VOLUME
33
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NUMBER
14
䡠
MAY
10
2015
JOURNAL OF CLINICAL ONCOLOGY
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O N C O L O G Y
teins (4.8 g/dL). Urinalysis revealed a protein content of more than 400 mg/dL, with a daily proteinuria of 33 g. The clinical presentation was thus suggestive of severe nephrotic syndrome (NS). Major disorders that are pathogenetic of NS, such as diabetes, renal amyloidosis, autoimmune diseases, and light chain–producing multiple myeloma, were excluded, whereas abdominal ultrasound revealed an exophytic lesion that measured 4.5 ⫻ 4.4 cm within the medial one third of the right kidney cortex (Fig 1A, asterisk). A whole-body computed tomography (CT) scan confirmed the presence of the renal mass and showed invasion toward the renal vessels as well as conglomerate nodes, 5.5 cm in diameter, surrounding the inferior vena cava (Fig 1B, asterisk). The patient was first treated for 3 days with intravenous
Paraneoplastic Focal Segmental Glomerulosclerosis in Sarcomatoid Renal Cell Cancer Case Report A 68-year-old white man was admitted to the Department of Biomedical Science and Clinical Oncology of the University of Bari for both weakness and anasarca. He suffered from mild hypertension and was overweight. Blood tests showed impaired renal function parameters with increased serum creatinine (3.1 mg/dL) and urea (95 mg/dL), defective creatinine clearance (28 mL/min), and reduced plasma pro-
A
B
C
D
Fig 1. e66
© 2014 by American Society of Clinical Oncology
Journal of Clinical Oncology, Vol 33, No 14 (May 10), 2015: pp e66-e70
Downloaded from jco.ascopubs.org on January 26, 2016. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
Proteinuria (g/L)
40 30
4.0
Proteinuria Serum creatinin
Prednisone Surgery
3.0
Chemotherapy
20
2.0
10
1.0
0
Serum Creatinine (mg/dL)
Diagnosis in Oncology
0 1
2
3
4
5
6
Time (months) Fig 2.
prednisone at a dose of 1 mg/kg for that was reduced by 10 mg weekly to modulate the protein loss, and then underwent radical nephrectomy with partial lymphadenectomy after discontinuing the corticosteroid treatment. Macroscopic examination revealed tumoral infiltration of both the Gerota capsule and the surrounding adipose tissue. Morphologic examination (Fig 1C) described poorly differentiated epithelial-like spindle-shaped cells, supporting the diagnosis of sarcomatoid renal cell carcinoma (RCC). Furthermore, immunohistochemistry assessment revealed the concurrent expression of cytokeratins AE1/AE2 (diffuse brown staining in Fig 1D) as well as vimentin, paired box gene 8, and epithelial membrane antigen. A classic clear-cell renal cancer was then excluded by both the morphology and the absence of the CD10 marker, and a rhabdoid tumor by the preservation of integrase interactor 1. By contrast, the high expression of cytokeratins AE1/AE2 confirmed the diagnosis of sarcomatoid RCC. Following the treatment combination of prednisone and nephrectomy, the patient’s performance status rapidly improved, with dramatic resolution of anasarca resulting in a weight loss of 20 kg, normalization of renal function parameters (creatinine, 1.1 mg/dL; urea, 25 mg/dL; creatinine clearance, 55 mL/min) and a progressive decline of daily proteinuria below 13.86 g (Fig 2). In relation to the hypothesis that the NS was of paraneoplastic origin, the renal tissue near the tumor was evaluated by histology to identify potential morphologic alterations consistent with the hypothesis of a paraneoplastic NS. The evaluation emphasized an increased glomerular volume (Fig 3A, green marker) associated with the presence of ischemic areas and parenchymal atrophy (Fig 3B, arrow), whereas several glomeruli showed segmental sclerosis surrounding the flocculus, with reactive podocytes adherent to Bowman’s capsule (Fig 3C). High microscopic magnification (⫻53) demonstrated typical foot process effacement that included the podocyte vacuolization with lysosomal inclusion and their detachment from the glomerular membrane (Figs 3D and 3E, asterisks). The arrow in Figure 3E points to a normal podocyte close to the glomerular membrane. Furthermore, arterial vessels were found to show moderate to severe intimal fibrosis and hyaline droplets within the arteriolar wall (Fig 3F). Immunofluorescence excluded the presence of immune deposits. Post-surgical staging was completed by both [18F] fluorodeoxyglucose positron emission tomography and a whole-body CT scan, which confirmed the persistence of pathologic tissue, 8.4 ⫻ 4.8 cm in size, surrounding the cava, as indicated in Figures 4A to 4C, originating from D10 and extending to L4 (Figs 4D to 4F). Glucose uptake (standardized uptake value) by the residual www.jco.org
