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Urethral caruncle: clinicopathologic features of 41 cases
Human Pathology (2012) 43, 1400–1404
www.elsevier.com/locate/humpath
Original contribution
Urethral caruncle: clinicopathologic features of 41 cases Miriam R. Conces MD a,1 , Sean R. Williamson MD a,1 , Rodolfo Montironi MD b , Antonio Lopez-Beltran MD c , Marina Scarpelli MD b , Liang Cheng MD a,d,⁎ a
Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA Department of Pathological Anatomy and Histopathology, School of Medicine, Polytechnic University of the Marche Region (Ancona), Ancona 60126, Italy c Department of Pathology, Cordoba University, Cordoba E-14004, Spain d Department of Urology, Indiana University School of Medicine, Indianapolis, IN 46202, USA b
Received 7 September 2011; revised 12 October 2011; accepted 14 October 2011
Keywords: Urinary bladder; Urinary tract; Urethra; Caruncle; Urethral polyp
Summary Urethral caruncle is a benign polypoid mass of the urethral meatus in primarily postmenopausal women. Although a conclusive association with malignancy, urologic disorder, or systemic disease has not been established, often the lesion carries a challenging clinical differential diagnosis that includes malignancy. Conversely, unexpected malignancy is identified in some cases resembling caruncle clinically. We examined clinical and histopathologic characteristics in 41 patients. Medical records were assessed for presentation, clinical diagnosis, associated urothelial carcinoma, radiation treatment, tobacco use, immunologic/urologic disorder, and treatment strategy/outcome. Average patient age was 68 years (range, 28-87 years). Presenting symptoms were pain (37%), hematuria (27%), and dysuria (20%), in contrast to asymptomatic (32%). Clinical diagnosis favored malignancy in 10% of cases. Concurrent or subsequent urothelial carcinoma was present for 5 patients (12%), although none developed urethral carcinoma. Histologic features included mixed hyperplastic urothelial and squamous lining, overlying a variably fibrotic, edematous, inflamed, and vascular stroma. Invaginations of urothelium extending into the stroma were common (68%), showing rounded nests with cystic or glandular luminal spaces, similar to urethritis cystica/glandularis, without intestinal metaplasia. Two lesions included an organizing thrombus, 1 with intravascular papillary endothelial hyperplasia. Twenty patients were treated with topical medications without resolution. Three lesions recurred (7%) after excision. A subset of patients had history of smoking or previous pelvic irradiation. Urethral caruncle is an uncommon lesion that may clinically mimic benign and malignant conditions. Awareness of the spectrum of clinical and histologic differential diagnoses is important in dealing with this unusual disease. © 2012 Elsevier Inc. All rights reserved.
1. Introduction ⁎ Corresponding author. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. E-mail address: [email protected] (L. Cheng). 1 These authors contributed equally to the study. 0046-8177/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2011.10.015
Urethral caruncle is a benign, pedunculated, or sessile polypoid lesion of the urethra [1], typically presenting as a fleshy, easily friable nodule of the posterior urethra near the meatus in postmenopausal women [2,3]. Microscopically, the lesion is composed of variable proportions of
Urethral caruncle subepithelial inflammation, edema, vascularity, and fibrosis, coupled with epithelial hyperplasia that may sometimes mimic a neoplasm [4]. Although patients are sometimes asymptomatic at diagnosis, some patients experience pain or bleeding [5]. Neither an association with urologic malignancy nor a risk of malignant transformation has been described in this setting [2]. However, pathologic confirmation of the diagnosis of urethral caruncle through biopsy or excision is often important because the clinical differential diagnosis includes a wide spectrum of benign and malignant entities [4], such as periurethral gland abscess, urethral diverticulum, carcinoma, squamous intraepithelial neoplasm, and melanoma [6-8]. As many as 5% of cases clinically suspected to be urethral caruncle may in fact represent true neoplasms, of which approximately half are malignant [4]. To shed light on the light microscopic morphology and clinicopathologic course of this uncommon lesion, we examined the histopathologic and clinical features in 41 cases of urethral caruncle.
2. Materials and methods Cases with a pathologic diagnosis of urethral caruncle were retrospectively retrieved from the surgical pathology files from the years 2000 to 2009. Medical records were reviewed, as available, and assessed for clinical presentation, clinical diagnosis, associated concurrent or previous urothelial carcinoma, previous radiation treatment, tobacco use, coexisting immunologic or urologic disorder, and treatment strategy/outcome in each patient. Light microscopic morphology was examined using hematoxylin and eosin–stained tissue sections for all 41 cases. Morphologic features were assessed for degree of subepithelial inflammation, edema, vascularity, and fibrosis, as well as lining by either hyperplastic squamous epithelium and/or urothelium [4].
