A 70 year-old man with a history of adenocarcinoma of the prostate Gleason score 7 was treated with
neoadjuvant hormone therapy and external beam radiotherapy. Two years following radiation the patient
presented with gross hematuria. At cystoscopy, an erythematous lesion was identified and biopsied.
The specimen consists of multiple TUR fragments of bladder tissue. In some tissue fragments, the
urothelium appears unremarkable. In the lamina propria, numerous hemosiderin-laden macrophages are
noted. Many of the stromal cells appear enlarged with hyperchromatic nuclei containing smudgy chromatin.
Occasional stromal cells are multinucleated. In a tissue fragments, there is a proliferation of
urothelial nests extending down into the superficial lamina propria. These nests are associated with
recent hemorrhage and hemosiderin deposition. In addition, many of the vessels in these foci are dilated
and associated with fibrin deposition. The urothelial nests show moderate cytological atypia with
occasional nuclear enlargement and prominent nucleoli. Only rare mitotic figures are identified and the
urothelium overlying these nests appears unremarkable. The muscularis propria is uninvolved.
Diagnosis: Pseudocarcinomatous Urothelial Hyperplasia following
Case 4 - Figure 1 - Low magnification image showing proliferation of urothelial nests into lamina propria.
Case 4 - Figure 2 - Intermediate magnification demonstrating nests of urothelium extending into the lamina propria. Note associated recent hemorrhage and overlying normal urothelium.
Case 4 - Figure 3 - Nests of urothelium associated with dilated congested vessels and fibrin deposition.
Case 4 - Figure 4 - Nests of urothelium associated with recent hemorrhage. Note moderate nuclear pleomorphism and occaisional prominent nucleoli.
Radiation Changes in the Bladder
Radiotherapy leads to urothelial cell enlargement, multinucleation, and vacuolization with maintenance
of abundant cytoplasm.1 It has been stated by some experts in the field that urothelial
radiation atypia persists for up to 3 months following cessation of treatment, although there is no data
on this phenomenon. However, just because there is urothelial atypia with a history of radiotherapy, one
cannot discount the possibility of CIS, as radiation is also associated with an increased risk of bladder
cancer. I consider the presence of atypia persisting over 6 months following radiation to suggest
neoplastic atypia. Histologically, the finding of mitotic figures in atypical urothelium is also more
consistent with CIS, as opposed to radiation atypia.
Even less familiar to pathologists is radiation-induced pseudocarcinomatous hyperplasia. The first
series to report this mimicker of invasive urothelial carcinoma was by Baker and Young in
2000.2 Four cases were described, with follow-up available in one patient, which was
benign. We have recently studied 15 cases with either radiation or chemotherapy induced
pseudocarcinomatous hyperplasia in the bladder; all 10 cases where follow-up information is available
have had a benign clinical course. All patients presented with hematuria. Twelve (80%) of the patients
were male with an age range of 40 years to 85 years (median 70). The median interval from radiation to
clinical presentation was 15.5 months. The longest interval in our study was 79 months and in the study
by Baker and Young 96 months. The lesion consists of irregular nests of urothelium proliferating into
the lamina propria. In addition to the architectural pattern mimicking cancer, most cases had prominent
nucleoli, mild to moderate pleomorphism, and a few cases demonstrated mitotic figures. Key features to
recognizing the nonneoplastic nature of this entity include the following features seen in the majority
of cases: edema, hemorrhage, hemosiderin, inflammation, and most importantly fibrin deposits with in
many cases the urothelial nests encircling the fibrin. The nests also do not extend irregularly down
into the lamina propria or muscularis propria as is seen with the urothelial carcinoma. Seen in 50% of
the cases were ulceration, epithelial vacuolization, and thick vessels, which are clues to the prior
irradiation. The atypical stromal cells may also reflect prior irradiation, although similar cells may
also be seen in the lamina propria without a history of prior radiotherapy, where the findings are
referred to as giant cell cystitis.
