Recently several low-grade renal cell tumors, distinct from those recognized by the 2004 World Health Organization classification of renal tumors, have been described. These tumors had similar clinicopathologic features, being low-stage tumors with cystic, tubuloacinar, and/or papillary architecture. The tumor cells were low grade with variable amounts of clear cytoplasm that was positive for cytokeratin 7 (CK7), but negative for CD10. Genetic changes characteristic of clear cell or papillary renal cell carcinoma were not seen in these tumors. We investigated the morphologic, immunohistochemical, and genetic features of 36 additional tumors. Immunohistochemistry was carried out for CK7, carbonic anhydrase 9, α-methylacyl-CoA racemase, CD10, TFE-3, and desmin. Interphase fluorescence in situ hybridization was carried out with centromeric probes for chromosomes 3, 7, 17, and a subtelomeric probe for 3p25. Sequencing of von Hippel-Lindau gene and analysis of the methylation status of the promoter region was also carried out in 2 tumors. Thirty-six tumors from 33 patients (mean age: 60.4 , range: 26 to 88; 17 men and 16 women) were studied. Three patients had bilateral tumors and 1 patient had von Hippel-Lindau disease. Follow-up was available in 60% (20/33) of the patients for a mean of 27.4 (range 1 to 85) months. No patient had evidence of the disease after surgery except for the patient with von Hippel-Lindau disease, who was alive with stable disease in the contralateral kidney. All 36 tumors were small (mean size 2.4 cm; range 0.9 to 4.5 cm) and low stage (pT1). The majority was cystic and had prominent fibrous capsule and stroma. The tumors were composed of variable amount of cysts, papillae, tubules, acini, and solid nests. The most characteristic histologic features were branching tubules and acini and anastomosing clear cell ribbons with low-grade nuclei. All tumors were strongly positive for CK7 and variably positive for CA9, but largely negative for CD10, and negative for α-methylacyl-CoA racemase and TFE-3. All but 1 tumor had no gains of chromosomes 7 and 17 and deletion of 3p. Only 1 tumor had low copy number gains of chromosomes 7 and 17. VHL gene mutation and promoter methylation were negative in 2 tumors analyzed. We show that these tumors, which we term as “clear cell tubulopapillary renal cell carcinoma,” constitute a unique subtype in the spectrum of renal epithelial neoplasia based on their characteristic morphologic and immunohistochemical features.

Recently several examples of low-grade renal cell
tumors, distinct from those recognized by the 2004
World Health Organization classification of renal tumors,
have been described. In 2000 and 2009 Michal et al
23,24
described, in 2 reports, 6 cases of benign or indolent
“renal angiomyoadenomatous tumor.” These were bi-
phasic tumors with a characteristic epithelial component
that exhibited immunopositivity for cytokeratin 7 (CK7),
but not for CD10, and an angioleiomyomatous stroma
that was HMB45 negative. No mutations in the von
Hippel-Lindau (VHL) gene, nor loss of heterozygocity
involving chromosome 3p, was found in these tumors.
Tickoo et al,
27
in their study of the epithelial neoplasms
in the end-stage renal diseases, described 15 “clear-cell
papillary renal cell carcinoma of the end-stage kidneys,”
which were predominantly cystic tumors and showed
prominent papillary architecture with purely clear-cell
cytology. Gobbo et al
10
later reported 7 clear cell papill-
ary renal cell carcinomas composed mainly of cells with
clear cytoplasm arranged in papillary patterns in the
kidneys unaffected by end-stage renal disease. All tumors
showed strong positive staining for CK7, but were
negative for CD10. None had gains of chromosome 7
or loss of Y chromosome, typical of papillary renal cell
carcinoma (PRCC), and none had deletion of 3p, a
finding seen in clear cell renal cell carcinoma (CCRCC).
Mai et al
20
described 21 small tumors from 10 patients that
had a distinct tubular, cystic, and papillary architecture.

These showed diffuse CK7 reactivity, but were negative for
CD10 and for this reason the designation sporadic clear cell
renal cell carcinoma with diffuse cytokeratin 7 immunor-
eactivity was applied.
Although bearing different names, the renal tumors
reported in these 5 studies had similar clinicopathologic
features, being low-stage tumors with cystic, tubuloacinar,
and/or papillary architecture. The tumor cells were low
grade with variable amounts of clear cytoplasm that was
positive for CK7 but negative for CD10. Genetic changes
characteristic of CCRCC or PRCC were not seen in these
tumors.
In this study, we have investigated the morphologic,
immunohistochemical, and genetic features of 36 additional
renal tumors that are similar to those described
in the earlier studies, and which seem to constitute a novel
form of low-grade renal malignancy. We propose the term
“clear cell tubulopapillary renal cell carcinoma (CCTP-
RCC)” for these tumors to emphasize their dominant
morphologic features. This new terminology would unify
this novel renal tumor that was reported under several
different names in the literature and clarify confusions
resulting from the polynomial nature of this tumor.

Original Article