—  SYMPOSIUM #54  —

Renal Neoplasia
Moderators: Dr. John Eble and Dr. Brett Delahunt

Section 5 - Renal Collecting Duct Carcinoma (CDC, Bellini Carcinoma) and Related Tumors

Annick Vieillefond
Paris, France


Histological Definition of Collecting Ducts
The collecting ducts (CD) as well as the ureter, the pelvis and the calices originate from the mesonephros. The Bellini duct, also called inner medullary CD, is the distal segment of the CD situated in the renal medullary pyramids. For some authors it is limited to the very distal tube that opens onto the tip of the papilla. The CD is lined by principal cells and intercalated cells. Principal cells are cylindrocubic, eosinophilic with a cytoplasmic apical protusion into the lumen which results in a "hobnail" appearance.

Putative Histogenesis of Renal Epithelial Tumors
Clear cell carcinomas are supposed to originate from the proximal part of the convoluted tubule and papillary carcinomas from the distal part. Chromophobe carcinomas and oncocytomas are supposed to originate from the CD intercalated cells. Collecting ducts carcinomas (CDC, Bellini carcinomas) are supposed to originate from the principal cells of the inner medullary CD.

CDC: an Evolving Concept
1955 : "Bellini epithelioma": P.Masson [1]. Cystic tumor located in the central region of the kidney with cysts lined by "hobnail cells" similar to the principal cells of the Bellini ducts.

1976 : Some papillary carcinomas with hyperplastic and atypical changes in normal adjacent collecting tubules may have a collecting duct origin ( Mancilla Jimenez [2] ).

1990 : 25 cases of CDC described in the literature [3, 4]. High grade aggressive subtype renal cell carcinoma located predominantly in the renal medulla and pelvis, with tubular and papillary patterns containing desmoplastic inflammatory stroma.

1994 : AFIP [5]: CDC are high grade tubular, trabecular and papillary carcinomas or low grade carcinomas with hobnail cystic patterns.

1997 and 1998 : Amin [6] and Srigley [7] and UICC/WHO 1998 consensus [8]. CDC is a spectrum of heterogeneous renal carcinomas : from low grade through high stage and high grade tumor (the most frequent) to renal medullary carcinoma (RMC), in patients with sickle trait disease and sarcomatoid carcinoma.

1997 : Low grade CDC are indolent cystic tumors "13 cases of low grade mucinous tubulocystic renal carcinoma of possible collecting duct origin" Mac Lennan [9].

2004 : WHO classification [10]: only 2 distinct categories: 1) high grade CDC and 2) RMC.

2006 : What about the"low grade mucinous tubulocystic renal carcinoma of possible collecting duct origin" ? They have been divided into 2 categories

  1. a new recognized entity:" low grade mucinous tubular and spindle cell renal carcinoma"

  2. an emerging new entity, not recognized in the 2004 WHO classification : the tubulocystic carcinoma : Amin 2004 and 2005 USCAP meetings [11, 12], Farah [13] and Mc Lennan [14].
This entity corresponds to the formerly Masson's Bellini epithelioma.

Collecting Duct Carcinomas (CDC) and Renal Medullary Carcinomas (RMC) : Emblematic Features
Clinical features : CDC share the same epidemiology as other renal or urothelial carcinomas: sex ratio 2M/1F, mean age 55 years. CDC are often symptomatic (abdominal pain, nephritis colitis, hematuria, palpable tumor, fever, loss of weight …) and present metastases at the time of diagnosis. The most striking difference between CDC and RMC is epidemiologic : RMC are observed in young black patients with sickle cell hemoglobinopathy disease or harboring sickle cell trait. In a large series of 40 RMC provided by the National Wilms Tumor Study Group (NWTSG) [15] the patients were 5 to 32 years old (mean 14,8) and presented with high stage tumors, widespread metastases and nodal involvement.

Gross examination : Macroscopic characteristics of RMC do not differ from CDC : large grey, white, extensive masses which infiltrate the medulla and the central part of the kidney . Hilar structures, cortex and perinephric fat can be also involved. Some necrotic or cystic changes can be seen.

The central location of the tumor is not really a clue for the collecting duct origin because it can be observed in all types of renal cell carcinomas (clear cell, papillary.. ). The relation with the urothelial pelvis is sometimes difficult to ascertain when the tumors extend along and protrude into the renal pelvis. Some distant nodules are usually seen in the kidney as well as vascular, adrenal or regional nodes invasion.

Microscopic features : The growth pattern displays tubular, papillary and solid cord-like features. The stroma is quite distinctive from the stroma of other renal carcinomas: abundant and fibrous, with important necrotic and inflammatory changes and remnants of nephron tubules and glomeruli. The carcinomatous cells are large or medium sized cylindrocubic with eosinophilic or basophilic cytoplasm (PAS +/-), they have a high nuclear cytoplasmic ratio and a frequent hobnail pattern. Atypical hyperplastic changes or carcinoma in situ are classically obseved in the adjacent collecting ducts but they are very rare and difficult to ascertain.