3. Results 3.1. Clinical features We identified cases from 41 female patients with a mean age of 68 years (range, 28-87 years). The polypoid lesions were present at the urethral meatus in all patients and occurred most frequently at the posterior lip (44%, 18 patients) and less frequently at the anterior lip (15%, 6 patients). The location within the urethral meatus was not further specified for 17 patients. Presenting complaints were persistent pain (37%), hematuria (27%), and dysuria (20%). Thirteen patients (32%) were asymptomatic. Eighteen patients (44%) were diagnosed clinically with urethral caruncle, whereas 7 (17%) carried a clinical diagnosis of urethral polyp, 6 (15%) urethral prolapse, 5 (12%)
1401 Table 1 Summary of clinical findings in 41 cases of urethral caruncles Total number of cases Age (y), mean Location at urethral meatus Posterior Anterior Distal urethra, not specified Symptoms Pain Hematuria Dysuria Asymptomatic Clinical diagnosis Urethral caruncle Urethral polyp Urethral prolapse Periurethral gland abscess Urethral carcinoma Diagnosis of urothelial carcinoma a Prior exposure to radiation Positive history of tobacco use Autoimmune disease
41 68 18 (44%) 6 (15%) 17 (41%) 15 (37%) 11 (27%) 8 (20%) 13 (32%) 18 (44%) 7 (17%) 6 (15%) 5 (12%) 3 (7%) 5 (12%) 4 (10%) 15 (37%) 2 (5%)
a Urothelial carcinoma was present concurrently or subsequent to the diagnosis of the urethral caruncle and was not present in the urethra.
periurethral gland abscess, 3 (7%) urethral carcinoma, and 1 (2%) high-grade vulvar intraepithelial neoplasia (Table 1). Fifteen patients (37%) had a positive history of cigarette smoking, and 4 underwent previous radiation of the pelvis or chemotherapy. Review of medical history revealed that 20 patients (49%) had documented disease involving the genitourinary/gynecologic tract, including leiomyoma (4 cases), chronic urethritis (4 cases), vulvar intraepithelial neoplasia III (1 case), interstitial cystitis (1 case), and urethral diverticulum (1 case). Pelvic floor prolapse was present in 1 patient, and 3 patients were diagnosed with both rectocele and cystocele. Concurrent or subsequent urothelial carcinoma was diagnosed in 5 patients. In 1 patient, concurrent urothelial carcinoma of the bladder was present at the time of excision of the urethral caruncle. In the remaining 4 patients, urothelial carcinoma was later diagnosed in the bladder (2 patients), ureter (1 patient), and renal pelvis (1 patient) after the excision of the urethral caruncle. Autoimmune diseases were documented in 2 patients, 1 with systemic lupus erythematosus and another with rheumatoid arthritis.
3.2. Patient follow-up and treatment Clinical follow-up information was available for 34 patients and ranged from 6 to 36 months in length (mean, 21 months). Three patients (7%) required treatment for recurrence of the lesion, although none developed carcinoma of the urethra. Most of the patients (93%) were treated with
1402 excision. One patient underwent laser treatment, whereas 2 were diagnosed with biopsy without documentation of further treatment. Twenty patients were treated with topical medications before excision. Of these patients, 9 received topical estrogen therapy without improvement of the lesion. Eleven patients, including 4 patients previously treated with estrogen, received topical anti-inflammatory medications but failed to respond.
3.3. Gross features Caruncle size ranged from 0.2 to 3 cm (mean, 0.95 cm) in greatest dimension. Grossly, the excision or biopsy specimens consisted of single or multiple fragments of pink-tan soft tissue, irregular or polypoid in shape.
M. R. Conces et al.
3.4. Microscopic features Histologically, the specimens demonstrated an epithelial lining composed of hyperplastic benign urothelium and squamous epithelium, with 3 cases (7%) showing keratinization (Fig. 1). Rounded nests of urothelial cells extending into the stroma were common (68%), typically arranged in single invaginations or with branched/lobular architecture, often with overlying squamous metaplasia. Cystic or glandular luminal spaces within the nests, similar to urethritis cystica or urethritis glandularis, were frequently present. Fifteen cases (37%) demonstrated ulceration of the surface urothelium. Significant cytologic atypia and atypical mitotic figures within the epithelial component were not present in any of the cases.
Fig. 1 Urethral caruncle. A, Low magnification, demonstrating a polypoid lesion lined by hyperplastic squamous epithelium with stromal inflammatory infiltrates and dilated blood vessels (40×). B and C, Intermediate and high magnification, showing lymphoplasmacytic infiltrates with intermingled acute inflammatory cells and extravasation of erythrocytes (B, 100×; C, 200×). D, Plasma cells are abundant, with occasional Mott cells (200×). E, Another case, showing hyperplastic urothelium overlying stromal pools of blood with organizing thrombus and dilated vessels (40×). F, A case with prominent stromal edema and scattered inflammatory cells (100×). G, Another case, showing a more sclerotic stroma with invaginations of urothelium, containing central cystic/glandular lumens within urothelial nests (40×). H, Subepithelial localization of the inflammatory cell infiltrate in another case (100×). I, Prominent extravasation of erythrocytes and stromal mononuclear cell infiltrates (100×).
Urethral caruncle The stromal compartment demonstrated variable degrees of edema, dilation of the subepithelial blood vessels, red blood cell extravasation, acute and chronic inflammatory cell infiltrates, and fibrosis. In 4 cases (10%), the subepithelial blood vessels were markedly dilated, containing large pools of erythrocytes. Of these, 2 included an organizing thrombus, 1 with intravascular papillary endothelial hyperplasia, similar to so-called Masson tumor. All cases demonstrated a chronic inflammatory cell infiltrate diffusely distributed within the stroma, composed of variable numbers of lymphocytes and plasma cells. Occasional cases showed Mott cells and Russell bodies. In 3 cases, the chronic inflammatory cell infiltrate was primarily localized directly beneath the epithelium. Conspicuous mitotic activity and cytologic atypia were not present within the stromal compartment for any case.
