Clear cell sarcoma of the kidney in a 62-year-old patient presenting with generalized pruritus
Clear cell sarcoma of the kidney (CCSK) is the second most common renal tumor in children following Wilms’ tumor. CCSK is extremely rare in adults, with only 25 adult cases reported in the medical literature.
We reported a 62-year-old man with a right renal mass presenting only with generalized pruritus who underwent radical right nephrectomy. With immunostaining, tumor cells were positive for expressed vimentin, neural cell adhesion molecule (NCAM, CD56), and Ki-67 and focally positive for p53, CD10 and Bcl-2. The histopathological diagnosis was CCSK. Two weeks after the operation, the generalized pruritus ended. One month after the operation, the patient started treatment with a regimen combining doxorubicin, vincristine, cyclophosphamide, and etoposide. At the 20-month follow-up visit, there was no evidence of local recurrence or metastases.
In a patient presenting with generalized pruritus, further evaluation for an underlying malignancy should be considered. It is difficult to distinguish CCSK from undifferentiated renal neoplasms. Immunohistochemistry could help to make exact histopathological diagnoses. The BCL-6 corepressor (BCOR) gene could play a significant role in CCSK tumorigenesis and be a good marker for CCSK diagnosis. Surgery with combination chemotherapy and radiation therapy could be used to treat CCSK in older patients.
KeywordsClear cell sarcoma of the kidney Pruritus Immunohistochemistry Vimentin BCL-6 corepressor Chemotherapy Doxorubicin
American Joint Committee on Cancer
clear cell sarcoma of the kidney
congenital mesoblastic nephroma
epithelial membrane antigen
erythrocyte sedimentation rate
hemopoietic cell kinase
internal tandem duplication
inferior vena cava
malignant rhabdoid tumor of kidney
- NCAM, CD56
neural cell adhesion molecule
neuron specific enolase
National Wilms Tumor Study
primitive neuroectodermal tumor
renal cell carcinoma
renal cell carcinoma marker
wilm’s tumor 1
Clear cell sarcoma of the kidney (CCSK) is the second most common renal tumor in children following Wilms’ tumor. The average age at diagnosis of CCSK is 3 years old. The tumor is prone to metastasize to bone, brain, and soft tissue . The symptoms of CCSK are abdominal or flank mass, abdominal pain, hematuria, asthenia, anorexia, weight loss, low-grade fever, nausea, vomiting, constipation, anemia, Stauffer syndrome, and high blood pressure . We present a case of a 62-year-old man with CCSK presenting only with generalized pruritus. We discuss the histopathologic diagnosis, genetic studies of CCSK and the efficacy of surgery with combination chemotherapy in elderly individuals (older than 60 years).
A right radical nephrectomy with a complete regional intraperitoneal lymphadenectomy with an anterior subcostal incision was performed in April 2017. No intraoperative or postoperative complications developed.
Two weeks after the operation, the generalized pruritus ended. One month after the operation, the patient started treatment with a regimen combining doxorubicin (DOX), vincristine (VCR), cyclophosphamide, and etoposide. Twenty months after the operation, CT of the abdomen and pelvis revealed no evidence of local recurrence in the right kidney. Other examinations revealed no evidence of distant metastases. The patient is still alive and without clinical evidence of progression. The patient can complete daily life activities, occasionally feeling tired and experiencing numbness at the incision site.
We report a case of CCSK in an aged patient presenting with generalized pruritus. CCSK was first described in 1970 by Kidd  and is prone to metastasize to bone, brain, and soft tissue. The symptoms of CCSK are abdominal or flank mass, pain in the abdomen, blood in the urine and high blood pressure [1, 2]. To the best of our knowledge, our present case is the first documented case of CCSK presenting with generalized pruritus. There are two kinds of pruritus associated with malignancy: itch induced by local reaction to malignancy and paraneoplastic itch (PI) . PI is defined as itch that may occur early during tumor formation or even precede clinical evidence of the malignancy. It is not caused by neoplastic mass invasion or compression and subsides after removal of the tumor . PI is also defined as a systemic (not local) reaction to the presence of a tumor or a hematological malignancy, neither of which is induced by the local presence of cancer cells or by tumor therapy. It usually disappears with remission of the tumor and can return with its relapse . We thought that the pruritus in our patient was PI. The epidemiological data of PI are limited. Kilic reported that generalized pruritus was present in 13% of 700 solid tumor and hematological cancer patients . Other studies investigated the underlying etiology of idiopathic generalized pruritus and found that malignancy is a cause in less than 10% of patients [8, 9, 10]. Lymphoma and leukemia were the most common malignancies. It can also be part of a rare paraneoplastic syndrome resulting from solid tumors, including those in the lung, colon, breast, stomach and prostate . The mechanism of pruritus caused by cancer is unclear . In a patient presenting with generalized itching, further evaluation for an underlying malignancy should be considered. Its recognition may lead to early diagnosis and improved outcome.