Ultrastructural studies demonstrated similar characteristics to principal cells of the CD.
Immunohistochemistry : The tumoral cells in CDC express EMA and diverse low and high molecular weight keratin: CK 7, 8, 18, 19, HMWK. They may express lectins (peanuts, UEA), aquaporine 3, racemase and vimentin [16, 17]. The immunoprofile of RMC is similar to CDC except the negativity of HMWK. VEGF and HIF may be positive [15]

Chromosomal analysis : Karyotypes are hypodiploid with a high rate of diverse numerical and structural aberrations, most frequently alterations of chromosome 1, 22,13 [18]. Loss of heterozygosity was demonstrated in 1q 32;1-32.2 and in 9p, 8p, 13q [19].

Among the 8 criteria proposed for the diagnosis of CDC only 3 are commonly observed*

  • Anatomic situation in the medulla

  • An infiltrative pattern*

  • No obvious proliferation of upper urinary tract

  • A papillary, tubular, solid and cystic growth pattern*

  • An extensive fibrous and inflammatory stroma*

  • Hobnails cells

  • HMWK +, Ulex+

  • The coexistence of carcinoma in situ in adjacent collecting tubules


Differential Diagnoses :
CDC present extensive overlaps with high grade type 2 papillary carcinomas and with urothelial carcinomas. It remains a diagnostic challenge for pathologists and often a diagnosis of exclusion.



Medullar location Pyelic protusion Infiltrative pattern Papillary cystic, solid growth Stroma fibrous, inflammatory CIS in adjacent collecting tubules Hobnails cells
CDC +++ -/+ ++ ++ ++ +/- +
RMC +++ -/+ ++ ++ ++ +/- +
High grade papillary carcinoma +/- -/+ + ++ -/+ - -
Urothelial Carcinoma ++/- +++ ++ -/+ + -/+ -




HMWK CK7 CK5/6 vimentin Ulex (UEA) Aquaporin 3 P504
CDC + + -/+ -/+ ++ +/- -/+
RMC -/+ + -/+ + -
High grade papillary carcinoma -/+ ++ +/- - - +
Urothelial Carcinoma -/+ +++ +/- -/+ ++ +/- -/+

Discussion
There are increasing arguments that a subset of CDC belongs to the spectrum of urothelial carcinoma. Collecting ducts and urothelium originate from the mesonephros. Urothelial tumor invading the kidney and CDC invading the pelvis can share the same gross aspect. CDC is in some cases associated with an urothelial pyelic carcinoma [20, 21]. Urothelial carcinoma variants can be composed of trabecular nests and cords of cohesive cells with tubular structures producing more or less mucin, like CDC.

In a recent series of high grade carcinomas considered as CDC [22] most of the tumors had a urothelial-like histological profile (UEA+, vimentin -, Aquaporine 3 +).

A molecular study on a clustering of 3583 genes in 2 RMC have also demonstrated their close relation with urothelial carcinoma [23].

Most importantly, several clinical studies have recently reported the clinical benefit of treating CDC patients with a combination of cisplatin and gemcitabine standardly used in urothelial carcinomas [24, 25, 26] .

In Conclusion
  1. Former "Bellini epithelioma" is a low grade tubulocystic carcinoma unrelated to a Bellini duct origin

  2. In the heterogeneous group of high grade renal carcinoma, two distinct entities CDC and RMC, are still considered to be related to a Bellini duct origin. They only differ by epidemiology (RMC occurs in young black patient with sickle trait hemoglobinopathy) and they represent < 1% of renal cell carcinomas.

  3. CDC and RMC are centrally located extensive tumors of the kidney with tubular and/or papillary patterns with an abundant fibrous inflammatory stroma.

  4. CDC and RMC are histologically and biologically more closely related to urothelial carcinoma than to renal carcinoma

  5. CDC and RMC require the same active chemotherapy regimen as urothelial carcinomas.


References :
  1. Masson P: Tumeurs humaines . Histologie, Diagnostics et techniques. 1956, 2ème. 1968, Paris: Librairie Maloine.

  2. Mancilla-Jimenez R, Stanley RJ, Blath RA. Papillary renal cell carcinoma: a clinical, radiologic, and pathologic study of 34 cases. Cancer.1976;38(6):2469-2480

  3. Fleming S, Lewi HJ: Collecting duct carcinoma of the kidney. Histopathology. 1986 10:1131-1141

  4. Kennedy SM, Merino MJ, Linehan WM, Roberts JR, Robertson CN, Neumann RD.Collecting duct carcinoma of the kidney. Hum Pathol. 1990 ; 21(4):449-56

  5. Murphy WM, Beckwith JB, Farrow GM. Atlas of Tumor Pathology; third series, Fascicule11, Tumors of the Kidney, Bladder, and Related Urinary Structures. Washington, D.C.Armed Forces Institute of Pathology. 1994

