- Email: [email protected]
Large clear cell sarcoma of the kidney mistaken as Wilms' tumor
J Ped Surg Case Reports 1 (2013) 235e238
Contents lists available at ScienceDirect
Journal of Pediatric Surgery CASE REPORTS journal homepage: www.jpscasereports.com
Large clear cell sarcoma of the kidney mistaken as Wilms’ tumorq Scott S. Short c, *, Osnat Zmora c, Catherine J. Hunter c, Larry Wang b, Stuart Siegel a, Henri R. Ford c a
Department of Hematology/Oncology, Children’s Hospital Los Angeles, 4650 Sunset Blvd., MS #100, Los Angeles, CA 90027, USA Department of Pathology, Children’s Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027, USA c Department of Surgery, Children’s Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 May 2013 Received in revised form 5 July 2013 Accepted 9 July 2013
Clear cell sarcoma of the kidney (CCSK) is a rare tumor. It has a wide histologic spectrum and often mimics other pediatric renal tumors, resulting in considerable diagnostic difficulty. We report the case of a two-year-old who presented with a large (14 cm) abdominal mass. Prior to neoadjuvant chemotherapy, a biopsy was performed, which revealed Wilms’ tumor. The final pathology diagnosis at the time of resection revealed CCSK. Ó 2013 The Authors. Published by Elsevier Inc. All rights reserved.
Key words: Clear cell sarcoma Wilms’ tumor Kidney
The differential diagnosis for an abdominal mass in a two-yearold child is broad and includes lesions of hepatic, renal, gastrointestinal, adrenal, and lymphatic origins. Of these, Wilms’ tumor and neuroblastoma are the most common tumors [1], with Wilms’ tumor representing 92% of renal masses in children [2]. Non-Wilms’ renal tumors, rhabdoid tumors, and clear cell sarcoma of the kidney (CCSK) are uncommon. In fact, CCSK is particularly rare and represents only 17% of non Wilms’ renal tumors in children with only 60 cases reported to the Surveillance Epidemiology and End Results (SEER) database between 1973 and 2005 [3]. In this report we present a child presenting with a huge renal mass consistent with Wilms’ tumor on computed tomography (CT) and initial biopsy. However, the final pathologic diagnosis after resection revealed a CCSK.
1. Case report A two-year-old boy presented with a one-year history of an enlarging abdominal mass. The patient was initially evaluated in Haiti and sent to the USNS Comfort Ship for further workup. CT at that time revealed a 14 cm heterogeneous mass arising from the
q This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. * Corresponding author. Tel.: þ1 323 361 2104; fax: þ1 323 361 8678. E-mail addresses: [email protected], [email protected] (S.S. Short).
right kidney, consistent with Wilms’ tumor. He was referred to a non-governmental organization, Angel Mission, which arranged transfer to a large pediatric hospital in the United States for definitive care. No other pertinent medical or surgical history was reported at the time of transfer. The patient presented to our institution with a very large abdominal mass that was associated with respiratory embarrassment, failure to thrive secondary to early satiety, and difficulty walking. There was no family history of malignancy. Physical exam revealed a malnourished, cachectic appearing child with a large palpable abdominal mass occupying the entire right upper, right lower and left lower quadrants. Marked superficial venous collateral circulation was noted on the anterior lower chest and upper mid-abdominal wall. He was hypertensive with a blood pressure of 125/86. Pertinent laboratory data included hemoglobin of 6.7 with a mean corpuscular volume of 58.1 and albumin of 2.6; he also was iron deficient. He was started on amlodipine, enalapril, and iron replacement therapy. Nasojejunal feeds were instituted to improve his nutritional status. CT of the chest, abdomen, and pelvis was performed and revealed a 17 20 17 cm heterogeneous mass arising from the right kidney, consistent with Wilms’ tumor (Fig. 1). The infrahepatic inferior vena cava (IVC) could not be visualized by CT or abdominal ultrasound. The intrahepatic vena cava, however, was patent by abdominal Doppler ultrasound. There was no evidence of metastatic diseases visualized. Given the massive size of the tumor, the patient’s poor nutritional status, and the possibility of tumor thrombus within the infrahepatic IVC the patient was taken to the operating room for open biopsy and
2213-5766/$ e see front matter Ó 2013 The Authors. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.epsc.2013.07.006
236
S.S. Short et al. / J Ped Surg Case Reports 1 (2013) 235e238
