Case 3 -
Acquired Cystic Kidney Disease-Specific Renal Cell Carcinoma
Joan & Sanford I.
Wiell Medical College of Cornell University
New York, NY
Click on each slide thumbnail image for an enlarged view
A 68-year-old female on hemodialysis for chronic renal failure was found to have a 4 cm solid mass in
her left kidney. Left simple nephrectomy was performed.
Case 3 - Figure 1 - Intermediate magnification view of the smaller tumor. Large eosinophilic cells arranged in cribriform, tubular and microcystic architecture. Numerous intratumoral oxalate crystals are present (open arrowheads).
Case 3 - Figure 2 - Higher magnification view of the smaller tumor showing the cytologic details, including Fuhrman's grade 3 nuclei, and abundant eosinophilic granular cytoplasm.
Case 3 - Figure 3 - The larger tumor with focal cribriform architecture. While most of the cells have eosinophilic granular cytoplasm, some cells in the lower half of the image show focal cytoplasmic clarity.
Case 3 - Figure 4 - An area of papillary growth pattern in the larger tumor.
Case 3 - Figure 5 - Focal clear cell (conventional) renal cell carcinoma-like features in the larger tumor.
Case 3 - Figure 6 - Marked cystic change in the residual renal parenchyma.
The renal parenchyma was almost completely replaced by thin-walled cysts that did not communicate with
the pelvicalyceal system. Most cysts contained pale-yellow clear fluid. Two masses, with the maximum
diameters of 4.3 and 2.5 cm, respectively, were identified in the lower and the mid portions of the
kidney. Both had a brown-tan cut surface, and the larger tumor showed large areas of hemorrhage and
necrosis. While the larger tumor appeared solid, the smaller one had a spongy cut surface with multiple
clear fluid-containing cysts ranging from less than 0.1 to 0.4 cm in size.
Slide #1 has been prepared from the larger tumor, and #2 from the smaller one. Both share the common
feature of areas with cribriform to (micro)cystic architecture, with cells containing abundant granular,
eosinophilic (oncocytic) cytoplasm and Fuhrman's grade 3 nuclei. Some cells in these areas exhibit
hobnailed appearance. The smaller tumor (slide #2) shows this morphology in almost its entirety, whereas
the larger tumor (slide #1) has a more variegated morphology. The larger tumor also contains areas with
papillary, as well as solid and acinar growth patterns. Some foci closely mimic clear cell
(conventional) renal cell carcinoma, with clear to finely vacuolated cytoplasm. The central part of the
tumor shows extensive necrosis. There is extensive calcium oxalate crystal deposition within both the
tumors, and foci of calcification, including psammomatous type, are also present. The small amount of
surrounding kidney in these sections shows multiple cysts, some lined by cells with eosinophilic
cytoplasm and others by clear cells.
Acquired Cystic Kidney Disease-Specific Renal Cell Carcinoma
Acquired Cystic Kidney Disease (ACKD) is characterized by the development of multiple cysts in the
kidneys of patients with End-Stage Renal Disease (ESRD), in the absence of congenital cystic
The prevalence and severity of ACKD progressively increases in patients on
dialysis (both hemo- and peritoneal-dialysis), being present in 20% of the cases on 1-3 years of
dialysis, and approximately 90% of the patients on dialysis for 5-10 years.
may develop in cases of ESRD who have never received any dialysis. 
There is almost a 100-fold increase in the prevalence of renal cell carcinoma in patients with ACKD as
compared to the general population.
Renal tumors arising in ACKD have variably been
reported to be papillary, clear cell (conventional), multilocular cystic, or chromophobe renal cell
carcinomas, with papillary renal cell carcinoma being considered as the commonest subtype in most
In our initial experience, we found many tumors in the setting of ACKD difficult to classify and often
not conforming to the usual and common subtypes of RCC. In a detailed morphologic evaluation of
nephrectomy specimens from 43 cases of ESRD, the results of which were presented by us at the 2003 USCAP
meeting,  we found that there are five distinct tumor subtypes that occur in this setting.
