Pediatr Blood Cancer 2015;62:1694–1699
REVIEW Renal Medullary Carcinoma and Sickle Cell Trait: A Systematic Review Ofelia Alvarez, MD,1* Maria M. Rodriguez, MD,2 Lanetta Jordan, Sickle cell trait (SCT) carries a small risk of renal medullary carcinoma (RMC). We conducted a systematic literature review and reported new four RMC cases (total N ¼ 217). Eighty eight percent had SCT and 8% had sickle cell disease; 50% were children. Males had 2.4 risk than females. Isolated hematuria or in combination with abdominal or flank pain was the presenting sign in 66% cases.
3 MD,
and Sharada Sarnaik, MD4
Tumor-related mortality was 95%. Four non-metastatic patients were long-term disease-free survivors. Although risk appears to be very low, individuals with SCT should be informed about the low risk of RMC with the hope of early diagnosis. Hematuria should prompt immediate investigation. Pediatr Blood Cancer 2015;62:1694–1699. © 2015 Wiley Periodicals, Inc.
Key words: cancer; rare tumors; renal; sickle cell disease; sickle cell trait; tumors
INTRODUCTION Sickle cell trait (SCT) affects about 300 million people worldwide.[1] It is estimated that there are 3.4 million carriers of hemoglobin S in the United States. The prevalence of the carrier state is one in 12 (8%) among African-Americans, who are 41.7 million according to estimated population in 2013.[2] Currently, the presence of heterozygosity for hemoglobin S or SCT is identified at birth in the United States and in many other countries, thanks to the implementation of newborn screening performed to detect sickle cell disease. Although it is thought to be a “benign” condition, there are several complications associated with SCT, including splenic infarction, kidney dysfunction, and sudden death associated with exercise-induced rhabdomyolysis, especially in the setting of extreme heat, exertion, and dehydration.[1,3] The kidneys promote sickling not only in individuals with sickle cell disease, but also in individuals with SCT. The renal medullary environment has partial oxygen pressure of 35–40 mm Hg, which is below the threshold for sickling (45 mm Hg).[4] A hyperosmolar environment draws water from erythrocytes so that intracellular hemoglobin S concentration increases, thus promoting hemoglobin S polymerization. Furthermore, an environment with acid pH promotes sickling.[5] Therefore, it is not surprising that there are pathologic findings from the chronic sickling process, including hyposthenuria,[1] infarction,[1,6] and hematuria[7,8] from papillary necrosis. Both individuals with sickle cell disease and SCT can develop gross and painless hematuria, which is usually unilateral and originates commonly in the left kidney, probably from increased venous pressure in the longer left renal vein.[6,9] Additionally, African-Americans with SCT have two times the prevalence of end-stage renal disease (ESRD) than individuals without this trait (15% prevalence compared to 7%, respectively). [10] Individuals with autosomal-dominant polycystic kidney disease who have SCT also develop ESRD at an earlier age than those without SCT.[7] Another kidney complication of SCT is renal medullary carcinoma (RMC), which was first described in 1995 by Davis; [11] this malignant neoplasm occurs almost exclusively in young individuals with sickle cell trait. RMC arises from the calyceal epithelium of the renal pelvis or near the renal papillae, which are specific locations within the kidney where sickling is more pronounced. However, it is unknown why sickling does not seem to promote cancer in other organs, such as the spleen where significant infarcts occur, or why RMC is rare. C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25592 Published online 5 June 2015 in Wiley Online Library (wileyonlinelibrary.com).
Although there are many reports of cases of RMC and SCT, a systematic review of this subject has not been performed. This systematic review aims to: (i) investigate the literature regarding prevalence, clinical presentation, management, and outcomes and (ii) discuss what implications of these findings are for individuals with SCT.
