Abstract
Sclerosing epithelioid fibrosarcoma (SEF) is a rare variant of fibrosarcoma. We report one case of primary kidney SEF occurring in a 38-year-old man. Microscopically, epithelioid neoplastic cells are mainly arranged in cords and nests embedded in the dense sclerosing stroma. Diffuse immunohistochemical staining for MUC4 in neoplastic cells and the presence of the EWSR1 gene split by fluorescence in situ hybridization (FISH) analysis confirmed the histological diagnosis. Primary kidney SEF is extremely rare, the differential diagnosis strategy broadly includes a series of tumors with epithelioid morphology and sclerosing matrix, mainly including sclerosing variants of clear cell sarcoma of the kidney (CCSK), renal synovial sarcoma (SS), renal solitary fibrous tumor (SFT), metanephric stromal tumor (MST), sclerosing perivascular epithelioid cell tumor (PEComa), and carcinomas, and immunohistochemical expression of MUC4 and evidence of the EWSR1 gene split are helpful in making a definite diagnosis.
Introduction
Sclerosing epithelioid fibrosarcoma (SEF) is a rare variant of fibrosarcoma characterized by epithelioid cells arranged in cords and nests and embedded in a dense sclerotic stroma. SEF was first described by Meis-Kindblom et al in 1995. 1 SEF usually arises in middle-aged to elderly adults with an equal sex distribution. It occurs most often in the upper or lower extremities or limb girdle, followed by the trunk, and head and neck, and rarely occurs in the pelvis, retroperitoneum, viscera, and bone. 2 Primary kidney SEF is extremely rare. Here, we report one case and discuss the clinicopathologic features, differential diagnoses and molecular pathogenesis of primary kidney SEF.
Case Report
A 38-year-old male underwent physical examination at a different hospital, and a computed tomography scan of the abdomen showed a mass at the lower pole and renal pelvis of the right kidney. One week later, he came to our hospital for further diagnosis and treatment. The patient had no flank pain, abdominal pain, or urination pain. Ultrasound revealed a 10 × 9 cm low-echo mass located at the lower pole and renal pelvis of the right kidney. Renal dynamic imaging showed that the left glomerular filtration rate was 70.2 mL/min, the right glomerular filtration rate was 76.6 mL/min, and the bilateral glomerular filtration rate was 146.8 mL/min, all of which were higher than the normal range. With a clinical suspicion of renal cell carcinoma, the patient underwent right radical nephrectomy under general anesthesia, without preoperative biopsy. The patient was further diagnosed with kidney SEF after surgery. The patient received no adjuvant treatment after surgery and had a disease-free survival time of 3 months with no recurrence and metastasis.
Grossly, the mass was 13 × 10 × 10 cm in size, located in the middle and lower pole of the renal pelvis of the kidney. The cut surface was white and firm with focal calcification (Figure 1). Microscopically, the tumor showed infiltration into the perirenal fat and the renal parenchyma (Figure 2A). Epithelioid neoplastic cells were mainly arranged in cords and nests embedded in the dense sclerosing stroma (Figure 2B). The tumor cells were medium-sized with clear cytoplasm and round-to-oval nuclei, the nucleoli were not obvious, and mitosis was rarely observed. Some nuclei presented a plasmacytoid (rhabdomyoid) shape (Figure 2C). Hypercellular areas alternated randomly with hypocellular areas. Acinar growth patterns (Figure 2D) and hemangiopericytoma-like vessels were observed. Focal calcification and ossification (Figure 2D) were also observed.
The cut surface was white and firm with focal calcification.
(A) Tumor cell infiltration into the renal parenchyma (HE 200×). (B) Epithelioid neoplastic cells were mainly arranged in cords and nests embedded in the dense sclerosing stroma (HE 200×). (C) Some nuclei exhibited a plasmacytoid (rhabdomyoid) shape (HE 400×). (D) Focal ossification (shown on the left, HE 100×) and acinar growth patterns (shown on the right, HE 100×).