4. Discussion Urethral caruncle is a benign polypoid lesion, occurring at the urethral meatus primarily in postmenopausal females and much less commonly in males [9] and prepubertal females [10]. A conclusive association with malignancy, other urologic disorder, or systemic disease has not been established [2]; however, the etiology and pathogenesis of urethral caruncle are not well understood. We analyzed 41 cases of urethral caruncle to better understand the spectrum of light microscopic morphology seen in these lesions and gather insight into the overall clinical course/response to treatment. Clinically, all patients in our study presented with features characteristic of urethral caruncle, consisting of polypoid nodules at the urethral meatus. The symptoms experienced by patients in our series ranged from asymptomatic (32%) to 68% experiencing symptoms such as pain, dysuria, or bleeding, as expected, based on the friability and vascular nature of the lesion [8]. The clinical differential diagnosis for a urethral or periurethral mass is broad and includes a number of lesions that may present similarly to caruncle, such as condyloma, urethral prolapse, periurethral gland abscess, or other benign or malignant neoplasm. Although uncommon, a spectrum of neoplasms may mimic urethral caruncle clinically, including adenocarcinoma, urothelial carcinoma, squamous cell carcinoma, melanoma, lymphoma, and sarcoma [4,11-13]. In such cases, biopsy or excision with histopathologic examination of excised tissue will identify the uncommon patient with a malignant neoplasm mimicking a caruncle [4,12]. A clinical diagnosis of urethral caruncle was made in 44% of the patients in our study. We also investigated the clinicopathologic relationship of urothelial carcinoma, smoking, and pelvic radiation with urethral caruncle. Radiation to the pelvis and smoking are
1403 associated with other fibrosing or neoplastic diseases of the genitourinary tract. In our series, 4 patients (10%) had been exposed to radiation treatment of the pelvis, and 15 patients had a prior or current history of smoking (37%). Similarly, 5 patients were diagnosed with urothelial carcinoma (12%), 4 of which developed after the diagnosis of urethral caruncle. Although these findings were present in a prominent subset of patients, a conclusive association was difficult to determine. Initial treatment is often conservative with medication such as topical estrogen and anti-inflammatory agents; however, patients with large, refractory, or symptomatic lesions have generally been considered to require more definitive management with excision [8]. Similarly, the lesion may recur after resection as seen in 3 of the included cases. In our study, estrogen and topical anti-inflammatory agent therapy were ineffective compared with excision; however, these results may be influenced by the fact that only cases with tissue specimens were studied. Histologic features in the studied cases included hyperplastic, benign epithelium, typically a mixture of squamous epithelium and urothelium, coupled with submucosal congestion, a lymphoplasmacytic inflammatory infiltrate, and dilated blood vessels within the lamina propria [14]. Many cases showed rounded nests of urothelial cells extending into the stroma, with cystic or glandular lumens, similar to urethritis cystica or urethritis glandularis (of the usual type). Intestinal metaplasia was not present [15]. Because the epithelium shows a tendency to invaginate into the stroma, this hyperplastic proliferation may mimic carcinoma. However, cytologic atypia and disorganized, infiltrative growth are not seen [2]. A classification system for urethral caruncle has been suggested [14], including granulomatous, papillomatous, and angiomatous types. The granulomatous designation may be considered a misnomer, as it refers to cases consisting primarily of granulation tissue. Likewise, papillomatous and angiomatous types show a lobular, tree-like growth pattern and prominent stromal blood vessels, respectively. However, a specific variant is rarely diagnosed pathologically because it does not affect the clinical treatment or prognosis [16]. Other entities in the pathologic differential diagnosis include condyloma acuminatum, hemangioma, fibroepithelial polyp, and inflammatory myofibroblastic tumor. Architecturally, condyloma accuminata are papillary lesions, as opposed to the typically polypoid appearance of caruncle, which generally lacks true papillary fibrovascular cores. Although both lesions may be lined by nonkeratinizing squamous epithelium overlying a fibrovascular stroma with lymphocytic infiltrate, urethral caruncle lacks the koilocytosis that characterizes a condyloma, in which stromal inflammation is typically less prominent [17]. The presence of dilated blood vessels within the stroma of caruncle may bring hemangioma into the differential diagnosis. Although rare in the urethra, potential symptoms may be similar, including hematuria and pain. In contrast, the significant
1404 lymphoplasmacytic infiltrate of caruncle is not a typical feature in hemangioma [18]. Although a subset of our studied cases showed large, dilated blood vessels, containing organizing thrombus in 2 cases, a true neoplastic vascular proliferation was not seen, nor did the vessels appear abnormal in character or number. Fibroepithelial polyps may be found in the lower urinary tract and female genital tract [19,20], and the fibrous stroma of these lesions may contain numerous blood vessels. In contrast to caruncle, however, fibroepithelial polyps are typically composed of fingerlike projections or a cloverleaf configuration of epithelium overlying a fibrous stroma, with infrequent inflammatory infiltrates. Likewise, fibroepithelial polyps are characteristically seen in younger patients with a male predilection [19,21]. Inflammatory myofibroblastic tumor may also enter the differential diagnosis because of its admixture of stromal cells and lymphoplasmacytic inflammatory cell infiltrate. Although a fibrous stroma may be present in urethral caruncle, an exuberant proliferation of myofibroblastic spindle cells is not a significant feature [22] and should prompt consideration of inflammatory myofibroblastic tumor as an alternative diagnosis. Cases of urethral caruncle with atypical stromal cells mimicking malignancy have also been described [16], although we did not encounter this finding in the current series. The precise etiology of urethral caruncle is unknown, but many theories have been proposed. Congestion of the urethra, urethral irritation and trauma, and estrogen deficiency have been suggested as potential etiologies [5]. Changes in estrogen level may affect the urethral epithelium, muscular wall, and submucosa. This phenomenon is considered to play a role in other disease processes of postmenopausal women, such as mucosal prolapse of the urethra, and may contribute to the development of caruncle by a similar mechanism [23]. Chronic irritation is often considered to be a significant contributing factor and consistent with the histologic findings of hemorrhage and chronic inflammation [8,24]. The female urethra is particularly susceptible to infection in addition to irritation. Further study into the pathogenesis of urethral caruncle may be interesting. In summary, we examined 41 patients with urethral caruncle, one of the largest series reported in the literature. Typical light microscopic features included a mixture of hyperplastic urothelial and squamous lining, overlying a variably fibrotic, edematous, inflamed, and vascular stroma, often with invaginations of focally cystic, benign urothelium. Organizing thrombus may be present within dilated vessels, and 1 case in our series showed intravascular papillary endothelial hyperplasia. A subset of patients had history of smoking, pelvic irradiation, or concurrent/subsequent urothelial carcinoma; however, we were not able to conclusively associate these factors with the development of urethral caruncle. Tissue examination is critical in cases carrying a clinical diagnosis of urethral caruncle, as a number