METHODS This investigation was not considered human research by the University of Miami and the Wayne State University School of Medicine Institutional Review Boards. Pub Med was searched for RMC, RMC and sickle cell trait, RMC and sickle cell disease, hematuria, and SCT; the search included all publications published between 1995 and 2014. The last day of search was August 1, 2014. The rationale to begin in 1995 is that this was the year when RMC was first described. In order to gather clinical data and outcomes, all published cases of RMC were included in the review protocol, regardless of whether the tumor occurred in individuals with hemoglobinopathies or not. Summaries, articles which did not report individual cases, and duplicate cases were excluded. Articles were read by one of the authors (OA), who extracted and collected data into Excel format for analysis. Four new cases were reported from Jackson Memorial Hospital in Miami and Children’s Hospital of Michigan. All authors shared the Excel file and were able to verify the accuracy of the information, by going back to manuscript sources. Descriptive statistics (frequencies, mean, and standard deviations) were used for the demographic and clinical data from all the reported cases. The Additional supporting information may be found in the online version of this article. 1
Division of Pediatric Hematology-Oncology, University of Miami, Miami, Florida; 2Division of Pediatric Pathology, University of Miami, Miami, Florida; 3Department of Public Health Sciences, University of Miami, Miami, Florida; 4Division of Pediatric Hematology-Oncology, Children’s Hospital of Michigan, Detroit, Michigan Grant sponsor: University of Miami Conflict of interest: Nothing to declare Correspondence to: Ofelia Alvarez, Division of Pediatric HematologyOncology, University of Miami, 1601 NW 12th Avenue, Mailman Center for Child Development, Room 5048, Miami, FL 33136. E-mail: [email protected]
Received 27 May 2014; Accepted 3 April 2015
Renal Medullary Carcinoma following data were extracted and analyzed from the literature: age in years, gender, hemoglobinopathy status, symptoms at presentation, kidney tumor laterality, primary tumor diameter, metastatic sites, treatment received, survival status, and survival time.
RESULTS Review of Renal Medullary Carcinoma Beginning in 1995, 64 articles[11–74] have been published in the world medical literature describing cases of RMC for a total of 213 cases. There are now 217 including our four cases summarized on Table I. Two of our cases had diagnosis of either SCT or sickle cell anemia, and two did not. Supplemental Figure 1 shows the PRISMA flow diagram of the articles included in this review. Eighteen articles were series of three cases or more (3–40).[11–28] Davis described the initial series of 34 patients.[11] Swartz et al. reviewed 40 cases from the files of the National Wilms’ Tumor Study Group Pathology Center between the years 1973 and 1998. [12] The rest were isolated single cases or two-case reports.[29–74] Four references appeared to have included the same patients; [16,19,57,69] thus these patients were counted once. There are no randomized controlled trials reported.
1695
Clinical Presentation and Diagnostic Evaluation RMC cases were young with a mean age of 24.3 23.6 years (median 22, range 5–69 years) at presentation; 96% of the cases were younger than 40 years of age. Fifty percent were children (21 years or younger). Male gender was predominant (151 males and 62 females; four unknown gender) with a male to female ratio of 2.4:1. Table II presents the hemoglobin genotypes from the known cases (N ¼ 176). Eighty eight percent of the cases occurred in people with SCT. Table III presents the signs and symptoms at the time of diagnosis. Contrary to the most common location for benign hematuria (left kidney), 70% of the tumors arose in the right kidney. Sixty six percent of the patients presented with either hematuria or abdominal or flank pain or a combination of hematuria and pain, occasionally associated with weight loss (16%). Frequently, hematuria was present for weeks or months prior to diagnosis. The primary tumor diameter at diagnosis was available for 90 tumors; mean diameter 6.8 3.0 cm (range 1.1–15 cm). Most cases had tumors measuring 4 cm or larger, with only nine cases being smaller. Many tumors had local lymphatic node involvement and extension to peri-renal soft tissue. Metastatic disease occurred very frequently, and the sites of metastasis were described in 158
TABLE I. New Reported Cases of Renal Medullary Carcinoma Age (Years) Gender
Hb type
24
M
AS
13
F
17
F
Beta Incidental ultrasound thal finding of mass in trait the upper pole of the left kidney. Ultrasound was obtained for enuresis work-up SS LUQ mass, microscopic hematuria
14
F
NA
Clinical presentation Abdominal pain and mass, dyspnea
Abdominal pain, nausea, and vomiting for 2 months
Metastatic Kidney Size sites laterality (cm)
Treatment
Follow-up (weeks)
Outcome
Lungs, adrenal, BM, lymph nodes, opposite kidney None
Right
4.5
None
4 weeks
Died from disease
Left
REVIEW Renal Medullary Carcinoma and Sickle Cell Trait: A Systematic Review Ofelia Alvarez, MD,1* Maria M. Rodriguez, MD,2 Lanetta Jordan, Sickle cell trait (SCT) carries a small risk of renal medullary carcinoma (RMC). We conducted a systematic literature review and reported new four RMC cases (total N ¼ 217). Eighty eight percent had SCT and 8% had sickle cell disease; 50% were children. Males had 2.4 risk than females. Isolated hematuria or in combination with abdominal or flank pain was the presenting sign in 66% cases.
