Urethral diverticulum carcinoma in females-a case series and review of the English and Japanese literature.

The aims of our study were to describe our case series of three urethral diverticulum carcinomas (UDC) in women and to review the literature on UDC in females to determine patient characteristics, presenting symptoms and outcomes along with optimal investigations and treatment modalities. A literature search was performed utilizing Medline, EMBASE and the Cochrane library for all papers including case reports on UDC in women published to date. The results along with those of our three cases are detailed. A total of 126 cases of UDC in women have been reported; 75% adenocarcinoma (Adenoca), 15% transitional cell carcinoma (TCC) and 10% squamous cell carcinoma (SCC). Median age at presentation was 53 years (range, 14-81 years). The commonest presenting symptoms were bleeding and retention. Cystoscopy, MRI and trans-urethral biopsy were the commonest methods of diagnosis. Treatment was radiotherapy +/- chemotherapy alone in 21%, local excision +/- radiotherapy in 44%, urethrectomy in 3% and anterior exenteration +/- radiotherapy in 32%. At last follow-up 63% were alive and well, 10% were alive with recurrent cancer and 25% had died from their disease. UDC is rare in women. It is predominantly adenocarcinoma. There is no established treatment and survival is at best moderate. An international registry and consensus on management is needed if this is to be improved.

Introduction

Urethral diverticulum carcinoma (UDC) in women is extremely rare with only 123 cases previously reported (). Relatively little is known about UDC in women. We detail three additional cases of UDC in women and review the literature on the subject to more clearly define patient characteristics, presenting symptoms, diagnostics, treatments and outcomes to determine optimal management strategies.

Table 1

Signs and symptoms of female urethral diverticulum cancer

Author	Age (years)	Race	Symptom 1	Symptom 2	Duration (months)	Histology
Allen and Nelson, 1978 (1)	68	–	Bleeding	–	–	Adenoca
	69	–	Bleeding	–	–	Adenoca
Awakura et al., 2003 (2)	75	A	Bleeding	Retention	7	Adenoca
Bracken et al., 1976 (3)	–	–	–	–	–	TCC
Brown et al., 1956 (4)	40	C	Bleeding	–	–	Adenoca
Carneiro Neto et al., 1973 (5)	–	H	–	–	–	Not known
Catalano et al., 1992 (6)	–	–	–	–	–	TCC
Cea et al., 1977 (7)	48	C	Bleeding	–	2	Adenoca
	53	C	Bleeding	–	–	Adenoca
Christofferson, 1974 (8)	–	–	–	–	–	Adenoca
Clayton et al., 1992 (9)	63	B	Urgency	Mass	–	SCC
	44	B	Bleeding	–	18	SCC
	35	B	Bleeding	UTIs	–	SCC
	44	B	Pain	–	–	Adenoca
	47	B	Bleeding	–	–	SCC
	67	B	Bleeding	–	–	Adenoca
Collado et al., 2000 (10)	65	–	Bleeding	–	–	Adenoca
Cruz-Ruiz et al., 2010 (11)	–	H	–	–	–	Adenoca
Davis et al., 2003 (12)	58	–	UTIs	–	–	Adenoca
Davis et al., 1999 (13)	48	–	UTIs	–	–	Adenoca
	48	–	Bleeding	–	–	Adenoca
Prudente de Toledo et al., 1978 (14)	65	C	Urgency	–	–	TCC
Dodson et al., 1995 (15)	–	–	–	–	–	Adenoca
Evans et al., 1981 (16)	47	B	Bleeding	–	–	Adenoca
Faulkner et al., 1959 (17)	57	–	Bleeding	–	–	TCC
Geisler et al., 1998 (18)	70	–	–	–	–	Adenoca
Ghoniem et al., 2004 (19)	71	–	Retention	Mass	–	Adenoca
Godec et al., 1984 (20)	52	C	Dysuria	–	2	Adenoca
Gonzalez et al., 1985 (21)	70	C	Bleeding	–	–	Adenoca
	14	C	Urgency	–	–	Adenoca
	27	C	Mass	–	–	Adenoca
	37	C	Bleeding	–	–	TCC
	40	H	Bleeding	Dyspareunia	5	TCC
	48	C	Retention	–	–	SCC
	36	C	Mass	–	–	SCC
Graf et al., 1962 (22)	65	C	Frequency	–	–	TCC
Ha et al., 2010 (23)	60	A	UTIs	Bleeding	36	Adenoca
Hamilton et al., 1951 (24)	53	–	Bleeding	–	–	Adenoca
Hickey et al., 2000 (25)	50	–	UTI	Bleeding	–	Adenoca
Hinman et al., 1960 (26)	40	–	Bleeding	–	–	Adenoca
	44	–	Bleeding	–	–	TCC
Hruby et al., 2000 (27)	–	–	–	–	–	Adenoca
						Adenoca
Huvos et al., 1969 (28)	58	B	Mass	–	–	SCC
Jensen et al., 1981 (29)	–	–	–	–	–	Adenoca
						Adenoca
Jimenzez de Leon et al., 1989 (30)	–	H	Bleeding	–	–	Adenoca
Kanno et al., 2002 (31)	81	A	Bleeding	–	–	Adenoca
Kasahara et al., 2017 (32)	48	A	Voiding dysfunction	–	5	Adenoca
Kato et al., 1998 (33)	71	A	Frequency	Dysuria	1	Adenoca
Klotz et al., 1974 (34)	67	C	Bleeding	–	–	Adenoca
Lang et al., 2008 (35)	54	C	Dysuria	Frequency	72	Adenoca
Manning et al., 2012 (36)	56	–	UI	Dysuria	60	TCC
Murayama et al., 1978 (37)	42	A	Pain	–	–	Adenoca
Marshall et al., 1977 (38)	64	–	Ulcer	–	12	Adenoca
	72	–	Bleeding	–	12	TCC
McLoughlin, 1975 (39)	51	B	UTI	–	–	TCC
Melnick and Birdsall, 1960 (40)	50	–	Bleeding	–	–	TCC
Nakamura et al., 1995 (41)	50	A	–	–	–	Adenoca
Nakatsuka et al., 2012 (42)	42	A	Bleeding	Pain	3	Adenoca
Ney et al., 1971 (43)	59	–	Retention	–	–	Adenoca
Noguchi and Ida, 1983 (44)	58	A	Dysuria	–	–	Adenoca
Okubo et al., 1996 (45)	44	A	Bleeding	Retention	3	Adenoca
Oliva and Young, 1996 (46)	–	–	–	–	–	Adenoca
						Adenoca
						Adenoca
						Adenoca
						Adenoca
						Adenoca
						Adenoca
						Adenoca
						Adenoca
						Adenoca
						Adenoca
						Adenoca
Patanephan et al., 1983 (47)	74	C	Retention	UTIs	–	Adenoca
	58	B	Mass	–	18	Adenoca
Rajan et al., 1993 (48)	31	B	Dyspaerunia	–	–	Adenoca
	47	B	Bleeding	–	–	Adenoca
	65	H	Bleeding	–	–	Adenoca
	52	B	Mass	–	–	Adenoca
Reheis et al., 1981 (49)	61	C	Bleeding	–	–	Adenoca
Rhamy et al., 1973 (50)	61	C	–	–	–	TCC
	72	B	Bleeding	–	–	Adenoca
Rosenfeld and Frachtman, 1964 (51)	52	B	Mass	Dyspareunia	10	TCC
Roth, 1955 (52)	40	B	Bleeding	–	–	TCC
Salvador Alvarez et al., 2011 (53)	57	H	Retention	Pyrexia	–	Adenoca
Scantling et al., 2013 (54)	47	B	UTI	Bleeding	–	Adenoca
Schileru et al., 1984 (55)	–	–	–	–	–	Adenoca
Schnoy and Leistenschneider, 1982 (56)	39	C	–	–	–	Adenoca
Seballos and Rich, 1995 (57)	58	–	Bleeding	–	3	Adenoca
Sekowska and Golajewski, 1961 (58)	–	–	–	–	–	Adenoca
Shalev et al., 2002 (59)	38	–	UTIs	Urgency	–	SCC
Sheahan and Vega Vega, 2013 (60)	54	–	Bleeding	Voiding dysfunction	12	Adenoca
Srinivas and Dow, 1983 (61)	52	–	Dysuria	–	–	TCC
Tanabe et al., 1982 (62)	50	C	Mass	Bleeding	2	Adenoca
Tesluk, 1981 (63)	46	–	Frequency	Urgency	–	Adenoca
	46		Frequency	Bleeding	2	Adenoca
	62		Retention	–	–	Adenoca
Thomas and McGuire, 1991 (64)	–	–	–	–	–	Adenoca
Thomas et al., 2008 (65)	Average 45	–	UI	UTIs	–	Adenoca
			UI	UTIs	–	Adenoca
			UTIs	UTIs	–	Adenoca
			Pain	UTIs	–	Adenoca
			–	UTIs	–	Adenoca
Thompson and Bivings, 1962 (66)	65	C	Mass	–	–	TCC
	46	C	Mass	–	–	SCC
Tines et al., 1982 (67)	56	B	Bleeding	–	–	Adenoca
	71	B	Bleeding	–	–	Adenoca
Torres and Quattlebaum, 1972 (68)	53	C	Pain	Dysuria	3	Adenoca
Uesaka et al., 2011 (69)	49	A	Asymptomatic—detected on smear	–	–	Adenoca
von Pechmann et al., 2003 (70)	69	–	UI	Voiding dysfunction	–	Adenoca
Washino et al., 2007 (71)	49	A	Dysuria	Bleeding	–	Adenoca
Weng et al., 2013 (72)	65	A	Bleeding	Frequency	6	Adenoca
Wheeler et al., 1992 (73)	56	C	Bleeding	Dyspareunia	5	Adenoca
	75	C	Bleeding	Urgency	5	Adenoca
Wishard and Nourse, 1952 (74)	39	C	Retention	–	–	TCC
Wishard et al., 1960 (75)	54	C	Bleeding	–	–	Adenoca
Wishard et al., 1963 (76)	43	–	Bleeding	–	–	SCC
Yamigawa et al., 1988 (77)	54	A	Dysuria	–	3	Adenoca
Young et al., 2007 (78)	41	–	Dysuria	UTI	24	SCC
UCLH, 2018	52	B	UTIs	Dysuria	18	Adenoca
	55	B	UTIs	Dysuria	20	Adenoca
	38	Ar	Pain	Dysuria	24	Adenoca