tumor was equal to 18.3. The patient was staged as T3N1M0 (stage III) in accordance with the American Joint Committee on Cancer classification. He underwent chemotherapy with an anthracycline (50 mg/ m2) and gemcitabine (1.5 g/m2) regimen twice per month, as suggested by international guidelines.1 As shown in Figure 2, the adjuvant treatment induced complete restoration of renal function with a reduction of proteinuria below 0.8 g/24 hours and resolution of the NS. In addition, a CT scan documented a partial response according to RECIST criteria (Figs 4G and 4H) after six chemotherapy cycles. In line with previous reports showing long-term response to chemotherapy,2,3 the patient continued to receive the anthracycline and gemcitabine regimen. Discussion Sarcomatoid RCC is an aggressive neoplasm showing histologic features of papillary, chromophobe, or collecting-duct renal carcinoma, with a similar age and sex distribution compared with conventional RCC.4 The prognosis is poor, with a median overall survival of 4 to 7 months. Stage, female sex, and age are also adverse prognostic factors.5 The pathogenesis is still undefined, although it has been postulated that sarcomatoid RCC is the result of accumulation of chromosomal defects that are responsible for the formation of spindle cells showing high atypia, increased proliferation, and morphologic features typical of a soft tissue sarcoma.6 These findings are corroborated by both genetic and morphologic evidence that suggests its origin from a dedifferentiated tumor deriving from the renal epithelium. The molecular profile of sarcomatoid RCCs includes mutations of p53 and low expression of nonmutated cKit,7-9 whereas hypoxiainducible factor-1, carbonic anhydrase IX, glucose transporter-1, and vascular endothelial growth factor are commonly overexpressed.10 Other markers that were also demonstrated in our patient included cytokeratins AE1 and AE2, as well as vimentin and antigens, supporting the phenotypic diagnosis.11,12 Sarcomatoid RCCs may spread to distant sites, including lung, liver, bone, and brain, whereas nodal involvement is considered a negative prognostic factor. Nephrectomy associated with local lymphadenectomy is the gold standard for localized disease.13 Immunotherapy for locally advanced disease has failed in the majority of studies, whereas the combination of anthracyclines and gemcitabine provided long-term responses with improvement in progression-free survival.2,3 Recently, tyrosine kinase inhibitors targeting the vascular endothelial growth factor pathway have shown promising results, and their association with alkylants is being studied in clinical trials.1,14 The peculiar clinical onset in our patient led us to investigate the existence of damage in the peritumoral renal parenchyma compatible with a paraneoplastic glomerulonephritis (GN). These disorders have been described in patients with epithelial tumors,15 membranous nephropathy being the most frequent histotype, whereas an NS as a result of minimal-change nephropathy is prominent in hematologic disorders. The onset of renal failure is frequently marked by an NS; the incidence of NS is a harbinger of the tumor in approximately 40% of patients. The pathogenetic mechanisms that lead to paraneoplastic renal disorders are prevalently immune mediated and based on aberrant antigen expression by tumor cells as well as on re-expressed fetal and/or viral antigens.16 Several immune-based events have been described in experimental models of GN, such as the Buffalo/Mna rat model of spontaneous thymoma showing a prevalent polarization of immune cells toward a T-helper 2 (Th2) profile, which was found to © 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on January 26, 2016. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
e67
Tucci et al
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Fig 3.