Besides the usual papillary renal cell carcinoma (RCC), clear cell (conventional) RCC, and chromophobe
RCC, we also found some tumors with clear cell cytology, but with extensive papillary architecture
(tentatively designated as papillary clear cell RCC by us). However, the most common tumor subtype that
we observed was what we designated as ACDK-specific RCC (AS-RCC). Two examples of this are represented
in the submitted slides on this case. Among the 43 cases of ESRD, we found the AS-RCC to be the dominant
tumor nodule in 15 cases, and in the setting of ESRD with ACKD AS-RCC formed approximately 50% of the
tumors. Such tumors were observed only in the kidneys with ACDK and not in the other ESRD kidneys
without ACKD. We have also never seen such a tumor in a non-ESRD setting.
AS-RCCs show a spectrum of morphologic features, but the presence of eosinophilic (oncocytic) cells
with at least grade 3 nuclei, arranged in cribriform as well as tubular and cystic patterns, is a
consistent finding. Areas with papillary and/or alveolar, solid-alveolar, or diffuse patterns may also
be seen, and sometimes variable proportion of the tumor may have clear-cell cytology. Most tumors also
possess intratumoral oxalate crystals. Because of these varied architectural patterns, it is not
difficult to understand how many of these could be classified as clear cell or papillary RCC in small
series of cases.
For example, in two of the more recent publications on small number of RCCs with intratumoral oxalate
crystals, three tumors were classified as papillary RCC, and one was classified as clear cell
Interestingly, all four of these cases were reported to have ACKD. On evaluation
of the published illustrations, we believe that at least some of these qualify as AS-RCC. Similarly, the
'cribriform lesion,' and the 10 mm renal cell carcinoma with histological features 'indeterminate between
papillary and clear cell types' illustrated by Cheuk et al  also appear to be similar to
AS-RCC. It is not surprising that the molecular/genetic findings reported on a few renal tumors in ACDK
have been confusing, at the best. Most such reports are based on the studies on a small number of
cases. The largest series on 18 tumors by Hughson et al  reported trisomies of 7 and 17 in 5
of 14 'papillary RCCs,' loss of 3p in 1 of 2 'clear cell RCCs,' and neither trisomies nor 3p losses in 2
tumors designated as 'solid eosinophilic cell' carcinomas. We analyzed 12 cases by FISH for trisomies 7
and 17 as well as deletion of VHL gene, and found 1 of 2 papillary RCC with
trisomy 7 and 17, 2 of 2 clear cell RCCs with VHL deletions, 1 of 2
chromophobe RCCs with monosomy of chromosome 17, and 4 papillary clear cell RCC with neither trisomy 7/17
nor 3p losses. Of the 4 AS-RCC tested, one showed a trisomy of 7/17 and another a monosomy 3, whereas
all 4 lacked any VHL losses. Thus, it appears that most of the AS-RCCs are
not only morphologically, but genetically as well, different from the usual clear cell or papillary RCC.
However, the presence of trisomies 7 and 17 in occasional tumors
suggests some still
to-be-clarified relationship with papillary RCCs.
The recognition and proper classification of the tumors in the setting of ACDK, rather, in any
setting, is essential for many reasons. We know that many renal tumors that bear superficial resemblance
to each other are in fact clinically and biologically different entities (e.g., renal oncocytoma vs.
chromophobe RCC- eosinophilic variant vs. clear cell RCC-eosinophilic variant). Proper morphologic
separation, however, very frequently lets us predict the likely biologic behavior in each tumor.
Additionally, and possibly more pertinent to the case under discussion, is the fact that it was the
recognition of chromophobe renal cell carcinoma and its eosinophilic variant as distinct entities in the
that has been a basis for the dramatic change in the way we understand and classify
renal tumors now. Therefore, recognition is the first step towards any logical progress in understanding
any tumor, be it its pathogenesis, biologic behavior, or management.
The biologic behavior of RCCs in ESRD is reported to be less aggressive than the RCCs in sporadic or
non-ESRD setting. Only rare cases have been reported to metastasize.
A possible reason
for this less aggressive behavior may be that these patients are usually under constant medical care,
with radiological evaluations possibly picking up most tumors quite early. Thus, the mean tumor size in
our series was 3.0 cm (median = 2.6). However, we did observe lymph node metastasis at presentation in 1
of our 15 cases of AS-RCC, and have recently found another case with large sarcomatoid areas. We,
therefore, believe that AS-RCCs are not benign or hyperplastic nodules, but are another subtype of renal
cell carcinoma; these tumors need to be recognized before any further progress can be made in
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