Case 8 -
Adenocarcinoma, Clear Cell Type
Chris S. Jensen
Department of Pathology
University of Iowa
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The patient is a 55 year old female with a several year history of recurrent urinary tract infections
and recurrent gross hematuria. Her past medical history is remarkable for a TAH/BSO five years
previously. Physical exam revealed a 2-3 cm smooth mass palpable at the mid urethra consistent with a
diverticulum. There was no palpable mass or stone in diverticulum and no urethral discharge on
palpation. The remainder of the exam was unremarkable. A catheterized urine cytology was collected.
MRI revealed a large (3.7 x 2.1 x 2.1 cm) complex left periurethral diverticulum with thick nodular
enhancing walls, (radiologic differential diagnosis includes malignancy in the diverticulum and an
infected diverticulum). Cystoscopy revealed no mucosal lesion and no discernable diverticular opening
associated with the previously noted submucosal mass lesion.
The catheterized urine specimen showed scattered three-dimensional clusters of atypical epithelial
cells in a background of fairly abundant granular acellular debris but little inflammation. The atypical
cells have large, irregular vesicular nuclei with variably coarse chromatin and prominent nucleoli. The
cytoplasm varied from scant to moderate and was granular to finely vacuolated with distinct cytoplasmic
borders. Some of the clusters had scalloped edges with a hobnail appearance. The cytologic diagnosis
was atypical cells, highly suspicious for adenocarcinoma.
Bladder washing cytology which was collected at the time of cystoscopy had a much more prominent
inflammatory background with numerous degenerated neutrophils. Similar three dimensional clusters of
atypical cells with scalloped borders were again noted. Nuclear atypia was again striking with prominent
nucleoli. Cytoplasmic vacuolation was a more prominent feature in some groups giving a suggestion of a
clear cell appearance. The cytologic diagnosis on the bladder washing cytology was "malignant cells,
favor adenocarcinoma" .
Histologic and clinical follow-up
Surgical pathology of needle biopsies of the periurethral mass and mucosal biopsies urinary bladder in
the region of the trigone also showed invasive adenocarcinoma.
After cystoscopy with biopsies, an anterior pelvic exenteration was performed. Gross surgical
pathology specimen from the anterior pelvic exenteration including urethra, urinary bladder and anterior
vaginal wall. There was a 2.0 cm polypoid lesion in the trigone and proximal urethra with an associated
pinpoint opening into a 2.0 cm diverticulum with an associated lumenal papillary tumor. Microscopically
the tumor was predominantly papillary with cystic, tubular and solid areas. The cells, in areas, showed
prominent clear cytoplasm. A hobnail morphology was noted in association with papillae and
cystic/glandular structures. Nuclei were variably pleomorphic with prominent nucleoli. Numerous mitotic
figures were noted in areas. The tumor cells infiltrated the periurethral tissue and extended onto the
Final Surgical Pathology Diagnosis:
Adenocarcinoma, clear cell type, arising in association with a urethral
diverticulum with extension into urinary bladder and periurethral soft tissue
Tumors of the urethra are uncommon and in comparison to other urinary tract sites are more likely to
be malignant. In addition, the urethra is the only site in the urinary tract where tumors are more
common in women than men with distinct clinicopathologic differences between the sexes reflecting the
distinct anatomic and histologic differences.
Squamous cell carcinomas are the most frequent carcinomas in both males and females and tend to occur
distally. Urothelial (transitional) carcinomas, the second most common, usually occur more proximally
corresponding to the predominant area lined by urothelium. Adenocarcinomas account for approximately 10%
of urethral carcinomas and may have a variety of histologic types as can be seen throughout the urinary
tract. Interestingly, clear cell adenocarcinomas represent a larger proportion of adenocarcinomas in the
urethra than other urinary tract sites. Urethral adenocarcinomas of both clear cell and non-clear cell
types are more frequently associated with diverticula than other histologic types.
