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Pseudocarcinomatous Hyperplasia of the Urinary Bladder.

STUDY CASE

A 64-year-old man presented with gross hematuria and bladder lesions seen on cystoscopy. Biopsies of these lesions revealed extensive proliferative urothelial nests within the lamina propria; some of these nests had abundant eosinophilic cytoplasm imparting a "squamoid" appearance (Figure 1, A). In other areas, these nests were irregular, appeared to be infiltrative, and had random, degenerative-type nuclear atypia (Figure 1, B). The overlying urothelium was flat and appeared to be reactive rather than neoplastic, with cells with enlarged yet round nuclei with cleared chromatin and prominent nucleoli and a prominent umbrella cell layer. Within the lamina propria, proliferative, dilated vessels, some with prominent thromboses, were present. In addition, background hyalinization, hemosiderin-laden macrophages, edema, and chronic inflammation were present (Figure 1, A and C). Upon examination of the patient records, it was discovered that the patient had undergone radiation therapy for prostatic adenocarcinoma 2 years prior. Based on the overall morphologic features, a diagnosis of pseudocarcinomatous hyperplasia (radiation cystitis) was rendered.

COMMENT

First described in 2000 by Baker and Young, (1) pseudocarcinomatous hyperplasia (also termed pseudocarcinomatous proliferation or radiation cystitis) is currently thought to be a benign, reactive condition most commonly seen in patients with a history of radiation therapy (1,2) ; approximately 75 unique cases have been described in the literature. Approximately 80% to 85% of reported cases occurred in men, owing to the predominance of irradiation for prostate cancer. The median/average ages in case series have ranged from 65 to 69 years, with patients as young as 33 years and as old as 85 years reported. Originally described exclusively in patients with a history of radiation therapy or chemotherapy, subsequent case series found an association in a subset of patients with any ischemic insult to the bladder. (1-4) In a study by Kryvenko and Epstein, (2) of (70) patients with pseudocarcinomatous hyperplasia, the most common associated risk factor was pelvic irradiation (75%), most commonly for prostatic adenocarcinoma, but also for urothelial, endometrial, cervical, and colorectal carcinomas. Other associated risk factors included vascular insufficiency, such as peripheral vascular disease, chemotherapy, chronic catheterization, or prior prostatectomy. Of note, in very rare cases, no associated risk factor is present. The average time interval in their study between radiation therapy and the diagnosis of radiation cystitis was 54.6 months, but diagnoses have been reported as far as 13 years from the time of irradiation. (2) Although risk factors are present in most patients with pseudocarcinomatous hyperplasia, it must be noted that since the irradiation may be remote, the pathologist may not receive the relevant clinical history at the time the biopsy specimen is received. In our experience, in most of our consultation cases of pseudocarcinomatous hyperplasia, the history of radiation therapy is not received but is found after a review of the patient's records and/or discussion with the clinician.

Patients with pseudocarcinomatous hyperplasia most often present with hematuria, but dysuria, lower abdominal pain, or patients undergoing surveillance biopsies for a prior diagnosis of urothelial carcinoma have also been reported. Usual cystoscopic findings include erythema or erythematous plaques, a papillary or polypoid lesion, edema, or shallow ulcers. (2)

Typical histologic features include irregular, sometimes infiltrative-appearing urothelial nests within the lamina propria, which can mimic invasive carcinoma. These nests can be quite proliferative and back to back (Figure 1, D and E); in one series by Chan and Epstein, (3) most of the cases (45%) had "marked" proliferations, meaning they occupied more than 50% of the lamina propria. These nests can range from being bland to having nuclear atypia; often the associated atypia is random, degenerative atypia commonly seen after radiation therapy. While mild to moderate atypia is common, marked atypia and marked, severe pleomorphism have not been reported. Nucleoli may be present. Mitoses most often are not present, but rarely, increased mitotic activity may be seen. Nuclear and cytoplasmic vacuoles are often present. Often, the nests will have abundant eosinophilic cytoplasm, and this cytoplasm may appear "glassy," imparting a "squamoid" appearance to the nests. (3) One potential histologic pitfall is that these squamoid nests may mimic reverse maturation, a histologic feature of invasive urothelial carcinoma. In well-oriented sections, these nests may have a sharply demarcated base, allowing a clue that the overall process is reactive (Figure 1, F). One feature which is unfortunately not seen in all cases but is rather characteristic is the presence of attenuated urothelial nests that appear to "wrap around" the thrombosed, dilated lamina propria vessels and fibrin thrombi. (1,3,4) Of note, in no reported cases have the nests extended into the muscularis propria. (1-4)

In the background lamina propria, proliferative dilated vessels, some with prominent thromboses, are often present; other reactive changes, such as stromal hemorrhage, edema, stromal hyalinization, hemosiderin-laden macrophages, inflammation, and ulceration/denudation, are also often present. The overlying urothelium may have random, degenerative-type atypia with "smudged" chromatin, nuclear or cytoplasmic vacuoles, or cytoplasmic ballooning; usually, even those cells with nuclear atypia and enlargement still have abundant cytoplasm. Overlying papillary neoplasia or flat urothelial carcinoma in situ should be absent. The key to correctly diagnosing this entity is to recognize enough reactive and therapy-related changes in the background; a history of radiation or chemotherapy can lend further support to the diagnosis.

