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Available online at www.sciencedirect.com

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Clinicopathological features of carcinoma of the distal penile urethra Catherine M. Corbishley, FRCPatha,n, Ramzi M. Rajab, FRCPatha, Nicholas A. Watkin, FRCSb a

Department of Cellular Pathology, St George's Healthcare NHS Trust, Blackshaw Road, Tooting SW17 0QT, London, UK b Department of Urology St George's Healthcare NHS Trust, Tooting, London, UK

article info

abstract

Keywords:

Distal urethral carcinomas are very rare and are similar in their pathology and behaviour to

Urethral cancer

tumours of the glans penis and foreskin. Similarly they are associated with penile

Penile cancer

intraepithelial neoplasia (PeIN) of both differentiated and undifferentiated types. Current

Squamous cell carcinoma

management is mainly surgical, but increasingly involves specialist penile-preserving

Basaloid carcinoma

techniques. Handling and dissection of the specimens is broadly the same as other primary

Penile intraepithelial neoplasia

penile tumours. The prognosis of distal urethral lesions is believed to be worse than penile tumours and better than prostatic urethral tumours, but the evidence is sparse. The staging system for urethral tumours does not distinguish between proximal and distal, apart from prostatic urethra, and has led to much confusion in the literature. Although the subtypes of tumours seen in the distal urethra are the same as those on the glans and foreskin, there is an increased proportion of basaloid squamous carcinoma and malignant melanoma whereas the majority of tumours seen in the proximal and prostatic urethra are of urothelial origin. In future, distal urethral tumours should be separately designated with site-specific staging/TNM and reporting system and pathologically classified in the same way as penile and foreskin tumours. Ultimately, this will improve the quality of data and produce evidence to inform management. & 2015 Elsevier Inc. All rights reserved.

Introduction Primary carcinoma of the urethra is very rare. Only a small proportion of such tumours arise in the distal urethra, with the majority found in the proximal and prostatic urethra.1,2 The proximal tumours are usually of urothelial origin,

although they may show evidence of squamous differentiation. The tumours found in the distal urethra are almost exclusively squamous in type, and are similar to those seen arising on the glans penis and foreskin.3–5 Distal urethral tumours are associated with precancerous lesions now known as penile intraepithelial neoplasia (PeIN)6 and also

Disclosure: Catherine Corbishley is the chair of the UK national penile pathology group “the Hobnobs” and is the lead author of the Royal College of Pathologists Penile and Distal Urethral dataset. n Corresponding author. E-mail address: [email protected] (C.M. Corbishley). http://dx.doi.org/10.1053/j.semdp.2014.12.015 0740-2570/& 2015 Elsevier Inc. All rights reserved.

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Table – TNM staging of tumours of the urethra (TNM7, 2009). Primary tumour (male and female) (excluding prostatic urethra) TX Primary tumour cannot be assessed. T0 No evidence of primary tumour. Noninvasive papillary, polypoid, or verrucous carcinoma.a Taa Tis Carcinoma in situ.b T1 Tumour invades subepithelial connective tissue. T2 Tumour invades any of the following: corpus spongiosum, prostate or periurethral muscle. T3 Tumour invades any of the following: corpus cavernosum, beyond prostatic capsule or bladder neck. T4 Tumour invades other adjacent organs. Regional lymph nodes NX N0 N1 N2

Regional lymph nodes cannot be assessed. No regional lymph node metastasis. Metastasis in a single lymph node 2 cm or less in greatest dimension. Metastasis in a single node more than 2 cm in greatest dimension, or in multiple nodes.

Distant metastasis M0 M1

No distant metastasis. Distant metastasis.

a b

The authors view is that the use of this category is to be avoided as it is not evidence based. Now designated as PeIN in the distal urethra.

with lichen sclerosus [previously known as balanitis xerotica obliterans (BXO)].7 In recent years, subspecialisation in urological surgery and the advent of penile-preserving surgery with reconstruction have led to penile and distal urethral tumours being referred to specialist surgical teams in some countries. In parts of the UK, the establishment of penile cancer supranetworks within the national cancer plan8 has formalised this approach, with specialist penile cancer centres in the England and Wales treating between 25 and 130 new cases per year. Even in the largest of these centres, the numbers of primary distal urethral cancers are relatively small.

Incidence and clinical findings Exact figures on incidence of distal urethral cancer are difficult to obtain as most of the literature lumps urethral cancer from proximal and distal urethra, prostatic urethra, and male and females together.1 Additionally, the current TNM classification does not distinguish tumours by site of origin within the urethra or gender, apart from separating those of the prostatic urethra9 (Table).

