Nonspecific urethritis is defined as the finding of irritative urethral symptoms such as burning micturition without evidence of an infectious etiology. With new molecular assays, many cases that might have been previously diagnosed as nonspecific urethritis are now found to have infectious etiology. Nonspecific urethritis has been reported in association with drug exposure including isotretinoin and alcohol and with contact to chemical irritants such as spermicides.⁴⁰,⁴² Nonspecific urethritis may also be part of the spectrum of Reiter syndrome (triad of urethritis, conjunctivitis, and arthritis), typically following dysenteric infections such as Shigella or Salmonella.⁴³

Papillary and polypoid urethritis is a nonneoplastic lesion that is usually secondary to an inflammatory process; however, unlike the bladder, it is not commonly associated with a catheter.⁴⁴,⁴⁵ Irritative urinary symptoms and hematuria are common presenting signs. Characteristically, the exophytic appearance results from edema in the lamina propria (Fig. 7-5A), but variable fibrosis, chronic inflammation, and associated dilated blood vessels are also present.⁴⁶ Older lesions tend to have less edema with more stromal fibrosis. The papillary component is usually broader at the base, but may also have a bulbous tip. Reactive urothelial changes are frequent and include urothelial hyperplasia, prominent nucleoli, and mitotic activity. The main differential consideration is a papillary urothelial neoplasm, but the inflammatory background and the simple papillary architecture usually aid in this distinction (Fig. 7-5B). These lesions usually regress with resolution of the inciting inflammatory condition.

Human papillomavirus (HPV) is a common source of urethritis.⁴⁷ HPV-related squamous dysplasia in the urethra is usually present in continuity with lesions of the external genitalia, anus, or perineum. Flat lesions range from low-grade squamous dysplasia with koilocytotic atypia to high-grade squamous dysplasia identical to that seen in the cervix. Flat intraepithelial squamous dysplasia is rarely biopsied de novo because most urethral lesions are subclinical⁴⁸,⁴⁹; however, it is common to find squamous dysplasia adjacent to invasive squamous cell carcinoma. Condyloma acuminatum is the most common HPV-related lesion, especially in the male urethra, and it commonly comes to clinical attention because of its intraluminal location with a resultant mass lesion, voiding symptoms, or bleeding.⁵⁰ These lesions are morphologically identical to the more common perineal counterparts and are characterized by an exophytic squamous proliferation with hyperkeratosis, prominent granular layer, and typical cytologic features of HPV infection (perinuclear halos, binucleation, nuclear hyperchromasia, and irregular nuclear membranes) (Fig. 7-6A and B). HPV types 6 and 11 are most commonly found in association with condyloma, but other types have been also reported.⁵¹,⁵² For condyloma acuminatum, the main differential diagnosis is the rare squamous papilloma of the urothelial tract. The latter occur predominantly in elderly women and are characterized by fibrovascular cores
lined by benign-appearing squamous epithelium without viral cytopathic effect; they are also HPV negative by in situ hybridization studies.⁵³ As in other sites, HPV-associated squamous dysplasia may progress to invasive squamous cell carcinoma, often associated with high-risk HPV types 16, 18, 31, 33, or 35. Therapy for squamous intraepithelial lesions is typically ablative, by surgery, laser, or topical agents.⁵⁴

Gonorrhea is a sexually transmitted infection caused by Neisseria gonorrhoeae, which is a Gram-negative diplococcus. Gonococcal urethritis typically affects teenagers or young adults. Patients typically present 2 to 5 days following infection with burning urination or a purulent urethral discharge.⁵⁵ Gonorrhea may be diagnosed by culture, but ELISA and molecular diagnostic testing are also available.⁵⁶,⁵⁷ Tissue biopsy evaluation is not performed routinely. Urethral fluid sampling typically yields neutrophils, and Gram stain may reveal intracellular diplococci. The most significant complication is urethral stricture. Patients with chronic gonorrheal infection also develop urethral fistulae (“watering can perineum”). Ascending infection causing epididymitis in men or pelvic inflammatory disease in women may occur. Chlamydia coinfection is also common. Antibiotic therapy is curative, but drug-resistant strains are emerging.⁵⁸ Postgonococcal urethritis is defined as persistent signs, symptoms, and/or laboratory evidence of urethritis 4 to 7 days following antibiotic treatment for documented gonorrhea. Most cases result from coinfection with Chlamydia or Ureaplasma infections; thus, the use of prophylactic multidrug treatment is advocated to cover possible coinfections.⁵⁹