Follow-up in various case series (average follow-up times ranging from 9 to 27 months) has shown that nearly all of the patients have had a benign course with no subsequent development of urothelial carcinoma. (1-4) In a study by Kryvenko and Epstein, (2) of 40 patients with follow-up, 3 developed subsequent urothelial carcinoma. Of note, however, 1 of these patients had a prior history of urothelial carcinoma treated with radiation and 1 patient had an unknown history. The third patient had a prior positive cytology and fluorescence in situ hybridization finding, and authors theorized that the patient had an unsampled urothelial carcinoma. These findings suggest that the development of urothelial carcinoma in these patients was due to urothelial neoplasia present elsewhere in the bladder, unrelated to their pseudocarcinomatous hyperplasia; therefore, although it is somewhat controversial whether radiation therapy itself is a risk factor for the development of urothelial carcinoma, pseudocarcinomatous hyperplasia itself is now thought to be a benign reactive condition with no proven increased risk for the development of subsequent urothelial carcinoma. (2)

The most clinically significant differential diagnoses for pseudocarcinomatous hyperplasia include invasive high-grade urothelial carcinoma and the nested variant of urothelial carcinoma. This is highlighted by the fact that in the study of Kryvenko and Epstein, (2) up to 20% of their consultation cases came with a contributing diagnosis of neoplasia or carcinoma by the referring pathologist.

When invasive urothelial carcinomas are high grade, pleomorphic, and have marked atypia and numerous mitoses, the distinction between invasive urothelial carcinoma and pseudocarcinomatous hyperplasia is not difficult. However, invasive urothelial carcinomas that are more monotonous or have more subtle atypia can be difficult to distinguish from pseudocarcinomatous hyperplasia; even urothelial carcinomas with more muted atypia, however, may have more uniformly enlarged or hyperchromatic nuclei with increased mitoses or apoptosis (Figure 2, A). Invasive urothelial carcinomas are more likely to have confluent nests or markedly irregular nests with associated infiltrating single cells or cords of cells (Figure 2, A and B). Often, urothelial carcinomas will have a haphazard, disordered growth with an irregular base to the lesion and may be deeply invasive into the muscularis propria. The presence of overlying papillary or flat urothelial carcinoma, retraction artifact, or a stromal response also favors invasive urothelial carcinoma. In contrast, while some areas in pseudocarcinomatous hyperplasia may have irregular nests, in other areas, round squamoid nests are often present. In well-oriented sections, the base of pseudocarcinomatous hyperplasia will typically have a somewhat linear delineation from the uninvolved lamina propria, and urothelial nests in pseudocarcinomatous hyperplasia should not be present in the muscularis propria. The presence of nests wrapping around fibrin or vessels, as well as background changes, such as thrombosed dilated vessels and stromal and endothelial cells with radiation-type changes, are helpful clues to the diagnosis of pseudocarcinomatous hyperplasia. (3)

Nested urothelial carcinoma is a specific variant of invasive urothelial carcinoma in which the invasive urothelial nests are deceptively cytologically bland and mimic von Brunn nests (5); despite their bland cytologic features, nested urothelial carcinomas can often be deeply invasive. (6,7) In general, nested urothelial carcinomas are composed of somewhat disordered, confluent, anastomosing urothelial nests (Figure 2, C). The base of nested urothelial carcinomas in well-oriented sections is generally irregular with an infiltrative edge compared to the generally linear, demarcated base seen in most cases of pseudocarcinomatous hyperplasia (Figure 2, D). While nested urothelial carcinomas are generally cytologically bland, some subtle cytologic atypia is often present; this atypia is often more pronounced toward the base of the carcinoma. Many nested urothelial carcinomas are deeply invasive, and presence of urothelial nests within the muscularis propria would essentially exclude the diagnosis of pseudocarcinomatous hyperplasia. (7) Finally, while it is possible that a nested urothelial carcinoma could arise in a patient with a history of radiation therapy, in general nested urothelial carcinoma would lack the background changes of radiation therapy as well as the characteristic urothelial nests that "wrap around" vessels and fibrin thrombi so commonly seen in pseudocarcinomatous hyperplasia.

CONCLUSION

Pseudocarcinomatous hyperplasia is a reactive process in which proliferative benign urothelial nests involve the lamina propria. Pathologists must be cognizant of this entity, as these urothelial nests can be quite extensive and can mimic an invasive urothelial carcinoma or a nested urothelial carcinoma. Unfortunately, as there are no immunostains or secondary studies that can help distinguish between pseudocarcinomatous hyperplasia and urothelial carcinoma, one must rely on distinguishing morphologic features. Careful attention to the overall morphology of the proliferative urothelial nests is necessary; in pseudocarcinomatous hyperplasia they are usually discrete and may be round, often have central squamoid features, may have a generally linear delineation at the base, and typically lack marked atypia or numerous mitoses. The most helpful feature in pseudocarcinomatous hyperplasia is the presence of background radiation therapy-related changes, in particular dilated, thrombosed vessels. Recognition of the relevant morphologic features may then trigger a review of the patient's records, as a history of radiation or other ischemic insult to the bladder may lend support to the diagnosis. Pathologists must be aware of this entity to avoid a potentially significant misdiagnosis.

