MEIS1::NCOA1 Primitive Spindle Cell Sarcoma of the Kidney : Report of 7 Cases of a Distinctive Clinicopathologic Entity

Abstract

Primitive sarcomas harboring the MEIS1::NCOA2 gene fusion were originally described in the kidney in 2018, and subsequently reported in other organs. These variably cellular neoplasms feature monomorphic primitive plump spindle cells forming nodules and whorls in addition to nondescript fascicular, solid, and storiform patterns. They lack skeletal muscle differentiation in contrast to the primarily intraosseous rhabdomyosarcomas that harbor the same gene fusion. We describe 7 new primary primitive renal sarcomas with MEIS1::NCOA1 gene fusions. Although their morphology overlaps with that described in MEIS1::NCOA2 renal sarcoma, 3 of the 7 cases contained adipose tissue. The majority had intimately admixed entrapped cystic epithelial elements and demonstrated patchy immunoreactivity for estrogen receptor and nuclear labeling for WT1 protein, leading to the differential diagnosis of malignant mixed epithelial stromal tumor (MEST) in 4 cases and metanephric stromal tumor in one. The neoplasms demonstrate a broad spectrum of clinicopathologic features ranging from a bland low-grade neoplasm that metastasized 9 years after diagnosis to a high-grade sarcoma with multiple recurrences, ultimately leading to patient death in under 1 year. In summary, MEIS1::NCOA1 primitive sarcomas overlap with the previously described MEIS1::NCOA2 primitive renal sarcomas and represent a distinctive renal neoplasm that can be mistaken for malignant MEST. Grade ranges from low to high but even low-grade neoplasms require long-term clinical follow-up.

Keywords: renal neoplasm; sarcoma; translocation.

Figure 1 ( case 2).

This lesion, which presented clinically as a complex cyst, at low power magnification demonstrates multicystic architecture with entrapped native renal tubules, some of which are markedly dilated, and variable stromal cellularity ranging from low to high (A). The neoplasm contains cysts lined by native renal tubular epithelium with hobnail pattern. The epithelium (but not the stroma) labeled for PAX8 (not shown) (B). The tumor contains cellular spindle cell whorls, and fat associated with entrapped benign renal tubules (C). Hypocellular areas of the neoplasm associated with entrapped tubules suggest the possibility of an underlying mixed epithelial stromal tumor (D). High power view demonstrating the prominent characteristic whorling of the tumor (E). The stromal cells demonstrate patchy labeling for estrogen receptor, particularly in association with less cellular areas adjacent to native renal tubules (F).

Figure 2 (case 3).

This spindle cell neoplasm of the kidney extends into the renal sinus to undermine the urothelium at the right. The neoplasm demonstrates variable cellularity, and entraps native renal tubules which undergo cystic change similar to that seen in mixed epithelial stromal tumor (A). At intermediate power, the neoplasm has an infiltrative border and permeates between the native renal tubules. (B). Higher power view demonstrates striking concentric “onion-skin” growth pattern surrounding native renal tubules (C). The tumor demonstrates unusual epithelioid foci adjacent to intratumoral capillaries mimicking the angiodysplasia of metanephric stromal tumor (D). High power view demonstrates the glomeruloid appearance of epithelioid cells surrounding capillaries (E). The neoplasm contains fat, as demonstrated in this area adjacent to native renal tubules (F).

Figure 3 (recurrence of case 3).

The retroperitoneal recurrence demonstrates variable cellularity and marked nodularity (A). The neoplasm demonstrates a striking whorled growth pattern (B). Intermediate high-power view demonstrates epithelioid growth around blood vessels, yielding a glomeruloid pattern (C, D). The neoplasm demonstrates diffuse nuclear labeling for WT1 (E). The neoplasm demonstrates patchy labeling for estrogen receptor (F).

Figure 4 (case 4).

At low power this renal neoplasm has a fibrous pseudocapsule to the left in which the tumor invades a blood vessel (A). Intermediate power view demonstrates intersecting short fascicles composed of plump spindle cells, remarkably similar to monophasic synovial sarcoma (B). The neoplasm demonstrates a high mitotic rate of up to 5 mitoses per high power field (C). Minimal nodular whorling is evident (D). The neoplastic cells demonstrate multifocal labeling for TLE1 (E) and patchy immunoreactivity for WT1 (F).

Figure 5 (case 5)

At low power, the neoplasm has both a solid component to the left and a cystic component to the right. The cysts are composed of dilated benign renal tubules (A). The hypocellular areas of the tumor at the upper portions of the figure permeate between native nephrons, similar to mixed epithelial stromal tumor (B). Intratumoral fat is evident between thyroidized entrapped renal tubules (C). Cellular sheets of epithelioid to spindled cells are mitotically active (D). Nodules of small round cells are present (E) Whorls of tumor cells also form nodules (F). The neoplastic cells demonstrate moderate nuclear labeling for estrogen receptor while entrapped native renal tubules are negative (G) and demonstrate strong nuclear labeling for WT1 with entrapped native renal tubules being negative (H).

Figure 6 (Case 7).

This primary renal neoplasm has a solid and cystic gross appearance which could be compatible with mixed epithelial stromal tumor (A). At low power this spindle cell neoplasm demonstrates cellular areas in addition to less cellular, edematous areas (B). The dominant pattern is storiform (C). The neoplastic cells are cytologically bland and have fine chromatin with essentially no mitotic activity (D).

Figure 7.

Chimeric transcripts and retained protein domains resulting from gene fusions identified by RNA-seq, highlighting the structural and functional implications of these gene fusions. (A) RNA transcripts with exon structures and corresponding protein domains in the genes involved in the fusions: MEIS1 exons are shown in grey, NCOA1 in green, and NCOA2 in blue. (B) Fusion transcripts MEIS1::NCOA1 and MEIS1::NCOA2, along with their retained functional protein domains identified in this study, compared to similar fusions reported in the literature. Untranslated regions (5′ UTR and 3′ UTR) are depicted as narrow bars, while exons are represented as numbered boxes. Protein domains are displayed in wider boxes behind exons and labeled with the following keys: MEIS1 protein domains: HB_MPN - Homeobox Meis and PKNOX1 at the N-terminal, HB-KN - Homeobox KN domain. NCOA1 and NCOA2 protein domains: HLH - Helix-loop-helix domain, PAS - PAS domain, NCOA_u2 - Unstructured region on the nuclear receptor coactivator protein, SRC-1 - Steroid receptor coactivator, DUF4927 - Domain of unknown function (DUF4927), NRCA - Nuc_rec_co-act, Nuclear receptor coactivator, Med15 - ARC105 or Med15 subunit of the Mediator complex (non-fungal), DUF1518 - Domain of unknown function (DUF1518), LsmAD - Lsm activation domain. The break-fusion points for MEIS1 are at the 3′ end of exon 6 or 7, for NCOA1 at the 5′ end of exon 12, 13, or 15 (domains in green dashed box may or may not be retained), and for NCOA2 at the 5′ end of exon 12, 13, or 14 (blue dashed box). Breakpoints from this study and renal cases in the literature are marked with orange arrows, while those from non-renal cases are marked with black arrows.