Synchronous clear cell renal cell carcinoma and tubulocystic carcinoma: genetic evidence of independent ontogenesis and implications of chromosomal imbalances in tumor progression
- Gabriela Quiroga-Garza†1,
- Sergio Piña-Oviedo†1,
- Karime Cuevas-Ocampo3,
- Richard Goldfarb4,
- Mary R Schwartz1,
- Alberto G Ayala1, 2, 5Email author and
- Federico A Monzon1, 2, 5, 6
© Quiroga-Garza et al; BioMed Central Ltd. 2012
Received: 28 December 2011
Accepted: 27 February 2012
Published: 27 February 2012
Seven percent of renal cell carcinoma (RCC) cases are diagnosed as "unclassified" RCC by morphology. Genetic profiling of RCCs helps define renal tumor subtypes, especially in cases where morphologic diagnosis is inconclusive. This report describes a patient with synchronous clear cell RCC (ccRCC) and a tubulocystic renal carcinoma (TCRC) in the same kidney, and discusses the pathologic features and genetic profile of both tumors. A 67 year-old male underwent CT scans for an unrelated medical event. Two incidental renal lesions were found and ultimately removed by radical nephrectomy. The smaller lesion had multiple small cystic spaces lined by hobnail cells with high nuclear grade separated by fibrous stroma. This morphology and the expression of proximal (CD10, AMACR) and distal tubule cell (CK19) markers by immunohistochemistry supported the diagnosis of TCRC. The larger lesion was a typical ccRCC, with Fuhrman's nuclear grade 3 and confined to the kidney. Molecular characterization of both neoplasms using virtual karyotyping was performed to assess relatedness of these tumors. Low grade areas (Fuhrman grade 2) of the ccRCC showed loss of 3p and gains in chromosomes 5 and 7, whereas oncocytic areas displayed additional gain of 2p and loss of 10q; the high grade areas (Fuhrman grade 3) showed several additional imbalances. In contrast, the TCRC demonstrated a distinct profile with gains of chromosomes 8 and 17 and loss of 9. In conclusion, ccRCC and TCRC show distinct genomic copy number profiles and chromosomal imbalances in TCRC might be implicated in the pathogenesis of this tumor. Second, the presence of a ccRCC with varying degrees of differentiation exemplifies the sequence of chromosomal imbalances acquired during tumor progression.
The virtual slide(s) for this article can be found here:
KeywordsRenal cell carcinoma Collecting duct carcinoma Tubulocystic carcinoma Cystic tubules Genetic profile Virtual karyotyping Tumor progression Fuhrman nuclear grade Synchronous tumor
Kidney cancer is among the ten most common causes of cancer-related death in adults . Over 64,700 new cases and over 13,500 deaths are expected to occur in the US in 2012 . Renal cell carcinoma (RCC) constitutes more than 80% of all primary renal neoplasms, and clear cell RCC (ccRCC) accounts for most of these cases (80%). While a specific histological diagnosis is possible by morphology and immunohistochemistry in the majority of cases, overlapping morphological features are still encountered in about 7% of cases in routine practice , and these cases fall in the category of "unclassified renal neoplasm." Recent updates to the histopathological diagnosis of kidney neoplasms are reflected in the latest World Health Organization (WHO) classification of genitourinary and kidney neoplasms . However, ongoing research has led to the description of new tumor entities that are not yet considered in this classification. One of these recently described entities is tubulocystic renal carcinoma (TCRC) with less than one hundred cases reported .
Genetic events play an important role in renal carcinogenesis, and most known renal tumor subtypes have recurrent specific chromosomal imbalances . Thus, genetic profiling of renal tumors has emerged as a practical diagnostic tool for the surgical pathologist, especially in those cases where morphologic diagnosis is not conclusive . Although the identification of key molecular targets involved in renal carcinogenesis has had direct impact in patient care, little is known about the genetic events involved in tumor progression .
Herein we describe the clinico-pathological features of a patient presenting with synchronous ccRCC and a TCRC and the molecular profiles of these tumors utilizing virtual karyotyping. Our results contrast the different profiles of these tumors as well as exemplify the chromosomal imbalances associated with histologic progression from low to highgrade ccRCC.
Gross and microscopic findings
We report a case of two synchronous non-related tumors, a TCRC and a ccRCC occurring in the same kidney with molecular characterization of both neoplasms.
TCRC was originally described by Masson who named it "Bellinian epithelioma" or "carcinoma of the collecting ducts" as he believed it originated from collecting ducts of Bellini . MacLennan et al.  in 1997 hypothesized that this tumor represented the low grade of the spectrum of collecting duct carcinoma, as it shares similar characteristics with the latter tumor (i.e., immunopositivity for 34βE12 and UEA-1). In 2004, Amin et al. named the tumor "tubulocystic carcinoma" in a series of 29 cases .