According to immunohistochemistry data, the tumor cells were diffusely positive for MUC4 (Figure 3A), vimentin, and CD99 and were negative for AE1/AE3, EMA, PAX8 (Figure 3B), Keratin 8/18, Keratin 7 (Figure 3C), CAIX, CD10, P504s, TFE3 (Figure 3D), desmin, SMA, STAT6, CD34, S100, SOX10, MyoD1, myogenin, and HMB45. The Ki67 index ranged from 2% to 5%. Fluorescence in situ hybridization (FISH) was carried out in paraffin-embedded tissues to assess EWSR1 and SS18 gene rearrangement using an EWSR1(22q12) break-apart probe and an SS18 break-apart probe. A total of 200 cells were assessed. The cut-off level for EWSR1 as positive was at least 30% cells showed a break-apart signal. FISH assays showed that the EWSR1 gene was split (Figure 4) and that the SS18 gene was not split.
(A) Tumor cells were diffusely positive for MUC4 (EnVision 100×). (B) Tumor cells were negative for PAX8 (EnVision 100×). (C) Tumour cells were negative for keratin 7 (EnVision 100×). (D) Tumor cells were negative for TFE3 (EnVision 200×).
Fluorescence in situ hybridization (FISH) assay showed split of EWSR1 gene (yellow arrows).
Discussion
SEF is a rare variant of fibrosarcoma, and primary kidney SEF is extremely rare.3–9 Including this case, only 12 primary kidney SEF cases have been reported in the literature (Table 1). Among the affected patients, there were seven females and five males with an age range from 4 to 61 years (mean, 34; median, 37.5 years). There is no sex or age predilection. Seven cases affected the left kidney, and four affected the right kidney; location information was not listed for one case. The maximum tumor diameter ranged from 4.2 cm to 25 cm (mean, 12; median, 11 cm). Clinically, patients mainly present with flank, back, and abdominal pain.
Summary of Clinicopathological Features of Primary Renal SEF.
Abbreviations: AWD: alive with disease; ANED: alive without evidence of disease; CT: chemotherapy; DOD: died of disease; DOC: died of complications; FISH: fluorescence in situ hybridization; NA: not available; RT: radiotherapy; RCT: radiochemotherapy; SER: sclerosing epithelioid fibrosarcoma.
Grossly, kidney SEF appears as white and firm tumors, with a related border. Large tumors always protrude into the renal pelvis. The morphologic features of kidney SEF are similar to those of other SEF types, and they are mainly characterized by cords or nests of epithelioid cells in a background of sclerotic fibrous stroma. Acinar growth patterns and hemangiopericytoma-like vessels were observed in this case. The tumor cells were small to medium in size with round or oval nuclei, clear or eosinophilic cytoplasm, and rare mitosis. Some nuclei, including those in this case, presented a plasmacytoid (rhabdomyoid) shape. 5 Tumor cells often invade the renal tubules and the renal glomerulus. Lined cells in renal tubules entrapped by the neoplasm may have papillary hyperplasia.4,6 Cellularity is variable within neoplasms, and hypercellular areas alternate randomly with hypocellular areas. Hypercellular areas occasionally contain vague nodules of collagen mimicking those seen in hyalinizing spindle cell tumor with giant rosettes (HSCTGR).4,6 Hypocellular areas occasionally contain a focal myxoid nodule of spindle cells in a swirling pattern closely resembling low-grade fibromyxoid sarcoma (LGFMS).4,8 Including this case, three cases exhibited focal ossification, 4 and two cases exhibited calcification. 7 Cellular pleomorphism 6 were present in 1 case, and tumor necrosis7,9 were present in two cases.