M. R. Conces et al. of true neoplasms occasionally demonstrate overlapping clinical features.
References [1] Reuter VE. Urethra. In: Bostwick D, Cheng L, editors. Urologic Surgical Pathology. Philadelphia: Mosby/Elsevier; 2008. p. 595-613. [2] Murphy W, Grignon D, Perlman E. Tumors of the kidney, bladder, and related urinary structures. Washington DC: Armed Forces Institute of Pathology; 2004. [3] Palmer JK, Emmett JL, McDonald JR. Urethral caruncle. Surg Gynecol Obstet 1948;87:611-20. [4] Marshall FC, Uson AC, Melicow MM. Neoplasms and caruncles of the female urethra. Surg Gynecol Obstet 1960;110:723-33. [5] Burkland CE. Common lesions of the urethra in women. Calif Med 1952;76:69-73. [6] Blaivas JG, Flisser AJ, Bleustein CB, Panagopoulos G. Periurethral masses: etiology and diagnosis in a large series of women. Obstet Gynecol 2004;103:842-7. [7] Neilson D, Grant JB, Smith CE. Squamous intra-epithelial neoplasia presenting as a urethral caruncle. Br J Urol 1989;64:200-1. [8] Rovner ES. Bladder and urethral diverticula. In: Campbell MF, Wein AJ, Kavoussi LR, editors. Campbell-Walsh urology. Philadelphia (Pa): Saunders Elsevier; 2007. p. 2384-5. [9] Karthikeyan K, Kaviarasan PK, Thappa DM. Urethral caruncle in a male: a case report. J Eur Acad Dermatol Venereol 2002;16:72-3. [10] Turkeri L, Simsek F, Akdas A. Urethral caruncle in an unusual location occurring in prepubertal girl. Eur Urol 1989;16:153-4. [11] Nakamoto T, Inoue Y, Ueki T, Niimi N, Iwasaki Y. Primary amelanotic malignant melanoma of the female urethra. Int J Urol 2007;14:153-5. [12] Omar A, Thomas A, Thompson I. Primary urethral transitional cell carcinoma presenting as a urethral caruncle. Int Urogynecol J Pelvic Floor Dysfunct 2007;18:1227-8. [13] Melicow MM, Lattes R, Pierre-Louis C. Lymphoma of the female urethra masquerading as a caruncle. J Urol 1972;108:748-9. [14] Becker LE. Urethral caruncle: a herald lesion for distal urethral stenosis? J Natl Med Assoc 1975;67:228-30. [15] Elbadawi A, Malhoski WE, Frank IN. Mucinous urethral caruncle. Urology 1978;12:587-90. [16] Young RH, Oliva E, Garcia JA, Bhan AK, Clement PB. Urethral caruncle with atypical stromal cells simulating lymphoma or sarcoma —a distinctive pseudoneoplastic lesion of females. A report of six cases. Am J Surg Pathol 1996;20:1190-5. [17] Cheng L, Leibovich BC, Cheville JC, Ramnani DM, Sebo TJ, Nehra A, et al. Squamous papilloma of the urinary tract is unrelated to condyloma acuminata. Cancer 2000;88:1679-86. [18] Tabibian L, Ginsberg DA. Thrombosed urethral hemangioma. J Urol 2003;170:1942. [19] Tsuzuki T, Epstein JI. Fibroepithelial polyp of the lower urinary tract in adults. Am J Surg Pathol 2005;29:460-6. [20] Nucci MR, Young RH, Fletcher CD. Cellular pseudosarcomatous fibroepithelial stromal polyps of the lower female genital tract: an underrecognized lesion often misdiagnosed as sarcoma. Am J Surg Pathol 2000;24:231-40. [21] Yamashita T, Masuda H, Yano M, Kobayashi T, Kawano K, Kihara K. Female urethral fibroepithelial polyp with stricture. J Urol 2004;171:357. [22] Cheng L, Foster SR, MacLennan GT, Lopez-Beltran A, Zhang S, Montironi R. Inflammatory myofibroblastic tumors of the genitourinary tract—single entity or continuum? J Urol 2008;180:1235-40. [23] Dmochowski RR, Ganabathi K, Zimmern PE, Leach GE. Benign female periurethral masses. J Urol 1994;152:1943-51. [24] Fletcher SG, Lemack GE. Benign masses of the female periurethral tissues and anterior vaginal wall. Curr Urol Rep 2008;9:389-96.