was performed to clearly identify tumor boundaries and define the vascular anatomy. The infrahepatic IVC was stretched over the tumor but patent. Great care was taken to preserve the left renal vein as well as the significantly enlarged left gonadal vein. A right radical nephrectomy was completed. The tumor measured 25.8 19.2 14.3 cm and weighed 3.1 kg (Fig. 3). Multiple enlarged aorto-caval lymph nodes were resected and the ascending and descending colon were fixed to the abdominal wall. The child tolerated the procedure well and recovered uneventfully from his procedure without any complication. The final pathologic diagnosis revealed CCSK as supported by the original immunohistochemical panel. A fine vascular pattern was appreciated on the gross specimen and review by a member of the Children’s Oncology Group Renal Pathology Center confirmed the diagnosis (Fig. 2B). Focal penetration of the capsule and nine negative lymph nodes were identified. The patient was observed in the pediatric intensive care unit overnight, and transferred to the ward the following day. By postoperative day number 3 he was tolerating a regular diet. His superficial collateral venous pattern resolved within the first 24 h after surgery. Following diagnosis of clear cell sarcoma, a metastatic workup, including a bone scan and magnetic resonance imaging (MRI) of the brain, was performed and was negative for metastatic disease. He underwent and completed a course of radiation therapy to the abdomen as well as a course of adjuvant chemotherapy (regimen I), which consisted of alternating courses of vincristine, doxorubicin, and cyclophosphamide followed by the combination of cyclophosphamide and etoposide. No evidence of recurrent tumor has been noted 15 months from surgery. 2. Discussion
Fig. 1. Computed tomography of the abdomen demonstrating a large heterogeneous mass with mass effect, ascites, and possible invasion of the inferior vena cava. A, B, and C demonstrate displacement of the abdominal viscera in the axial, coronal and sagittal planes respectively.
port placement prior to neoadjuvant chemotherapy. Generous biopsies of the tumor were obtained and sent for pathology. Pathology revealed primitive tumor cells with hyperchromatic nuclei, small amount of cytoplasm and indistinctive cell borders consistent with a Wilms’ tumor with favorable histology (Fig. 2A). FISH was negative for rearrangement of 22q12 EWSR1 and RT-PCR did not demonstrate translocations in EWS-FT1, EWS-EGR, PAX-FOX01, SYT-SSX, EWSWT1, and ETV6-NTKR3. Further staining with vimentin, CD99 (Mic-2), CD56, and BCL-2 were positive. WT-1, cytokeratin, epithelial membrane antigen (EMA), desmin, S100, CD34, tyrosine hydroxylase, synaptophysin, and chromgranin A were negative. The child underwent neoadjuvant chemotherapy consisting of vincristine, dactinomycin and adriamycin (regimen DD4A) for 6 weeks followed by repeat imaging. The CT revealed virtually no response to chemotherapy, and no new areas of progressive or metastatic disease. After multidisciplinary discussion it was felt that surgical resection was the best option for this child. Exploratory laparotomy revealed a gigantic right-sided tumor with associated lymphadenopathy. Bilateral medial visceral rotation
CCSK is a tumor that is frequently misdiagnosed due to its rarity and lack of specific features. Most patients present between two and three years of age [4] and show a 2:1 male to female predominance [5]. Clinical features are nonspecific making diagnosis of CCSK difficult. Workup should follow standard algorithms for an abdominal mass. CT and ultrasonography do not provide discriminatory findings that would differentiate between CCSK and Wilms’ tumor [6]. Suspicion of CCSK should be heightened in children with evidence of bony metastases, which may develop in up to 60% of patients with CCSK compared to a 2% incidence of bony metastases in Wilms’ tumor [4]. CCSK may also have a higher predilection to metastasize to liver, brain, and lung [7]. While not routine in the United States, preoperative percutaneous biopsy of suspected Wilms’ tumors has been described and adopted by the United Kingdom Children’s Cancer Study Group (UKCCSG). They recommend this approach for pathologic diagnosis prior to chemotherapy because they have found a high concordance between percutaneous biopsy and final surgical pathology in 94%e99% of cases [8]. Furthermore, use of pretreatment biopsy has not been associated with any increase in recurrence or complication [9]. Unfortunately, this patient fell into the small cohort of patients whose diagnosis on initial biopsy is discordant with the final pathologic diagnosis. CCSK is a malignant mesenchymal neoplasm characterized by undifferentiated cells with abundant extracellular matrix that are separated into cords and nests by a fine vascular network. Although the majority of CCSK have “classic” features on pathologic examination it is well known that CCSK is difficult to differentiate from other “renal blue round cell lesions” such as blastemal Wilms’ tumor and primitive neuroectodermal tumor. The primary contribution of immunohistochemical analysis in the diagnosis of CCSK is the exclusion of other pediatric renal neoplasms, whereas immunohistochemical study has a limited role in the
S.S. Short et al. / J Ped Surg Case Reports 1 (2013) 235e238
237
Fig. 2. A. Wilms’ e H&E slide shows a cellular tumor composed of primitive tumor cells with hyperchromatic nuclei, small amount of cytoplasm and indistinctive cell borders. Mitotic figures are noted. B. Clear cell sarcoma of the kidney (CCSK) e H&E slide shows tumor cells are separated by pale-pink vascular-rich stroma and contain nuclei with finely dispersed chromatin.
