, Schnoeller TJ, Schrader AJ, Moeller P, et al. The role of histologic subtype, p16(INK4a) expression, and presence of human papillomavirus DNA in penile squamous cell carcinoma. BMC Cancer. 2015;15:220.
⁶⁰ De Bacco MW, Carvalhal GF, MacGregor B, Marçal JMB, Wagner MB, Sonpavde GP, et al. PD-L1 and p16 Expression in Penile Squamous Cell Carcinoma From an Endemic Region. Clin Genitourin Cancer. 2020;18:e254-e259.

Publication Dates

Publication in this collection
01 Sept 2023
Date of issue
Sep-Oct 2023

History

Received
07 Mar 2023
Accepted
11 May 2023
Published
30 May 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

[1] ¹ Montes Cardona CE, García-Perdomo HA. Incidence of penile cancer worldwide: systematic review and meta-analysis. Rev Panam Salud Publica. 2017;41:e117.

[2] ² Coelho RWP, Pinho JD, Moreno JS, Garbis DVEO, do Nascimento AMT, Larges JS, et al. Penile cancer in Maranhão, Northeast Brazil: the highest incidence globally? BMC Urol. 2018;18:50.

[3] ³ Vieira CB, Feitoza L, Pinho J, Teixeira-Júnior A, Lages J, Calixto J, et al. Profile of patients with penile cancer in the region with the highest worldwide incidence. Sci Rep. 2020;10:2965.

[4] ⁴ Favorito LA, Nardi AC, Ronalsa M, Zequi SC, Sampaio FJ, Glina S. Epidemiologic study on penile cancer in Brazil. Int Braz J Urol. 2008;34:587-91; discussion 591-3.

[5] ⁵ Azevedo RA, Roxo AC, Alvares SHB, Baptista DP, Favorito LA. Use of flaps in inguinal lymphadenectomy in metastatic penile cancer. Int Braz J Urol. 2021;47:1108-19.

[6] ⁶ Ficarra V, Akduman B, Bouchot O, Palou J, Tobias-Machado M. Prognostic factors in penile cancer. Urology. 2010;76(2 Suppl 1):S66-73.

[7] ⁷ Srinivas V, Morse MJ, Herr HW, Sogani PC, Whitmore WF Jr. Penile cancer: relation of extent of nodal metastasis to survival. J Urol. 1987;137:880-2.

[8] ⁸ Chaux A, Caballero C, Soares F, Guimarães GC, Cunha IW, Reuter V, et al. The prognostic index: a useful pathologic guide for prediction of nodal metastases and survival in penile squamous cell carcinoma. Am J Surg Pathol. 2009;33:1049-57.

[9] ⁹ Jia Y, Zhao H, Hao Y, Zhu J, Li Y, Wang Y. Analysis of the related risk factors of inguinal lymph node metastasis in patients with penile cancer: A cross-sectional study. Int Braz J Urol. 2022;48:303-13.

[10] ¹⁰ Barros R, Favorito LA, Nahar B, Almeida R Jr, Ramasamy R. Changes in male sexuality after urologic cancer: a narrative review. Int Braz J Urol. 2023;49:175-83.

[11] ¹¹ McDougal WS. Carcinoma of the penis: improved survival by early regional lymphadenectomy based on the histological grade and depth of invasion of the primary lesion. J Urol. 1995;154:1364-6.

[12] ¹² Leone A, Diorio GJ, Pettaway C, Master V, Spiess PE. Contemporary management of patients with penile cancer and lymph node metastasis. Nat Rev Urol. 2017;14:335-47.

[13] ¹³ Kroon BK, Horenblas S, Lont AP, Tanis PJ, Gallee MP, Nieweg OE. Patients with penile carcinoma benefit from immediate resection of clinically occult lymph node metastases. J Urol. 2005;173:816-9.

[14] ¹⁴ Djajadiningrat RS, van Werkhoven E, Horenblas S. Prophylactic pelvic lymph node dissection in patients with penile cancer. J Urol. 2015;193:1976-80.

[15] ¹⁵ Graafland NM, Lam W, Leijte JA, Yap T, Gallee MP, Corbishley C, et al. Prognostic factors for occult inguinal lymph node involvement in penile carcinoma and assessment of the high-risk EAU subgroup: a two-institution analysis of 342 clinically node-negative patients. Eur Urol. 2010;58:742-7.

