Journal of Kidney Cancer and VHL 2014; 1(5): 56-62. Doi: http://dx.doi.org/10.15586/jkcvhl.2014.13
Review
Article
Tubulocystic Renal Cell Carcinoma: A Rare Renal Tumor
1Department
of Surgery, Providence Hospital & Medical Centers, Southfield, MI,
USA; 2Department of Pathology, University of Toledo, Toledo, OH, USA
Abstract
Tubulocystic
renal cell carcinoma of the kidney is a rare entity with less than one
hundred cases reported so far. It was previously considered to have
some similarities to various other renal cancers although this tumor
has distinct macroscopic, microscopic and immuno-histochemical
features. It is now a well-established entity in renal neoplastic
pathology and has been recognized as a distinct entity in the 2012
Vancouver classification of renal tumors. This review aims to give an
overview of tubulocystic renal cell carcinoma after extensive
literature search using PubMed and CrossRef. Copyright: The
Authors.
Received: 19 August 2014; Accepted after revision: 27 August 2014; Published: 01 September 2014
Author
for correspondence: Dr.
Jasneet Singh Bhullar MD, MS, Department of Surgery, Providence
Hospital & Medical Centers, Southfield, MI, USA. E-mail: [email protected]
How
to cite: Bhullar,
JS, Bindroo, S, Varshney N, Mittal, V. Tubulocystic renal cell
carcinoma: A rare renal tumor. Journal of Kidney Cancer and VHL 2014;
1(5):56-62.
Doi: http://dx.doi.org/10.15586/jkcvhl.2014.13
Introduction
Tubulocystic renal cell carcinoma of
the kidney is a recently established entity in renal neoplastic pathology. It
was first described by Pierre Masson in 1956 who described cystic neoplasm of
the kidney with hobnail cells in the central region of the kidney (3). It was
thought to be in collecting duct and was hence called carcinoma of Bellini
(Collecting) duct. It was later found to be low grade and differ significantly
in behavior when compared to classic type which was far more aggressive.
Accordingly, it was termed as “low-grade collecting duct carcinoma”. In 1997
MacLennan et al. hypothesized that this tumor represented the low grade of the
spectrum of collecting duct carcinoma (CDC), as it shares similar
characteristics with the latter tumor (4). A recent study by Osunkoya et al.
has shown that tubulocystic renal cell carcinoma is distinct from CDC at the
molecular level (5). It received its
current name in 2004 in a series of 31 cases presented in an abstract at the
United States and Canadian Academy of Pathology meeting by Amin et al (6).
Tubulocystic renal cell carcinoma was not included in the WHO 2004
classification. However, it was recognized as a distinct identity in 2010 by
the American Joint Committee on Cancer. In 2012, it was included in the
Vancouver Classification of renal cancer (7).
Search Criteria
We performed English literature search
using Pubmed and Crossref on 10th August 2014, which yielded more than 80
results of published material on Pubmed. The search terms used were
“tubulocystic renal cell cancer” and “tubulocystic carcinoma pathology /
metastasis / immunohistochemistry” and “uncommon cystic renal tumors”. We have
critically analyzed and included most of the important case series, reports and
previous reviews from 1970- August 2014 in our review. Cases appear to be
focusing on tumor histology and differentiation with other similar subtypes of
renal tumors. There has been a surge in the reports and reviews in the past 7 –
8 years indicating a recent interest among researchers in the study and
management of this tumor. Here in, we review the literature about tubulocystic
renal cell carcinoma.
Clinical features
Clinically, tubulocystic renal cell
carcinoma is a tumor of adults mostly presenting in the fifth and sixth decade
with a wide age range, 29–94 years. It shows a strong male predominance with a
male/ female ratio of 7:1. Reported tumors are more often left sided (8). Tubulocystic
renal cell carcinoma is usually solitary; however, based on the literature,
multifocality appears to be a common phenomenon in up to 23% of cases (8-9).
They are less aggressive than other renal cell carcinomas. Patients are often
asymptomatic, although they may present with abdominal pain, distension and
hematuria. Most present with small tumors (pT1), however, occasional pT2 and
pT3 lesions have been reported. They rarely progress, recur, or metastasize
(10). In the vast majority of reports, this has been an incidental finding on
autopsy, nephrectomy for a separate disease process, or imaging (6). Clinical
characteristics reported in different studies have been explained in Table 1.