Urethral diverticula and carcinoma
Urethral diverticula are relatively
common in females and are typically located in the mid to distal urethra posteriorly. Although
diverticula may be either congenital or acquired, most are thought to be acquired lesions associated with
inflammation and dilatation of periurethral glands. This association with periurethral glands is
interesting given histologic types of carcinoma associated with diverticula which is essentially the
inverse of urethral carcinoma in general with adenocarcinoma followed by urothelial and squamous cell
carcinomas. An association between squamous carcinomas diverticular stones has been noted.
Clear cell adenocarcinoma is an unusual tumor which is indistinguishable
from clear cell tumors of the female gynecologic tract. These tumors are most frequently seen in the
urethra of older women and are often associated with diverticula. Although clear cell adenocarcinoma can
occur throughout the urinary tract, the prevalence in the urethra and similarity to gynecologic tumors is
interesting and has led to speculation about pathogenesis. However, unlike gynecologic clear cell
carcinomas, no association with DES exposure has been noted.
The tumors of urethral clear cell adenocarcinoma are most commonly located in the posterior urethra
and are associated with a urethral diverticulum in greater than 50% of the reported cases. Typically the
tumors are larger than 2 cm and may be polypoid. Clinical findings include urinary tract obstruction /
infection, hematuria, dysuria, dyspareunia and vaginal mass.
Histologic patterns include papillary, tubular, cystic and diffuse with several patterns typically
being present within the same tumor. The characteristic cytologic features include cells with abundant
clear cytoplasm and characteristic hobnail cells. Significant nuclear pleomorphism is typical and
prominent nucleoli are commonly noted along with variable numbers of mitotic figures.
Histologic differential diagnosis includes nephrogenic adenoma (atypical nephrogenic metaplasia), a
benign lesion which may also occur in association with urethral diverticula and typically has a papillary
architecture. Clear cell change may be seen in nephrogenic adenoma, although it is almost always focal,
as is cytologic atypia. Additionally, clear cell adenocarcinoma must be distinguished from urothelial
carcinoma with clear cell features, non-clear cell adenocarcinomas of the bladder or urethra, prostatic
adenocarcinoma in males, and metastatic clear cell tumors from the kidney and gynecologic sites.
Nephrogenic adenoma, which can be confused with clear cell adenocarcinoma, is typically a small
polypoid lesion which occurs in association with some type of injury to the urothelium in most cases.
Similar to clear cell carcinoma, nephrogenic adenoma may have papillary, tubulocystic and focally diffuse
patterns. In addition, hobnail morphology is quite common and occasional lesions also have clear cell
areas, although these are seldom dominant. Further confusion may result from the occasional association
of nephrogenic adenoma with urethral diverticula. Although nephrogenic adenoma may show focal nuclear
atypia, mitoses are rare and the identification of more than occasional mitoses should lead to
consideration of clear cell carcinoma. The most frequent problems in distinction relate to small biopsy
samples which may not show the atypia or mitotic activity. In many cases correlation with clinical
findings when available can be helpful.
Immunohistochemical analysis has fueled speculation about pathogenesis but has not proved particularly
helpful in the distinction of clear cell adenocarcinoma from other lesions. The immunohistochemical
profile is identical to gynecologic clear cell carcinoma, but is not very specific and overlaps with
urothelial carcinoma, non-clear cell adenocarcinoma of the urothelial tract and prostatic adenocarcinoma.
There has been much speculation about the pathogenesis of clear cell carcinoma of the urethra and
urinary tract. Although early thoughts included mesonephric remnants, there has been no convincing
evidence. Similarly, despite some reports of association with nephrogenic adenoma, the current thinking
of most authors has not supported nephrogenic adenoma as a precursor lesion. Although some cases of
clear cell carcinoma in the urinary bladder appear to be associated with Mullerian lesions or remnants,
this association in the urethra has only rarely been noted and it seems doubtful this accounts for most
cases. The presence of prostatic antigens in rare cases has also led to speculation about origin in
Skene's glands, the embryologic analog of the prostate gland in the female, although again it is unlikely
this accounts for most cases. Current thinking favors an alternative pathway possibly associated with
paraurethral glands which could also account for the frequent association with diverticula.