be consistent with the development of glomerular lesions. Furthermore, the overexpression of Th2 cytokines, such as interleukin-13 in transgenic rats, induces minimal changes in the disease evolution. However, the molecular mechanisms underlying the development of renal damage, such as a paraneoplastic syndrome, are still undefined.17,18 Other GNs, such as focal segmental glomerulosclerosis (FSGS), membrano-proliferative, immunoglobulin A nephropathy, and rapidly progressive GN, are also described as paraneoplastic GNs, e68
© 2014 by American Society of Clinical Oncology
although their association with mesenchyma-derived tumors has not been proven.19 Although the microscopic examination of the extratumoral renal tissue confirmed the clinical hypothesis, the histologic pattern was compatible with an FSGS rather than a membranous proliferative GN, which may frequently occur in cancer. FSGS usually develops with elevated proteinuria, hypertension, and definite renal failure.20 However, its association with malignancy is rare and is primarily reported JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on January 26, 2016. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
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podocytes as well as their detachment from the glomerular basement membrane, thus causing proteinuria. We found these phenomena in our patient, whose peritumoral kidney tissue showed hypertrophic podocytes surrounding the whole circumference of glomeruli, as well as an increased glomerular volume and damage of the basal membrane. However, although a rapid resolution of the NS occurred with the administration of corticosteroid treatment followed by surgical removal of the tumor, the pathogenetic mechanisms driving this rare paraneoplastic syndrome remain unclear. In conclusion, the simultaneous presentation and long-term remission of the NS in our patient support the diagnosis of a paraneoplastic renal disease induced by a nephrotoxic factor(s) produced by malignant cells. This may be in line with the partial reduction of daily proteinuria that was induced by corticosteroid treatment, whereas both the patient’s overweight status and hypertension may have exacerbated the renal damage.28
Marco Tucci, Stefania Stucci, Simona Vallarelli, Loreto Gesualdo, and Oronzo Brunetti University of Bari Aldo Moro, Bari, Italy
Angelo Paolo Dei Tos Treviso General Hospital, Treviso, Italy
Francesco Silvestris University of Bari Aldo Moro, Bari, Italy
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES
G
H
Fig 4.
in hematologic disorders,21 or, rarely, in undifferentiated rectal adenocarcinoma, lung mesothelioma, and RCC.22 FSGS was originally reported in a single case of soft tissue sarcomas.23 Approximately 80% of FSGS are idiopathic, although a few experimental models24 suggested an intrarenal accumulation of tumor-related soluble factors, such as fibroblast-derived growth factors and transforming growth factor-. Given that podocytes are frequently damaged, other factors, such as overexpression of Th1 cytokines, angiotensin II, and growth factors,25-27 have been postulated as major causes of FSGS, thus explaining the recruitment of inflammatory cells within the kidney as well as the progressive derangement of the cytoskeleton and variations of the podocyte surface charge. These events promote apoptosis in www.jco.org
1. Nanus DM, Garino A, Milowsky MI, et al: Active chemotherapy for sarcomatoid and rapidly progressing renal cell carcinoma. Cancer 101:1545-1551, 2004 2. Dutcher JP, Nanus D: Long-term survival of patients with sarcomatoid renal cell cancer treated with chemotherapy. Med Oncol 28:1530-1533, 2011 3. Haas NB, Lin X, Manola J, et al: A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECOG 8802. Med Oncol 29:761-767, 2012 4. Delahunt B: Sarcomatoid renal carcinoma: The final common dedifferentiation pathway of renal epithelial malignancies. Pathology 31:185-190, 1999 5. Kuroda N, Toi M, Hiroi M, et al: Review of sarcomatoid renal cell carcinoma with focus on clinical and pathobiological aspects. Histol Histopathol 18:551-555, 2003 6. de Peralta-Venturina M, Moch H, Amin M, et al: Sarcomatoid differentiation