Table 1: Clinical characteristics of TCRC
Number of cases |
Age range (years) |
Sex |
Size range (cm) |
Location (kidney) |
Nature of tumor (recurrence) |
Metastasis |
Ref |
13 |
36-94 |
10(M) : 3(F) |
0.5 – 8.5 |
R=6; L=7 |
Nil |
1 case: local lymph nodes |
9 |
20 |
36-87 |
16(M) : 4(F) |
0.2 – 6.1 |
R>L |
Only 1 case recurred |
1 case: local 1 case: distant |
17 |
11 |
30-80 |
11 (M) |
1.7 – 7 |
Data not available |
Nil |
Nil |
13 |
31 |
34-74 |
27(M): 4(F) |
0.7-17 |
L>R |
Nil |
2 cases: local |
6 |
6 |
29-83 |
3(M): 3(F) |
1.9-4.0 |
R=5; L=1 |
Nil |
1 case: local lymph node |
18 |
5 |
29-70 |
4 (M) One is missing |
5.1 – 6.7 |
R>L; 3 |
1 case: recurrence; 1 death |
2 case: distant metastasis |
19 |
1 |
33 |
M |
5x2.7 |
L |
Recurrence in peritoneum |
Distant metastasis |
12 |
1 |
43 |
M |
- |
R |
- |
- |
15 |
1 |
28 |
F |
12 |
R |
Solitary |
Local metastasis |
20 |
4 |
30-74 |
3(M): 1(F) |
1.9 – 14.5 |
L>R |
No recurrence reported |
No metastasis reported |
21 |
3 |
50-70 |
3(M) |
3.8-14.0 |
|
No recurrence reported |
1 vascular invasion 2 perinephric adipose tissue |
22 |
1 |
70 |
M |
15.1x11.6x9. |
L |
No recurrence |
Bone Metastasis |
23 |
1 |
35 |
F |
0 10x12 |
L |
No recurrence reported |
No metastasis reported |
24 |
|
|
|
|
Summary |
|
|
|
~98 |
29-94 |
M>F |
0.2 – 17 |
L>R |
Less chances of recurrence |
Local and distant metastasis |
|
Only a few cases so far have been
reported of metastases to lymph node, bone, pleura, and liver (11). Its
relationship to collecting duct carcinoma is controversial, and recent studies
have linked it with papillary RCC. Only one case of tubulocystic carcinoma with
sarcomatoid features has been reported where the patient developed multiple
peritoneal metastases and died 14 months after diagnosis (12).
Gross Description
Grossly, it is usually solitary,
although multifocal examples may be seen. The tumors show a variable size,
ranging from 0.3 to 17 cm, with a mean of 4 cm. The tumors are well
circumscribed and usually un-encapsulated involving mainly the renal cortex. The
cut surface of tumor is white or gray often compared to “bubble wrap”. It
reveals small multilocular cystic spaces reminiscent of the appearance of a ‘‘sponge’’
or ‘‘Swiss cheese’’ (9).
Microscopic Description
Microscopically, tubulocystic renal cell carcinoma is composed of tightly packed tubules and cysts measuring up to a few millimeters in diameter, separated by bland fibrous stroma. The lining cells are cuboidal to columnar and may have an attenuated appearance. Hobnail cells are commonly seen (Figure 1A & B).
Figure 1. Microscopic appearance of tubulocystic renal cell
carcinoma. A, hematoxylin and eosin
(H & E) staining shows tubulopapillary pattern with cystic spaces lined
with cells having hobnail appearance (x200); B, H & E shows tubular and tubulopapillary structures in a
hyalinized and fibrous stroma (x200).
The cells have abundant eosinophilic or
amphophilic cytoplasm and the nuclei are large and have prominent nucleoli. The
nuclear grade generally corresponds to Fuhrman grade 3, but grade 2 or even
grade 1 may be seen (8,13). Nuclear chromatin is evenly dispersed. A solid
sheet pattern is absent (9). Occasional cells with low grade nuclear changes
may be seen but they rarely predominate. Rarely minor areas with clear cell or
papillary features are noted (17). Foam cells, calcospherites and hemosiderin
encrustation are not found, unless there is an accompanying papillary renal
cell carcinoma (4). Electron microscopy reveals abundant microvilli in most
cells with a brush border appearance resembling proximal convoluted tubules.