A, Asian; Ar, Arabic; B, Black; C, Caucasian; H, Hispanic; Adenoca, adenocarcinoma.

Methods

We performed a literature search using the keywords; urethral diverticulum, cancer, carcinoma, tumour and malignancy. Databases searched were Medline, EMBASE and the Cochrane library. The data collected included patient demographics, presenting symptoms, diagnostic investigations, treatment modality and outcome at last follow-up in terms of disease free survival, recurrence and mortality. Ethnicity was determined according to the Office of National Statistics recommendations (79). For our own case series, we retrospectively reviewed patient records to glean symptoms at presentation, diagnostic modalities utilised, pathological stage and grade and management. Written informed consents were obtained from the patients for publication of their cases and any accompanying images.

Case presentations

Case 1

A 38-year-old Arabic female presented with an 18-month history of a palpable vaginal lump, dysuria, dyspareunia, urinary dribble, mixed urinary incontinence (UI), urinary tract infections (UTIs) and pain during urination. Per vaginal examination revealed a palpable hard and indurated mass.

Trans urethral (TUR) biopsy performed prior to referral revealed inflammation only. Pre-operative pelvic magnetic resonance imaging (MRI) showed a circumferential complex urethral diverticulum (UD) and videourodynamics (VUDS) indicated the presence of both idiopathic detrusor overactivity (IDO) and bladder outflow obstruction (BOO).

Initial management was excision of the UD with a modified Martius labial fat pad flap (MFP). Histological examination demonstrated a G3 adenocarcinoma of the UD with positive vaginal and proximal margins. She was counseled regarding all treatment and reconstructive options and went on to have a radical cystourethrectomy, pelvic lymph node dissection and ileal conduit formation 4 weeks after preliminary diverticulum excision. Formal histological analysis revealed a pT3N0M0 G3 adenocarcinoma. She remains under surveillance and is alive with a solitary lung recurrence at 72 months post diverticulectomy.

Case 2

A 55-year-old black female presented with a 9-month history of dysuria, urethral pain and poor flow. Clinical examination revealed a palpable non-tender vaginal mass. MRI pelvis showed a circumferential loculated complex UD and VUDS indicated the presence of BOO. Transvaginal biopsy indicated inflammation only.

She proceeded to excision of the UD with MFP interposition. Histological examination revealed pT2 G3 adenocarcinoma of the UD with negative margins. Formal staging with CT chest, abdomen and pelvis and bone scan indicated her to be N0M0. She was counseled regarding all treatment options and declined any further therapy. She died from metastatic adenocarcinoma 22 months following her diverticulectomy.

Case 3

A 52-year-old black female presented with an 8-month history of dysuria, dyspareunia, UTIs and urethral pain. On clinical examination she had a palpable vaginal mass.