In our experience of operating on over 1000 cases of primary penile and distal urethral cancers and precancers over the last 14 years in the South East of England, we have found 6% (57 cases) originate in the distal urethra (unpublished observations). Tumours may present in a number of ways including visible lesions around the meatus, haematuria or discharge, obstruction, penile mass, fistula, or metastases, usually to inguinal nodes7 (Figs. 1 and 2).

Management The surgical management of distal urethral tumours is similar to that currently undertaken for penile tumours and includes radical or subtotal penectomy as well as penilepreserving procedures such as glansectomy or distal urethrectomy2,10 (Figs. 3–8). Surgical resection margins may need to be more generous than for penile carcinoma as these tumurs may spread submucosally. Intraoperative frozen section assessment of margins may be helpful in some cases.2,7 These tumours metastasise initially to inguinal nodes rather than

Fig. 1 – Glansectomy (left) and radical penectomy (right) for urethral tumours presenting with meatal lesions.

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Fig. 2 – Radical penectomy for urethral tumour presenting as penile mass with ulcerated fistula. intraabdominal nodes; therefore, criteria for node dissection and/or sentinel node procedures might be assumed to be similar to those in penile cancer management, although this is not defined in current guidelines. The TNM (version 7) for urethral tumour node involvement does not include N3 for nodes showing extranodal spread, which has been shown in penile carcinoma to be an adverse prognostic factor (Table).11 Chemotherapy and/or radiotherapy may be used for inoperable tumours or in the postoperative multidisciplinary management of metastatic disease as in penile cancer.2,10

Specimen handling and dissection Currently there is little or nothing in current textbooks, protocols, and datasets to provide help with handling and reporting distal urethral specimens. However, the new editions of the Royal College of Pathologists Cancer datasets now separate out distal urethral tumours from other urethral and urothelial tumours, and they will be incorporated in the penile tumour dataset from 2015.12 Distal urethral specimens are best handled and dissected in the same way as similar resections undertaken for penile cancer in the context of the complex anatomy of this region.12,13 Additional care should be taken to sample the proximal urethral margin and circumferential margins of

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urethrectomies with differential ink marking of resection margins as required. Large specimens, such as glansectomies and partial and radical penectomies, should be sliced longitudinally along the line of the urethra and between the corporal heads. Some pathologists may prefer to use transverse sections of the proximal shaft in radical penectomies. Resection margins of the urethra and corporal heads should be marked or blocked prior to slicing if necessary. Large format (megablock) sections are invaluable in assessing these tumours as they facilitate evaluation of surgical extent and staging (Figs. 4, 5, 8, and 9). Urethrectomies should be orientated with proximal and distal margins separately designated and sampled and then sliced transversely in sequence. These specimens are usually small enough to be blocked in their entirety.

Association with lichen sclerosus and penile intraepithelial neoplasia In recent years, the terminology of precancerous lesions of the penis has changed with the use of the unifying pathological term penile intraepithelial neoplasia, which has both differentiated and undifferentiated subtypes.14 These changes are seen in the squamous epithelium lined distal urethra as well as on the glans penis and foreskin. Full-thickness atypia with warty/basaloid features is designated undifferentiated PeIN (previously called severe dysplasia/carcinoma in situ) and those involving only the basal layers and associated with architectural atypia and aberrant keratinisation described as differentiated PeIN. Undifferentiated PeIN is usually p16 positive and is HPV16 associated. Differentiated PeIN is usually p16 negative.15 The presence and subtype of PeIN should be reported together with its margin status independent of associated invasive tumour. Clinically defined terms such as Erythroplasia of Queyrat, Bowen's disease and Bowenoid papulosis are no longer recommended in pathological reporting. It is recommended that neither differentiated nor undifferentiated PeIN is graded either as neither low/high grade nor grades 1–3.14 Severe lichen sclerosus may involve the distal urethra causing strictures and is associated with differentiated PeIN. Tumours arising in a background of differentiated PeIN may be of usual type but verrucous and pseudohyperplastic tumours are also seen. Undifferentiated PeIN is associated with usual-type, basaloid and warty tumours.16–18 Primary penile tumours may also involve the urethra.6 Urethral tumours often involve the urethral meatus and glans penis, and sometimes, it may be difficult or impossible to determine where they arise particularly when the tumour is advanced. The presence of PeIN in the urethra rather than on the glans favours a urethral origin.

Tumour subtypes

Fig. 3 – Radical penectomy for tumour of distal urethra that infiltrates corporal heads.

The subtypes of squamous cell carcinoma seen in the distal urethra are identical to those seen on the glans penis and foreskin and will not be further described here. Basaloid and usual-type squamous cell carcinomas are the most common

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Fig. 4 – Macroscopic photograph and scanned histological slide of longitudinal section of partial penectomy for distal urethral carcinoma involving corporal heads.