in renal cell carcinoma: A study of 101 cases. Am J Surg Pathol 25:275-284, 2001 7. Oda H, Nakatsuru Y, Ishikawa T: Mutations of the p53 gene and p53 protein overexpression are associated with sarcomatoid transformation in renal cell carcinomas. Cancer Res 55:658-662, 1995 8. Kanamaru H, Li B, Miwa Y, et al: Immunohistochemical expression of p53 and bcl-2 proteins is not associated with sarcomatoid change in renal cell carcinoma. Urol Res 27:169-173, 1999 9. Sengupta S, Cheville JC, Corless CL, et al: Rare expression of KIT and absence of KIT mutations in high grade renal cell carcinoma. J Urol 175:53-56, 2006 10. Tickoo SK, Alden D, Olgac S, et al: Immunohistochemical expression of hypoxia inducible factor-1alpha and its downstream molecules in sarcomatoid renal cell carcinoma. J Urol 177:1258-1263, 2007 11. DeLong W, Grignon DJ, Eberwein P, et al: Sarcomatoid renal cell carcinoma: An immunohistochemical study of 18 cases. Arch Pathol Lab Med 117:636-634, 1993 12. Cates JM, Dupont WD, Barnes JW, et al: Markers of epithelialmesenchymal transition and epithelial differentiation in sarcomatoid carcinoma: Utility in the differential diagnosis with sarcoma. Appl Immunohistochem Mol Morphol 16:251-262, 2008 13. Leibovich BC, Han KR, Bui MH, et al: Scoring algorithm to predict survival after nephrectomy and immunotherapy in patients with metastatic renal cell
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on January 26, 2016. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
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carcinoma: A stratification tool for prospective clinical trials. Cancer 98:25662575, 2003 14. Golshayan AR, George S, Heng DY, et al: Metastatic sarcomatoid renal cell carcinoma treated with vascular endothelial growth factor–targeted therapy. J Clin Oncol 27:235-241, 2009 15. Davison AM: Renal diseases associated with malignancies. Nephrol Dial Transplant 16:13-24, 2001 16. Bacchetta J, Juillard L, Cochat P, et al: Paraneoplastic glomerular diseases and malignancies. Crit Rev Oncol Hematol 70:39-58, 2009 17. Glassock RJ: The pathogenesis of membranous nephropathy: Evolution and revolution. Curr Opin Nephrol Hypertens 21:235-242, 2012 18. Tipping PG, Kitching AR: Glomerulonephritis, Th1 and Th2: What’s new? Clin Exp Immunol 142:207-215, 2005 19. Lien YH, Lai LW: Pathogenesis, diagnosis and management of paraneoplastic glomerulonephritis. Nat Rev Nephrol 7:85-95, 2011 20. D’Agati VD: Pathobiology of focal segmental glomerulosclerosis: New developments. Curr Opin Nephrol Hypertens 21:243-250, 2012 21. Mallouk A, Pham PT, Pham PC: Concurrent FSGS and Hodgkin’s lymphoma: Case report and literature review on the link between nephrotic glomerulopathies and hematological malignancies. Clin Exp Nephrol 10:284-289, 2006
22. Konoshita T, Itoh M, Hatakeyama S, et al: Nephrotic syndrome due to focal glomerulosclerosis and undifferentiated carcinoma. Clin Nephrol 54:404-408, 2000 23. Loi S, Perry GJ, Standish J, et al: Glomerulosclerosis: A paraneoplastic phenomenon? Nephrology (Carlton) 9:387-391, 2004 24. Meyrier A: Focal and segmental glomerulosclerosis: Multiple pathways are involved. Semin Nephrol 31:326-332, 2011 25. Schwartz MM: The role of podocyte injury in the pathogenesis of focal segmental glomerulosclerosis. Ren Fail 22:663-684, 2000 26. Durvasula RV, Petermann AT, Hiromura K, et al: Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int 65:30-39, 2004 27. Lee HS, Song CY: Effects of TGF-beta on podocyte growth and disease progression in proliferative podocytopathies. Kidney Blood Press Res 33:24-29, 2010 28. Darouich S, Goucha R, Jaafoura MH, et al: Clinicopathological characteristics of obesity-associated focal segmental glomerulosclerosis. Ultrastruct Pathol 35:176-182, 2011
DOI: 10.1200/JCO.2013.50.0413; published online ahead of print at www.jco.org on March 24, 2014
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Downloaded from jco.ascopubs.org on January 26, 2016. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
33
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NUMBER
14
䡠
MAY
10
2015
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
I N
O N C O L O G Y