The prognosis for urethral tumors in general tends to be worse when compared to the bladder, possibly
related to higher stage at presentation in many cases. Clear cell carcinoma appears to have a slightly
better prognosis than non-clear cell tumors of the urethra for reasons which are not understood.
Cytologic features of adenocarcinoma of clear cell type
There have been relatively few reports of the cytologic features of clear cell adenocarcinoma of the
urinary tract. The cytologic features reported are similar to those noted in the current case and are
similar to those of clear cell adenocarcinoma of the female gynecologic tract . Several reports have
described a dimorphic tumor cell population
. The first cell type is described as clear cells with
abundant clear or vacuolated cytoplasm and central nuclei. These cells have been described as resembling
the cells of renal cell carcinoma . Cells of this type were noted only in the bladder washing from
the current case. The second population described was the dominant cell type in the current case. These
cells tend to occur in clusters and are variably described as cuboidal to columnar. The cells have high
nuclear to cytoplasmic ratio. Nuclei are large and tend to be eccentrically located with irregular
nuclear contours and prominent nucleoli. These cellular clusters may have a hobnail appearance
corresponding to a characteristic histologic feature of clear cell adenocarcinoma. Similar cells have
also been described as a cytologic finding in clear cell adenocarcinoma of the female genital tract.
Although these cytologic features may suggest the diagnosis, a specific cytologic diagnosis of clear
cell adenocarcinoma may not be possible in most cases. The recognition of the malignant features is the
primary goal. The potential value of recognizing the features of clear cell adenocarcinoma may be
related to the clinical distribution of tumor noted above. The cytopathologist could alert the clinician
to the increased likelihood of tumor within the urethra or an associated diverticulum. Additionally,
close correlation with clinical history is necessary to exclude a clear cell carcinoma metastatic from
the gynecologic tract
The cytologic differential diagnosis includes non-clear cell adenocarcinoma
(primary or metastatic), urothelial carcinoma, nephrogenic adenoma and reactive changes with prominent
cytoplasmic vacuolation. Certainly distinction from the benign reactive changes and nephrogenic adenoma
is essential. Fortunately, given the overtly malignant nuclei seen in clear cell adenocarcinoma this is
likely not problematic in most cases. The diagnosis of malignancy with clear cell features should never
be made on the basis of cytoplasmic clarity alone in the absence of characteristic nuclear atypia with
prominent nucleoli. Despite the potential confusion histologically with nephrogenic adenoma, most
cytologic descriptions of nephrogenic adenoma describe bland cells and papillary groups without
significant nuclear atypia. Rare atypical cells with vacuolated cells may occasionally be noted in
cytologic specimens .
By contrast, high grade urothelial carcinoma (UC), shares malignant nuclear atypia with clear cell
carcinoma. Nucleoli, as characteristically seen in clear cell carcinoma, are not typically a prominent
feature in UC. In addition, cytoplasmic clearing or vacuolation is usually only focal. Occasional UC do
show sufficient cytoplasmic clearing to raise the consideration of clear cell carcinoma, but these tumors
again typically lack the characteristic nuclear features. Similarly, non-clear cell adenocarcinoma,
either primary or metastatic, may have cytoplasmic vacuolation. More typically, these cells are columnar
or stratified and lack a hobnail configuration. Background mucinous material or signet ring cells may
also be clues to non-clear cell differentiation. Distinction from metastatic renal cell carcinoma rests
on clinical history and the absence of hobnail morphology. Clear cell carcinoma metastatic from the
gynecologic tract is indistinguishable cytologically from primary clear cell carcinoma.
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