Immunotherapy and Chemotherapy Changes in the Bladder
In addition to the awareness of radiation induced pseudoneoplastic changes in the bladder,
pathologists must also be familiar with changes that can be attributable to immunotherapy and
chemotherapy. Immunotherapy with Bacillus Calmette-Guerin (BCG) is used to treat CIS along with
noninvasive and superficially invasive papillary urothelial carcinoma at high risk of recurrence and/or
progression. BCG treatment results in noncaseating and caseating granulomas with at most nonspecific
reactive urothelial atypia due to inflammation. As such, significant urothelial atypia cannot be
ascribed to BCG and must represent urothelial neoplasia.
Two other intravesicle agents are also used to treat superficial bladder cancer. Thiotepa and
mitomycin C are used in patients who cannot tolerate BCG therapy. Another role is for these agents to be
instilled into the bladder immediately following the TUR of lesions with a high likelihood of recurrence.
BCG cannot be used in this setting as BCG administration must wait several weeks following TUR to prevent
systemic tuberculous infection. Both thiotepa and mitomycin C produce identical histologic changes.
Fortunately for pathologists, these agents give rise to changes within the umbrella cells, which can be
easily distinguished from CIS on tissue sections. Umbrella cells become large, vacuolated, and
multinucleated.1,3,4 These agents also work by truncating off the tips of the papillae
of papillary urothelial neoplasms, giving rise to stubby papillae lined by neoplastic cells.
Another chemotherapeutic agent used in a variety of malignancies and various miscellaneous conditions
can cause histological changes in the urothelium mimicking bladder cancer. Cyclophosphamide (cytoxan)
may result in hemorrhagic cystitis along with the pseudocarcinomatous hyperplasia described resulting
from radiation.5-7 We have also seen identical findings following cisplatin
chemotherapy. Cytoxan may also give rise to reactive urothelial atypia, which tends to effect the
umbrella cells and hence is more of a diagnostic dilemma in evaluating cytological
- Lopez-Beltran A, Luque RJ, Mazzucchelli R, Scarpelli M, Montironi R. Changes produced in the
urothelium by traditional and newer therapeutic procedures for bladder cancer. J Clin Pathol 2002;
- Balker PM, Young RH. Radiation-induced pseudocarcinomatous proliferations of the urinary bladder: A
report of 4 cases. Hum Pathol 2000; 31:678-683.
- Lopez-Beltran A. Bladder treatment: immunotherapy and chemotherapy. Urol Clin N America
- Murphy WM, Soloway MS, Finebaum PJ. Pathological changes associated with topical chemotherapy for
superficial bladder cancer. J Urol 1981; 126:461-464.
- Stillwell TJ, Benson RC Jr. Cyclophosphamide-induced hemorrhagic cystitis: A review of 100
patients. Cancer 1988; 61:451-457.
- Rubin JS, Rubin RT. Cyclophosamide hemorrhagic cystitis. J Urol 1966; 96:313-316.
- Goldman RL, Warner NE. Hemorrhagic cystitis and cytomegalic inclusions in the bladder associated
with cyclophosphamide therapy.
- Forni AM, Koss LG, Geller W. Cytological study of the effect of cyclophosphamide on the epithelium of
the urinary bladder in man. Cancer 1964:17:1348-1355.
RADIATION CHANGES IN THE PROSTATE
The use of radiotherapy as a primary treatment for clinically localized prostate cancer has been
increasing. Typically, following radiotherapy the serum PSA level will decrease to a nadir level. In
some men, the PSA will then subsequently rise, prompting a needle biopsy to verify recurrent prostate
cancer. Often pathologists will not get a history of prior irradiation, such that it is necessary for
them to recognize the histologic features of radiation atypia in benign glands so as to avoid a
misdiagnosis of cancer.
Within the non-neoplastic prostatic glands, radiation results in glandular atrophy, squamous
metaplasia, and cytologic atypia.1 Though one may find vascular radiation changes, the
stromal atypia characteristic of radiation in other organs is not usually seen.