She underwent simple excision of her UD at her local hospital and was referred when histological review revealed a pT3 G2 adenocarcinoma with positive urethral margins. Post excision MRI performed at our centre indicated partial excision of a circumferential complex UD. Additional staging with CT chest, abdomen and pelvis and bone scan indicated that she was N0M0. After full counseling regarding treatment options she elected to undergo radical urethrectomy, bladder neck closure with MFP interposition, pelvic lymph node dissection and formation of Mitrofanoff channel. Histological examination of the excised specimen confirmed pT3N0 G2 adenocarcinoma. She remains alive and disease free at 21 months post diverticulectomy.

Epidemiology

Primary urethral carcinoma in females is extremely rare, accounting for only 0.02% of genitourinary tract malignancies (2-6). Squamous cell carcinoma (SCC) predominates, accounting for 70% of urethral carcinoma, followed by urothelial (20%) and then clear cell adenocarcinoma (CCA) (10%) (1,3,78,80,81).

UDC represents just 5% of all female urethral carcinoma or 0.001% of female genitourinary tract malignancies (81,82). Unlike in primary urethral carcinoma, adenocarcinoma is the commonest type of UDC, accounting for 75% of UDC (). Transitional cell carcinoma (TCC) (15%) is the next most common and SCC the least common (10%) (9,16,42,59). The first patient with UDC was reported by Hamilton in 1951 (24), and since then only 124 cases (including the 3 in this current series) have been reported in the world literature.