pathologic evaluation of Wilms’ tumor. Similar to blastemal and stromal cells of Wilms’ tumor, CCSK regularly expresses vimentin, but other differentiation markers including epithelial markers (cytokeratin, EMA), desmin, S100 protein and neuron specific enolase are usually absent. Furthermore, immunohistochemical reaction for WT1 protein in Wilms’ tumor is variable and correlation with tumor histology is still required. Further, while WT1 immunoreactivity may be useful in distinguishing between blastemal Wilms’ tumor (high WT1 expression) and other primitive tumors, it is not useful in tumors with only stromal differentiation, as seen in this CCSK case. Other factors known to be uniformly negative in CCSK include CD99 (Mic-2) and CD56, which are positive in this case [10]. Others have reported that the muscle specific actin may sometimes show positivity and vimentin staining may be much stronger in CCSK, which may be helpful in distinguishing CCSK from Wilms’ tumor [11]. However, no single immunohistochemical reaction is universally diagnostic for Wilms’ tumor as well as CCSK. Other clues to the diagnosis of CCSK include well separated nuclear spacing, fine chromatin, and younger mean age of patient [5]. While these differences may help distinguish CCSK from other pathology it remains the most commonly misdiagnosed pediatric renal tumor with authors reporting confusion with Wilms’ and mesoblastic nephroma [5,12,13]. This has prompted investigation into methods to better discern CCSK from other entities. Ueno and colleagues recently sought to characterize the molecular signature
of different pediatric renal neoplasms. They evaluated specimens from 83 pediatric patients including 21 with CCSK and 41 with Wilms’. They found that CCSK is generally hypermethylated particular at the site THBS1 CPG, a suspected angiogenic factor. All children with CCSK were found to be hypermethylated at this loci and all children with an alternative renal neoplasm were not hypermethylated [14]. Others have evaluated and reported different genetic mutations associated with CCSK including rearrangement of YWAE on chromosome 17, translocation of t(10;17)(q22;p13), EFGR amplification, and deletions in chromosome 14q [7,15]. However, these genetic mutations appear sporadic with no familial cases of CCSK reported to date [7]. Currently there are no defined algorithms and most authors recommend referral of samples to pathologists with experience evaluating pediatric renal neoplasms, which were helpful for successful diagnosis in this case. Once diagnosis of CCK is confirmed treatment is radical nephrectomy followed by adjuvant chemoradiation. The National Wilms’ Tumor Study Group (NWTSG) guidelines call for cyclophosphamide, etoposide, vincristine, and doxorubicin for any stage of CCSK [16]. Doxorubicin has been reported to impart significant improvements in survival [5] and prolonged chemotherapy regimens may improve relapse free survival [17]. Although some have withheld adjuvant radiotherapy in children with stage I disease, the addition of radiotherapy (10 Gy) to the tumor bed is standard in protocols for patients of any stage with CCSK [18]. Despite having unfavorable histology associated long term survival is reasonable with nearly 79% of patients alive at 10 years [3]. TNM staging classification for CCSK is the same as Wilms’ and prognosis varies by respective stage. Overall survival of 100% for stage I, 97% for stage II, 87% for stage III, and 45% for stage IV disease have been reported [19]. 3. Conclusion In summary, CCSK is an uncommon tumor of renal origin that is challenging to diagnose and should be considered in the differential diagnosis of a pediatric patient presenting with a palpable abdominal mass. Further research is needed to develop better methods of diagnosis and tissue should undergo evaluation by pathologists familiar with subtleties between pediatric renal neoplasms. Consent
Fig. 3. Intra-operative image of a large renal mass with distorted anatomy and displacement of the IVC.