TCRC is a rare entity that characteristically has a small size at presentation (mean 2 cm) and rarely progresses, recurs, or metastasizes [7, 8, 12, 13]. It has been reported in association with other RCCs, primarily papillary RCC . Recent immunohistochemical, ultrastuctural, and molecular studies (RNA expression levels and genomic profile analyses) have shown that TCRC is different from collecting duct carcinoma and may be related to papillary RCCs [5, 7, 8, 13–15]. Supportive findings include the expression of proximal convoluted tubule markers (CD10 and AMACR), distal nephron proteins (parvalbumin, HMWCK and CK19) [5, 7], and the detection of cells reminiscent of proximal tubule and intercalated cells by electron microscopy [5, 13–15]. Further supporting the notion that TCRC is related to papillary RCC is the report of one group that described that TCRC has a gene expression profile similar to that of papillary RCCs using cluster analysis . However, another study showed a distinct gene expression profile characterized by expression of cell cycle and biomolecule metabolism genes although this group did not compare this profile directly to papillary tumors . Using fluorescence in situ hybridization (FISH) and array-based comparative genomic hybridization (aCGH), Zhou et al.  and Yang et al.  have shown gains in chromosome 17, as is seen with papillary RCCs and thus have proposed that these two entities are closely related.
Our case showed classic features of TCRC, such as positive immunohistochemistry for CD10, AMACR and CK19, as well as gains of chromosome 17 in the virtual karyotyping analysis. In addition, the TCRC also showed gains in chromosome 8 and loss of chromosome 9 (Figure 5). The chromosomal imbalance pattern observed in our TCRC case is distinct from that found in papillary RCC which commonly shows gains of 7 and 17 and rarely shows gains of 8 or loss of 9 . Importantly, loss of chromosome 9 and gain of 17 seem to be recurrent chromosomal imbalances in TCRC tumors (Monzon and Amin, unpublished observations). If this is confirmed in a large case series, it could help establish TCRC as a genetically separate entity from papillary RCC. It is important to note that the cystic and somewhat paucicellular nature of the tumor may be an important consideration when performing molecular analyses of this tumor subtype, since stromal cells may play a role as contaminants. Also, the role of stromal cells in the pathogenesis of TCRC remains uncertain, since metastatic cases not only show the cystic glandular configurations but also the intervening stroma .
The differential diagnosis of TCRC includes mixed epithelial and stromal tumor and cystic nephroma . The former, another variant of RCC, is easily ruled out as typically displays an ovarian-like stroma that is usually estrogen receptor positive and occurs predominantly in female patients [17, 18]. The so-called cystic nephroma has become basically a non-existent entity [17, 19]. In the WHO classification of renal tumors  there is an illustration of a cystic nephroma which looks identical to the TCRC. We suspect that the "cystic nephroma" is actually the tumor now known as TCRC.
There are sporadic reports about the coexistence of TCRC with other renal tumors of different subtypes. Yang et al. reported 5 cases of TCRC associated with either papillary RCC or papillary adenomas . Gonul et al. reported a case of synchronous ccRCC, micropapillary urothelial carcinoma and TCRC in a 57-year-old male with hematuria . Brennan et al. presented a case of a 72-year-old male with end stage renal disease who developed a TCRC, a type 2 papillary RCC, a clear cell papillary and cystic RCC as well as renal oncocytosis, hybrid tumors and chromophobe RCC . More recently, Deshmukh et al. reported a synchronous TCRC and papillary RCC in a young female with metastatic papillary RCC in para-aortic lymph nodes . Thus, although TCRC has been reported in association with multiple other renal cell tumor subtypes, it appears that there is a slight predominance for synchronous TCRC and papillary tumors. An interesting question raised by the coexistence of TCRC with other renal tumors is whether there are common predisposing factors for these histologically different tumors.
The ccRCC in this case showed a spectrum of morphologic variations ranging from low grade to high grade and a distinct nodule with oncocytic changes which allowed us to inquire about molecular differences within morphologic progression in a single tumor. We analyzed the areas in the ccRCC showing different grade and morphology using virtual karyotyping and demonstrated that a higher Fuhrman grade correlated with an increase in chromosomal imbalances (Figure 5). In a similar fashion, studies on chromophobe RCCs have shown that multiple chromosomal gains are associated with sarcomatoid transformation . More recently, Patani et al. using high-resolution aCGH and FISH have also demonstrated that morphologically distinct regions from a case of triple-negative breast carcinoma (apocrine vs. non-apocrine areas) correlate with different genetic aberrations .
In addition to the somatically acquired genetic changes in the tumors, the patient's tumor had regions of inherited uniparental disomy (UPD, i.e. two chromosomal regions inherited from one parent only) in chromosomes 2 and 6 (Figure 5, asterisks). The presence of these genetic lesions in the normal kidney tissue suggests a possible inherited origin. Although uniparental disomy has been implicated as a risk factor for colon and other cancers, its role in the predisposition of renal tumors is currently unknown .