www.elsevier.com/locate/humpath
Original contribution
Urethral caruncle: clinicopathologic features of 41 cases Miriam R. Conces MD a,1 , Sean R. Williamson MD a,1 , Rodolfo Montironi MD b , Antonio Lopez-Beltran MD c , Marina Scarpelli MD b , Liang Cheng MD a,d,⁎ a
Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA Department of Pathological Anatomy and Histopathology, School of Medicine, Polytechnic University of the Marche Region (Ancona), Ancona 60126, Italy c Department of Pathology, Cordoba University, Cordoba E-14004, Spain d Department of Urology, Indiana University School of Medicine, Indianapolis, IN 46202, USA b
Received 7 September 2011; revised 12 October 2011; accepted 14 October 2011
Keywords: Urinary bladder; Urinary tract; Urethra; Caruncle; Urethral polyp
Summary Urethral caruncle is a benign polypoid mass of the urethral meatus in primarily postmenopausal women. Although a conclusive association with malignancy, urologic disorder, or systemic disease has not been established, often the lesion carries a challenging clinical differential diagnosis that includes malignancy. Conversely, unexpected malignancy is identified in some cases resembling caruncle clinically. We examined clinical and histopathologic characteristics in 41 patients. Medical records were assessed for presentation, clinical diagnosis, associated urothelial carcinoma, radiation treatment, tobacco use, immunologic/urologic disorder, and treatment strategy/outcome. Average patient age was 68 years (range, 28-87 years). Presenting symptoms were pain (37%), hematuria (27%), and dysuria (20%), in contrast to asymptomatic (32%). Clinical diagnosis favored malignancy in 10% of cases. Concurrent or subsequent urothelial carcinoma was present for 5 patients (12%), although none developed urethral carcinoma. Histologic features included mixed hyperplastic urothelial and squamous lining, overlying a variably fibrotic, edematous, inflamed, and vascular stroma. Invaginations of urothelium extending into the stroma were common (68%), showing rounded nests with cystic or glandular luminal spaces, similar to urethritis cystica/glandularis, without intestinal metaplasia. Two lesions included an organizing thrombus, 1 with intravascular papillary endothelial hyperplasia. Twenty patients were treated with topical medications without resolution. Three lesions recurred (7%) after excision. A subset of patients had history of smoking or previous pelvic irradiation. Urethral caruncle is an uncommon lesion that may clinically mimic benign and malignant conditions. Awareness of the spectrum of clinical and histologic differential diagnoses is important in dealing with this unusual disease. © 2012 Elsevier Inc. All rights reserved.
1. Introduction ⁎ Corresponding author. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. E-mail address: [email protected] (L. Cheng). 1 These authors contributed equally to the study. 0046-8177/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2011.10.015
Urethral caruncle is a benign, pedunculated, or sessile polypoid lesion of the urethra [1], typically presenting as a fleshy, easily friable nodule of the posterior urethra near the meatus in postmenopausal women [2,3]. Microscopically, the lesion is composed of variable proportions of
Urethral caruncle subepithelial inflammation, edema, vascularity, and fibrosis, coupled with epithelial hyperplasia that may sometimes mimic a neoplasm [4]. Although patients are sometimes asymptomatic at diagnosis, some patients experience pain or bleeding [5]. Neither an association with urologic malignancy nor a risk of malignant transformation has been described in this setting [2]. However, pathologic confirmation of the diagnosis of urethral caruncle through biopsy or excision is often important because the clinical differential diagnosis includes a wide spectrum of benign and malignant entities [4], such as periurethral gland abscess, urethral diverticulum, carcinoma, squamous intraepithelial neoplasm, and melanoma [6-8]. As many as 5% of cases clinically suspected to be urethral caruncle may in fact represent true neoplasms, of which approximately half are malignant [4]. To shed light on the light microscopic morphology and clinicopathologic course of this uncommon lesion, we examined the histopathologic and clinical features in 41 cases of urethral caruncle.
2. Materials and methods Cases with a pathologic diagnosis of urethral caruncle were retrospectively retrieved from the surgical pathology files from the years 2000 to 2009. Medical records were reviewed, as available, and assessed for clinical presentation, clinical diagnosis, associated concurrent or previous urothelial carcinoma, previous radiation treatment, tobacco use, coexisting immunologic or urologic disorder, and treatment strategy/outcome in each patient. Light microscopic morphology was examined using hematoxylin and eosin–stained tissue sections for all 41 cases. Morphologic features were assessed for degree of subepithelial inflammation, edema, vascularity, and fibrosis, as well as lining by either hyperplastic squamous epithelium and/or urothelium [4].
3. Results 3.1. Clinical features We identified cases from 41 female patients with a mean age of 68 years (range, 28-87 years). The polypoid lesions were present at the urethral meatus in all patients and occurred most frequently at the posterior lip (44%, 18 patients) and less frequently at the anterior lip (15%, 6 patients). The location within the urethral meatus was not further specified for 17 patients. Presenting complaints were persistent pain (37%), hematuria (27%), and dysuria (20%). Thirteen patients (32%) were asymptomatic. Eighteen patients (44%) were diagnosed clinically with urethral caruncle, whereas 7 (17%) carried a clinical diagnosis of urethral polyp, 6 (15%) urethral prolapse, 5 (12%)
1401 Table 1 Summary of clinical findings in 41 cases of urethral caruncles Total number of cases Age (y), mean Location at urethral meatus Posterior Anterior Distal urethra, not specified Symptoms Pain Hematuria Dysuria Asymptomatic Clinical diagnosis Urethral caruncle Urethral polyp Urethral prolapse Periurethral gland abscess Urethral carcinoma Diagnosis of urothelial carcinoma a Prior exposure to radiation Positive history of tobacco use Autoimmune disease
41 68 18 (44%) 6 (15%) 17 (41%) 15 (37%) 11 (27%) 8 (20%) 13 (32%) 18 (44%) 7 (17%) 6 (15%) 5 (12%) 3 (7%) 5 (12%) 4 (10%) 15 (37%) 2 (5%)
a Urothelial carcinoma was present concurrently or subsequent to the diagnosis of the urethral caruncle and was not present in the urethra.