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
238
S.S. Short et al. / J Ped Surg Case Reports 1 (2013) 235e238
References [1] Golden CB, Feusner JH. Malignant abdominal masses in children: quick guide to evaluation and diagnosis. Pediatr Clin North Am 2002;49:1369e92 [viii]. [2] Dome JS. Identification and management of high risk Wilms’ tumors. Erasmus University Rotterdam; 2009. [3] Zhuge Y, Cheung MC, Yang R, Perez EA, Koniaris LG, Sola JE. Pediatric nonWilms renal tumors: subtypes, survival, and prognostic indicators. J Surg Res 2010;163:257e63. [4] Franco A, Dao TV, Lewis KN, Biddinger PW. A case of clear cell sarcoma of the kidney. J Radiol Case Rep 2011;5:8e12. [5] Argani P, Perlman EJ, Breslow NE, Browning NG, Green DM, D’Angio GJ, et al. Clear cell sarcoma of the kidney: a review of 351 cases from the National Wilms Tumor Study Group Pathology Center. Am J Surg Pathol 2000; 24:4. [6] Glass R, Davidson A, Fernbach S. Clear cell sarcoma of the kidney: CT, sonographic, and pathologic correlation. Radiology 1991;180:715. [7] Gooskens SL, Furtwangler R, Vujanic GM, Dome JS, Graf N, van den HeuvelEibrink MM. Clear cell sarcoma of the kidney: a review. Eur J Cancer 2012;48: 2219e26. [8] Vujani c GM, Kelsey A, Mitchell C, Shannon RS, Gornall P. The role of biopsy in the diagnosis of renal tumors of childhood: results of the UKCCSG Wilms tumor study 3. Med Pediatr Oncol 2003;40:18e22. [9] Mitchell C, Pritchard-Jones K, Shannon R, Hutton C, Stevens S, Machin D, et al. Immediate nephrectomy versus preoperative chemotherapy in the management of non-metastatic Wilms’ tumour: results of a randomised trial (UKW3) by the UK Children’s Cancer Study Group. Eur J Cancer 2006;42: 2554e62.
[10] Vasei M, Moch H, Mousavi A, Kajbafzadeh AM, Sauter G. Immunohistochemical profiling of Wilms tumor: a tissue microarray study. Appl Immunohistochem Mol Morphol 2008;16:128e34. [11] Looi LM, Cheah PL. An immunohistochemical study comparing clear cell sarcoma of the kidney and Wilms’ tumor. Pathology 1993;25:106e9. [12] Alavi S, Khoddami M, Yazdi MK, Dehghanian P, Esteghamati S. Clear cell sarcoma of the kidney misdiagnosed as mesoblastic nephroma: a case report and review of the literature. Ecancermedicalscience 2013;7:311. [13] Boo YJ, Fisher JC, Haley MJ, Cowles RA, Kandel JJ, Yamashiro DJ. Vascular characterization of clear cell sarcoma of the kidney in a child: a case report and review. J Pediatr Surg 2009;44:2031e6. [14] Ueno H, Okita H, Akimoto S, Kobayashi K, Nakabayashi K, Hata K, et al. DNA methylation profile distinguishes clear cell sarcoma of the kidney from other pediatric renal tumors. PloS One 2013;8:e62233. [15] O’Meara E, Stack D, Lee CH, Garvin AJ, Morris T, Argani P, et al. Characterization of the chromosomal translocation t(10;17)(q22;p13) in clear cell sarcoma of kidney. J Pathol 2012;227:72e80. [16] Ahmed HU, Arya M, Levitt G, Duffy PG, Sebire NJ, Mushtaq I. Part II: treatment of primary malignant non-Wilms’ renal tumours in children. Lancet Oncol 2007;8:842e8. [17] Seibel NL, Li S, Breslow NE, Beckwith JB, Green DM, Haase GM, et al. Effect of duration of treatment on treatment outcome for patients with clear-cell sarcoma of the kidney: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 2004;22:468e73. [18] Halperin EC, Constine LS, Tarbell NJ, Kun LE. Pediatric radiation oncology. Lippincott Williams & Wilkins; 2010. [19] Geller E, Kochan PS. Renal neoplasms of childhood. Radiol Clin North Am 2011;49:689e709.