Fig. 5 – Macroscopic photograph and scanned histological slide of longitudinal section of glansectomy for urethral tumour. Tumour is seen reaching the deep periurethral margin.

Fig. 6 – Distal urethrectomy for superficial squamous cell carcinoma of distal urethra. The sutures indicate the proximal and distal urethral margins.

and mixed tumours, with a variety of tumour patterns may be seen. We have found a much higher proportion of basaloid squamous cell carcinoma in the distal urethra than on the glans and foreskin with 42% of urethral tumours having this pattern in our series (unpublished data: distal penile urethral carcinoma) as opposed to 4–10% of penile tumours in the general literature.10 Basaloid tumours are usually HPV16 and hence p16 positive and are always high grade19 (Fig. 10). Lymphovascular invasion is more frequently associated with basaloid carcinoma than other subtypes,3,4 and they have a

Fig. 7 – Longitudinal section of radical penectomy for extensive urethral tumour involving corporal heads and extending into scrotal skin and subcutaneous fat.

higher incidence of lymph node metastases at presentation (Fig. 11). Lower grade tumours such as verrucous carcinomas associated with lichen sclerosus are also seen, which are often multifocal (Fig. 12). Malignant melanoma is commoner in the penile urethra than on the glans and foreskin but is an exceptionally rare tumour at these sites20,21 (Fig. 13). It is usually associated with preinvasive melanocytic lesions. Malignant melanoma of the urethra has a very poor prognosis similar to that seen in other mucosal primary melanomas. Staging of melanomas

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Fig. 8 – Longitudinal section and microscopic slide of glansectomy with foreskin for urethral carcinoma. Tumour involves the deep margin, and early revision surgery is usually undertaken in such cases.

Fig. 9 – Longitudinal section of radical penectomy and microscopic slides showing extensive tumour involving glans and foreskin (left) and discrete blood-borne metastatic tumour nodules in the corporal heads.

Fig. 10 – Glansectomy for basaloid squamous cell carcinoma of the distal penis and urethra.

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Fig. 11 – Basaloid squamous cell carcinoma microscopy showing abrupt comedo-type necrosis (left) and vascular invasion of corporal heads at deep margin.

Fig. 12 – Glansectomy for recurrent mixed verrucous and usual-type squamous cell carcinoma involving both glans penis and distal urethra. Longitudinal section of specimen and microscope slide.

Fig. 13 – Glansectomy with urethrectomy for malignant melanoma of the urethra. Urethral mucosa has been inverted by the surgeon. The melanoma is seen in the mid part of the specimen inferiorly as a dark nodule. Histological image shows extensive melanin within tumour cells.

should use the melanoma TNM rather than the penile or urethral staging system.9,12 Primary urothelial carcinoma arising in the distal urethra is, in our opinion, exceptionally rare. GATA3 staining, which is usually positive in urothelial carcinoma and negative in squamous carcinoma, may assist in clarifying tumour type22; however, careful light microscopy is usually sufficient to determine tumour type and subtype. Secondary tumours in the urethra are rare with the exception of urothelial carcinoma. The origin of this tumour is usually the prostatic urethra or bladder, and both invasive and sometimes pagetoid spread may be seen. Urethral

involvement by metastatic tumours to the penis is usually consequent to involvement of the corporal heads. Advanced penile carcinomas often involve the urethra in continuity with the main tumour. Basaloid carcinoma of the penis may also spread along the urethra via the lymphatics in the urethral mucosa.

Prognosis and outcomes The prognosis of distal urethral tumours is thought to be better than that of proximal urethral tumours but is worse than primary penile cancers overall. This may be explained at

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least in part by the more concealed nature of the primary tumour and the increased proportion of high-grade basaloid tumours when compared with penile lesions. The confused nature of the literature in this area makes precise data difficult to extract at present. The availability of penile and urethral preserving surgery in specialist centres with more careful data collection will ultimately provide better information on these very rare tumours.

Conclusions Recent detailed descriptions of both cancerous and precancerous lesions of the penis and the increasing centralisation and specialisation of penile cancer services have led to a better understanding of distal urethral tumours and their similarities to their penile counterparts. The literature on distal urethral tumours is sparse and muddled because of the lumping of all urethral tumours under one TNM system and needs separate defined specific staging systems for different urethral tumour sites including the addition of an N3 category for nodes showing extranodal spread. There is a much higher proportion of HPV16-associated basaloid tumours over other types of squamous cell carcinoma in the distal urethra, which may in part, along with anatomical considerations and their propensity for lymphovascular invasion, explain the perceived worse prognosis of these tumours over penile carcinomas generally. However, there is much work yet to be done in analysing these tumours and their outcomes in order to produce better evidence-based clinical and pathological literature.