periurethral gland abscess, 3 (7%) urethral carcinoma, and 1 (2%) high-grade vulvar intraepithelial neoplasia (Table 1). Fifteen patients (37%) had a positive history of cigarette smoking, and 4 underwent previous radiation of the pelvis or chemotherapy. Review of medical history revealed that 20 patients (49%) had documented disease involving the genitourinary/gynecologic tract, including leiomyoma (4 cases), chronic urethritis (4 cases), vulvar intraepithelial neoplasia III (1 case), interstitial cystitis (1 case), and urethral diverticulum (1 case). Pelvic floor prolapse was present in 1 patient, and 3 patients were diagnosed with both rectocele and cystocele. Concurrent or subsequent urothelial carcinoma was diagnosed in 5 patients. In 1 patient, concurrent urothelial carcinoma of the bladder was present at the time of excision of the urethral caruncle. In the remaining 4 patients, urothelial carcinoma was later diagnosed in the bladder (2 patients), ureter (1 patient), and renal pelvis (1 patient) after the excision of the urethral caruncle. Autoimmune diseases were documented in 2 patients, 1 with systemic lupus erythematosus and another with rheumatoid arthritis.
3.2. Patient follow-up and treatment Clinical follow-up information was available for 34 patients and ranged from 6 to 36 months in length (mean, 21 months). Three patients (7%) required treatment for recurrence of the lesion, although none developed carcinoma of the urethra. Most of the patients (93%) were treated with
1402 excision. One patient underwent laser treatment, whereas 2 were diagnosed with biopsy without documentation of further treatment. Twenty patients were treated with topical medications before excision. Of these patients, 9 received topical estrogen therapy without improvement of the lesion. Eleven patients, including 4 patients previously treated with estrogen, received topical anti-inflammatory medications but failed to respond.
3.3. Gross features Caruncle size ranged from 0.2 to 3 cm (mean, 0.95 cm) in greatest dimension. Grossly, the excision or biopsy specimens consisted of single or multiple fragments of pink-tan soft tissue, irregular or polypoid in shape.
M. R. Conces et al.
3.4. Microscopic features Histologically, the specimens demonstrated an epithelial lining composed of hyperplastic benign urothelium and squamous epithelium, with 3 cases (7%) showing keratinization (Fig. 1). Rounded nests of urothelial cells extending into the stroma were common (68%), typically arranged in single invaginations or with branched/lobular architecture, often with overlying squamous metaplasia. Cystic or glandular luminal spaces within the nests, similar to urethritis cystica or urethritis glandularis, were frequently present. Fifteen cases (37%) demonstrated ulceration of the surface urothelium. Significant cytologic atypia and atypical mitotic figures within the epithelial component were not present in any of the cases.
Fig. 1 Urethral caruncle. A, Low magnification, demonstrating a polypoid lesion lined by hyperplastic squamous epithelium with stromal inflammatory infiltrates and dilated blood vessels (40×). B and C, Intermediate and high magnification, showing lymphoplasmacytic infiltrates with intermingled acute inflammatory cells and extravasation of erythrocytes (B, 100×; C, 200×). D, Plasma cells are abundant, with occasional Mott cells (200×). E, Another case, showing hyperplastic urothelium overlying stromal pools of blood with organizing thrombus and dilated vessels (40×). F, A case with prominent stromal edema and scattered inflammatory cells (100×). G, Another case, showing a more sclerotic stroma with invaginations of urothelium, containing central cystic/glandular lumens within urothelial nests (40×). H, Subepithelial localization of the inflammatory cell infiltrate in another case (100×). I, Prominent extravasation of erythrocytes and stromal mononuclear cell infiltrates (100×).
Urethral caruncle The stromal compartment demonstrated variable degrees of edema, dilation of the subepithelial blood vessels, red blood cell extravasation, acute and chronic inflammatory cell infiltrates, and fibrosis. In 4 cases (10%), the subepithelial blood vessels were markedly dilated, containing large pools of erythrocytes. Of these, 2 included an organizing thrombus, 1 with intravascular papillary endothelial hyperplasia, similar to so-called Masson tumor. All cases demonstrated a chronic inflammatory cell infiltrate diffusely distributed within the stroma, composed of variable numbers of lymphocytes and plasma cells. Occasional cases showed Mott cells and Russell bodies. In 3 cases, the chronic inflammatory cell infiltrate was primarily localized directly beneath the epithelium. Conspicuous mitotic activity and cytologic atypia were not present within the stromal compartment for any case.