Urethritis secondary to Chlamydia trachomatis, an obligate intracellular bacteria, is a sexually transmitted disease common in teenagers and young adults. Chlamydia is the most common sexually transmitted disease in the United States with over 1,000,000 infections reported to the Center for Disease Control in 2006.⁶⁰ Chlamydia is asymptomatic in many patients but may present with painful/burning urination or urethral discharge 1 to 3 weeks after exposure.⁶¹ The diagnosis of Chlamydia may be based on culture, antigen detection by ELISA or direct fluorescent antibody (DFA), and/or molecular identification with methods such as nucleic acid amplification. The long-term complications of untreated cases are similar to gonorrhea, including epididymitis and pelvic inflammatory disease. In addition, genital chlamydial infection may be associated with urethritis, conjunctivitis, and arthritis (i.e., Reiter syndrome)⁶² or with reactive arthritis alone. Chlamydia is curable with antibiotic therapy.

Other bacteria responsible for infectious urethritis include Ureaplasma urealyticum and Mycoplasma genitalium. Evidence suggests that Ureaplasma parvum commonly colonizes the urethra without resultant clinical symptoms.⁶³ Viral etiologies of urethritis include HSV-1 and adenovirus, and being both associated with oral sexual habits.⁶⁴ Urethral tuberculosis is exceedingly rare (male > female) and occurs secondarily to infection of the upper urinary (most commonly prostate) or female genital tracts. Predisposing factors include previous infection, immunosuppression, or prior BCG treatment for bladder carcinoma. In the urethra, the most common presentation is acute urethritis with or without discharge, or if untreated, stricture and/or fistulae. The microscopic appearance is characteristic and shows caseating granulomas. If chronic, extensive fibrosis may be seen. The standard treatment requires the use of antituberculous drugs for up to 9 months. However, as often patients present with complications, surgery is still a mainstay of treatment.⁶⁵ Wegener granulomatosis can also rarely affect the urethra. Patients may have a known history but occasionally, this location may be the first manifestation of the disease. In males, the gross appearance can be quite worrisome,
and clinically misdiagnosed as carcinoma, especially in the penile urethra where Wegener granulomatosis may present as painful fungating mass or extensive ulceration (Fig. 7-7A). Histologic examination may not be diagnostic, only showing extensive necrosis as oftentimes the first diagnostic procedure is a biopsy (Fig. 7-7B). However, the classical morphology includes geographic areas of eosinophilic necrosis associated with palisading histiocytes. Vascular involvement typically shows granulomatous vasculitis with giant cells, but it is not always seen. Methotrexate is the treatment of choice, but patients still often require surgery due to local complications.⁶⁶, ⁶⁷, ⁶⁸ The urethra is the least common site of involvement by sarcoidosis in the genitourinary tract. On gross examination, it may grossly simulate cancer.⁶⁹ The morphology is that of noncaseating loose granulomas, but this histologic appearance is nondiagnostic and can be seen in infections and other processes including malignancy (typically at its periphery). However, these patients often have a well-established history of sarcoidosis.⁷⁰

This benign lesion occurs mainly in women between 20 and 60 years of age (Table 7-1). It appears to be reactive and frequently related to trauma.⁸⁴ Patients may present with dysuria or spotting or be asymptomatic. Caruncles are typically seen at the posterior wall of the urethra near the meatus. Grossly, they are pedunculated or broad-based with a dusky red or gray appearance. From the histologic point of view, three patterns have been recognized in the older literature: (a) granulomatous where the granulation tissue is the most striking component, (b) papillomatous with a prominent lobulated growth of the epithelium, and (c) angiomatous or telangiectatic rich in blood vessels.⁸⁴ However, this classification is not used in routine practice as it lacks clinical or pathologic significance. Caruncles are typically lined by urothelium or less commonly squamous epithelium that may be hyperplastic (Fig. 7-10A). Metaplastic epithelial changes (intestinal glands) have been reported. The lamina propria is typically rich in acute and chronic inflammatory cells that are associated with abundant small blood vessels and edema (Fig. 7-10A). In some instances, atypical spindled to round mononucleated or rarely binucleated stromal cells arranged either in clusters or diffusely and showing large nuclei and prominent nucleoli may be seen (Fig. 7-10B).⁸⁵,⁸⁶ Myeloid metaplasia has been reported.⁸⁷ The urothelial hyperplasia and striking invaginations of the surface epithelium frequently associated with caruncles may raise the possibility of a low-grade urothelial carcinoma. However, there is a bulbous rather than delicate papillary architecture, the nests of epithelium seen in the superficial stroma are rounded and do not elicit stromal response, and the cells lack any degree of cytologic atypia. When atypical cells are present in the stroma, the differential diagnosis include lymphoma,⁸⁸,⁸⁹ malignant melanoma,⁹⁰ and even more rarely, spindle cell sarcoma.⁸⁵ The small size of the lesion, scarcity of mitotic activity, as well as immunostaining limited to vimentin, smooth muscle actin, and rarely desmin exclude these possibilities.⁸⁵ Surgical excision is the treatment of choice.