Table 2

Diverticulum location and diagnostic modalities

Author	Location	Diagnostics	Findings	Histology
Allen and Nelson, 1978 (1)	Proximal; UK	–	–	–
Awakura et al., 2003 (2)	Proximal	Cytology	Malignant cells	Adenoca
		Cystoscopy	Mass in diverticulum
		Urethrogram	Filling defect
		MRI	Urethral mass
		TUR biopsy	Adenoca
		OE	Anterior vaginal wall mass
Bracken et al., 1976 (3)	Proximal	–	–	TCC
Brown et al., 1956 (4)	Distal	–	–	Adenoca
Carneiro Neto et al., 1973 (5)	UK	–	–	UK
Catalano et al., 1992 (6)	UK	–	–	TCC
Cea et al., 1977 (7)	Middle	–	–	Adenoca
	Proximal	–	–	Adenoca
Christofferson, 1974 (8)	UK	–	–	Adenoca
Clayton et al., 1992 (9)	Middle	OE	Anterior vaginal wall mass	SCC
	Middle	Cystoscopy	Tumour in diverticulum	SCC
		OE	Anterior vaginal wall mass
		TUR Biopsy	SCC
	Proximal	OE	Anterior vaginal wall mass	SCC
	Middle	OE	Anterior vaginal wall mass	Adenoca
	Middle	OE	Anterior vaginal wall mass	SCC
	Proximal	OE	Anterior vaginal wall mass	Adenoca
Collado et al., 2000 (10)	UK	USS	Mass in urethra	Adenoca
		Urethrogram	Intravesical cavity
		Cystoscopy	Diverticulum in urethra
		CT	Mass in anterior vaginal wall
		TV Biopsy	Adenoca
		OE	Anterior vaginal wall mass
Cruz-Ruiz et al., 2010 (11)	UK	–	–	Adenoca
Davis et al., 2003 (12)	UK	CT	Mass in urethra	Adenoca
		TV biopsy	SCC
		OE	Anterior vaginal wall mass
Davis et al., 1999 (13)	Distal	–	–	Adenoca
	UK	–	–	Adenoca
Prudente de Toledo et al., 1978 (14)	Proximal	VCUG	Diverticulum	TCC
		IVU	NAD
		OE	Anterior vaginal wall mass
		TUR biopsy	TCC
Dodson et al., 1995 (15)	UK	–	–	Adenoca
Evans et al., 1981 (16)	Middle	–	–	Adenoca
Faulkner et al., 1959 (17)	Distal	–	–	TCC
Geisler et al., 1998 (18)	Posterior	–	–	Adenoca
Ghoniem et al., 2004 (19)	UK	MRI	Mass in urethra	Adenoca
		OE	Anterior vaginal wall mass
		TV Biopsy	Adenoca
Godec et al., 1984 (20)	Middle	–	–	Adenoca
Gonzalez et al., 1985 (21)	Anterior	–	–	Adenoca
	Middle	–	–	Adenoca
	Distal	–	–	Adenoca
	Distal	–	–	TCC
	Distal	Cystoscopy	Mass in diverticulum	TCC
		TUR biopsy	TCC
	Distal	–	–	SCC
	Middle	–	–	SCC
Graf et al., 1962 (22)	Middle	–	–	TCC
Ha et al., 2010 (23)	UK	Cystoscopy	Mass in diverticulum	Adenoca
		Urethrogram	Urethral stricture
		MRI	Urethral mass
		OE	Anterior vaginal wall mass
Hamilton et al., 1951 (24)	Posterior	–	–	Adenoca
Hickey et al., 2000 (25)	Posterolateral	Cytology	Malignant cells	Adenoca
		Cystoscopy	Mass in diverticulum
		USS	Mass in diverticulum
		OE	Anterior vaginal wall mass
		TV biopsy	Adenoca
Hinman et al., 1960 (26)	Middle	–	–	Adenoca
	Middle	–	–	TCC
Hruby et al., 2000 (27)	UK	–	–	Adenoca
	UK	–	–	Adenoca
Huvos et al., 1969 (28)	Proximal	OE	Anterior vaginal wall mass	SCC
Jensen et al., 1981 (29)	UK	–	–	Adenoca
	UK	–	–	Adenoca
Jimenez de León et al., 1989 (30)	UK	OE	Anterior vaginal wall mass	Adenoca
		TUR biopsy	Adenoca
Kanno et al., 2002 (31)	UK	MRI	Urethral mass	Adenoca
		CT	Urethral mass
		OE	Anterior vaginal wall mass
		TV biopsy	Adenoca
Kasahara et al., 2017 (32)	Proximal	MRI	Urethral mass	Adenoca
		OE	Anterior vaginal wall mass
		TV biopsy	Adenoca
Kato et al., 1998 (33)	UK	Cytology	Malignant cells	Adenoca
		Cystoscopy	Mass in diverticulum
		MRI	Mass in diverticulum
		OE	Anterior vaginal wall mass
		TUR biopsy	Adnoca
Klotz et al., 1974 (34)	Middle	–	–	Adenoca
Lang et al., 2008 (35)	UK	MRI	Mass in diverticulum	Adenoca
		OE	Anterior vaginal wall mass
Manning et al., 2012 (36)	UK	Cytology	NAD	TCC
		MRI	Diverticulum
		OE	Anterior vaginal wall mass
Murayama et al., 1978 (37)	Posterior	–	–	Adenoca
Marshall et al., 1977 (38)	Middle	–	–	Adenoca
	Middle	–	–	TCC
McLoughlin, 1975 (39)	Middle	–	–	TCC
Melnick and Birdsall, 1960 (40)	Proximal	–	–	TCC
Nakamura et al., 1995 (41)	UK	–	–	Adenoca
Nakatsuka et al., 2012 (42)	UK	Cytology	Adenoca	Adenoca
		MRI	Mass entire urethra
		Cystoscopy	Mass in diverticulum
		CT	Mass entire urethra
		TUR biopsy	Adenoca
Ney et al., 1971 (43)	Proximal	–	–	Adenoca
Noguchi and Ida, 1983 (44)	UK	OE	Anterior vaginal wall mass	Adenoca
Okubo et al., 1996 (45)	Proximal	Cytology	Malignant cells	Adenoca
		Cystoscopy	Mass in diverticulum
		OE	Anterior vaginal wall mass
		TUR biopsy	Adenoca
Oliva and Young, 1996 (46)	UK	–	–	Adenoca
	UK	–	–	Adenoca
	UK	–	–	Adenoca
	UK	–	–	Adenoca
	UK	–	–	Adenoca
	UK	–	–	Adenoca
	UK	–	–	Adenoca
	UK	–	–	Adenoca
	UK	–	–	Adenoca
	UK	–	–	Adenoca
	UK	–	–	Adenoca
	UK	–	–	Adenoca
Patanephan et al., 1983 (47)	UK	–	–	Adenoca
	UK	–	–	Adenoca
Rajan et al., 1993 (48)	Proximal	OE	Anterior vaginal wall mass	Adenoca
	Proximal	OE	Anterior vaginal wall mass	Adenoca
	Proximal	OE	Anterior vaginal wall mass	Adenoca
	UK	OE	Anterior vaginal wall mass	Adenoca
Reheis et al., 1981 (49)	Proximal	–	–	Adenoca
Rhamy et al., 1973 (50)	UK	–	–	TCC
	Proximal	–	–	Adenoca
Rosenfeld and Frachtman, 1964 (51)	Proximal	Urethrogram	Diverticulum	TCC
		OE	Anterior vaginal wall mass
Roth, 1955 (52)	Proximal	–	–	TCC
Salvador Álvarez et al., 2011 (53)	UK	MRI	Cystic mass between vagina and urethra	Adenoca
		PET-CT	High metabolic rate
		Cystoscopy	Mass in urethra
		OE	Anterior vaginal wall mass
		TUR biopsy	Adenoca
Scantling et al., 2013 (54)	UK	Cystoscopy	Mass in diverticulum	Adenoca
		MRI	Mass in diverticulum with enlarged LN
		CT	As per MRI
		Bone scan	NAD
		OE	Anterior vaginal wall mass
Schileru et al., 1984 (55)	UK	–	–	Adenoca
Schnoy and Leistenschneider, 1982 (56)	Proximal	–	–	Adenoca
Seballos and Rich, 1995 (57)	UK	Cystoscopy	Diverticulum	Adenoca
		Urethrogram	Diverticulum
		OE	Anterior vaginal wall mass
Sekowska and Golajewski, 1961 (58)	UK	–	–	Adenoca
Shalev et al., 2002 (59)	UK	Urinalysis	Microhaematuria	SCC
		IVU	Diverticulum
		OE	Anterior vaginal wall mass
Sheahan and Vega Vega, 2013 (60)	UK	USS	Mass in urethra	Adenoca
		MRI	Mass in urethral diverticulum
		Cytology	Malignant cells
		Cystoscopy	Mass in diverticulum
		OE	Anterior vaginal wall mass
		TUR biopsy	Adenoca
		TV biopsy	Adenoca
Srinivas and Dow, 1983 (61)	Middle	–	–	TCC
Tanabe et al., 1982 (62)	Proximal	–	–	Adenoca
Tesluk, 1981 (63)	Proximal	–	–	Adenoca
	Proximal	–	–	Adenoca
	Proximal	–	–	Adenoca
Thomas and McGuire, 1991 (64)	UK	–	–	Adenoca
Thomas et al., 2008 (65)	UK	–	–	Adenoca
	UK	–	–	Adenoca
	UK	–	–	Adenoca
	UK	–	–	Adenoca
	UK	–	–	Adenoca
Thompson and Bivings, 1962 (66)	UK	–	–	TCC
	UK	–	–	SCC
Tines et al., 1982 (67)	Middle	–	–	Adenoca
	Middle	–	–	Adenoca
Torres and Quattlebaum, 1972 (68)	Middle	Cystoscopy; urethrogram	Diverticulum	Adenoca
Uesaka et al., 2011 (69)	Proximal	PET-CT	Proximal urethral uptake	Adenoca
		Cystoscopy	Mass in diverticulum
		MRI	Mass in diverticulum
		OE	Anterior vaginal wall mass
		TUR Biopsy	Adenoca
von Pechmann et al., 2003 (70)	Middle	Urinalysis	Microscopic haematuria	Adenoca
		Cystoscopy	Diverticulum
		Urethrogram	Urethral stricture
		OE	Anterior vaginal wall mass
		TUR biopsy	Adenoca
Washino et al., 2007 (71)	UK	Cytology	Malignant cells	Adenoca
		MRI	Mass in diverticulum
		Cystoscopy	Mass in diverticulum
		CT	Mass in diverticulum
		OE	Anterior vaginal wall mass
		TUR biopsy	Adenoca
Weng et al., 2013 (72)	UK	Cystoscopy	Mass in diverticulum	Adenoca
		IVU	NAD
		MRI	Mass anterior to vagina
		TUR biopsy	Adenoca
Wheeler et al., 1992 (73)	Proximal	Urinalysis	Microscopic haematuria	Adenoca
		IVU	Filling defect bladder base
		Urethrogram	Mass in diverticulum
		Cystoscopy	NAD
		OE	Anterior vaginal wall mass
		TV biopsy	No malignancy
	Posterior	Urinalysis	Microscopic haematuria	Adenoca
		IVU	Elevated bladder base
		Cystoscopy	Diverticulum
		TUR biopsy	Mass in urethra
			Adenoca
Wishard and Nourse, 1952 (74)	Proximal	–	–	TCC
Wishard et al., 1960 (75)	Distal	–	–	Adenoca
Wishard et al., 1963 (76)	Proximal	–	–	SCC
Yamigawa et al., 1988 (77)	Proximal	IVU	Elevated bladder	Adenoca
		Cystoscopy	Mass in diverticulum
		OE	Anterior vaginal wall mass
		TUR biopsy	Adenoca
Young et al., 2007 (78)	Anterior	VCUG	Diverticulum	SCC
		Cystoscopy	Mass in diverticulum
		OE	Anterior vaginal wall mass
UCLH, 2018	Proximal	Urinalysis	Microhaematuria	Adenoca
		OE	Anterior vaginal wall mass
	Proximal	MRI	Suspicious diverticulum	Adenoca
		Cystoscopy	Diverticulum
		OE	Anterior vaginal wall mass
		TV biopsy	Negative
	Proximal	MRI	Suspicious diverticulum	Adenoca
		Cystoscopy	Diverticulum
		OE	Anterior vaginal wall mass
		TUR biopsy	Negative

UK, unknown; TUR, transurethral resection; OE, on examination; TV, transvaginal; VCUG, voiding cystourethrogram; IVU, intravenous urogram; NAD, no abnormality detected.