teins (4.8 g/dL). Urinalysis revealed a protein content of more than 400 mg/dL, with a daily proteinuria of 33 g. The clinical presentation was thus suggestive of severe nephrotic syndrome (NS). Major disorders that are pathogenetic of NS, such as diabetes, renal amyloidosis, autoimmune diseases, and light chain–producing multiple myeloma, were excluded, whereas abdominal ultrasound revealed an exophytic lesion that measured 4.5 ⫻ 4.4 cm within the medial one third of the right kidney cortex (Fig 1A, asterisk). A whole-body computed tomography (CT) scan confirmed the presence of the renal mass and showed invasion toward the renal vessels as well as conglomerate nodes, 5.5 cm in diameter, surrounding the inferior vena cava (Fig 1B, asterisk). The patient was first treated for 3 days with intravenous
Paraneoplastic Focal Segmental Glomerulosclerosis in Sarcomatoid Renal Cell Cancer Case Report A 68-year-old white man was admitted to the Department of Biomedical Science and Clinical Oncology of the University of Bari for both weakness and anasarca. He suffered from mild hypertension and was overweight. Blood tests showed impaired renal function parameters with increased serum creatinine (3.1 mg/dL) and urea (95 mg/dL), defective creatinine clearance (28 mL/min), and reduced plasma pro-
A
B
C
D
Fig 1. e66
© 2014 by American Society of Clinical Oncology
Journal of Clinical Oncology, Vol 33, No 14 (May 10), 2015: pp e66-e70
Downloaded from jco.ascopubs.org on January 26, 2016. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
Proteinuria (g/L)
40 30
4.0
Proteinuria Serum creatinin
Prednisone Surgery
3.0
Chemotherapy
20
2.0
10
1.0
0
Serum Creatinine (mg/dL)
Diagnosis in Oncology
0 1
2
3
4
5
6
Time (months) Fig 2.
prednisone at a dose of 1 mg/kg for that was reduced by 10 mg weekly to modulate the protein loss, and then underwent radical nephrectomy with partial lymphadenectomy after discontinuing the corticosteroid treatment. Macroscopic examination revealed tumoral infiltration of both the Gerota capsule and the surrounding adipose tissue. Morphologic examination (Fig 1C) described poorly differentiated epithelial-like spindle-shaped cells, supporting the diagnosis of sarcomatoid renal cell carcinoma (RCC). Furthermore, immunohistochemistry assessment revealed the concurrent expression of cytokeratins AE1/AE2 (diffuse brown staining in Fig 1D) as well as vimentin, paired box gene 8, and epithelial membrane antigen. A classic clear-cell renal cancer was then excluded by both the morphology and the absence of the CD10 marker, and a rhabdoid tumor by the preservation of integrase interactor 1. By contrast, the high expression of cytokeratins AE1/AE2 confirmed the diagnosis of sarcomatoid RCC. Following the treatment combination of prednisone and nephrectomy, the patient’s performance status rapidly improved, with dramatic resolution of anasarca resulting in a weight loss of 20 kg, normalization of renal function parameters (creatinine, 1.1 mg/dL; urea, 25 mg/dL; creatinine clearance, 55 mL/min) and a progressive decline of daily proteinuria below 13.86 g (Fig 2). In relation to the hypothesis that the NS was of paraneoplastic origin, the renal tissue near the tumor was evaluated by histology to identify potential morphologic alterations consistent with the hypothesis of a paraneoplastic NS. The evaluation emphasized an increased glomerular volume (Fig 3A, green marker) associated with the presence of ischemic areas and parenchymal atrophy (Fig 3B, arrow), whereas several glomeruli showed segmental sclerosis surrounding the flocculus, with reactive podocytes adherent to Bowman’s capsule (Fig 3C). High microscopic magnification (⫻53) demonstrated typical foot process effacement that included the podocyte vacuolization with lysosomal inclusion and their detachment from the glomerular membrane (Figs 3D and 3E, asterisks). The arrow in Figure 3E points to a normal podocyte close to the glomerular membrane. Furthermore, arterial vessels were found to show moderate to severe intimal fibrosis and hyaline droplets within the arteriolar wall (Fig 3F). Immunofluorescence excluded the presence of immune deposits. Post-surgical staging was completed by both [18F] fluorodeoxyglucose positron emission tomography and a whole-body CT scan, which confirmed the persistence of pathologic tissue, 8.4 ⫻ 4.8 cm in size, surrounding the cava, as indicated in Figures 4A to 4C, originating from D10 and extending to L4 (Figs 4D to 4F). Glucose uptake (standardized uptake value) by the residual www.jco.org
