Clear cell sarcoma of the kidney (CCSK) is a rare malignant tumor of kidney which occurs predominantly in the pediatric setting, with aggressive clinical behavior.^1-4  Recent molecular studies demonstrated BCOR-ITD  in most cases, and a YWHAE::NUTM2 fusion in a few cases, with the remaining cases having other genetic rearrangements, including BCOR::CCNB3 fusion and EGFR alterations.¹

CCSK represent 3-5% of primary pediatric renal tumors with a male: female ratio of 2:1. Average age at diagnosis is 2-4 years. ¹

Tumor frequently arise in the renal sinus and may reach a huge size, up to 3,000 grams.  Symptoms are abdominal distension, palpable abdominal mass, with abdominal pain, hematuria, occasionally fever.  Rarely pathological fractures due to metastatic tumor may represent the presentation symptoms.

The denomination “Clear cell” sarcoma of kidney derives from the clear appearance of nuclei, cytoplasm, or extracellular matrix.  The classic pattern includes: a) plump ovoid cells with monomorphic nuclei containing homogeneous chromatin without prominent nucleoli, b) cells arranged in trabeculae or nests with arborizing fibrous septa containing typical thin walled capillaries and c) common abundant sclerotic extracellular matrix. Rare mitoses and isolated nephrons entrapped by the tumor. ² However the   histological patterns are highly variable:  cellular (mitotically active), myxoid, sclerosing, epithelioid, palisading, spindle cell.  Anaplasia in 3% of cases, probably associated with TP53 gene mutation. ⁵

A combination CCND1, TLE1, and BCOR are compelling markers in aiding CCSK diagnosis, regardless of genotype. ⁶

Since the first report of t(10;17)(q22;p13) (Fig.1) in 1989,  a few other additional cases were described .⁹ The t(10;17) results in an in-frame fusion transcript YWHAE::NUTM2 fusion with either NUTM2B or NUTM2E gene,  detectable in approximately 12% of CCSK. ^10,11

 Fig 1: Partial GTG-banded karyotype showing t(10;17)(q22;p13), which is the cytogenetic hallmark of YWHAE::NUTM2 rearrangement in a subgroup of clear cell sarcoma of the kidney (Courtesy of Dr. Mark Pettenati).

However, different internal tandem duplications of exon 15 of the BCOR gene (BCOR-ITD) , involving the PUFD domain  has been demonstrated in the majority of CCSK. ^12-17 BCOR-ITD and YWHAE::NUTM2 fusion are mutually exclusive. ^18-20

A minority of patients with CCSK do not have BCOR-ITD or YWHAE::NUTM2 fusion, including  a BCOR::CCNB3 fusion , sharing a similar gene expression profiles with BCOR-ITD–positive CCSK. ^15,21-23

Other report genetic alterations in CCSK include: 2 novel karyotypes with t(2;13)(q13;q22) and  t(3:17)(q29;p11.2), both with diffuse and strong nuclear cyclin D1 staining, ²⁴  and  IRX2::TERT gene fusion as result of an interstitial deletion of 5p15.33.²⁵

EGFR aberrations as amplification, point mutation (T790M), ²⁶ and internal tandem  (ITD) duplication.²⁷

TP53 deletion in CCSK, was often associated with adverse clinical outcomes. ²⁰

CCSK may show over-expression of several genes, including neural markers (nerve growth factor receptor) genes involved in the Sonic hedgehog pathway and the P13K/Akt cell proliferation pathway. ²⁸

Both YWHAE::NUTM2 and BCOR-ITD  has been reported in endometrial stromal sarcomas, ²⁹ in high grade  uterine sarcomas (within the family of endometrial stromal neoplasia), ³⁰ in a subgroup of central nervous systemhigh-grade neuroepithelial tumors (CNS-HGNET) ,³¹ in half of infantile soft tissue undifferentiated round cell sarcomas (URCS) and in most primitive myxoid mesenchymal tumor of infancy (PMMTI) cases, but not in other pediatric sarcomas. ^17,32
BCOR::CCNB3 gene fusion,  resulting from a cryptic inv(X) (p11.4p11.22) has been found  in renal and extra renal neoplasms, including  undifferentiated round cell sarcomas of bone and soft tissue in children and adults ^33-38, in a subset of primary renal sarcomas indistinguishable from CCSK with BCOR-ITD. ^{15,21,22,39,40}