The distinction between irradiated non-neoplastic prostatic glands and carcinoma is best made on the
low magnification architectural pattern of the glands. Within the radiated normal prostate, glands
maintain their normal architectural lobular configuration. In contrast to carcinoma, the non-neoplastic
glands are separated by a modest amount of prostatic stroma. On higher magnification, whereas glands of
prostatic carcinoma are lined by a single cell layer, there is piling up of the nuclei within irradiated
normal prostate as well as an occasional recognizable basal cell layer. This piling up of the cells in
radiated benign glands frequently appears slightly spindled resembling transitional cell metaplasia. The
finding of scattered markedly atypical nuclei within well-formed acini is typical of radiated benign
glands and rare in prostate carcinoma. Prostate carcinomas that are sufficiently differentiated to form
glands rarely manifest the degree of atypia seen with radiation, and if present would be more uniformly
present in all cells. Radiated nuclei also have a degenerative, hyperchromatic smudgy appearance as
opposed to malignant prostatic nuclei that usually contain prominent nucleoli. Irradiated non-neoplastic
glands often are atrophic, in contrast to gland forming prostatic adenocarcinomas that typically have
abundant cytoplasm. It has been demonstrated that high molecular weight cytokeratin immunohistochemistry
can aid in the diagnosis of irradiated prostate by identifying basal cells within benign radiated
Radiated adenocarcinoma of the prostate may show either no recognizable difference from non-radiated
cancer or the effects of radiation damage. In order to diagnose either pattern of cancer, the key
feature is that architecturally the findings are inconsistent with benign glands. The presence of
closely packed glands with a haphazard infiltrative growth pattern is typical of adenocarcinoma and
cannot be attributed to radiation change. Similarly, the presence of infiltrating individual epithelial
cells is diagnostic of carcinoma. Cancers not showing any treatment effect have typical prostate cancer
nuclei with prominent nucleoli and glands with a modest amount of cytoplasm. Cancers with radiation
effect demonstrate either glands or individual cells with abundant vacuolated cytoplasm or single cells
with indistinct cytoplasm. Nuclei lack apparent nucleoli and are either large with bizarre shapes or
pyknotic with smudged chromatin.3
We have recently shown that there is more atypia in cases treated with brachytherapy than external
beam radiotherapy (XRT).4 Whereas there was no change over time in epithelial atypia in
men treated with brachytherapy. With XRT, there was less epithelial atypia in cases biopsied more than
48 months after treatment compared to those with a shorter interval between biopsy and treatment.
Radiation atypia in benign prostate glands may persist for a long time after the initial treatment,
resulting in a significant pitfall in evaluating prostate biopsies. Prominent radiation effect was
detected up to 72 months in one of the patients treated with brachytherapy.
Post-radiotherapy biopsies can be classified into three groups, positive, negative, or indeterminate
(cancer with treatment effect).5 When signing out post-radiotherapy biopsies, we
diagnose them as "benign", "cancer without treatment effect" (a Gleason grade is assigned), or "cancer
showing treatment effect" (no Gleason grade assigned).
- Bostwick DG, Egbert BM, Fajardo LF. Radiation injury of the normal and neoplastic prostate. Am J
Surg Pathol 1982;6:501-551.
- Brawer MK, Nagle RB, Pitts W, et.al. Keratin immunoreactivity as an aid to the diagnosis of
persistent adenocarcinoma following prostatic irradiation. Cancer 1989;63:454-460.
- Crook JM, Bahadur YA, Robertson SJ, et al. Evaluation of radiation effect, tumor differentiation,
and prostate specific antigen staining in sequential prostate biopsies after external beam radiotherapy
for patients with prostate carcinoma. Cancer 1997; 79:81-89.
- Magi-Galluzzi C, Sanderson H, Epstein JI. Atypia in non-neoplastic prostate glands after
radiotherapy for prostate cancer: duration of atypia and relation to type of radiotherapy. Am J Surg
Pathol (in press).
- Crook J, Malone S, Perry G, et al. Postradiotherapy prostate biopsies: What do they really mean?
Results for 498 patients. Int J Rad Onc Biology Physics 2000;48:355-67.