Table 3

Stage and grade of female urethral diverticulum carcinoma

Author	Histology	Stage	Grade
Allen and Nelson, 1978 (1)	Adenoca	T1	–
	Adenoca	T1	–
Awakura et al., 2003 (2)	Adenoca	T3N0M0	–
Bracken et al., 1976 (3)	TCC	T1	–
Brown et al., 1956 (4)	Adenoca	T2	–
Carneiro Neto et al., 1973 (5)	UK	–	–
Catalano et al., 1992 (6)	TCC	–	–
Cea et al., 1977 (7)	Adenoca	T3N0MO	–
	Adenoca	T2N0MO	–
Christofferson, 1974 (8)	Adenoca	–	–
Clayton et al., 1992 (9)	SCC	T2	–
	SCC	T3	–
	SCC	T4N+M0	G3
	Adenoca	T3	–
	SCC	T3	–
	Adenoca	T3	–
Collado et al., 2000 (10)	Adenoca	T2N0MO	–
Cruz-Ruiz et al., 2010 (11)	Adenoca	–	–
Davis et al., 2003 (12)	Adenoca	T2N1M0	–
Davis et al., 1999 (13)	Adenoca; Adenoca	–	–
Prudente de Toledo et al., 1978 (14)	TCC	T4	–
Dodson et al., 1995 (15)	Adenoca	–	–
Evans et al., 1981 (16)	Adenoca	T2	–
Faulkner et al., 1959 (17)	TCC	T2	G1
Geisler et al., 1998 (18)	Adenoca	–	–
Ghoniem et al., 2004 (19)	Adenoca	–	–
Godec et al., 1984 (20)	Adenoca	T3N0M0	G2
Gonzalez et al., 1985 (21)	Adenoca	–	G1
	Adenoca	–	G1
	Adenoca	–	G3
	TCC	–	G3
	TCC	–	G3
	SCC	–	G1
	SCC	–	G3
Graf et al., 1962 (22)	TCC	T1	G2
Ha et al., 2010 (23)	Adenoca	T3N0M0	–
Hamilton et al., 1951 (24)	Adenoca	–	–
Hickey et al., 2000 (25)	Adenoca	–	–
Hinman et al., 1960 (26)	Adenoca	–	–
	TCC	–	G3
Hruby et al., 2000 (27)	Adenoca	–	–
	Adenoca	–	–
Huvos et al., 1969 (28)	SCC	T3N+	G1
Jensen et al., 1981 (29)	Adenoca	–	–
	Adenoca	–	–
Jimenez de León et al., 1989 (30)	Adenoca	–	–
Kanno et al., 2002 (31)	Adenoca	–	–
Kasahara et al., 2017 (32)	Adenoca	T4N2	–
Kato et al., 1998 (33)	Adenoca	–	–
Klotz et al., 1974 (34)	Adenoca	T3	G3
Lang et al., 2008 (35)	Adenoca	T3	–
Manning et al., 2012 (36)	TCC	Tis	G3
Murayama et al., 1978 (37)	Adenoca	T3N0M0	–
Marshall et al., 1977 (38)	Adenoca	T2	G1
	TCC	T1	–
McLoughlin, 1975 (39)	TCC	–	–
Melnick and Birdsall, 1960 (40)	TCC	–	–
Nakamura et al., 1995 (41)	Adenoca	–	–
Nakatsuka et al., 2012 (42)	Adenoca	–	–
Ney et al., 1971 (43)	Adenoca	–	–
Noguchi and Ida, 1983 (44)	Adenoca	–	–
Okubo et al., 1996 (45)	Adenoca	–	–
Oliva and Young, 1996 (46)	Adenoca	–	–
	Adenoca	–	–
	Adenoca	–	–
	Adenoca	–	–
	Adenoca	–	–
	Adenoca	–	–
	Adenoca	–	–
	Adenoca	–	–
	Adenoca	–	–
	Adenoca	–	–
	Adenoca	–	–
	Adenoca	–	–
Patanephan et al., 1983 (47)	Adenoca	–	–
	Adenoca	–	–
Rajan et al., 1993 (48)	Adenoca	–	–
	Adenoca	–	–
	Adenoca	–	–
	Adenoca	–	–
Reheis et al., 1981 (49)	Adenoca	T3	G1
Rhamy et al., 1973 (50)	TCC	–	–
	Adenoca	–	–
Rosenfeld and Frachtman, 1964 (51)	TCC	T2	–
Roth, 1955 (52)	TCC	–	–
Salvador Álvarez et al., 2011 (53)	Adenoca	–	–
Scantling et al., 2013 (54)	Adenoca	T3N0M0	G2
Schileru et al., 1984 (55)	Adenoca	–	–
Schnoy and Leistenschneider, 1982 (56)	Adenoca	T2	–
Seballos and Rich, 1995 (57)	Adenoca	–	–
Sekowska and Golajewski, 1961 (58)	Adenoca	–	–
Shalev et al., 2002 (59)	SCC	–	–
Sheahan and Vega Vega, 2013 (60)	Adenoca	T2N1M0	G2
Srinivas and Dow, 1983 (61)	TCC	T3	G3
Tanabe et al., 1982 (62)	Adenoca	T3N0M0	G3
Tesluk, 1981 (63)	Adenoca	T3	G3
	Adenoca	T3	G3
	Adenoca	T3	G3
Thomas and McGuire, 1991 (64)	Adenoca	–	–
Thomas et al., 2008 (65)	Adenoca	–	–
	Adenoca	–	–
	Adenoca	–	–
	Adenoca	–	–
	Adenoca	–	–
Thompson and Bivings, 1962 (66)	TCC	T2	–
	SCC	T3N0M+	–
Tines et al.,1982 (67)	Adenoca	–	–
	Adenoca	–	–
Torres and Quattlebaum, 1972 (68)	Adenoca	T3N0M0	–
Uesaka et al., 2011 (69)	Adenoca	T2	–
von Pechmann et al., 2003 (70)	Adenoca	T3N2M0	–
Washino et al., 2007 (71)	Adenoca	T3	–
Weng et al., 2013 (72)	Adenoca	T4N0M0	G3
Wheeler et al., 1992 (73)	Adenoca	–	–
	Adenoca	–	–
Wishard and Nourse, 1952 (74)	TCC	T2	G1
Wishard et al., 1960 (75)	Adenoca	T2	G1
Wishard et al., 1963 (76)	SCC	T3	G3
Yamigawa et al., 1988 (77)	Adenoca	–	–
Young et al., 2007 (78)	SCC	CIS	–
UCLH, 2018	Adenoca	T3N0M0	G2
	Adenoca	T3N0M0	G3
	Adenoca	T3NOM0	G3

TCC, transitional cell carcinoma; SCC, squamous cell carcinoma; Adenoca, adenocarcinoma; UK, unknown; CIS, carcinoma in situ.