[16] ¹⁶ Moses KA, Sfakianos JP, Winer A, Bernstein M, Russo P, Dalbagni G. Non-squamous cell carcinoma of the penis: single-center, 15-year experience. World J Urol. 2014;32:1347-53.

[17] ¹⁷ Bhambhvani HP, Greenberg DR, Parham MJ, Eisenberg ML. A population-level analysis of nonsquamous penile cancer: The importance of histology. Urol Oncol. 2021;39:136.e1-136.e10.

[18] ¹⁸ Leiter U, Stadler R, Mauch C, Hohenberger W, Brockmeyer N, Berking C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2016;17:757-67.

[19] ¹⁹ Ornellas AA, Frota R, Lopes da Silva LF, Dauster B, Quirino R, de Santos Schwindt AB, et al. Sebaceous carcinoma of the penis. Urol Int. 2009;82:477-80.

[20] ²⁰ Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours. Eur Urol. 2016;70:93-105.

[21] ²¹ Martins VA, Pinho JD, Teixeira Júnior AAL, Nogueira LR, Silva FF, Maulen VE, et al. P16INK4a expression in patients with penile cancer. PLoS One. 2018;13:e0205350.

[22] ²² Kidd LC, Chaing S, Chipollini J, Giuliano AR, Spiess PE, Sharma P. Relationship between human papillomavirus and penile cancer-implications for prevention and treatment. Transl Androl Urol. 2017;6:791-802.

[23] ²³ Sánchez-Ortiz RF, Pettaway CA. The role of lymphadenectomy in penile cancer. Urol Oncol. 2004;22:236-44; discussion 244-5.

[24] ²⁴ Guimarães GC, Cunha IW, Soares FA, Lopes A, Torres J, Chaux A, et al. Penile squamous cell carcinoma clinicopathological features, nodal metastasis and outcome in 333 cases. J Urol. 2009;182:528-34; discussion 534.

[25] ²⁵ Velazquez EF, Melamed J, Barreto JE, Aguero F, Cubilla AL. Sarcomatoid carcinoma of the penis: a clinicopathologic study of 15 cases. Am J Surg Pathol. 2005;29:1152-8.

[26] ²⁶ Sanchez DF, Rodriguez IM, Piris A, Cañete S, Lezcano C, Velazquez EF, et al. Clear Cell Carcinoma of the Penis: An HPV-related Variant of Squamous Cell Carcinoma: A Report of 3 Cases. Am J Surg Pathol. 2016;40:917-22.

[27] ²⁷ Aita GA, Zequi SC, Costa WH, Guimarães GC, Soares FA, Giuliangelis TS. Tumor histologic grade is the most important prognostic factor in patients with penile cancer and clinically negative lymph nodes not submitted to regional lymphadenectomy. Int Braz J Urol. 2016;42:1136-43.

[28] ²⁸ Kakies Ch, Lopez-Beltran A, Comperat E, Erbersdobler A, Grobholz R, Hakenberg OW, et al. Reproducibility of histopathologic tumor grading in penile cancer--results of a European project. Virchows Arch. 2014;464:453-61.

[29] ²⁹ Solsona E, Iborra I, Rubio J, Casanova JL, Ricós JV, Calabuig C. Prospective validation of the association of local tumor stage and grade as a predictive factor for occult lymph node micrometastasis in patients with penile carcinoma and clinically negative inguinal lymph nodes. J Urol. 2001;165:1506-9.

[30] ³⁰ Velazquez EF, Ayala G, Liu H, Chaux A, Zanotti M, Torres J, et al. Histologic grade and perineural invasion are more important than tumor thickness as predictor of nodal metastasis in penile squamous cell carcinoma invading 5 to 10 mm. Am J Surg Pathol. 2008;32:974-9.

[31] ³¹ Ficarra V, Martignoni G, Maffei N, Cerruto MA, Novara G, Cavalleri S, et al. Predictive pathological factors of lymph nodes involvement in the squamous cell carcinoma of the penis. Int Urol Nephrol. 2002;34:245-50.