tumor was equal to 18.3. The patient was staged as T3N1M0 (stage III) in accordance with the American Joint Committee on Cancer classification. He underwent chemotherapy with an anthracycline (50 mg/ m2) and gemcitabine (1.5 g/m2) regimen twice per month, as suggested by international guidelines.1 As shown in Figure 2, the adjuvant treatment induced complete restoration of renal function with a reduction of proteinuria below 0.8 g/24 hours and resolution of the NS. In addition, a CT scan documented a partial response according to RECIST criteria (Figs 4G and 4H) after six chemotherapy cycles. In line with previous reports showing long-term response to chemotherapy,2,3 the patient continued to receive the anthracycline and gemcitabine regimen. Discussion Sarcomatoid RCC is an aggressive neoplasm showing histologic features of papillary, chromophobe, or collecting-duct renal carcinoma, with a similar age and sex distribution compared with conventional RCC.4 The prognosis is poor, with a median overall survival of 4 to 7 months. Stage, female sex, and age are also adverse prognostic factors.5 The pathogenesis is still undefined, although it has been postulated that sarcomatoid RCC is the result of accumulation of chromosomal defects that are responsible for the formation of spindle cells showing high atypia, increased proliferation, and morphologic features typical of a soft tissue sarcoma.6 These findings are corroborated by both genetic and morphologic evidence that suggests its origin from a dedifferentiated tumor deriving from the renal epithelium. The molecular profile of sarcomatoid RCCs includes mutations of p53 and low expression of nonmutated cKit,7-9 whereas hypoxiainducible factor-1, carbonic anhydrase IX, glucose transporter-1, and vascular endothelial growth factor are commonly overexpressed.10 Other markers that were also demonstrated in our patient included cytokeratins AE1 and AE2, as well as vimentin and antigens, supporting the phenotypic diagnosis.11,12 Sarcomatoid RCCs may spread to distant sites, including lung, liver, bone, and brain, whereas nodal involvement is considered a negative prognostic factor. Nephrectomy associated with local lymphadenectomy is the gold standard for localized disease.13 Immunotherapy for locally advanced disease has failed in the majority of studies, whereas the combination of anthracyclines and gemcitabine provided long-term responses with improvement in progression-free survival.2,3 Recently, tyrosine kinase inhibitors targeting the vascular endothelial growth factor pathway have shown promising results, and their association with alkylants is being studied in clinical trials.1,14 The peculiar clinical onset in our patient led us to investigate the existence of damage in the peritumoral renal parenchyma compatible with a paraneoplastic glomerulonephritis (GN). These disorders have been described in patients with epithelial tumors,15 membranous nephropathy being the most frequent histotype, whereas an NS as a result of minimal-change nephropathy is prominent in hematologic disorders. The onset of renal failure is frequently marked by an NS; the incidence of NS is a harbinger of the tumor in approximately 40% of patients. The pathogenetic mechanisms that lead to paraneoplastic renal disorders are prevalently immune mediated and based on aberrant antigen expression by tumor cells as well as on re-expressed fetal and/or viral antigens.16 Several immune-based events have been described in experimental models of GN, such as the Buffalo/Mna rat model of spontaneous thymoma showing a prevalent polarization of immune cells toward a T-helper 2 (Th2) profile, which was found to © 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on January 26, 2016. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
e67
Tucci et al
A
B
C
D
E
F
Fig 3.