Table 4

Treatment modalities and survival patterns iTn urethral diverticulum carcinoma

Author	Primary treatment	Survival in months	Outcome at last review	Histology
Allen and Nelson, 1978 (1)	Radiotherapy	48	Alive and well	Adenoca
	Radiotherapy	24	Alive and well	Adenoca
Awakura et al., 2003 (2)	Chemotherapy + radiotherapy	24	Alive and well	Adenoca
Bracken et al., 1976 (3)	Radiotherapy	30	Died	TCC
Brown et al., 1956 (4)	Excision	30	Alive and well	Adenoca
Carneiro Neto et al., 1973 (5)	UK	–	–	UK
Catalano et al., 1992 (6)	UK	–	–	TCC
Catalano et al., 1992 (7)	Excision + cystourethrectomy 12 m	24	Alive with recurrence	Adenoca
	Cystectomy	12	Alive and well	Adenoca
Christofferson, 1974 (8)	UK	–	–	Adenoca
Clayton et al., 1992 (9)	Excision	36	Died	SCC
	Radiotherapy	30	Died	SCC
	Excision	24	Died	SCC
	Excision + radiotherapy	12	Alive and well	Adenoca
	Excision + radiotherapy	12	Died	SCC
	Excision	18	Died	Adenoca
Collado et al., 2000 (10)	Cysto-urethrectomy + ileal conduit	16	Alive and well	Adenoca
Cruz-Ruiz et al., 2010 (11)	UK	–	–	Adenoca
Davis et al., 2003 (12)	Chemotherapy + radiotherapy + anterior exenteration + gracilis flap	10	Alive and well	Adenoca
Davis et al., 1999 (13)	Excision	–	–	Adenoca
	Excision + vaginal wall reconstruction	39	Alive and well	Adenoca
Prudente de Toledo et al., 1978 (14)	Chemotherapy + radiotherapy + cysto-urethrectomy + ureterosigmoidostomy	30	Alive and well	TCC
Dodson et al., 1995 (15)	UK	–	–	Adenoca
Evans et al., 1981 (16)	Excision	–	–	Adenoca
Faulkner et al., 1959 (17)	Radiotherapy	12	Alive and well	TCC
Geisler et al., 1998 (18)	Cystourethrectomy	3	Died	Adenoca
Ghoniem et al., 2004 (19)	Anterior exenteration + Florida pouch	12	Alive and well	Adenoca
Godec et al., 1984 (20)	Cystourethrectomy	12	Alive and well	Adenoca
Gonzalez et al., 1985 (21)	Radiotherapy	60	Alive and well	Adenoca
	Radiotherapy	120	Alive and well	Adenoca
	Excision	12	Died	Adenoca
	Radiotherapy	30	Died	TCC
	Radiotherapy	12	Alive and well	TCC
	Radiotherapy	120	Alive and well	SCC
	Radiotherapy	12	Died	SCC
Graf et al., 1962 (22)	Excision	12	Alive and well	TCC
Ha et al., 2010 (23)	Laparoscopic anterior exenteration	6	Alive and well	Adenoca
Hamilton et al., 1951 (24)	Excision	18	Alive with recurrence	Adenoca
Hickey et al., 2000 (25)	Excision and radiotherapy	18	Alive and well	Adenoca
Hinman et al., 1960 (26)	Excision	48	Alive and well	Adenoca
	Excision	72	Alive and well	TCC
Hruby et al., 2000 (27)	Excision + radiotherapy	–	–	Adenoca
				Adenoca
Huvos et al., 1969 (28)	Radiotherapy	12	Died	SCC
Jensen et al., 1981 (29)	–	–	–	Adenoca
				Adenoca
Jimenez de León et al., 1989 (30)	Radical urethrectomy + pelvic and inguinal LN dissection + urethral reconstruction	–	–	Adenoca
Kanno et al., 2002 (31)	Urethrectomy + TAH + BSO + anterior vaginal wall excision	8	Alive and well	Adenoca
Kasahara et al., 2017 (32)	Anterior exenteration + pelvic LN dissection + chemotherapy	5	Alive and well	Adenoca
Kato et al., 1998 (33)	Anterior exenteration+ continent diversion	12	Alive and well	Adenoca
Klotz et al., 1974 (34)	Cystourethrectomy	–	–	Adenoca
Lang et al., 2008 (35)	Excision + radiotherapy	18	Alive and well	Adenoca
Manning et al., 2012 (36)	Excision	–	–	TCC
Murayama et al., 1978 (37)	Cystectomy	–	–	Adenoca
Marshall et al., 1977 (38)	Excision	60	Alive and well	Adenoca
	Excision	12	Alive and well	TCC
McLoughlin, 1975 (39)	Excision	12	Alive and well	TCC
Melnick, Birdsall, 1960 (40)	Radiotherapy	–	–	TCC
Nakamura et al., 1995 (41)	Excision	–	–	Adenoca
Nakatsuka et al., 2012 (42)	Cystourethrectomy + partial resection of vaginal wall	–	–	Adenoca
Ney et al., 1971 (43)	Radiotherapy	24	Alive and well	Adenoca
Noguchi and Ida, 1983 (44)	Excision	9	Alive and well	Adenoca
Okubo et al., 1996 (45)	Anterior exenteration + pelvic LN dissection + Indiana pouch + radiotherapy	16	Alive and well	Adenoca
Oliva and Young, 1996 (46)	–	–	–	Adenoca
				Adenoca
				Adenoca
				Adenoca
				Adenoca
				Adenoca
				Adenoca
				Adenoca
				Adenoca
				Adenoca
				Adenoca
				Adenoca
Patanephan et al., 1983 (47)	–	–	–	Adenoca
				Adenoca
Rajan et al., 1993 (48)	Radiotherapy + chemotherapy	12	Died	Adenoca
	Cystourethrectomy	29	Alive and well	Adenoca
	Cystourethrectomy	44	Alive and well	Adenoca
	–	–	–	Adenoca
Reheis et al., 1981 (49)	Cystourethrectomy	12	Alive and well	Adenoca
Rhamy et al., 1973 (50)	Radiotherapy	72	Alive and well	TCC
	Radiotherapy	12	Alive and well	Adenoca
Rosenfeld and Frachtman, 1964 (51)	Excision	12	Died	TCC
Roth, 1955 (52)	Excision	24	Alive and well	TCC
Salvador Álvarez et al., 2011 (53)	Anterior exenteration	–	–	Adenoca
Scantling et al., 2013 (54)	Robotic anterior exenteration + Indiana pouch	12	Alive and well	Adenoca
Schileru et al., 1984 (55)	–	–	–	Adenoca
Schnoy and Leistenschneider 1982 (56)	Cystourethrectomy	24	Alive and well	Adenoca
Seballos and Rich, 1995 (57)	Excision	–	–	Adenoca
Sekowska and Golajewski, 1961 (58)	–	–	–	Adenoca
Shalev et al., 2002 (59)	Excision	6	Alive with recurrence	SCC
Sheahan and Vega Vega, 2013 (60)	Anterior exenteration + pelvic LN dissection + ileal conduit	12	Alive with recurrence	Adenoca
Srinivas and Dow, 1983 (61)	Radiotherapy + cystourethrectomy	4	Alive and well	TCC
Tanabe et al., 1982 (62)	Radiotherapy	30	Alive and well	Adenoca
Tesluk, 1981 (63)	Cystourethrectomy	36	Died	Adenoca
	Cystourethrectomy	–	–	Adenoca
	Cystourethrectomy	12	Alive and well	Adenoca
Thomas and McGuire, 1991 (64)	–	–	–	Adenoca
Thomas et al., 2008 (65)	Anterior exenteration + ileal conduit	36	Died	Adenoca
	Anterior exenteration + ileal conduit	11	Died	Adenoca
	Anterior exenteration + ileal conduit	–	–	Adenoca
	Anterior exenteration + ileal conduit	–	–	Adenoca
	Anterior exenteration + ileal conduit	–	–	Adenoca
Thompson and Bivings, 1962 (66)	Excision	12	Died	TCC
	Radiotherapy	12	Died	SCC
Tines et al., 1982 (67)	Cystourethrectomy	–	–	Adenoca
	Radiotherapy	–	–	Adenoca
Torres and Quattlebaum, 1972 (68)	Anterior pelvic exenteration with ureterosigmoidostomy and adjuvant radiotherapy	–	Alive and well	Adenoca
Uesaka et al., 2011 (69)	Urethrectomy + cutaneous vesicostomy	5	Alive and well	Adenoca
von Pechmann et al., 2003 (70)	Cystourethrectomy + vaginectomy + partial vulvectomy + TAH + pelvic LN dissection +ileal conduit	3	Alive with recurrence	Adenoca
Washino et al., 2007 (71)	Excision	6	Alive with recurrence	Adenoca
Weng et al., 2013 (72)	Urethrectomy + anterior exenteration + ileal conduit	24	Alive and well	Adenoca
Wheeler et al., 1992 (73)	Excision + radical cystourethrectomy	30	Alive and well	Adenoca
	Anterior exenteration + pelvic LN dissection	24	Alive and well	Adenoca
Wishard and Noursem 1952 (74)	Excision	96	Alive and well	TCC
Wishard et al., 1960 (75)	Excision	12	Alive and well	Adenoca
Wishard et al., 1963 (76)	Excision	24	Died	SCC
Yamigawa et al., 1988 (77)	Cystourethrectomy + pelvic LN dissection + ileal conduit	17	Alive and well	Adenoca
Young et al., 2007 (78)	Excision	24	Alive and well	SCC
UCLH, 2018	Excision + urethrectomy + bladder neck closure + Mitrofanoff	21	Alive and well	Adenoca
	Excision	22	Died	Adenoca
	Excision + anterior exenteration + ileal conduit	72	Alive with recurrence	Adenoca