CCSK is the second most common renal tumor in children following Wilms’ tumor and forms approximately 5% of pediatric renal tumors. The average age at the time of diagnosis of CCSK is 3 years old . CCSK is extremely rare in adults. We reviewed the literature in PubMed and found that there were only 25 cases reported from 1989 to 2018 [12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30]. In the 25 adult cases, excluding our case, the mean age was 34.5 years (from 16 to 70 years). There were only two cases of CCSK in patients older than 60 years [26, 30]. Here, we report the third elderly case of CCSK. CCSK tends to occur in children, with a male preponderance (male/female ratio 2/1) . For the 25 adult cases, the ratio between males and females was 17:8, which was similar to that in children.
In our case, there was a tumor thrombus in the right renal vein without infiltration into the vessel wall. In the 25 adult cases, excluding our case, there were three cases with IVC tumor thrombus [17, 24, 27] and two cases with tumor thrombus extending into the right atrium [21, 23]. The mean age was 38.6 years (from 22 to 55 years). The ratio between males and females was 4:1, and the incidence rate of tumor thrombus was 20% (5/25). We report on the oldest CCSK patient with a tumor thrombus.
The pathological diagnosis of CCSK is very difficult. Kidd firstly reported that CCSK was a distinct clinicopathologic entity in 1970 . Then the distinctive histopathologic features of CCSK were reported in 1978 [31, 32, 33]. It has been emphasized that CCSK showed tremendous morphologic diversity, ranging from epithelioid to spindle cell patterns . CCSK has several histological pattern variants, including myxoid, sclerosing, cellular, epithelioid (trabecular or acinar type), palisading, spindle cell, storiform, and anaplastic. The typical gross features of CCSK are large size, mucoid texture, foci of necrosis, and prominent cyst formation. The tumors are most commonly described as tan– grey, soft, and mucoid on cut section. There are common discrete foci of necrosis and hemorrhage in the tumors. The classical light microscopic features of CCSK are defined as nests or cords of cells separated by regularly spaced, arborizing fibrovascular septa. Classical CCSK is composed of nests and cords of cells with scant cytoplasm and high nuclear-cytoplasmic ratios. The nuclei are characterized by a fine chromatin pattern, and mitotic structures are generally rarely identified. The tumor has a prominent vascular network and abundant collagenous extracellular matrix material, and isolated nephrons are entrapped by the tumor [1, 2]. The renal tumors showing the typical macroscopic and microscopic pathological findings of CCSK should be further identified by immunohistochemistry (see below). The pathologic features of CCSK in aged patients are unclear, but we found they were similar to those in pediatric patients in our case. We suggested that.
CCSK is rare in elderly patients. To exclude renal cell carcinoma (RCC), we examined the histological variation within the large tumor. Twelve specimens were obtained from the tumor randomly and examined carefully. Microscopic examinations showed the same pathologic features in the twelve specimens. There were no other neoplastic components in the tumor. We used silver staining to further examine the twelve specimens. As shown in Fig. 3d, silver impregnation clearly demonstrated reticular fibers often outlining individual tumor cells, which showed that the tumor might be a sarcoma but not a carcinoma. RCCs sometimes exhibit a sarcomatoid appearance known as sarcomatoid renal cell carcinoma . Some studies have demonstrated epithelial features even in the sarcomatoid component of this tumor [35, 36]. The correct diagnosis of undifferentiated RCCs is difficult. The undifferentiated RCCs can be misdiagnosed as renal sarcomas. The accurate pathological diagnosis of renal tumor is very important because the undifferentiated RCCs do not benefit from any adjuvant therapy at the moment, whereas renal sarcoma might be a candidate to specific adjuvant therapies. RCCs frequently react with antibodies to brush border antigens and low-molecular-weight cytokeratins such as CK8, CK18, CK19, AE1, and CAM 5.2 [37, 38, 39]. RCC-Ma is a monoclonal antibody against a normal renal proximal tubule antigen whose expression is relatively specific for major RCCs [37, 40]. The majority of RCCs react positively for EMA . However, these markers are negative in CCSK . In our case, the results of immunostaining showed that CAM5.2, CK7, EMA and RCC-Ma were negative in the tumor, indicating that this tumor was not an RCC.