r e f e r e n c e s

1. Swartz MA, Porter MP, Lin DW, Weiss NS. Incidence of primary urethral carcinoma in the United States. Urology. 2006;68: 1164–1168. 2. Gakis G, Witjes JA, Comperat E, et al. EAU guidelines on primary urethral carcinoma. Eur Urol. 2013;64:823–830. 3. Cubilla AL, Dillner J, Schellhamer PF, et al. Tumours of the penis. Malignant epithelial tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. World Health Organization Classification of Tumours. Lyon: IARC press; 2004;279–298. 4. Epstein JI, Cubilla AL, Humphrey PA. Tumors of the Prostate Gland, Seminal Vesicles, Penis, and Scrotum (AFIP Atlas of Tumor Pathology), 14. Washington, DC: American Registry of Pathology and AFIP; 2011. 5. Chaux A, Velazquez EF, Barreto JE, Ayala E, Cubilla AL. New pathologic entities in penile carcinomas: an update of the 2004 world health organization classification. Semin Diagn Pathol. 2012;29:59–66. 6. Velazquez EF, Soskin A, Bock A, et al. Epithelial abnormalities and precancerous lesions of anterior urethra in patients with penile carcinoma: a report of 89 cases. Mod Pathol. 2005;18: 917–923.

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7. Smith Y, Hadway P, Ahmed S, Perry MJ, Corbishley CM, Watkin NA. Penile-preserving surgery for male distal urethral carcinoma. BJU Int. 2007;100:82–87. 8. NHS Cancer Quality Improvement Network System: Manual for Cancers Services. Urology Measures. NHS national peer review programme. 〈http://www.cquins.nhs.uk/?menu=resources〉; 2014. 9. TNM Classification of Malignant Tumours (7th Edition). In: Sobin L, Gospodrowics M, Wittekind C (eds.): AJCC Cancer Staging Manual. 7th ed. New York, NY: Wiley Blackwell; Penis, pp 239-242, Urethra pp266-269, Malignant Melanoma pp172176. 10. Hakenberg OW, Compérat S, Necchi A, et al. Guidelines on Penile Cancer: European Association of Urology. 〈http://www. uroweb.org/gls/pdf/12%20Penile%20Cancer_LR.pdf〉; 2014. 11. Lam W, Alnajjar HM, La-Touche S, et al. Dynamic sentinel lymph node biopsy in patients with invasive squamous cell carcinoma of the penis: a prospective study of the long-term outcome of 500 inguinal basins assessed at a single institution. Eur Urol. 2013;63:657–663. 12. Dataset for Penile and Distal Urethral Cancer Histopathology Reports. (ed. 2). 〈http://www.rcpath.org/publications-media/ publications/datasets〉. 13. Cubilla AL, Piris A, Pfannl R, Rodriguez I, Aguero F, Young RH. Anatomic levels: important landmarks in penectomy specimens: a detailed anatomic and histologic study based on examination of 44 cases. Am J Surg Pathol. 2001;25: 1091–1094. 14. Velazquez EF, Chaux A, Cubilla AL. Histologic classification of penile intraepithelial neoplasia. Semin Diagn Pathol. 2012;29: 96–102. 15. 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;34:385–392. 16. 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;43:1020–1027. 17. Cubilla AL, Velazquez EF, Young RH. Pseudohyperplastic squamous cell carcinoma of the penis associated with lichen sclerosus. An extremely well-differentiated, nonverruciform neoplasm that preferentially affects the foreskin and is frequently misdiagnosed: a report of 10 cases of a distinctive clinicopathologic entity. Am J Surg Pathol. 2004;28:895–900. 18. Chaux A, Cubilla AL. Diagnostic problems in precancerous lesions and invasive carcinomas of the penis. Semin Diagn Pathol. 2012;29:72–82. 19. Cubilla AL, Reuter VE, Gregoire L, et al. Basaloid squamous cell carcinoma: a distinctive human papilloma virus-related penile neoplasm: a report of 20 cases. Am J Surg Pathol. 1998;22:755–761. 20. Sanchez-Ortiz R, Huang SF, Tamboli P, et al. Melanoma of the penis, scrotum and male urethra: a 40-year single institution experience. J Urol. 2005;173:1958–1965. 21. Oxley JD, Corbishley C, Down L, Watkin N, Dickerson D, Wong NA. Clinicopathological and molecular study of penile melanoma. J Clin Pathol. 2012;65:228–231. 22. Chaux A, Han JS, Lee S, et al. Immunohistochemical profile of the penile urethra and differential expression of GATA3 in urothelial versus squamous cell carcinomas of the penile urethra. Hum Pathol. 2013;44:2760–2767.

Clinicopathological features of carcinoma of the distal penile urethra.

Distal urethral carcinomas are very rare and are similar in their pathology and behaviour to tumours of the glans penis and foreskin. Similarly they a...
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