[32] ³² Cubilla AL. The role of pathologic prognostic factors in squamous cell carcinoma of the penis. World J Urol. 2009;27:169-77.

[33] ³³ Caballero C, Barreto J, Riveros M, Cubilla, AL. Carcinoma epidermoide de glande peneano: parâmetros patológicos predictores de metastasis ganglionar inguinal. Patol Spain .1991; 24: 1137–41.

[34] ³⁴ Koifman L, Hampl D, Ginsberg M, Castro RB, Koifman N, Ornellas P, et al. The role of primary inguinal surgical debulking for locally advanced penile cancer followed by reconstruction with myocutaneous flap. Int Braz J Urol. 2021;47:1162-75.

[35] ³⁵ Djajadiningrat RS, Jordanova ES, Kroon BK, van Werkhoven E, de Jong J, Pronk DT, et al. Human papillomavirus prevalence in invasive penile cancer and association with clinical outcome. J Urol. 2015;193:526-31.

[36] ³⁶ Nascimento ADMTD, Pinho JD, Júnior AALT, Larges JS, Soares FM, Calixto JRR, et al. Angiolymphatic invasion and absence of koilocytosis predict lymph node metastasis in penile cancer patients and might justify prophylactic lymphadenectomy. Medicine (Baltimore). 2020;99:e19128.

[37] ³⁷ de Paula AA, Netto JC, Freitas R Jr, de Paula LP, Mota ED, Alencar RC. Penile carcinoma: the role of koilocytosis in groin metastasis and the association with disease specific survival. J Urol. 2007;177:1339-43; discussion 1343.

[38] ³⁸ Mentrikoski MJ, Stelow EB, Culp S, Frierson HF Jr, Cathro HP. Histologic and immunohistochemical assessment of penile carcinomas in a North American population. Am J Surg Pathol. 2014;38:1340-8.

[39] ³⁹ Mannweiler S, Sygulla S, Tsybrovskyy O, Razmara Y, Pummer K, Regauer S. Clear-cell differentiation and lymphatic invasion, but not the revised TNM classification, predict lymph node metastases in pT1 penile cancer: a clinicopathologic study of 76 patients from a low incidence area. Urol Oncol. 2013;31:1378-85.

[40] ⁴⁰ Ornellas AA, Nóbrega BL, Wei Kin Chin E, Wisnescky A, da Silva PC, de Santos Schwindt AB. Prognostic factors in invasive squamous cell carcinoma of the penis: analysis of 196 patients treated at the Brazilian National Cancer Institute. J Urol. 2008;180:1354-9.

[41] ⁴¹ Pizzocaro G, Algaba F, Horenblas S, Solsona E, Tana S, Van Der Poel H, et al. EAU penile cancer guidelines 2009. Eur Urol. 2010;57:1002-12.

[42] ⁴² Aita G, da Costa WH, de Cassio Zequi S, da Cunha IW, Soares F, Guimaraes GC, et al. Pattern of invasion is the most important prognostic factor in patients with penile cancer submitted to lymph node dissection and pathological absence of lymph node metastasis. BJU Int. 2015;116:584-9.

[43] ⁴³ Hu J, Cui Y, Liu P, Zhou X, Ren W, Chen J, et al. Predictors of inguinal lymph node metastasis in penile cancer patients: a meta-analysis of retrospective studies. Cancer Manag Res. 2019;11:6425-41.

[44] ⁴⁴ Guimarães GC, Lopes A, Campos RS, Zequi Sde C, Leal ML, Carvalho AL, et al. Front pattern of invasion in squamous cell carcinoma of the penis: new prognostic factor for predicting risk of lymph node metastases. Urology. 2006;68:148-53.

[45] ⁴⁵ da Cunha IW, Souza MJ, da Costa WH, Amâncio AM, Fonseca FP, Zequi Sde C, et al. Epithelial-mesenchymal transition (EMT) phenotype at invasion front of squamous cell carcinoma of the penis influences oncological outcomes. Urol Oncol. 2016;34:433.e19-26.