In conclusion, this case allowed us to explore two uses of whole genome analysis with virtual karyotyping. The first was to confirm that ccRCC and TCRC have distinct genomic copy number profiles and that TCRC appears to have recurrent gains in chromosome 17 which might be implicated in the pathogenesis of this tumor. Second, the presence of a ccRCC with varying degrees of differentiation allowed us to evaluate the sequence of chromosomal imbalances acquired during tumor progression. These findings support the concept that chromosomal imbalances are associated with tumor progression , and possibly explain why Fuhrman grading is a strong prognostic factor in ccRCC  even when high grade cells are present in a minority of the specimen .
This study was conducted under a local IRB approved protocol for the molecular characterization of renal tumors.
Karla Alvarez, BS
- Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61: 69-90. 10.3322/caac.20107.View ArticlePubMed
- Siegel R, Naishadham D, Jemal A: Cancer Statistics 2012. CA Cancer J Clin. 2012, 62 (1): 10-29. 10.3322/caac.20138.View ArticlePubMed
- Kim HJ, Shen SS, Ayala AG, Ro JY, Truong LD, Alvarez K, Bridge JA, Gatalica Z, Hagenkord JM, Gonzalez-Berjon JM, Monzon FA: Virtual-karyotyping with SNP microarrays in morphologically challenging renal cell neoplasms: a practical and useful diagnostic modality. Am J Surg Pathol. 2009, 33: 1276-1286. 10.1097/PAS.0b013e3181a2aa36.View ArticlePubMed
- World Health Organization Classification of Tumors. Pathology and genetics of tumors of the urinary system and male genital organs. Edited by: Eble JN, Sauter G, Epstein JI, Sesterhenn IA. 2004, Lyon: IARC Press
- Amin MB, MacLennan GT, Gupta R, Grignon D, Paraf F, Vieillefond A, Paner GP, Stovsky M, Young AN, Srigley JR, Cheville JC: Tubulocystic carcinoma of the kidney: clinicopathologic analysis of 31 cases of a distinctive rare subtype of renal cell carcinoma. Am J Surg Pathol. 2009, 33: 384-392. 10.1097/PAS.0b013e3181872d3f.View ArticlePubMed
- Hagenkord JM, Gatalica Z, Jonasch E, Monzon FA: Clinical genomics of renal epithelial tumors. Cancer Genet. 2011, 204: 285-297. 10.1016/j.cancergen.2011.06.001.View ArticlePubMed
- Azoulay S, Vieillefond A, Paraf F, Pasquier D, Cussenot O, Callard P, Sibony M: Tubulocystic carcinoma of the kidney: a new entity among renal tumors. Virchows Arch. 2007, 451: 905-909. 10.1007/s00428-007-0483-7.View ArticlePubMed
- Yang XJ, Zhou M, Hes O, Shen S, Li R, Lopez J, Shah RB, Yang Y, Chuang ST, Lin F, et al.: Tubulocystic carcinoma of the kidney: clinicopathologic and molecular characterization. Am J Surg Pathol. 2008, 32: 177-187. 10.1097/PAS.0b013e318150df1d.View ArticlePubMed
- Masson P: Tumeurs humaines. Histologie, Diagnostics et techniques. 1968, Paris: Librairie Maloine
- MacLennan GT, Farrow GM, Bostwick DG: Low-grade collecting duct carcinoma of the kidney: report of 13 cases of low-grade mucinous tubulocystic renal carcinoma of possible collecting duct origin. Urology. 1997, 50: 679-684. 10.1016/S0090-4295(97)00335-X.View ArticlePubMed
- Amin MB, MacLennan GT, Paraf F, et al.: Tubulocystic carcinoma of the kidney: clinicopathologic analysis of 29 cases of a distinctive rare subtype of renal carcinoma. Mod Pathol. 2004, 17 (suppl): 137A-
- Hora M, Urge T, Eret V, Stransky P, Klecka J, Kreuzberg B, Ferda J, Hyrsl L, Breza J, Holeckova P, et al.: Tubulocystic renal carcinoma: a clinical perspective. World J Urol. 2011, 29: 349-54. 10.1007/s00345-010-0614-7.View ArticlePubMed
- Zhou M, Yang XJ, Lopez JI, Shah RB, Hes O, Shen SS, Li R, Yang Y, Lin F, Elson P, et al.: Renal tubulocystic carcinoma is closely related to papillary renal cell carcinoma: implications for pathologic classification. Am J Surg Pathol. 2009, 33: 1840-1849. 10.1097/PAS.0b013e3181be22d1.View ArticlePubMed