Admixed cells with short, sparse microvilli and complex cytoplasmic
interdigitation, reminiscent of intercalated cells of collecting duct are also
seen (8).
Immunohistochemistry demonstrates a
poor relationship between tubulocystic renal cell carcinoma and collecting duct
tumors. These tumors show expression of proteins of proximal convoluted tubules
(CD10 and P504S), distal tubules (CK19) and intercalated collecting duct cells
(parvalbumin). They also show vimentin, p53 and alpha methylacyl CoA racemase
(AMACR) over-expression in contrast to CDC. High molecular weight cytokeratin
(34BE12) is nearly always negative (5).
Gene expression microarray analysis by
Yang et al. (9) demonstrated a unique molecular signature of tubulocystic renal
cell carcinoma in comparison to other renal tumors and normal renal tissue.
Clustering analysis of that data revealed tubulocystic renal cell carcinoma to
be closely related to papillary RCC. Both types 1 and 2 dimensional clustering
placed tubulocystic carcinoma between low and high grade papillary RCC. The
most common karyotypic changes in papillary RCC are trisomy 7 and 17 with loss
of Y chromosome. Yang et al. (9) also reported that tubulocystic renal cell
carcinoma showed gain of chromosome 17, but not chromosome 7. Thus, although
tubulocystic renal cell carcinoma has been reported in association with
multiple other renal cell tumor subtypes, it appears that there is a slight
predominance for synchronous tubulocystic carcinoma and papillary tumors. These
reports of coexistence thus raise an interesting question about presence of
common predisposing factors for these histologically different tumors.
Diagnostic investigations play a very
pertinent role as several differential diagnoses are to be considered. This is
especially important since tubulocystic renal cell carcinoma may be associated
with malignant behavior, that is, a high vigilance for potential metastatic
disease. As the tumors have cystic elements, the radiological differential
diagnostic spectrum is broad, including lesions that may be classified as a
Bosniak type III or IV.
Differential diagnoses
The clinical and pathological aspects
of tubulocystic carcinoma are still not well studied. A combination of
histology, electron microscopy and immunohistochemistry are required for proper
diagnosis. The main differential diagnosis of tubulocystic carcinoma includes
collecting duct carcinoma and other cystic tumors including cystic nephroma,
multilocular cystic RCC, and oncocytoma (14). Cystic nephroma is characterized
by larger cysts with hyalinized or fibrotic stroma. The cysts are lined by flat
to attenuated cells with occasional hobnailing. However, unlike tubulocystic
renal cell carcinoma, the nuclei are typically benign with absent or
inconspicuous nucleoli. Cystic nephroma has a characteristic ovarian-like
stroma between the cyst, which is often positive for estrogen and progesterone
receptors. In addition, cystic nephroma occurs almost always in females,
whereas tubulocystic renal cell carcinoma is more common in males. Multilocular
cystic renal cell carcinoma is characterized by variably sized cystic spaces
lined by flattened to cuboidal clear cells separated by fibrous stroma
containing small groups of clear cells of low Fuhrman nuclear grade. Oncocytoma
may have in a minority of cases prominent dilated tubules, which can resemble
tubulocystic renal cell carcinoma, as they both have abundant eosinophilic
cytoplasm and can have cells with prominent nucleoli. However, the nuclei in
oncocytoma are round or, if irregular, have degenerative atypia; whereas in
tubulocystic renal cell carcinoma, the nuclei are irregular without
degenerative features. Collecting duct carcinoma and renal medullary carcinoma
occur in the renal medulla; and demonstrate a poorly differentiated
adenocarcinoma, inflammatory infiltration, frequent perirenal fat invasion,
lymphovascular invasion, intraluminal mucin and high nuclear grade (5).
Management and outcome
Radical nephrectomy is generally
recommended, but partial nephrectomy may be performed for small tumors located
in the superficial renal cortex. Sunitinib, a tyrosine kinase inhibitor, may
exhibit a partial response or temporary effect for this tumor (15).