[46] ⁴⁶ Mohamed H, Haglund C, Jouhi L, Atula T, Hagström J, Mäkitie A. Expression and Role of E-Cadherin, β-Catenin, and Vimentin in Human Papillomavirus-Positive and Human Papillomavirus-Negative Oropharyngeal Squamous Cell Carcinoma. J Histochem Cytochem. 2020;68:595-606.

[47] ⁴⁷ Maiche AG, Pyrhönen S, Karkinen M. Histological grading of squamous cell carcinoma of the penis: a new scoring system. Br J Urol. 1991;67:522-6.

[48] ⁴⁸ Zhou X, Zhong Y, Song L, Wang Y, Wang Y, Zhang Q, et al. Nomograms to predict the presence and extent of inguinal lymph node metastasis in penile cancer patients with clinically positive lymph nodes. Transl Androl Urol. 2020;9:621-8.

[49] ⁴⁹ Li J, Wang B, Zheng SS, Zhou FJ, Yang JA, Yuan DZ, et al. [Independent external verification of the nomograms for predicting lymph node metastasis in penile cancer]. Zhonghua Nan Ke Xue. 2018;24:399-403. Chinese.

[50] ⁵⁰ Maciel CVM, Machado RD, Morini MA, Mattos PAL, Dos Reis R, Dos Reis RB, et al. External validation of nomogram to predict inguinal lymph node metastasis in patients with penile cancer and clinically negative lymph nodes. Int Braz J Urol. 2019;45:671-8.

[51] ⁵¹ Zargar-Shoshtari K, Spiess PE, Berglund AE, Sharma P, Powsang JM, Giuliano A, et al. Clinical Significance of p53 and p16(ink4a) Status in a Contemporary North American Penile Carcinoma Cohort. Clin Genitourin Cancer. 2016;14:346-51.

[52] ⁵² Gunia S, Kakies C, Erbersdobler A, Hakenberg OW, Koch S, May M. Expression of p53, p21 and cyclin D1 in penile cancer: p53 predicts poor prognosis. J Clin Pathol. 2012;65:232-6.

[53] ⁵³ Martins AC, Faria SM, Cologna AJ, Suaid HJ, Tucci S Jr. Immunoexpression of p53 protein and proliferating cell nuclear antigen in penile carcinoma. J Urol. 2002;167:89-92; discussion 92-3.

[54] ⁵⁴ Lopes A, Bezerra AL, Pinto CA, Serrano SV, de MellO CA, Villa LL. p53 as a new prognostic factor for lymph node metastasis in penile carcinoma: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. J Urol. 2002;168:81-6.

[55] ⁵⁵ Protzel C, Knoedel J, Zimmermann U, Woenckhaus C, Poetsch M, Giebel J. Expression of proliferation marker Ki67 correlates to occurrence of metastasis and prognosis, histological subtypes and HPV DNA detection in penile carcinomas. Histol Histopathol. 2007;22:1197-204.

[56] ⁵⁶ Zhu Y, Zhou XY, Yao XD, Dai B, Ye DW. The prognostic significance of p53, Ki-67, epithelial cadherin and matrix metalloproteinase-9 in penile squamous cell carcinoma treated with surgery. BJU Int. 2007;100:204-8.

[57] ⁵⁷ Berdjis N, Meye A, Nippgen J, Dittert D, Hakenberg O, Baretton GB, et al. Expression of Ki-67 in squamous cell carcinoma of the penis. BJU Int. 2005;96:146-8.

[58] ⁵⁸ Stankiewicz E, Ng M, Cuzick J, Mesher D, Watkin N, Lam W, et al. The prognostic value of Ki-67 expression in penile squamous cell carcinoma. J Clin Pathol. 2012;65:534-7.

[59] ⁵⁹ Steinestel J, Al Ghazal A, Arndt A, Schnoeller TJ, Schrader AJ, Moeller P, et al. The role of histologic subtype, p16(INK4a) expression, and presence of human papillomavirus DNA in penile squamous cell carcinoma. BMC Cancer. 2015;15:220.

[60] ⁶⁰ De Bacco MW, Carvalhal GF, MacGregor B, Marçal JMB, Wagner MB, Sonpavde GP, et al. PD-L1 and p16 Expression in Penile Squamous Cell Carcinoma From an Endemic Region. Clin Genitourin Cancer. 2020;18:e254-e259.