- Osunkoya AO, Young AN, Wang W, Netto GJ, Epstein JI: Comparison of gene expression profiles in tubulocystic carcinoma and collecting duct carcinoma of the kidney. Am J Surg Pathol. 2009, 33: 1103-1106. 10.1097/PAS.0b013e3181a13e7b.View ArticlePubMed
- Radhakrishnan A, Maclennan GT, Hennigar RA, et al.: Ultrastructural and immunohistochemical (IHC) appraisal of tubulocystic carcinoma (TCCa) of the kidney: histogenetic and diagnostic implications. Mod Pathol. 2005, 18: 160A-
- Lane BR, Campbell SC, Remer EM, Fergany AF, Williams SB, Novick AC, Weight CJ, Magi-Galluzzi C, Zhou M: Adult cystic nephroma and mixed epithelial and stromal tumor of the kidney: clinical, radiographic, and pathologic characteristics. Urology. 2008, 71: 1142-1148. 10.1016/j.urology.2007.11.106.View ArticlePubMed
- Turbiner J, Amin MB, Humphrey PA, Srigley JR, De Leval L, Radhakrishnan A, Oliva E: Cystic nephroma and mixed epithelial and stromal tumor of kidney: a detailed clinicopathologic analysis of 34 cases and proposal for renal epithelial and stromal tumor (REST) as a unifying term. Am J Surg Pathol. 2007, 31: 489-500. 10.1097/PAS.0b013e31802bdd56.View ArticlePubMed
- Mohanty SK, Parwani AV: Mixed epithelial and stromal tumors of the kidney: an overview. Arch Pathol Lab Med. 2009, 133: 1483-1486.PubMed
- Madewell JE, Goldman SM, Davis CJ, Hartman DS, Feigin DS, Lichtenstein JE: Multilocular cystic nephroma: a radiographic-pathologic correlation of 58 patients. Radiology. 1983, 146: 309-321.View ArticlePubMed
- Gonul II, Cakr A, Sozen S, Ataoglu O, Alkibay T: A case of tubulocystic carcinoma simultaneously occuring with clear cell type renal cell carcinoma and micropapillary urothelial carcinoma of bladder. South Med J. 2009, 102: 754-757. 10.1097/SMJ.0b013e3181a819c1.View ArticlePubMed
- Brennan C, Srigley JR, Whelan C, Cooper J, Delahunt B: Type 2 and clear cell papillary renal cell carcinoma, and tubulocystic carcinoma: a unifying concept. Anticancer Res. 2010, 30: 641-644.PubMed
- Deshmukh M, Shet T, Bakshi G, Desai S: Tubulocystic carcinoma of kidney associated with papillary renal cell carcinoma. Indian J Pathol Microbiol. 2011, 54: 127-130. 10.4103/0377-4929.77363.View ArticlePubMed
- Brunelli M, Gobbo S, Cossu-Rocca P, Cheng L, Hes O, Delahunt B, Pea M, Bonetti F, Mina MM, Ficarra V, et al.: Chromosomal gains in the sarcomatoid transformation of chromophobe renal cell carcinoma. Mod Pathol. 2007, 20: 303-309. 10.1038/modpathol.3800739.View ArticlePubMed
- Patani N, Barbashina V, Lambros MB, Gauthier A, Mansour M, Mackay A, Reis-Filho JS: Direct evidence for concurrent morphological and genetic heterogeneity in an invasive ductal carcinoma of triple-negative phenotype. J Clin Pathol. 2011, 64: 822-828. 10.1136/jclinpath-2011-200135.View ArticlePubMed
- Bacolod MD, Schemmann GS, Giardina SF, Paty P, Notterman DA, Barany F: Emerging paradigms in cancer genetics: some important findings from high-density single nucleotide polymorphism array studies. Cancer Res. 2009, 69: 723-727. 10.1158/0008-5472.CAN-08-3543.PubMed CentralView ArticlePubMed
- Monzon FA, Alvarez K, Peterson L, Truong L, Amato RJ, Hernandez-McClain J, Tannir N, Parwani AV, Jonasch E: Chromosome 14q loss defines a molecular subtype of clear-cell renal cell carcinoma associated with poor prognosis. Mod Pathol. 2011, 24: 1470-1479. 10.1038/modpathol.2011.107.View ArticlePubMed
- Amin MB, Amin MB, Tamboli P, Javidan J, Stricker H, de-Peralta Venturina M, Deshpande A, Menon M: Prognostic impact of histologic subtyping of adult renal epithelial neoplasms: an experience of 405 cases. Am J Surg Pathol. 2002, 26: 281-291. 10.1097/00000478-200203000-00001.View ArticlePubMed
- Fuhrman SA, Lasky LC, Limas C: Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982, 6: 655-663. 10.1097/00000478-198210000-00007.View ArticlePubMed
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.