Contents lists available at ScienceDirect
Journal of Pediatric Surgery CASE REPORTS journal homepage: www.jpscasereports.com
Large clear cell sarcoma of the kidney mistaken as Wilms’ tumorq Scott S. Short c, *, Osnat Zmora c, Catherine J. Hunter c, Larry Wang b, Stuart Siegel a, Henri R. Ford c a
Department of Hematology/Oncology, Children’s Hospital Los Angeles, 4650 Sunset Blvd., MS #100, Los Angeles, CA 90027, USA Department of Pathology, Children’s Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027, USA c Department of Surgery, Children’s Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 May 2013 Received in revised form 5 July 2013 Accepted 9 July 2013
Clear cell sarcoma of the kidney (CCSK) is a rare tumor. It has a wide histologic spectrum and often mimics other pediatric renal tumors, resulting in considerable diagnostic difficulty. We report the case of a two-year-old who presented with a large (14 cm) abdominal mass. Prior to neoadjuvant chemotherapy, a biopsy was performed, which revealed Wilms’ tumor. The final pathology diagnosis at the time of resection revealed CCSK. Ó 2013 The Authors. Published by Elsevier Inc. All rights reserved.
Key words: Clear cell sarcoma Wilms’ tumor Kidney
The differential diagnosis for an abdominal mass in a two-yearold child is broad and includes lesions of hepatic, renal, gastrointestinal, adrenal, and lymphatic origins. Of these, Wilms’ tumor and neuroblastoma are the most common tumors [1], with Wilms’ tumor representing 92% of renal masses in children [2]. Non-Wilms’ renal tumors, rhabdoid tumors, and clear cell sarcoma of the kidney (CCSK) are uncommon. In fact, CCSK is particularly rare and represents only 17% of non Wilms’ renal tumors in children with only 60 cases reported to the Surveillance Epidemiology and End Results (SEER) database between 1973 and 2005 [3]. In this report we present a child presenting with a huge renal mass consistent with Wilms’ tumor on computed tomography (CT) and initial biopsy. However, the final pathologic diagnosis after resection revealed a CCSK.
1. Case report A two-year-old boy presented with a one-year history of an enlarging abdominal mass. The patient was initially evaluated in Haiti and sent to the USNS Comfort Ship for further workup. CT at that time revealed a 14 cm heterogeneous mass arising from the
q This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. * Corresponding author. Tel.: þ1 323 361 2104; fax: þ1 323 361 8678. E-mail addresses: [email protected], [email protected] (S.S. Short).
right kidney, consistent with Wilms’ tumor. He was referred to a non-governmental organization, Angel Mission, which arranged transfer to a large pediatric hospital in the United States for definitive care. No other pertinent medical or surgical history was reported at the time of transfer. The patient presented to our institution with a very large abdominal mass that was associated with respiratory embarrassment, failure to thrive secondary to early satiety, and difficulty walking. There was no family history of malignancy. Physical exam revealed a malnourished, cachectic appearing child with a large palpable abdominal mass occupying the entire right upper, right lower and left lower quadrants. Marked superficial venous collateral circulation was noted on the anterior lower chest and upper mid-abdominal wall. He was hypertensive with a blood pressure of 125/86. Pertinent laboratory data included hemoglobin of 6.7 with a mean corpuscular volume of 58.1 and albumin of 2.6; he also was iron deficient. He was started on amlodipine, enalapril, and iron replacement therapy. Nasojejunal feeds were instituted to improve his nutritional status. CT of the chest, abdomen, and pelvis was performed and revealed a 17 20 17 cm heterogeneous mass arising from the right kidney, consistent with Wilms’ tumor (Fig. 1). The infrahepatic inferior vena cava (IVC) could not be visualized by CT or abdominal ultrasound. The intrahepatic vena cava, however, was patent by abdominal Doppler ultrasound. There was no evidence of metastatic diseases visualized. Given the massive size of the tumor, the patient’s poor nutritional status, and the possibility of tumor thrombus within the infrahepatic IVC the patient was taken to the operating room for open biopsy and
2213-5766/$ e see front matter Ó 2013 The Authors. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.epsc.2013.07.006
236
S.S. Short et al. / J Ped Surg Case Reports 1 (2013) 235e238
