|Ahead of print
Acquired cystic disease-associated renal cell carcinoma: A clinicopathologic study of eight tumors with clinical follow-up
Magdalena Chrabańska1, Jakub Ryszawy2, Bogna Drozdzowska1
1 Departments Chair of Pathomorphology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
2 Clinic of Urology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
|Date of Submission||01-Jul-2020|
|Date of Decision||16-Jul-2020|
|Date of Acceptance||06-Oct-2020|
|Date of Web Publication||14-Sep-2021|
Departments Chair of Pathomorphology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice
Source of Support: None, Conflict of Interest: None
Acquired cystic disease-associated renal cell carcinoma (ACD-RCC) is the major RCC subtype in patients with end-stage renal disease, specifically those with ACD on dialysis. Three patients with a total of eight tumors have been selected. The aim of this study was to analyze clinicopathologic, immunohistochemical, and prognostic features of eight ACD-RCCs. Three patients with end-stage renal disease (ESRD) were in the age range of 34–45 years and being treated with hemodialysis. All eight tumors were resected by radical nephrectomy. Two patients had a single ACD-RCC, while one patient had bilateral and multifocal ACD-RCCs. Microscopically, combinations of architectural patterns were identified in all tumors. Intracytoplasmic and intraluminal vacuoles, eosinophilic granular cytoplasm, and prominent nucleoli were universal characteristics of these tumors. Atypical cysts were present in three out of four resected kidneys. Immunohistochemistry (IHC) staining revealed all tumors were strongly and diffusely positive for pan-cytokeratin and α-methylacyl-CoA racemase and variably positive for CK7, CD10, PAX8, EMA, vimentin, cytokeratin, high molecular weight cytokeratin (CK HMW). All cases were negative for Napsin A, CK20, CD117, and CD57. After an average follow-up of 27.5 months (range 3–54 months), all our patients are alive without neoplastic (metastatic or recurrent) disease. Our study supports the finding that ACD-RCC has specific morphologic features and a broad spectrum of architectural patterns. We have found that the immunoprofile of ACD-RCC is distinct from that in other RCCs; however, nonspecific and interpretation of microscopic features in the context of the clinical history can aid the diagnosis. We confirm also the favorable prognosis in ACD-RCC.
Keywords: Acquired cystic disease-associated renal cell carcinoma, acquired cystic kidney disease, end-stage renal disease, immunohistochemistry, renal cell carcinoma
|How to cite this URL:|
Chrabańska M, Ryszawy J, Drozdzowska B. Acquired cystic disease-associated renal cell carcinoma: A clinicopathologic study of eight tumors with clinical follow-up. Indian J Cancer [Epub ahead of print] [cited 2021 Sep 28]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=325983
| » Introduction|| |
Acquired cystic disease-associated renal cell carcinoma (ACD-RCC), as a new subtype of RCC, was recently established and incorporated into the 2013 International Society of Urologic Pathology and 2016 World Health Organization Classification., It is the major RCC subtype in patients with end-stage renal disease (ESRD), specifically those with acquired cystic kidney disease (ACKD) on dialysis.,, The risk of ACD-RCC is positively associated with dialysis duration of more than 10 years.,,, Standard treatment for ACD-RCC is nephrectomy., ACD-RCC is considered to have more favorable prognosis and lower metastatic potential compared to sporadic RCC.,,,
The aim of this study was to analyze the clinicopathologic, immunohistochemical, and prognostic features of eight ACD-RCC tumors.