Undifferentiated renal neoplasm
Blastema-predominant Wilms’ tumor
vimentin, NSE, desmin, WT1, cytokeratin cocktail CK22
CD99, NSE, vimentin, S100, synaptophysin, CD57
Vimentin, cytokeratin, EMA, S100, NSE, synaptophysin, CD57
vimentin, desmin, muscle actin (HHF-35), alpha Smooth muscle Actin
The tumorigenesis of CCSK is unclear. Karlsson considered that CCSK might originate from embryonic mesenchymal progenitor cells . The BCL-6 corepressor (BCOR) gene was found to regulate mesenchymal stem cell function by epigenetic mechanisms . Ueno-Yokohata found 100% internal tandem duplications (ITDs) in exon 15 of the BCOR gene in 20 cases of CCSK . Other studies also found BCOR ITDs in CCSK [53, 54, 55]. Argani considered BCOR to be a sensitive and specific marker for pediatric CCSK . BCOR ITDs could also be detected in circulating tumor DNA in CCSK preoperative cases . Thus, BCOR could play a significant role in CCSK tumorigenesis and be a good marker for CCSK diagnosis. Gene fusions, including YWHAE-NUTM2B/E and IRX2-TERT, were discovered in a minority subgroup of CCSKs [58, 59]. However, the role of YWHAE-NUTM2B/E and IRX2-TERT fusion was not clear. It is interesting that the presence of the BCOR ITDs is mutually exclusive with the presence of the YWHAE-NUTM2B/E fusion in CCSKs . Gooskens analyzed changes in chromosome copy number, mutations, rearrangements, global gene expression and global DNA methylation in CCSKs. They identified no recurrent segmental chromosomal copy number changes or somatic variants. They found a single case with the YWHAE-NUTM2 fusion in 13 cases of CCSK. The promoter hypermethylation and low expression of the tumor suppressor gene TCF21 were identified in all CCSKs except the case with a YWHAE-NUTM2 fusion. The hypermethylation of TCF21, a transcription factor known to be active early in renal development, might lie within the pathogenic pathway of most CCSKs . Hence, the exact molecular pathogenesis of CCSKs remains poorly understood, especially that of adult CCSKs. The status of BCOR ITDs, YWHAE-NUTM2B/E fusion and hypermethylation of TCF21 in adult CCSKs is not clear. Unfortunately, the changes in BCOR ITDs, YWHAE-NUTM2B/E fusion and hypermethylation of TCF21 were not examined in our case. Future studies are needed to reveal the tumorigenesis of adult CCSKs.
The survival of patients with CCSK has increased from only 20 to 70% [1, 61]. Kusumakumary et al. reported that the relapse rate of CCSK was approximately 65% and the mortality rate was 48%. Half of the deaths occurred within the first two years. The prognosis for low-grade or early stage CCSK has improved with the addition of DOX to chemotherapy regimens . Important predictors of improved survival are low stage, young age at diagnosis, treatment with DOX, and absence of tumor necrosis .
Therapeutic outcome of CCSK from NWTS studies
NWTS 1–2 NWTS 3
NWST 4 NWST 5
In conclusion, further evaluation for malignancy should be considered in patients who present with generalized pruritus. The pathologic features and treatment of CCSK in older patients were similar to that in pediatric patients. It is difficult to distinguish CCSK from undifferentiated adult renal neoplasms, although immunohistochemistry could help to make histopathological diagnoses. Surgery with combination chemotherapy and radiation therapy could be used to treat CCSK in these patients. The tumorigenesis of adult CCSKs should be characterized in the future.
YZ: literature search and manuscript writing; YZ, JL: patient follow-up examination, analysis and interpretation of data; YW: histopathological analysis. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Consent for publication
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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