was performed to clearly identify tumor boundaries and define the vascular anatomy. The infrahepatic IVC was stretched over the tumor but patent. Great care was taken to preserve the left renal vein as well as the significantly enlarged left gonadal vein. A right radical nephrectomy was completed. The tumor measured 25.8 19.2 14.3 cm and weighed 3.1 kg (Fig. 3). Multiple enlarged aorto-caval lymph nodes were resected and the ascending and descending colon were fixed to the abdominal wall. The child tolerated the procedure well and recovered uneventfully from his procedure without any complication. The final pathologic diagnosis revealed CCSK as supported by the original immunohistochemical panel. A fine vascular pattern was appreciated on the gross specimen and review by a member of the Children’s Oncology Group Renal Pathology Center confirmed the diagnosis (Fig. 2B). Focal penetration of the capsule and nine negative lymph nodes were identified. The patient was observed in the pediatric intensive care unit overnight, and transferred to the ward the following day. By postoperative day number 3 he was tolerating a regular diet. His superficial collateral venous pattern resolved within the first 24 h after surgery. Following diagnosis of clear cell sarcoma, a metastatic workup, including a bone scan and magnetic resonance imaging (MRI) of the brain, was performed and was negative for metastatic disease. He underwent and completed a course of radiation therapy to the abdomen as well as a course of adjuvant chemotherapy (regimen I), which consisted of alternating courses of vincristine, doxorubicin, and cyclophosphamide followed by the combination of cyclophosphamide and etoposide. No evidence of recurrent tumor has been noted 15 months from surgery. 2. Discussion
Fig. 1. Computed tomography of the abdomen demonstrating a large heterogeneous mass with mass effect, ascites, and possible invasion of the inferior vena cava. A, B, and C demonstrate displacement of the abdominal viscera in the axial, coronal and sagittal planes respectively.
port placement prior to neoadjuvant chemotherapy. Generous biopsies of the tumor were obtained and sent for pathology. Pathology revealed primitive tumor cells with hyperchromatic nuclei, small amount of cytoplasm and indistinctive cell borders consistent with a Wilms’ tumor with favorable histology (Fig. 2A). FISH was negative for rearrangement of 22q12 EWSR1 and RT-PCR did not demonstrate translocations in EWS-FT1, EWS-EGR, PAX-FOX01, SYT-SSX, EWSWT1, and ETV6-NTKR3. Further staining with vimentin, CD99 (Mic-2), CD56, and BCL-2 were positive. WT-1, cytokeratin, epithelial membrane antigen (EMA), desmin, S100, CD34, tyrosine hydroxylase, synaptophysin, and chromgranin A were negative. The child underwent neoadjuvant chemotherapy consisting of vincristine, dactinomycin and adriamycin (regimen DD4A) for 6 weeks followed by repeat imaging. The CT revealed virtually no response to chemotherapy, and no new areas of progressive or metastatic disease. After multidisciplinary discussion it was felt that surgical resection was the best option for this child. Exploratory laparotomy revealed a gigantic right-sided tumor with associated lymphadenopathy. Bilateral medial visceral rotation
CCSK is a tumor that is frequently misdiagnosed due to its rarity and lack of specific features. Most patients present between two and three years of age [4] and show a 2:1 male to female predominance [5]. Clinical features are nonspecific making diagnosis of CCSK difficult. Workup should follow standard algorithms for an abdominal mass. CT and ultrasonography do not provide discriminatory findings that would differentiate between CCSK and Wilms’ tumor [6]. Suspicion of CCSK should be heightened in children with evidence of bony metastases, which may develop in up to 60% of patients with CCSK compared to a 2% incidence of bony metastases in Wilms’ tumor [4]. CCSK may also have a higher predilection to metastasize to liver, brain, and lung [7]. While not routine in the United States, preoperative percutaneous biopsy of suspected Wilms’ tumors has been described and adopted by the United Kingdom Children’s Cancer Study Group (UKCCSG). They recommend this approach for pathologic diagnosis prior to chemotherapy because they have found a high concordance between percutaneous biopsy and final surgical pathology in 94%e99% of cases [8]. Furthermore, use of pretreatment biopsy has not been associated with any increase in recurrence or complication [9]. Unfortunately, this patient fell into the small cohort of patients whose diagnosis on initial biopsy is discordant with the final pathologic diagnosis. CCSK is a malignant mesenchymal neoplasm characterized by undifferentiated cells with abundant extracellular matrix that are separated into cords and nests by a fine vascular network. Although the majority of CCSK have “classic” features on pathologic examination it is well known that CCSK is difficult to differentiate from other “renal blue round cell lesions” such as blastemal Wilms’ tumor and primitive neuroectodermal tumor. The primary contribution of immunohistochemical analysis in the diagnosis of CCSK is the exclusion of other pediatric renal neoplasms, whereas immunohistochemical study has a limited role in the
S.S. Short et al. / J Ped Surg Case Reports 1 (2013) 235e238
237
Fig. 2. A. Wilms’ e H&E slide shows a cellular tumor composed of primitive tumor cells with hyperchromatic nuclei, small amount of cytoplasm and indistinctive cell borders. Mitotic figures are noted. B. Clear cell sarcoma of the kidney (CCSK) e H&E slide shows tumor cells are separated by pale-pink vascular-rich stroma and contain nuclei with finely dispersed chromatin.