Tubulocystic renal cell carcinoma of the kidney with sarcomatoid change has
responded poorly to sorafenib (12). The antiangiogenic targeted therapeutic
protocols such as VHL/HIF, RTK/MAPK and PI3K/Akt/mTOR seem to have no rationale
of general recommendation (16). In the three largest series totaling 34 cases
with follow-up, only 3 developed metastases to lymph node, bone and liver. In contrast, in a series of 3 cases by Al
Hussain et al. (22), one was with vascular invasion and two were with invasion
to perinephric adipose tissue. This study reported 2 cases with poorly
differentiated areas consisting of collecting duct–like carcinoma areas, and
one with focal high-grade features with marked nuclear atypia and prominent
nucleoli. Apart from this, there is only one similar description in the
literature. Bhullar et al. recently reported 1 case of tubulocystic renal cell
carcinoma with tubulopapillary pattern and focal sarcomatoid areas that
developed multiple peritoneal metastases, and the patient died 14 months after
diagnosis (12). Limited work has been reported in this regard and it raises
concern that tubulocystic renal cell carcinoma with poorly differentiated areas
increases the risk of aggressive behavior above that of usual tubulocystic
renal cell carcinoma.
Conclusion
Tubulocystic renal cell carcinoma is a
distinct group of renal carcinoma with specific macroscopic, microscopic and
immunohistochemical findings. It appears to have a close relation to papillary
carcinoma. Tubulocystic renal cell carcinoma should be considered in
differential diagnosis of cystic kidney lesions, along with cystic nephroma,
multilocular cystic renal cell carcinoma, oncocytoma with prominent tubules and
cysts, and mixed epithelial and stromal tumor of the kidney. However, it is
distinctly different from these entities with regard to radiological findings,
including growth pattern, the presence of cystic components and also in their
biological aggressiveness. Tubulocystic renal cell carcinoma with poorly
differentiated areas increases the risk of aggressive behavior above that of
usual tubulocystic renal cell carcinoma. To date, no established guidelines
have been given for the management of this tumor. The examination of more cases
is required to understand its biology and ascertain true prognosis and
appropriate treatment.
Conflict of interest: None
References
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer
statistics. CA: A Cancer Journal for Clinicians 2011; 61:69–90.
Doi: http://dx.doi.org/10.3322/caac.20107
2. "Cancer of the kidney and Renal Pelvis – SEER Stat Fact sheets". National Cancer Institute, U.S. National Institutes of Health. Retrieved 2014-02-07.
3. Masson P. Tumeurs Humaines 1955. Human Tumors, Histology, Diagnosis and Technique. Detroit, MI: Wayne State University Press; 1970.
4. 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.
Doi: http://dx.doi.org/10.1016/S0090-4295(97)00335-X
5. 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. American Journal of Surgical Pathology2009; 33:1103–1106.
Doi: http://dx.doi.org/10.1097/PAS.0b013e3181a13e7b
6. Amin MB, MacLennan GT, Gupta R, et al. Tubulocystic carcinoma of the
kidney: clinicopathologic analysis of 31cases of a distinctive rare subtype of
renal cell carcinoma. Am J Surg Pathol. 2009; 33:384-392.
Doi: http://dx.doi.org/10.1097/PAS.0b013e3181872d3f
7. Srigley JR, Delahunt B, Eble JN, et al. ISUP Renal Tumor Panel. The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia. Am.J.Surg.Pathol. 2013; 37;1469-489. [Pubmed]
8. Amin MB, Maclennan GT, Gupta R, et al. 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.
Doi: http://dx.doi.org/10.1097/PAS.0b013e3181872d3f
9. Yang XJ, Zhou M, Ondrej H, et al. Tubulocystic carcinoma of the kidney.
Clinicopathologic and molecular characterization. Am J Surg Pathol 2008;
32:177-187.
Doi: http://dx.doi.org/10.1097/PAS.0b013e318150df1d
10. Azoulay S, Vieillefond A, Paraf F, Pasquier D, Cussenot O, Callard P,
et al. Tubulocystic carcinoma of the kidney: a new entity among renal tumors.
Virchows Archiv 2007; 451:905–909.