be consistent with the development of glomerular lesions. Furthermore, the overexpression of Th2 cytokines, such as interleukin-13 in transgenic rats, induces minimal changes in the disease evolution. However, the molecular mechanisms underlying the development of renal damage, such as a paraneoplastic syndrome, are still undefined.17,18 Other GNs, such as focal segmental glomerulosclerosis (FSGS), membrano-proliferative, immunoglobulin A nephropathy, and rapidly progressive GN, are also described as paraneoplastic GNs, e68
© 2014 by American Society of Clinical Oncology
although their association with mesenchyma-derived tumors has not been proven.19 Although the microscopic examination of the extratumoral renal tissue confirmed the clinical hypothesis, the histologic pattern was compatible with an FSGS rather than a membranous proliferative GN, which may frequently occur in cancer. FSGS usually develops with elevated proteinuria, hypertension, and definite renal failure.20 However, its association with malignancy is rare and is primarily reported JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on January 26, 2016. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
A
B
C
D
E
F
podocytes as well as their detachment from the glomerular basement membrane, thus causing proteinuria. We found these phenomena in our patient, whose peritumoral kidney tissue showed hypertrophic podocytes surrounding the whole circumference of glomeruli, as well as an increased glomerular volume and damage of the basal membrane. However, although a rapid resolution of the NS occurred with the administration of corticosteroid treatment followed by surgical removal of the tumor, the pathogenetic mechanisms driving this rare paraneoplastic syndrome remain unclear. In conclusion, the simultaneous presentation and long-term remission of the NS in our patient support the diagnosis of a paraneoplastic renal disease induced by a nephrotoxic factor(s) produced by malignant cells. This may be in line with the partial reduction of daily proteinuria that was induced by corticosteroid treatment, whereas both the patient’s overweight status and hypertension may have exacerbated the renal damage.28
Marco Tucci, Stefania Stucci, Simona Vallarelli, Loreto Gesualdo, and Oronzo Brunetti University of Bari Aldo Moro, Bari, Italy
Angelo Paolo Dei Tos Treviso General Hospital, Treviso, Italy
Francesco Silvestris University of Bari Aldo Moro, Bari, Italy
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES
G
H
Fig 4.