This benign papillary lesion occurs in adult males. It is typically found in the posterior urethra (more frequently in the verumontanum and prostatic urethra) and less commonly in the bladder or ureteral orifice.⁹¹, ⁹², ⁹³, ⁹⁴, ⁹⁵ It often presents with painless gross or microscopic hematuria, voiding symptoms, or hematospermia⁹¹,⁹⁶, ⁹⁷, ⁹⁸ although it may be an incidental finding.⁹⁴ Grossly, it appears as an exophytic papillary to filiform or infrequently sessile lesion <1 cm in size.⁹⁴ Histologically, prostatic-type polyps are composed of irregular polypoid growths or papillary fronds lined by a double layer of cells identical to that seen in prostatic acini with cuboidal to columnar cells displaying basally located nuclei and abundant clear to slightly eosinophilic cytoplasm overlying flattened basal cells (Fig. 7-11A). Urothelium may be interspersed with the prostatic epithelium on the surface. The underlying stroma may contain prostatic acini that may show luminal corpora amylacea. The prostatic epithelium is positive for PSA and prostatic acid phosphatase (Fig. 7-11B).⁹⁴,⁹⁹, ¹⁰⁰, ¹⁰¹, ¹⁰²

This benign lesion should be distinguished from prostatic adenocarcinoma, especially in older that secondary involve the urethra¹⁰¹; however, in the latter, prostatic acini are lined by a single layer of malignant epithelial cells with prominent nucleoli. Ductal carcinoma, the most common variant of prostate carcinoma, if low grade, may enter in the differential diagnosis of a prostatic-type polyp. Grossly, the tumor may be seen as an exophytic mass protruding into the prostatic urethra, although it is typically larger than prostatic-type polyps.¹⁰³ Cytologically, even though the tumor forms glands that may superficially mimic the low-power appearance seen in a prostatic-type polyp, in contrast to the latter, there is often some degree of cytologic atypia and absence of basal cells. Furthermore, in most cases, a component of acinar carcinoma may be seen. From the immunohistochemical point of view, 34bE12 is helpful to separate ductal carcinoma (except when intraductal) from a prostatic-type polyp, as the former lacks basal cells.¹⁰³ Rarely, a primary papillary adenocarcinoma of the urethra or the bladder may enter in the differential diagnosis, but these lesions typically display higher degree of cytologic atypia. The histogenesis of this benign polyp is a matter of debate. It has been postulated that it may represent either a metaplastic process (supported by the fact that the prostate normally develops from an anlage of the urothelium of the urethra) or a defect of embryogenesis.⁹⁴ Surgical excision is the treatment of choice with only rare recurrences being reported.

This is a nonneoplastic lesion with a marked male predominance occurring typically in the first decade of life⁹²,¹⁰⁴; however, it can also be seen in adult and female patients.¹⁰⁵, ¹⁰⁶, ¹⁰⁷ It is more often located in the urethra (verumontanum) and urinary bladder.¹⁰⁶,¹⁰⁷ The most common clinical manifestations include hematuria and obstructive symptoms, but it may be an incidental finding.¹⁰⁴,¹⁰⁷,¹⁰⁸ On gross examination, fibroepithelial polyps are typically polypoid, soft, and <4 cm in dimension.⁹²,¹⁰⁵,¹⁰⁷,¹⁰⁹ Histologically, at low power magnification, they may display (a) club-like projections (most common pattern) associated with florid cystitis cystica and glandularis in the stalk; (b) abundant small, plump and rounded fibrovascular cores associated with abundant connective tissue; and (c) simple finger-like projections. They are lined by unremarkable urothelium, but rarely columnar epithelium may be seen.¹⁰⁷ Surface squamous metaplasia and ulceration may occur. Infrequently, the nonsurface epithelial component may show anastomosing nests of urothelium or back to back glands. The stroma may be edematous and may contain atypical stromal cells and calcifications. Entities that more commonly may cause problems in differential diagnosis include florid cystitis glandularis cystica, polypoid or papillary cystitis, and urothelial papilloma. Distinguishing features include absent polypoid or papillary architecture (florid cystitis glandularis); prominent edema and inflammation; and history of instrumentation/trauma (polypoid or papillary cystitis), more delicate stalks or/and associated connective tissue (urothelial papilloma). As this lesion occurs more frequently in early childhood, the differential diagnosis should include botryoid embryonal rhabdomyosarcoma. However, the latter is characterized by a dense “blue” cambium layer under the surface epithelium composed of small immature cells with high nuclear to cytoplasmic ratio and frequent mitotic activity that may alternate with fully developed rhabdomyoblasts showing prominent eosinophilic cytoplasm and cross-striations.¹¹⁰ After surgical excision, these lesions generally do not recur.