Doi: http://dx.doi.org/10.1007/s00428-007-0483-7
11. Bhullar JS, Varshney N, Bhullar AK, Mittal VK. A New Type of Renal
Cancer—Tubulocystic Carcinoma of the Kidney: A Review of the Literature. Int J
Surg Pathol Int J Surg Pathol. 2013 Nov 14; 22:297-302.
Doi: http://dx.doi.org/10.1177/1066896913509007
12. Bhullar JS, Thamboo T, Esuvaranathan K. Unique case of tubulocystic
carcinoma of the kidney with sarcomatoid features: a new entity. Urology 2011;
78:1071-2.
Doi: http://dx.doi.org/10.1016/j.urology.2011.01.038
13. Azoulay S, Vieillefond A, Paraf F, Pasquier D, Cussenot O, Callard P,
et al. Tubulocystic carcinoma of the kidney: a new entity among renal tumors.
Virchows Archiv 2007; 451:905–909
Doi: http://dx.doi.org/10.1007/s00428-007-0483-7
14. Srigley JR, Delahunt B. Uncommon and recently described renal
carcinomas. Mod Pathol 2009; 22(Suppl 2):S2–S23.
Doi: http://dx.doi.org/10.1038/modpathol.2009.70
15. Mego M, Sycova-Mila Z, Rejlekova K, et al. Sunitinib in the treatment
of tubulocystic carcinoma of the kidney. A case report. Ann Oncol 2008; 19:
1655-1661.
Doi: http://dx.doi.org/10.1093/annonc/mdn408
16. Steiner P, Hora M, Stehlik J, et al. Tubulocystic renal cell carcinoma:
Is there a rational reason for target therapy using angiogenic inhibition?
Analysis of seven cases. Virchows Arch 2013;462: 183-192.
Doi: http://dx.doi.org/10.1007/s00428-012-1367-z
Doi: http://dx.doi.org/10.1097/PAS.0b013e3181be22d1
18. Amin MB, Gupta R, Ondrej H, et al. Primary thyroid like follicular
carcinoma of the kidney. Report of 6 cases of a histologically distinctive
adult renal epithelial neoplasm. Am J Surg Pathol. 2009; 33:393-400.
Doi: http://dx.doi.org/10.1097/PAS.0b013e31818cb8f5
19. Hora M, Michal M, Hes O. Re: Rodolfo Montironi, Roberta Mazzuccelli,
Antonio Lopez-Beltran, et al. Cystic nephroma and mixed epithelial and stromal
tumour of the kidney: opposite ends of the spectrum of the same entity? Eur
Urol 2008; 54:1237-1246.
Doi: http://dx.doi.org/10.1016/j.eururo.2009.01.020
20. Deshmukh M, Shet T, Bakshi G, Desai S. Tubulocystic carcinoma of kidney
associated with papillary renal cell carcinoma. Indian Journal of Pathology and
Microbiology 2011; 54:127–130.
Doi: http://dx.doi.org/10.4103/0377-4929.77363
21. Borislav AA, Drachenberg CB. Tubulocystic carcinoma of the kidney: a
histologic, immunohistochemical, and ultrastructural study. Virchows Arch.
2013; 462:575-581.
Doi: http://dx.doi.org/10.1007/s00428-013-1398-0
22. Al-Hussain TO, Cheng L, Zhang S, Epstein JI. Tubulocystic carcinoma of
the kidney with poorly differentiated foci: a series of 3 cases with
fluorescence in situ hybridization analysis. Hum Pathol. 2013; 44:1406-1411.
Doi: http://dx.doi.org/10.1016/j.humpath.2012.11.015
23. Iakovleva G, Iakovlev V, Ordon M, Srigley J, Yousef GM. Tubulocystic
Carcinoma of Kidney: a Challenging Diagnostic Entity Mimicking Multicystic
Kidney and Presenting with Bone Metastasis. Histopathology. 2014 Aug 11.
Doi: http://dx.doi.org/10.1111/his.12502
24. Ishibashi Y, Koie T, Fujita N, Satoh T, Mikami J, Hatakeyama S, Ohyama
C, Tobisawa Y, Yoneyama T. Tubulocystic renal cell carcinoma in the left
kidney: a case report. J Med Case Rep. 2014; 8:265.
Doi: http://dx.doi.org/10.1186/1752-1947-8-265