| » Methods|| |
During December 2015 and March 2020, three patients with a total of eight tumors have been selected for this study. The case of one of the patients has been previously reported. Clinical, macroscopic, microscopic, and immunohistochemical (IHC) findings, as well as therapy, duration of follow-up, and outcome, were retrospectively evaluated for each case. Clinical history included age, sex, native kidney disease, the type of dialysis, the time interval between the start of dialysis and tumor detection, symptoms, and imaging findings. During gross examinations of the nephrectomy specimens following features were evaluated: number of gross tumors, the largest dimension of the tumor, the color of the tumor, cut surface, presence of necrosis and hemorrhage, and tumor growth within a cystic space. All hematoxylin and eosin (H and E) stained glass slides from tumors were reviewed by one of the study pathologists. To characterize the morphologic spectrum of ACD-RCC, the following parameters were assessed: cytoplasmic characteristics, architectural patterns, International Society of Urological Pathology (ISUP) grade, presence of intratumoral oxalate crystals, microscopic lymphovascular invasion, tumor necrosis, rhabdoid and sarcomatoid transformation, presence of associated secondary changes within the tumor, and the subtype of other kidney lesions. IHC staining was performed on representative paraffin-embedded tissue blocks. Tissue sections were cut and stained with Autostainer Link 48 Immunohistochemistry Staining System, Dako, Carpinteria, California. A broad panel of IHC stains was chosen, the antibodies used, along with their source and dilutions are tabulated [Table 1]. The staining was independently reviewed by two authors and graded as negative (0–5% cells positive), focal (6–25% cells positive), or positive (>25% cells positive). To determine the tumor cell cycle, immunostain for Ki-67, a marker for proliferating cells, was performed, and the results were expressed as the number of positive tumor cell nuclei/10 high-power fields.
|Table 1: Summary of antibodies utilized in the immunohistochemical analysis|
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The literature was reviewed, and the features of reported cases of ACD-RCC were compared with those of our cases.
| » Results|| |
- Clinical features:
Clinical characteristics are summarized in [Table 2]. Of the three patients with ACD-RCC, 2 were men and one was a woman in the age range of 34–45 years (mean age of 40.3 years).
All patients had ESRD. The underlying kidney disease causing chronic renal failure was diabetes mellitus, hypertension, amyloidosis, and systemic lupus erythematosus. All patients had a known history of hemodialysis. The interval from the start of dialysis to the diagnosis of ACD-RCC ranged from 4 to 14 years (mean = 9.5 years). Two patients had a single ACD-RCC. The remaining patient had non-simultaneous bilateral and multifocal ACD-RCCs—one tumor in the left kidney and 2 years later five tumors in the right kidney, presenting with flank pain for left renal tumor and asymptomatic presentation in right renal tumors. Of all eight tumors, only in the case of one tumor, the imaging studies revealed a lesion highly suspicious of malignancy (cyst classified as Bosniak III/IV). In the remaining cases, tumors were found incidentally during grossing.
- Macroscopic findings:
Macroscopic findings are summarized in [Table 3]. The size of tumors ranged from 0.7 to 3.5 cm. The cut surface of the tumors showed various shades of yellow to brown to tan red [Figure 1]. Hemorrhage and necrosis were identified in four and three tumors, respectively. Six tumors arose within a cyst, whereas two tumors were not related to the cyst.
- Microscopic findings:
Microscopic features are summarized in [Table 4]. Architectural patterns varied considerably. Combinations of different patterns of growth were identified in all tumors. The most common pattern of growth was papillary [Figure 2]a. Necrosis was identified in three cases. The deposition of intratumoral oxalate crystals identifiable on H and E alone was common [Figure 2]b. All tumors (at least at part) consisted of intracytoplasmic and intraluminal vacuoles, imparting a “sieve-like” appearance [Figure 2]c. Deeply eosinophilic granular cytoplasm was a universal characteristic of all tumors [Figure 2]d. Over half of the cases had some areas of cytoplasmic clearing and cytoplasmic hemosiderin deposition [Figure 2]e. The cells had prominent eosinophilic nucleoli. The renal parenchyma exhibited changes of ESRD (tubular atrophy, sclerotic glomeruli, and vascular intimal thickening), with atypical cysts (cortical cysts consisting of at least focal atypical cells growing in a stratified or papillary pattern) present in almost all kidneys [Figure 2]f.
- Immunohistochemical results:
All cases had material available for IHC; however, in the case of tumor number 4, the scanty material allowed to perform only part of the staining. The results are summarized in [Table 5]. Interestingly, multifocal tumors in the same kidney have a different IHC profile. All cases had a strong and diffuse expression of CK AE1/AE3 [Figure 3]a and AMACR [Figure 3]b. Unexpectedly, all available tumors expressed CK HMW, which was diffusely expressed in six out of seven available cases [Figure 3]c. Strong and diffuse CD10 and PAX8 [Figure 3]d distribution was seen in six and four tumors, respectively, whereas focal reactivity was observed in two and four cases, respectively. CK7 expression was heterogeneous—two cases showed complete lack of expression, three cases had patchy expression [Figure 3]e, whereas diffuse expression was seen in the remaining cases. In contrast, Napsin A [Figure 3]f, CK20, CD117, and CD57 were negative in all available cases. The proliferation index determined by Ki-67 was very low. Summarizing, the most useful antibodies with a constant expression profile are pan-cytokeratin, AMACR, Napsin A, CK20, CD117, and CD57.