pathologic evaluation of Wilms’ tumor. Similar to blastemal and stromal cells of Wilms’ tumor, CCSK regularly expresses vimentin, but other differentiation markers including epithelial markers (cytokeratin, EMA), desmin, S100 protein and neuron specific enolase are usually absent. Furthermore, immunohistochemical reaction for WT1 protein in Wilms’ tumor is variable and correlation with tumor histology is still required. Further, while WT1 immunoreactivity may be useful in distinguishing between blastemal Wilms’ tumor (high WT1 expression) and other primitive tumors, it is not useful in tumors with only stromal differentiation, as seen in this CCSK case. Other factors known to be uniformly negative in CCSK include CD99 (Mic-2) and CD56, which are positive in this case [10]. Others have reported that the muscle specific actin may sometimes show positivity and vimentin staining may be much stronger in CCSK, which may be helpful in distinguishing CCSK from Wilms’ tumor [11]. However, no single immunohistochemical reaction is universally diagnostic for Wilms’ tumor as well as CCSK. Other clues to the diagnosis of CCSK include well separated nuclear spacing, fine chromatin, and younger mean age of patient [5]. While these differences may help distinguish CCSK from other pathology it remains the most commonly misdiagnosed pediatric renal tumor with authors reporting confusion with Wilms’ and mesoblastic nephroma [5,12,13]. This has prompted investigation into methods to better discern CCSK from other entities. Ueno and colleagues recently sought to characterize the molecular signature
of different pediatric renal neoplasms. They evaluated specimens from 83 pediatric patients including 21 with CCSK and 41 with Wilms’. They found that CCSK is generally hypermethylated particular at the site THBS1 CPG, a suspected angiogenic factor. All children with CCSK were found to be hypermethylated at this loci and all children with an alternative renal neoplasm were not hypermethylated [14]. Others have evaluated and reported different genetic mutations associated with CCSK including rearrangement of YWAE on chromosome 17, translocation of t(10;17)(q22;p13), EFGR amplification, and deletions in chromosome 14q [7,15]. However, these genetic mutations appear sporadic with no familial cases of CCSK reported to date [7]. Currently there are no defined algorithms and most authors recommend referral of samples to pathologists with experience evaluating pediatric renal neoplasms, which were helpful for successful diagnosis in this case. Once diagnosis of CCK is confirmed treatment is radical nephrectomy followed by adjuvant chemoradiation. The National Wilms’ Tumor Study Group (NWTSG) guidelines call for cyclophosphamide, etoposide, vincristine, and doxorubicin for any stage of CCSK [16]. Doxorubicin has been reported to impart significant improvements in survival [5] and prolonged chemotherapy regimens may improve relapse free survival [17]. Although some have withheld adjuvant radiotherapy in children with stage I disease, the addition of radiotherapy (10 Gy) to the tumor bed is standard in protocols for patients of any stage with CCSK [18]. Despite having unfavorable histology associated long term survival is reasonable with nearly 79% of patients alive at 10 years [3]. TNM staging classification for CCSK is the same as Wilms’ and prognosis varies by respective stage. Overall survival of 100% for stage I, 97% for stage II, 87% for stage III, and 45% for stage IV disease have been reported [19]. 3. Conclusion In summary, CCSK is an uncommon tumor of renal origin that is challenging to diagnose and should be considered in the differential diagnosis of a pediatric patient presenting with a palpable abdominal mass. Further research is needed to develop better methods of diagnosis and tissue should undergo evaluation by pathologists familiar with subtleties between pediatric renal neoplasms. Consent
Fig. 3. Intra-operative image of a large renal mass with distorted anatomy and displacement of the IVC.