in hematologic disorders,21 or, rarely, in undifferentiated rectal adenocarcinoma, lung mesothelioma, and RCC.22 FSGS was originally reported in a single case of soft tissue sarcomas.23 Approximately 80% of FSGS are idiopathic, although a few experimental models24 suggested an intrarenal accumulation of tumor-related soluble factors, such as fibroblast-derived growth factors and transforming growth factor-. Given that podocytes are frequently damaged, other factors, such as overexpression of Th1 cytokines, angiotensin II, and growth factors,25-27 have been postulated as major causes of FSGS, thus explaining the recruitment of inflammatory cells within the kidney as well as the progressive derangement of the cytoskeleton and variations of the podocyte surface charge. These events promote apoptosis in www.jco.org
1. Nanus DM, Garino A, Milowsky MI, et al: Active chemotherapy for sarcomatoid and rapidly progressing renal cell carcinoma. Cancer 101:1545-1551, 2004 2. Dutcher JP, Nanus D: Long-term survival of patients with sarcomatoid renal cell cancer treated with chemotherapy. Med Oncol 28:1530-1533, 2011 3. Haas NB, Lin X, Manola J, et al: A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECOG 8802. Med Oncol 29:761-767, 2012 4. Delahunt B: Sarcomatoid renal carcinoma: The final common dedifferentiation pathway of renal epithelial malignancies. Pathology 31:185-190, 1999 5. Kuroda N, Toi M, Hiroi M, et al: Review of sarcomatoid renal cell carcinoma with focus on clinical and pathobiological aspects. Histol Histopathol 18:551-555, 2003 6. de Peralta-Venturina M, Moch H, Amin M, et al: Sarcomatoid differentiation in renal cell carcinoma: A study of 101 cases. Am J Surg Pathol 25:275-284, 2001 7. Oda H, Nakatsuru Y, Ishikawa T: Mutations of the p53 gene and p53 protein overexpression are associated with sarcomatoid transformation in renal cell carcinomas. Cancer Res 55:658-662, 1995 8. Kanamaru H, Li B, Miwa Y, et al: Immunohistochemical expression of p53 and bcl-2 proteins is not associated with sarcomatoid change in renal cell carcinoma. Urol Res 27:169-173, 1999 9. Sengupta S, Cheville JC, Corless CL, et al: Rare expression of KIT and absence of KIT mutations in high grade renal cell carcinoma. J Urol 175:53-56, 2006 10. Tickoo SK, Alden D, Olgac S, et al: Immunohistochemical expression of hypoxia inducible factor-1alpha and its downstream molecules in sarcomatoid renal cell carcinoma. J Urol 177:1258-1263, 2007 11. DeLong W, Grignon DJ, Eberwein P, et al: Sarcomatoid renal cell carcinoma: An immunohistochemical study of 18 cases. Arch Pathol Lab Med 117:636-634, 1993 12. Cates JM, Dupont WD, Barnes JW, et al: Markers of epithelialmesenchymal transition and epithelial differentiation in sarcomatoid carcinoma: Utility in the differential diagnosis with sarcoma. Appl Immunohistochem Mol Morphol 16:251-262, 2008 13. Leibovich BC, Han KR, Bui MH, et al: Scoring algorithm to predict survival after nephrectomy and immunotherapy in patients with metastatic renal cell
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on January 26, 2016. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
e69
Tucci et al
carcinoma: A stratification tool for prospective clinical trials. Cancer 98:25662575, 2003 14. Golshayan AR, George S, Heng DY, et al: Metastatic sarcomatoid renal cell carcinoma treated with vascular endothelial growth factor–targeted therapy. J Clin Oncol 27:235-241, 2009 15. Davison AM: Renal diseases associated with malignancies. Nephrol Dial Transplant 16:13-24, 2001 16. Bacchetta J, Juillard L, Cochat P, et al: Paraneoplastic glomerular diseases and malignancies. Crit Rev Oncol Hematol 70:39-58, 2009 17. Glassock RJ: The pathogenesis of membranous nephropathy: Evolution and revolution. Curr Opin Nephrol Hypertens 21:235-242, 2012 18. Tipping PG, Kitching AR: Glomerulonephritis, Th1 and Th2: What’s new? Clin Exp Immunol 142:207-215, 2005 19. Lien YH, Lai LW: Pathogenesis, diagnosis and management of paraneoplastic glomerulonephritis. Nat Rev Nephrol 7:85-95, 2011 20. D’Agati VD: Pathobiology of focal segmental glomerulosclerosis: New developments. Curr Opin Nephrol Hypertens 21:243-250, 2012 21. Mallouk A, Pham PT, Pham PC: Concurrent FSGS and Hodgkin’s lymphoma: Case report and literature review on the link between nephrotic glomerulopathies and hematological malignancies. Clin Exp Nephrol 10:284-289, 2006
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DOI: 10.1200/JCO.2013.50.0413; published online ahead of print at www.jco.org on March 24, 2014
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