4. Discussion Urethral caruncle is a benign polypoid lesion, occurring at the urethral meatus primarily in postmenopausal females and much less commonly in males [9] and prepubertal females [10]. A conclusive association with malignancy, other urologic disorder, or systemic disease has not been established [2]; however, the etiology and pathogenesis of urethral caruncle are not well understood. We analyzed 41 cases of urethral caruncle to better understand the spectrum of light microscopic morphology seen in these lesions and gather insight into the overall clinical course/response to treatment. Clinically, all patients in our study presented with features characteristic of urethral caruncle, consisting of polypoid nodules at the urethral meatus. The symptoms experienced by patients in our series ranged from asymptomatic (32%) to 68% experiencing symptoms such as pain, dysuria, or bleeding, as expected, based on the friability and vascular nature of the lesion [8]. The clinical differential diagnosis for a urethral or periurethral mass is broad and includes a number of lesions that may present similarly to caruncle, such as condyloma, urethral prolapse, periurethral gland abscess, or other benign or malignant neoplasm. Although uncommon, a spectrum of neoplasms may mimic urethral caruncle clinically, including adenocarcinoma, urothelial carcinoma, squamous cell carcinoma, melanoma, lymphoma, and sarcoma [4,11-13]. In such cases, biopsy or excision with histopathologic examination of excised tissue will identify the uncommon patient with a malignant neoplasm mimicking a caruncle [4,12]. A clinical diagnosis of urethral caruncle was made in 44% of the patients in our study. We also investigated the clinicopathologic relationship of urothelial carcinoma, smoking, and pelvic radiation with urethral caruncle. Radiation to the pelvis and smoking are
1403 associated with other fibrosing or neoplastic diseases of the genitourinary tract. In our series, 4 patients (10%) had been exposed to radiation treatment of the pelvis, and 15 patients had a prior or current history of smoking (37%). Similarly, 5 patients were diagnosed with urothelial carcinoma (12%), 4 of which developed after the diagnosis of urethral caruncle. Although these findings were present in a prominent subset of patients, a conclusive association was difficult to determine. Initial treatment is often conservative with medication such as topical estrogen and anti-inflammatory agents; however, patients with large, refractory, or symptomatic lesions have generally been considered to require more definitive management with excision [8]. Similarly, the lesion may recur after resection as seen in 3 of the included cases. In our study, estrogen and topical anti-inflammatory agent therapy were ineffective compared with excision; however, these results may be influenced by the fact that only cases with tissue specimens were studied. Histologic features in the studied cases included hyperplastic, benign epithelium, typically a mixture of squamous epithelium and urothelium, coupled with submucosal congestion, a lymphoplasmacytic inflammatory infiltrate, and dilated blood vessels within the lamina propria [14]. Many cases showed rounded nests of urothelial cells extending into the stroma, with cystic or glandular lumens, similar to urethritis cystica or urethritis glandularis (of the usual type). Intestinal metaplasia was not present [15]. Because the epithelium shows a tendency to invaginate into the stroma, this hyperplastic proliferation may mimic carcinoma. However, cytologic atypia and disorganized, infiltrative growth are not seen [2]. A classification system for urethral caruncle has been suggested [14], including granulomatous, papillomatous, and angiomatous types. The granulomatous designation may be considered a misnomer, as it refers to cases consisting primarily of granulation tissue. Likewise, papillomatous and angiomatous types show a lobular, tree-like growth pattern and prominent stromal blood vessels, respectively. However, a specific variant is rarely diagnosed pathologically because it does not affect the clinical treatment or prognosis [16]. Other entities in the pathologic differential diagnosis include condyloma acuminatum, hemangioma, fibroepithelial polyp, and inflammatory myofibroblastic tumor. Architecturally, condyloma accuminata are papillary lesions, as opposed to the typically polypoid appearance of caruncle, which generally lacks true papillary fibrovascular cores. Although both lesions may be lined by nonkeratinizing squamous epithelium overlying a fibrovascular stroma with lymphocytic infiltrate, urethral caruncle lacks the koilocytosis that characterizes a condyloma, in which stromal inflammation is typically less prominent [17]. The presence of dilated blood vessels within the stroma of caruncle may bring hemangioma into the differential diagnosis. Although rare in the urethra, potential symptoms may be similar, including hematuria and pain. In contrast, the significant
1404 lymphoplasmacytic infiltrate of caruncle is not a typical feature in hemangioma [18]. Although a subset of our studied cases showed large, dilated blood vessels, containing organizing thrombus in 2 cases, a true neoplastic vascular proliferation was not seen, nor did the vessels appear abnormal in character or number. Fibroepithelial polyps may be found in the lower urinary tract and female genital tract [19,20], and the fibrous stroma of these lesions may contain numerous blood vessels. In contrast to caruncle, however, fibroepithelial polyps are typically composed of fingerlike projections or a cloverleaf configuration of epithelium overlying a fibrous stroma, with infrequent inflammatory infiltrates. Likewise, fibroepithelial polyps are characteristically seen in younger patients with a male predilection [19,21]. Inflammatory myofibroblastic tumor may also enter the differential diagnosis because of its admixture of stromal cells and lymphoplasmacytic inflammatory cell infiltrate. Although a fibrous stroma may be present in urethral caruncle, an exuberant proliferation of myofibroblastic spindle cells is not a significant feature [22] and should prompt consideration of inflammatory myofibroblastic tumor as an alternative diagnosis. Cases of urethral caruncle with atypical stromal cells mimicking malignancy have also been described [16], although we did not encounter this finding in the current series. The precise etiology of urethral caruncle is unknown, but many theories have been proposed. Congestion of the urethra, urethral irritation and trauma, and estrogen deficiency have been suggested as potential etiologies [5]. Changes in estrogen level may affect the urethral epithelium, muscular wall, and submucosa. This phenomenon is considered to play a role in other disease processes of postmenopausal women, such as mucosal prolapse of the urethra, and may contribute to the development of caruncle by a similar mechanism [23]. Chronic irritation is often considered to be a significant contributing factor and consistent with the histologic findings of hemorrhage and chronic inflammation [8,24]. The female urethra is particularly susceptible to infection in addition to irritation. Further study into the pathogenesis of urethral caruncle may be interesting. In summary, we examined 41 patients with urethral caruncle, one of the largest series reported in the literature. Typical light microscopic features included a mixture of hyperplastic urothelial and squamous lining, overlying a variably fibrotic, edematous, inflamed, and vascular stroma, often with invaginations of focally cystic, benign urothelium. Organizing thrombus may be present within dilated vessels, and 1 case in our series showed intravascular papillary endothelial hyperplasia. A subset of patients had history of smoking, pelvic irradiation, or concurrent/subsequent urothelial carcinoma; however, we were not able to conclusively associate these factors with the development of urethral caruncle. Tissue examination is critical in cases carrying a clinical diagnosis of urethral caruncle, as a number