TCC, transitional cell carcinoma; SCC, squamous cell carcinoma; Adenoca, adenocarcinoma; UK, unknown; LN, lymph node; TAH, total abdominal hysterectomy.

Female urethral diverticula are in themselves rare entities—affecting between 0.02–6% of the female population (83,84). First described in 1805, they are benign, localized, epithelium-lined urethral outpouchings (85,86). Histologically, they are difficult to distinguish from paraurethral cysts. Their lining is composed of squamous epithelial cells in 42%, columnar epithelial cells in 32%, a combination of both squamous and columnar cells in 18% and cuboidal cells alone in 14% (87). The majority of diverticula (77%) show signs of inflammation, and ulceration is often present (87).

Rarely, diverticula are congenital, arising from embryonic Gartner duct remnants, persistence of Müllerian rest cells or the faulty union of primordial folds (88). The majority of diverticula are acquired; arising from rupture of chronically obstructed and infected periurethral glands into the lumen of the urethra (89,90). Risk factors for the development of urethral diverticula are: recurrent infection of the periurethral glands, vaginal birth trauma and previous vaginal or urethral surgery (91-95).

Pathogenesis

There are 3 theories regarding the origin of UDC (15,81,94). The first is that they arise from periurethral gland changes occurring due to persistent/continued infection and obstruction to drainage (20,21,61). The second theory suggests a metaplastic origin with neoplastic squamous, glandular or TCC development resulting from chronic inflammation and urethritis glandularis (65). The final theory is that the malignant change originates in retained Gartner or mesonephric duct remnants (78,96).

Many UDC are considered to originate from the paraurethral duct, which may be homologous to the prostate gland because it is prostate-specific antigen (PSA) positive in some cases (33,42,97). Ogihara and Kato suggested that the adenocarcinomas that arise from urethral diverticula are either CEA-positive columnar and/or mucin-producing and originate from the proximal portion of the paraurethral duct, or are PSA positive clear cell-type arising from the distal part of the paraurethral duct (96).

Occasionally premalignant lesions such as villous adenomas, intestinal metaplasia and high-grade dysplasia may arise (9,65). There are very occasional instances of benign tumour, such as leiomyoma and nephrogenic adenoma (9,65).

Age and race

The median age at presentation of UDC is 53 years (range, 14–81 years). There may be a higher incidence in the black population, possibly related to the higher incidence of UD amongst black women (9,21) although this is disputed (25). Our latest review of the literature indicates that 38% of cases are in white women, 32% in black women, 22% in Asian women and 8% in Hispanic women (N=65). In our series of 100 women having UD excision 82% with benign UD were white whilst UDC was found in 2 black and 1 Asian female suggesting a preponderance of UDC in black and Asian women. The median age of presentation of women with benign diverticulum also tended to be younger than those with UDC at 44 years (N=97). This contrasts with a median age at diagnosis of 53 in those with UDC (N=3) (98).

Presentation

There are no pathognomonic signs and symptoms of UDC. As can be seen in UDC may present with signs and symptoms of UD—classically dysuria (13%), dyspareunia (7%) and/or post micturition dribble/UI (3%). UDC more commonly presents with urethral bleeding or hematuria in 55%, urethral obstruction/voiding dysfunction in 16%, urethral/introital mass in 13%, UTIs in 13% and localized pain in 6% (N=89). A painless mass of the anterior vaginal wall can be found on examination in the majority of patients (1,9,16,80,81,90,96). This mass may feel much like a benign diverticulum but is noted to be firm or hard in some cases.