Immunohistochemically, tumor cells in all kidney SEFs showed diffuse staining for MUC4, a sensitive and specific immunohistochemistry marker for SEF. 10 In addition to MUC4, these tumor cells are frequently positive for vimentin, CD99, and BCL2 and are occasionally positive for EMA; they are typically negative for AE1/AE3, desmin, S100 protein, CD34, melan-A, HMB-45, CD10, CD117, PAX8, Keratin 8/18, Keratin 7, CAIX, P504s, TFE3, CD56, WT-1, and myogenin. INI-1 immunostaining is retained. SEF and LGFMS show overlapping morphologic and immunophenotypic features in some cases, but at the molecular level, 3 approximately 90% of LGFMS display FUS-CREB3L2 gene fusion. In contrast, pure SEF mainly displays EWSR1-CREB3L1 gene fusion and splits and deletions of the EWSR1 and/or CREB3L1 genes. Hybrid LGFMS/SEF has a FUS-CREB3L2 gene fusion similar to LGFMS. Among these kidney SEF cases, there was only one case where the FISH results could not be evaluated due to poor tissue preservation or the effect of chemotherapy. 5 Including this case, five cases demonstrated splitting of the EWSR1 gene by FISH detection with an EWSR1 break-apart probe.3,5,8 Two cases exhibited the EWSR1-CREB3L1 fusion gene by FISH detection with the EWSR1-CREB3L1 fusion probe. 4 Splits of the EWSR1 and EWSR1-CREB3L1 fusion genes were confirmed in the other four cases using these two probes.6,7,9 A site mutation in NOTCH1 and a frameshift mutation in TMEM30A were revealed in one case. 9
The differential diagnosis strategy for renal SEF broadly includes a series of tumors with epithelioid morphology and sclerosing matrix, mainly including sclerosing variants of clear cell sarcoma of the kidney (CCSK), renal synovial sarcoma (SS), renal solitary fibrous tumour (SFT), metanephric stromal tumour (MST), sclerosing perivascular epithelioid cell tumour (PEComa), and carcinomas. The classic pattern of CCSK is characterized by nests or cords of cells separated in a branching capillary vasculature, and the sclerosing variant of CCSK are characterized by extensive hyaline sclerosis surrounding epithelioid cells. CCSK is positive for cyclin D1 and BCL-2, expresses the BCOR gene and the YWHAE-NUTM2 gene fusion. 11 Renal SS may have an hemangiopericytomatous structure but is typically a monophasic spindle cell tumor with strands of collagen and a lack of epithelial components. These tumors are diffusely immunoreactive for TLE1 and BCL2 and carry an SS18-SSX fusion transcript. 12 Renal SFTs always have hemangiopericytoma-like vessels and extensive fibrosis/sclerosis. SFTs often show immunological reactions for CD34, BCL2, and STAT6. 13 MST characteristically encircles entrapped native renal tubules in an “onion-skin” pattern and frequently induces angiodysplasia, juxtaglomerular cell hyperplasia, and heterologous differentiation (glia or cartilage). MST often shows immunological reactivity for CD34 14 and frequent BRAF V600E mutations. 15 Sclerosing PEComa is a variant of PEComa characterized by extensive stromal hyalinization, and tumor cells are sharply demarcated from the normal renal parenchyma. PEComas usually express melanoma markers (HMB-45 and MiTF) and muscle markers (SMA and desmin). 16 SEF is a difficult diagnosis in visceral organs because of its epithelioid morphology, closely mimicking carcinomas, primary or metastatic. MUC4 is overexpressed or aberrantly expressed in many carcinomas, 10 which increased the difficulty for differential diagnosis. MUC4 expression 10 is also seen in biphasic synovial sarcomas, ossifying fibromyxoid tumors, epithelioid gastrointestinal stromal tumors, and myoepithelial carcinoma.
SEF has a more aggressive clinical course than LGFMS, with recurrence in approximately 50% of cases and metastatic spread in more than 40% of cases, most often affecting the lungs, pleura, bone, and central brain. Poor prognostic features include large tumor size and proximal location. Among these kidney SEFs, one case was recurrent, and four cases were already metastatic at the time of presentation. The main sites of metastases were the lung, bone and lymph nodes, with one metastasis to the liver. Three patients died of disease, and three patients were alive with disease at the study endpoint. The other five patients were alive without evidence of disease, possibly due to limited follow-up. At present, surgery remains the main treatment in SEF. SEF has limited responsiveness to conventional chemotherapy. 17 In a recent study, 18 SNP array analysis detected DMD microdeletions in SEF, CD24 was strongly upregulated, and CD24 and DMD were identified as potential therapeutic targets. Renal SEF is very rare and requires further study and more case studies.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