Please Note: Illustration(s) are not available due to copyright restrictions.

The author would like to thank Robin Kunkel, MS, for her assistance with the figures.

References

(1.) Baker PM, Young RH. Radiation-induced pseudocarcinomatous proliferations of the urinary bladder: a report of 4 cases. Hum Pathol. 2000; 31(6):678-683.

(2.) Kryvenko ON, Epstein JI. Pseudocarcinomatous urothelial hyperplasia of the bladder: clinical findings and followup of 70 patients. J Urol. 2013; 189(6):2083-2086.

(3.) Chan TY, Epstein JI. Radiation or chemotherapy cystitis with "pseudocarcinomatous" features. Am J Surg Pathol. 2004; 28(7):909-913.

(4.) Lane Z, Epstein JI. Pseudocarcinomatous epithelial hyperplasia in the bladder unassociated with prior irradiation or chemotherapy. Am J Surg Pathol. 2008; 32(1):92-97.

(5.) Murphy WM, Deana DG. The nested variant of transitional cell carcinoma: a neoplasm resembling proliferation of Brunn's nests. Mod Pathol. 1992; 5(3): 240-243.

(6.) Drew PA, Furman J, Civantos F, Murphy WM. The nested variant of transitional cell carcinoma: an aggressive neoplasm with innocuous histology. Mod Pathol. 1996; 9(10):989-994.

(7.) Wasco MJ, Daignault S, Bradley D, Shah RB. Nested variant of urothelial carcinoma: a clinicopathologic and immunohistochemical study of 30 pure and mixed cases. Hum Pathol. 2010; 41(2):163-171.

Angela Wu, MD

Accepted for publication June 4, 2014.

From the Department of Pathology, University of Michigan Medical School, Ann Arbor.

The author has no relevant financial interest in the products or companies described in this article.

Presented in part at the New Frontiers in Pathology: An Update for Practicing Pathologists meeting; University of Michigan; September 26-28, 2013; Ann Arbor, Michigan.

Reprints: Angela Wu, MD, Department of Pathology, University of Michigan, 1500 E Medical Center Dr, 2G332 UH, Ann Arbor, MI 48109 (e-mail: angelawu@med.umich.edu).

Caption: Figure 1. Bladder biopsy specimen from our study case of a 64-year-old man who presented with hematuria. A, Extensive proliferative urothelial nests were present in the lamina propria; many of these nests were rounded and had central squamoid appearance (black arrow). Background hyalinization was also present (white arrow). B, In some areas, the nests had a pseudoinfiltrative architecture; these nests had some random, degenerative nuclear atypia. C, Within the background, there were numerous dilated, thrombosed vessels; stromal edema and hemorrhage; and enlarged reactive stromal cells. The final diagnosis was pseudocarcinomatous hyperplasia. D, Another example of pseudocarcinomatous hyperplasia in which the lamina propria was extensively involved by round, relatively bland, urothelial nests; note the proliferative background thrombosed vessels (arrow). E, Another example of pseudocarcinomatous hyperplasia; while many of the nests are irregular and have a pseudoinfiltrative appearance, the nests are relatively cytologically bland and have a squamoid appearance. There is background stromal edema and hemorrhage. F, In pseudocarcinomatous hyperplasia, in well-oriented sections, the nests often have a sharply demarcated linear base. One characteristic feature is the presence of nests that appear to "wrap around" vessels or fibrin thrombi (arrow) (hematoxylin-eosin, original magnifications x40 [A through C, E and F] and x20 [D]).

Caption: Figure 2. The differential diagnoses for pseudocarcinomatous hyperplasia include invasive urothelial carcinoma and the nested variant of urothelial carcinoma. A, Invasive urothelial carcinoma often has more confluent architecture, compared to the more discrete nests typically seen in pseudocarcinomatous hyperplasia. While the atypia is somewhat muted in this example, there is some nuclear monotony and diffuse enlargement. B, This invasive carcinoma is difficult to distinguish from pseudocarcinomatous hyperplasia owing to the lack of cytologic atypia in the nests; however, the nests again have a confluent architecture. Toward the base, there are some infiltrative cords and single cells, which would be more compatible with an invasive neoplasm (arrow). C, The nested variant of urothelial carcinoma is composed of bland urothelial nests; however, the nests are usually more confluent and irregular than those in pseudocarcinomatous hyperplasia. D, Nested urothelial carcinomas usually have an infiltrative, irregular base; the presence of urothelial nests within the muscularis propria (arrow) essentially rules out the diagnosis of pseudocarcinomatous hyperplasia (hematoxylin-eosin, original magnifications x100 [A and C] and x40 [B and D]).
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Author:Wu, Angela
Publication:Archives of Pathology & Laboratory Medicine
Date:Oct 1, 2014
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