- Therapy, follow-up duration, and clinical outcome:
The results are summarized in [Table 3]. All tumors have been resected by radical nephrectomy. Two patients had a unilateral nephrectomy. Both the kidneys were removed in one patient. Adjuvant therapy was not performed in any patient. The follow-up was available with all patients and ranged from 3 to 54 months (average 27.5 months). Regarding the outcome, all patients are alive without disease. There was no evidence of lymph node or distant metastases. Two patients continued to receive dialysis, while kidney transplantation has been performed 4 years after the nephrectomy in patient number 1.
|Figure 1: Gross photograph showing a well-circumscribed, yellow-brown tumor. Atrophic renal parenchyma immediately adjacent to the tumor contains multiple cysts|
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|Figure 2: Microscopic findings of acquired cystic disease-associated renal cell carcinoma: (a) Papillary growth (H and E, original magnification ×100), (b) oxalate crystals (H and E, original magnification ×200), (c) “sieve-like” appearance (H and E, original magnification ×200), (d) neoplastic cells with round nuclei and granular eosinophilic cytoplasm (H and E, original magnification ×400), (e) hemosiderin accumulation (H and E, original magnification ×400), (f) atypical cyst (H and E, original magnification ×100)|
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|Figure 3: Immunohistochemical staining showing acquired cystic disease-associated renal cell carcinoma: (a) positive for CK AE1/AE3 (original magnification ×100), (b) positive for AMACR (original magnification ×100), (c) positive for CK HMW (original magnification ×100), (d) positive for PAX8 (original magnification ×200), (e) only focally positive for CK7 (original magnification ×100), (f) negative for Napsin A (original magnification ×100)|
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|Table 2: Clinical summary of acquired cystic disease-associated renal cell carcinoma (ACD-RCC)|
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|Table 3: Macroscopic findings of tumors, therapy, follow-up (after the diagnosis of renal tumor) and outcome|
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|Table 4: Microscopic findings of acquired cystic disease-associated renal cell carcinoma|
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|Table 5: Immunohistochemical profile of acquired cystic disease-associated renal cell carcinoma|
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| » Discussion|| |
ACKD is defined as ≥3 cysts per kidney, or cysts accounting for >25% of the renal parenchyma in a patient without polycystic kidney disease. Both the prevalence and severity of ACKD increase with the duration of ESRD. About 60% of people were on dialysis for 2–4 years and almost all patients on dialysis for more than 10 years who develop ACKD., Approximately 3–7% of patients with ACKD develop renal cell tumors.,,, Although numerous RCC subtypes have been described in the setting of ACKD, the predominant subtype being ACD-RCC., ACD-RCCs occur exclusively in patients with ACKD, constitute 36% of all epithelial neoplasms arising in ESRD and 46% of these are in ESRD with ACKD., The risk of developing RCC increases with the length of time a patient is on dialysis (>10 years)., The interval from the start of the dialysis to the diagnosis of ACD-RCC in our patients ranged from 4 to 14 years. Interestingly, in a patient who has been on dialysis for more than 10 years, we have observed bilateral and multifocal tumors, whereas in patients who have been on dialysis for less than 10 years only solitary ACD-RCC has been observed. However, such an association should be investigated in larger series. The vast majority of ACD-RCCs are detected incidentally during the periodical radiologic follow-up in patients with chronic renal disease., However, in our study only one out of eight tumors imaging examination showed lesion highly suspicious of malignancy. The remaining seven tumors were missed at radiologic evaluation and found incidentally on grossing. Thus, pathologists have to be careful during cut-up to search cautiously for a tumor in these patients with a history of ACKD on long-term dialysis. Bilaterality is observed in >20% of ACD-RCC and multifocality in >50% of cases.,,, In cases with multifocal tumors, nodules vary in gross appearance, which was also observed in our study. Many tumors arise within a cyst.,, Our case further supports this observation because six out of eight tumors had an intracystic growth. Tumors are generally well circumscribed. The cut surface has variable appearances form gray-tan homogenous to predominantly cystic, and variegated. Focal hemorrhage and necrosis have been described.,,