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
238
S.S. Short et al. / J Ped Surg Case Reports 1 (2013) 235e238
References [1] Golden CB, Feusner JH. Malignant abdominal masses in children: quick guide to evaluation and diagnosis. Pediatr Clin North Am 2002;49:1369e92 [viii]. [2] Dome JS. Identification and management of high risk Wilms’ tumors. Erasmus University Rotterdam; 2009. [3] Zhuge Y, Cheung MC, Yang R, Perez EA, Koniaris LG, Sola JE. Pediatric nonWilms renal tumors: subtypes, survival, and prognostic indicators. J Surg Res 2010;163:257e63. [4] Franco A, Dao TV, Lewis KN, Biddinger PW. A case of clear cell sarcoma of the kidney. J Radiol Case Rep 2011;5:8e12. [5] Argani P, Perlman EJ, Breslow NE, Browning NG, Green DM, D’Angio GJ, et al. Clear cell sarcoma of the kidney: a review of 351 cases from the National Wilms Tumor Study Group Pathology Center. Am J Surg Pathol 2000; 24:4. [6] Glass R, Davidson A, Fernbach S. Clear cell sarcoma of the kidney: CT, sonographic, and pathologic correlation. Radiology 1991;180:715. [7] Gooskens SL, Furtwangler R, Vujanic GM, Dome JS, Graf N, van den HeuvelEibrink MM. Clear cell sarcoma of the kidney: a review. Eur J Cancer 2012;48: 2219e26. [8] Vujani c GM, Kelsey A, Mitchell C, Shannon RS, Gornall P. The role of biopsy in the diagnosis of renal tumors of childhood: results of the UKCCSG Wilms tumor study 3. Med Pediatr Oncol 2003;40:18e22. [9] Mitchell C, Pritchard-Jones K, Shannon R, Hutton C, Stevens S, Machin D, et al. Immediate nephrectomy versus preoperative chemotherapy in the management of non-metastatic Wilms’ tumour: results of a randomised trial (UKW3) by the UK Children’s Cancer Study Group. Eur J Cancer 2006;42: 2554e62.
[10] Vasei M, Moch H, Mousavi A, Kajbafzadeh AM, Sauter G. Immunohistochemical profiling of Wilms tumor: a tissue microarray study. Appl Immunohistochem Mol Morphol 2008;16:128e34. [11] Looi LM, Cheah PL. An immunohistochemical study comparing clear cell sarcoma of the kidney and Wilms’ tumor. Pathology 1993;25:106e9. [12] Alavi S, Khoddami M, Yazdi MK, Dehghanian P, Esteghamati S. Clear cell sarcoma of the kidney misdiagnosed as mesoblastic nephroma: a case report and review of the literature. Ecancermedicalscience 2013;7:311. [13] Boo YJ, Fisher JC, Haley MJ, Cowles RA, Kandel JJ, Yamashiro DJ. Vascular characterization of clear cell sarcoma of the kidney in a child: a case report and review. J Pediatr Surg 2009;44:2031e6. [14] Ueno H, Okita H, Akimoto S, Kobayashi K, Nakabayashi K, Hata K, et al. DNA methylation profile distinguishes clear cell sarcoma of the kidney from other pediatric renal tumors. PloS One 2013;8:e62233. [15] O’Meara E, Stack D, Lee CH, Garvin AJ, Morris T, Argani P, et al. Characterization of the chromosomal translocation t(10;17)(q22;p13) in clear cell sarcoma of kidney. J Pathol 2012;227:72e80. [16] Ahmed HU, Arya M, Levitt G, Duffy PG, Sebire NJ, Mushtaq I. Part II: treatment of primary malignant non-Wilms’ renal tumours in children. Lancet Oncol 2007;8:842e8. [17] Seibel NL, Li S, Breslow NE, Beckwith JB, Green DM, Haase GM, et al. Effect of duration of treatment on treatment outcome for patients with clear-cell sarcoma of the kidney: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 2004;22:468e73. [18] Halperin EC, Constine LS, Tarbell NJ, Kun LE. Pediatric radiation oncology. Lippincott Williams & Wilkins; 2010. [19] Geller E, Kochan PS. Renal neoplasms of childhood. Radiol Clin North Am 2011;49:689e709.