Preoperative diagnosis of UDC remains difficult because of its nonspecific presentation. The differential diagnosis of a peri-urethral mass in women includes; UD, urethrocele and/or cystocele, vaginal inclusion cyst, Müllerian cyst, endometriosis, and urethral or vaginal carcinoma. (33,61,81,88,97).

Diagnosis

Diagnostic modalities used in the diagnosis and pre-operative planning of UDC are outlined in . Urine cytology may be a useful initial screening test and has been reported to be positive in 10/11 (91%) cases in which it was utilised (2,25,31,36,41,42,45,60,69,71,77,96,98). Imaging modalities that have been used to aid the diagnosis of UDC include ultrasound, intravenous urography, voiding cystourethrography, computed tomography (CT), MRI, and cystourethroscopy (2,9,25,31,36,41,45,60,69,71,77,80,96,98,99). The gold standard investigations to date appear to be a combination of gadolinium-enhanced MRI which can be used for diagnosis, staging and surveillance followed by transvaginal trucut or transurethral biopsies of the UD mass for definitive diagnosis. Case 2 above describes a 55-year-old lady with UD diagnosed on an initial MRI () with a follow up contrast enhanced study 2 months later (). The differential diagnosis of increasing debris or thickening within the diverticulum includes infection and inflammatory change within the UD and biopsies may yield no evidence of malignancy as in 2/3 of our UDC cases. Cystoscopy was unhelpful in our cases but may play an important role in the pathological diagnosis and in localization of the tumor origin (1) with neoplasm in the diverticulum or urethra noted on cystoscopy in 23/29 (79%) cases in those series reporting its use (7,9,10,12,21,23,31,42,53,54,57,72,73,77,96,98,100).

Figure 1

MRI at presentation. Axial (A) and sagittal (B) fast spin-echo T2-weighted sequence show a large fluid filled urethral diverticulum (*) displacing the urethra (U) anteriorly. Heterogeneous low T2 signal in the anterior portion (arrows).

Figures 2

MRI study performed 2 months later. Axial (A) and sagittal (B) fast spin-echo T2-weighted sequences show the posterior fluid component (*) has reduced in size and now contains a fluid level (arrowhead) due to debris. The anterior intermediate signal (arrows) has significantly increased in size and displaces the urethra (U) posteriorly; (C,D) axial T1 spin-echo fast suppressed pre- (C) and post- (D) contrast sequences. The solid anterior component (arrows) is isointense on the pre-contrast sequence and shows heterogeneous enhancement on the post-contrast studies, confirming this is a solid tumour rather than simple debris.

A CT or an isotope bone scan may be used to assess for lymph node enlargement, distant tissue and bone metastasis (80). In our experience a T2 weighted thin slice post void pelvic MRI should be performed to diagnose the presence of a UD and if history, examination or MRI are suspicious for cancer an urgent urethral diverticulectomy should be performed as a definitive “excision biopsy”.

Pathology

Macroscopically

There is usually a mass within the diverticulum, which may be encroaching into the true urethral lumen or invading past the diverticulum walls into the surrounding paraurethral or paravaginal tissues (80).

Microscopically

Whilst only 10% of urethral cancers are adenocarcinoma, 30% of these originate from UD (1,3,78,80,81). Adenocarcinoma has two subtypes; clear cell and mucin producing (33). The microscopic features of the CCA are similar to those of other CCA of the female genital tract and include; cells with abundant clear cytoplasm, some forms of pleomorphism, mitotic activity and a mostly flat shape. Focally, a hobnail appearance may be present. CCA of a UD may present patterns that are either tubule-cystic, papillary or diffuse (78). In a urine sample, the presence of malignant clear cells with the appearance of mirror balls is highly suggestive for CCA arising from UD (9,16,42).

TCC accounts for around 15% of UDC and is histologically the same as that originating in the bladder although with a tendency to be of a higher stage at diagnosis due to the absence of a muscle layer within a UD. SCC is the least common form of UDC. SCC may be associated with the presence of calculus in a UD; Clayton found this to be the case in 56% (9).

Staging

Staging of UDC is very difficult because of the location of the periurethral glands inside the periurethral space abutting the paravaginal fascia. The TNM staging system has been used in some cases (83). Most cancers are at an advanced stage at diagnosis because there is little muscle underlying them; 83% of UDC were T2 and above at time of presentation in the 54 patients in whom the stage was known at diagnosis () (9,16,99). They also tend to be high grade with 73% grade 2 or 3 at presentation (N=40) (9,16,99).

Treatment

The mainstay of treatment is surgical with the options including:

Urethral diverticulectomy alone or with adjuvant radiotherapy or chemotherapy (9,36,100);

Urethrectomy +/− pelvic or inguinal lymph node dissection +/− adjuvant therapy (31,81);

Anterior exenteration (excision of the urethra, bladder, anterior vaginal wall, uterus and pelvic lymph nodes) +/− inguinal lymph node dissection +/− adjuvant therapy (12,13,31,45,68);

Radiotherapy +/− adjuvant chemotherapy alone (1,3,9).

The results from the various treatment options are summarized in . Accepting the limited (generally < 2 years) length of follow-up in most series, simple urethral diverticulectomy appears to be curative in 55% of the 22 patients who underwent same in which follow up was specified with a further 14% alive with recurrence at a mean of 26 months follow-up (4,9,16,21,22,24,26,36,38,39,41,44,51,52,57,59,66,71,74-76,78). Urethrectomy appears to be curative in 100% at a mean of 13 months follow up (N=3) (30,31,69).

Occasionally cisplatinum-based chemotherapy alone and chemoradiotherapy has been used, without formal documentation of its effectiveness (3,80). Other chemotherapeutic agents utilized include 5-fluorouracil and leucovorin.

Prognosis

Patients with adenocarcinoma and TCC of a UD fare better than those with SCC. The % of patients alive with no evidence of disease (NED) at last follow-up is:

72% for those with adenocarcinoma (median 48 months) (N=54);

78% for those with TCC (median 18 months) (N=18);

25% for those with SCC (median 48 months) (N=12).

Conclusions

UDC is an extremely rare condition and presents a serious situation due to non-specific presentation and delayed diagnosis. UDC needs aggressive treatment as survival is at best moderate and is particularly poor for those with SCC. Optimal treatment remains to be determined but appears to be radical surgery. Consideration should be given to adjuvant radiotherapy +/− chemotherapy in patients with SCC or high-grade adenocarcinoma or TCC. An international registry and consensus on treatment would greatly aid the management of this problematic condition.