M. R. Conces et al. of true neoplasms occasionally demonstrate overlapping clinical features.
References [1] Reuter VE. Urethra. In: Bostwick D, Cheng L, editors. Urologic Surgical Pathology. Philadelphia: Mosby/Elsevier; 2008. p. 595-613. [2] Murphy W, Grignon D, Perlman E. Tumors of the kidney, bladder, and related urinary structures. Washington DC: Armed Forces Institute of Pathology; 2004. [3] Palmer JK, Emmett JL, McDonald JR. Urethral caruncle. Surg Gynecol Obstet 1948;87:611-20. [4] Marshall FC, Uson AC, Melicow MM. Neoplasms and caruncles of the female urethra. Surg Gynecol Obstet 1960;110:723-33. [5] Burkland CE. Common lesions of the urethra in women. Calif Med 1952;76:69-73. [6] Blaivas JG, Flisser AJ, Bleustein CB, Panagopoulos G. Periurethral masses: etiology and diagnosis in a large series of women. Obstet Gynecol 2004;103:842-7. [7] Neilson D, Grant JB, Smith CE. Squamous intra-epithelial neoplasia presenting as a urethral caruncle. Br J Urol 1989;64:200-1. [8] Rovner ES. Bladder and urethral diverticula. In: Campbell MF, Wein AJ, Kavoussi LR, editors. Campbell-Walsh urology. Philadelphia (Pa): Saunders Elsevier; 2007. p. 2384-5. [9] Karthikeyan K, Kaviarasan PK, Thappa DM. Urethral caruncle in a male: a case report. J Eur Acad Dermatol Venereol 2002;16:72-3. [10] Turkeri L, Simsek F, Akdas A. Urethral caruncle in an unusual location occurring in prepubertal girl. Eur Urol 1989;16:153-4. [11] Nakamoto T, Inoue Y, Ueki T, Niimi N, Iwasaki Y. Primary amelanotic malignant melanoma of the female urethra. Int J Urol 2007;14:153-5. [12] Omar A, Thomas A, Thompson I. Primary urethral transitional cell carcinoma presenting as a urethral caruncle. Int Urogynecol J Pelvic Floor Dysfunct 2007;18:1227-8. [13] Melicow MM, Lattes R, Pierre-Louis C. Lymphoma of the female urethra masquerading as a caruncle. J Urol 1972;108:748-9. [14] Becker LE. Urethral caruncle: a herald lesion for distal urethral stenosis? J Natl Med Assoc 1975;67:228-30. [15] Elbadawi A, Malhoski WE, Frank IN. Mucinous urethral caruncle. Urology 1978;12:587-90. [16] Young RH, Oliva E, Garcia JA, Bhan AK, Clement PB. Urethral caruncle with atypical stromal cells simulating lymphoma or sarcoma —a distinctive pseudoneoplastic lesion of females. A report of six cases. Am J Surg Pathol 1996;20:1190-5. [17] Cheng L, Leibovich BC, Cheville JC, Ramnani DM, Sebo TJ, Nehra A, et al. Squamous papilloma of the urinary tract is unrelated to condyloma acuminata. Cancer 2000;88:1679-86. [18] Tabibian L, Ginsberg DA. Thrombosed urethral hemangioma. J Urol 2003;170:1942. [19] Tsuzuki T, Epstein JI. Fibroepithelial polyp of the lower urinary tract in adults. Am J Surg Pathol 2005;29:460-6. [20] Nucci MR, Young RH, Fletcher CD. Cellular pseudosarcomatous fibroepithelial stromal polyps of the lower female genital tract: an underrecognized lesion often misdiagnosed as sarcoma. Am J Surg Pathol 2000;24:231-40. [21] Yamashita T, Masuda H, Yano M, Kobayashi T, Kawano K, Kihara K. Female urethral fibroepithelial polyp with stricture. J Urol 2004;171:357. [22] Cheng L, Foster SR, MacLennan GT, Lopez-Beltran A, Zhang S, Montironi R. Inflammatory myofibroblastic tumors of the genitourinary tract—single entity or continuum? J Urol 2008;180:1235-40. [23] Dmochowski RR, Ganabathi K, Zimmern PE, Leach GE. Benign female periurethral masses. J Urol 1994;152:1943-51. [24] Fletcher SG, Lemack GE. Benign masses of the female periurethral tissues and anterior vaginal wall. Curr Urol Rep 2008;9:389-96.