Cowper glands, or bulbourethral glands, are present as paired glands in the bulbomembranous urethra, to which they are connected through small ducts. Their acini form small lobules and are composed of cells with abundant mucin.¹¹¹ Cowper gland cyst, also known as syringocele, is a cystic dilatation of the main ducts. It is typically detected in children (congenital) or young adult males (acquired) who present with lower urinary tract symptoms including frequency, urgency, dysuria, postvoid incontinence, recurrent infections and/or hematuria, but it may be asymptomatic.¹¹², ¹¹³, ¹¹⁴, ¹¹⁵, ¹¹⁶ In children, it may be associated with other congenital abnormalities, most often of the urinary tract.¹¹³ The diagnosis is easily confirmed by urethrography,¹¹² and rarely, these specimens undergo pathologic examination. Histologically, the wall of the syringocele may be denuded and associated with prominent inflammation as well as fibrosis of the wall. Treatment consists of marsupialization, and follow-up is uneventful.³⁹,¹¹²

Skene glands and ducts, the homologue of the male prostate gland, are located in the floor of the distal urethra.¹¹⁷ Skene cysts are rare and frequently occur due to obstruction of the ducts most often secondary to infection. They are seen in female patients who may present with dysuria or obstructive voiding symptoms or be asymptomatic.¹¹⁸ Grossly, the cysts vary in size, and on microscopic examination they are lined by stratified squamous epithelium.¹¹⁹ The most common differential diagnosis is with a urethral diverticulum, a distinction that should be made on cystourethroscopy and pelvic MRI findings. Other entities to consider include cystocele and Gartner duct cyst.¹¹⁸ Surgical excision is the treatment of choice.

This is a rare pseudoneoplastic lesion that occurs most commonly in adult males, although it can be seen in
children and females, in the latter frequently in association with a urethral diverticulum.¹²⁰, ¹²¹, ¹²² The urethra is the second most frequent location (15%) following the bladder.¹²³ In most instances, nephrogenic adenoma is an incidental finding at cystoscopy performed for other reasons, but if large it may cause symptoms related to obstruction. In these cases, it may be potentially confused with a malignant tumor, most commonly a low-grade papillary urothelial carcinoma. On microscopic examination, nephrogenic adenoma shows tubular, cystic, papillary, and rarely solid growths, but not infrequently an admixture thereof.¹²²,¹²³ The tubules vary in size and shape and may be solid on rare occasions (Fig. 7-12A). An appreciable basement membrane may be seen surrounding some of the tubules. Of note, the tubules of nephrogenic adenoma may be intermixed with muscle fibers of the muscle fibers present in the wall of the prostatic urethra when the specimen is obtained from transurethral resection (Fig. 7-12B).¹²⁰,¹²⁴,¹²⁵
Recently, a fibromyxoid variant of nephrogenic adenoma has been reported characterized by very small tubules associated with prominent fibromyxoid background that may closely mimic the appearance of an infiltrating carcinoma (Chapter 5).¹²⁶ Cysts are frequently admixed with tubules, but they are not striking in most cases (Fig. 7-12A). The papillae are simple without branching, and they are rarely seen in the absence of tubules. The solid pattern is very rare and, when present, typically represents a minor component. The cells of nephrogenic adenoma are cuboidal to columnar to flattened with variable eosinophilic to slightly clear and granular cytoplasm, and exceptionally they may be spindled.¹²⁶ Hobnail cells are typically present, most often lining the cysts, but are rarely conspicuous.¹²³,¹²⁷ The cells lining tiny tubules have a compressed nucleus with a single vacuole containing basophilic material resembling signet ring cells (Fig. 7-12C). The nuclei are round to oval with minimal cytologic atypia. Nucleoli are inconspicuous, and mitotic figures are rare (<1/10 HPFs) and seen in 5% of the lesions.¹²³ The term “atypical nephrogenic adenoma,” has been used for lesions characterized by nuclear enlargement, nuclear hyperchromasia, and enlarged nucleoli.¹²⁷ There is no known clinical or biologic significance to this designation. The stroma associated with nephrogenic adenoma is focally edematous and contains variable amounts of inflammatory cells. Stromal calcification may be seen.

The immunohistochemical profile of nephrogenic adenoma includes positivity for CK7, epithelial membrane antigen (EMA), vimentin, and PAX2 and PAX8 (the latter two, antigens expressed during embryogenesis),¹²⁸, ¹²⁹, ¹³⁰

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