The morphologic findings in all our cases validate what has been described in prior descriptions of ACD-RCC. The universal features of these neoplasms are abundant, deeply eosinophilic cytoplasm with round or oval nuclei and prominent nucleoli, multiple intracytoplasmic, and intraluminal microlumen formations, variety of growth patterns (in variable combinations and proportions within the same tumor), as well as the presence of calcium oxalate crystals. However, crystal deposition is neither necessary nor sufficient for the diagnosis.,,,,,,, Some tumors may show sarcomatoid or rhabdoid differentiation; however, we did not observe them.,,, Secondary changes described in association with ACD-RCC were also commonly observed in our study: hemorrhage, intracytoplasmic hemosiderin deposition, intratumoral foamy histiocytes, cytoplasmic clearing, and tumoral calcifications.,,,,, Additionally, other lesions such as clear cell RCC, papillary RCC, papillary adenoma, or atypical cysts (cysts with epithelial proliferation) may be often associated with ACD-RCC, as observed in our study., Some studies suggest that atypical cysts can be precursor lesions of ACD-RCC.,,,, Our study further supports the frequent association of ACD-RCC with atypical cysts which coexist with ACD-RCC in seven out of eight tumors.
The immunoprofile of ACD-RCC is separate from that in other RCCs. However, because of the limited literature, the utility of IHC in the diagnosis of ACD-RCC is limited. ACD-RCC arises from the proximal nephron cells, thus the neoplastic cells have apparent proximal tubular differentiation marker expression (CD10, RCC marker, AMACR, and GST-a), but it may also aberrantly express distal tubule markers (EMA, CK HMW).,, Expression of AMACR is typically very strong and diffuse. Cytokeratin stain for AE1/AE3 is generally positive.,, PAX8 expression is frequent, but not present in all of the cases. Napsin A may express in this subtype of RCC., CK7 is typically not expressed, sometimes focally positive or occasionally diffuse in a subset of cases.,, CD117 expression is absent, a finding that could be useful in differential diagnosis from other renal neoplasms with eosinophilic cytoplasm (oncocytoma, chromophobe RCC).,, Variable results are obtained for EMA, VIM, and CD57.,,,,, Proliferation index (Ki-67) is low (2.85–6.2%).,, The IHC profile of our ACD-RCC cases was consistent with what has been previously described. Surprisingly, all our tumors aberrantly expressed distal tubule marker—CK HMW.
The standard treatment for ACD-RCC is nephrectomy, either total or partial., All tumors in our study were resected by radical nephrectomy. Targeted therapy and chemotherapeutic agents have not been evaluated for ACD-RCC.
Generally, RCC in ESRD is considered to be less aggressive and have a favorable prognosis than sporadic RCC.,,, Indolent behavior is likely because of the early detection of tumors in patients on long-term periodic follow-up for chronic renal disease. Clinical outcomes in our study further support the relatively low risk for aggressive behavior in ACD-RCC—none of our patients had adverse events. However, rare cases with sarcomatoid or rhabdoid features can behave in an aggressive manner and metastasize.,
In summary, our study supports the finding that ACD-RCC has specific morphologic features and a broad spectrum of architectural patterns. We have found that the immunoprofile of ACD-RCC is distinct from that in other RCCs; however, it is relatively nonspecific and interpretation of microscopic features in the context of the surrounding kidney tissue morphology and clinical history is helpful for establishing the correct diagnosis. Although most tumors are found incidentally in the periodical follow-up imaging, some lesions may be missed at radiologic evaluation and found unexpectedly on scrupulous grossing. Thus, pathologists have to carefully investigate the kidney of the patient with a history of ACKD and long-term dialysis. We have observed that in a patient who has been on dialysis for more than 10 years bilateral and multifocal tumors were present, whereas in patients who have been on dialysis for less than 10 years only solitary ACD-RCC has developed. In addition, we confirm the relatively low risk for aggressive behavior in ACD-RCC. We hope that our experience will enrich the limited database and will be helpful for the diagnosis and treatment of ACD-RCC in the future.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This work was supported by the Medical University of Silesia, Katowice, Poland [KNW-1-168/N/9/0].
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]