  6. Amin B, Varma MD, Tickoo SK, Ro JY. Collecting duct carcinoma of the kidney. Adv anat pathol 1997, 4, 2, 85-94

  7. Srigley JR, Eble JN. Collecting duct carcinoma of kidney. Semin Diagn Pathol.1998; 15(1):54-67

  8. Bostwick D. G., Eble J.N., Murphy G.P. Conference Summary : Diagnosis and prognosis of Renal Cell Carcinoma: Cancer.1997; 80 (5), 975-99

  9. MacLennan GT., Farrow G.M. and Bostwick D.G. Low-grade collecting duct carcinoma of the kidney : Report of 13 cas of low-grade mucinous tubulocystic renal carcinoma of possible collecting duct origin. Urology 1997, 50, 679-68

  10. Eble, J.N., et al., World Health Organization. Classification of tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. World Health Organization Classification of Tumours. 2004, Lyon : IARCC Press

  11. Amin MB, Mac Lennan, Paraf F,Cheville JC, Vieillefond A, Radhakrishan A,Che M, Srigley JR,Grignon DJ.Tubulocystic carcinoma of the kidney : Clinicopathological analysis of a distinctive rare subtype of renal cell carcinoma. Mod Pathol 2004; 17(Suppl.1): 137 A.

  12. Radhakrishnan, A., et al., Ultrastructural and immunohistochemical (IHC) appraisal of tubulocystic carcinoma (TCCa) of the kidney : histogenetic and diagnostic implications. Mod Pathol, 2005. 18: p. 160A.

  13. Farah R, Ben-Izhak O, Munichor M, Cohen H. Low-grade renal collecting duct carcinoma. A case report with histochemical, immunohistochemical, and ultrastructural study. Ann Diagn Pathol. 2005 Feb;9(1):46-8

  14. MacLennan GT, Bostwick DG. Tubulocystic Carcinoma, Mucinous Tubular and Spindle Cell Carcinoma and Other Recently Described Rare Renal Tumors. Clin Lab Med. 2005 Jun;25(2): 393-416

  15. Swartz MA, Karth J, Schneider DT, Rodriguez R, Beckwith JB, Perlman EJ. Renal medullary carcinoma: clinical, pathologic, immunohistochemical, and genetic analysis with pathogenetic implications.Urology. 2002 Dec;60(6):1083-9

  16. Skinnider BF, Amin MB. An immunohistochemical approach to the differential diagnosis of renal tumors. Semin Diagn Pathol. 2005 Feb;22(1):51-68.

  17. Zhou M, Roma A, Magi-Galluzzi C.The usefulness of immunohistochemical markers in the differential diagnosis of renal neoplasms. Clin Lab Med. 2005 Jun;25(2):247-57.

  18. Antonelli A, Portesi E, Cozzoli A, Zanotelli T, Tardanico R, Balzarini P, Grigolato PG, Cosciani Cunico S.The collecting duct carcinoma of the kidney: a cytogenetical study. Eur Urol. 2003 Jun;43(6):680-5

  19. Kuroda N, Toi M, Hiroi M, Enzan H. Review of collecting duct carcinoma with focus on clinical and pathobiological aspects. Histol Histopathol. 2002 Oct;17(4):1329-34.

  20. Orsola A, Trias I, Raventos CX, Espanol I, Cecchini L, Orsola IUrology. Renal collecting (Bellini) duct carcinoma displays similar characteristics to upper tract urothelial cell carcinoma 2005 Jan;65(1):49-54

  21. Matei DV, Rocco B, Varela R, Verweij F, Scardino E, Renne G, De Cobelli O. Synchronous collecting duct carcinoma and papillary renal cell carcinoma: a case report and review of the literature. Anticancer Res. 2005 Jan-Feb;25(1B):579-86.

  22. Kafé H, Verbavatz JM, Cochand-Priollet B, Castagnet P,Vieillefond. A Collecting duct carcinoma: an entity to be redefined ? Virchows Arch. 2004 Dec;445(6):637-40

  23. Yang XJ, Sugimura J, Tretiakova MS, Furge K, Zagaja G, Sokoloff M, Pins M, Bergan R, Grignon DJ, Stadler WM, Vogelzang NJ, Teh BT. Gene expression profiling of renal medullary carcinoma: potential clinical relevance. Cancer. 2004 Mar 1;100(5):976-85

  24. Milowsky MI, Rosmarin A, Tickoo SK, et al: Active chemotherapy for collecting duct carcinoma of the kidney: a case report and review of the literature. Cancer 94:111-116, 2002

  25. Fakhrai N, Haitel A, Balassy C, Zielinski CC, Schmidinger M. Major response and clinical benefit following third-line treatment for Bellini duct carcinoma. Wien Klin Wochenschr. 2005 Jan;117(1-2):63-5.

  26. Oudard S, Banu E,Vieillefond A, Fournier L, Priou F, Langlois D, Banu A, Duclos B, Rolland F, Arakelyan N,Culine S et al.Prospective Multicenter Phase II Trial of Gemcitabine plus Platinum Salt for Metastatic Collecting Duct Carcinoma Patients. Results of a GETUG study. Submitted