3 MD,
and Sharada Sarnaik, MD4
Tumor-related mortality was 95%. Four non-metastatic patients were long-term disease-free survivors. Although risk appears to be very low, individuals with SCT should be informed about the low risk of RMC with the hope of early diagnosis. Hematuria should prompt immediate investigation. Pediatr Blood Cancer 2015;62:1694–1699. © 2015 Wiley Periodicals, Inc.
Key words: cancer; rare tumors; renal; sickle cell disease; sickle cell trait; tumors
INTRODUCTION Sickle cell trait (SCT) affects about 300 million people worldwide.[1] It is estimated that there are 3.4 million carriers of hemoglobin S in the United States. The prevalence of the carrier state is one in 12 (8%) among African-Americans, who are 41.7 million according to estimated population in 2013.[2] Currently, the presence of heterozygosity for hemoglobin S or SCT is identified at birth in the United States and in many other countries, thanks to the implementation of newborn screening performed to detect sickle cell disease. Although it is thought to be a “benign” condition, there are several complications associated with SCT, including splenic infarction, kidney dysfunction, and sudden death associated with exercise-induced rhabdomyolysis, especially in the setting of extreme heat, exertion, and dehydration.[1,3] The kidneys promote sickling not only in individuals with sickle cell disease, but also in individuals with SCT. The renal medullary environment has partial oxygen pressure of 35–40 mm Hg, which is below the threshold for sickling (45 mm Hg).[4] A hyperosmolar environment draws water from erythrocytes so that intracellular hemoglobin S concentration increases, thus promoting hemoglobin S polymerization. Furthermore, an environment with acid pH promotes sickling.[5] Therefore, it is not surprising that there are pathologic findings from the chronic sickling process, including hyposthenuria,[1] infarction,[1,6] and hematuria[7,8] from papillary necrosis. Both individuals with sickle cell disease and SCT can develop gross and painless hematuria, which is usually unilateral and originates commonly in the left kidney, probably from increased venous pressure in the longer left renal vein.[6,9] Additionally, African-Americans with SCT have two times the prevalence of end-stage renal disease (ESRD) than individuals without this trait (15% prevalence compared to 7%, respectively). [10] Individuals with autosomal-dominant polycystic kidney disease who have SCT also develop ESRD at an earlier age than those without SCT.[7] Another kidney complication of SCT is renal medullary carcinoma (RMC), which was first described in 1995 by Davis; [11] this malignant neoplasm occurs almost exclusively in young individuals with sickle cell trait. RMC arises from the calyceal epithelium of the renal pelvis or near the renal papillae, which are specific locations within the kidney where sickling is more pronounced. However, it is unknown why sickling does not seem to promote cancer in other organs, such as the spleen where significant infarcts occur, or why RMC is rare. C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25592 Published online 5 June 2015 in Wiley Online Library (wileyonlinelibrary.com).
Although there are many reports of cases of RMC and SCT, a systematic review of this subject has not been performed. This systematic review aims to: (i) investigate the literature regarding prevalence, clinical presentation, management, and outcomes and (ii) discuss what implications of these findings are for individuals with SCT.
METHODS This investigation was not considered human research by the University of Miami and the Wayne State University School of Medicine Institutional Review Boards. Pub Med was searched for RMC, RMC and sickle cell trait, RMC and sickle cell disease, hematuria, and SCT; the search included all publications published between 1995 and 2014. The last day of search was August 1, 2014. The rationale to begin in 1995 is that this was the year when RMC was first described. In order to gather clinical data and outcomes, all published cases of RMC were included in the review protocol, regardless of whether the tumor occurred in individuals with hemoglobinopathies or not. Summaries, articles which did not report individual cases, and duplicate cases were excluded. Articles were read by one of the authors (OA), who extracted and collected data into Excel format for analysis. Four new cases were reported from Jackson Memorial Hospital in Miami and Children’s Hospital of Michigan. All authors shared the Excel file and were able to verify the accuracy of the information, by going back to manuscript sources. Descriptive statistics (frequencies, mean, and standard deviations) were used for the demographic and clinical data from all the reported cases. The Additional supporting information may be found in the online version of this article. 1
Division of Pediatric Hematology-Oncology, University of Miami, Miami, Florida; 2Division of Pediatric Pathology, University of Miami, Miami, Florida; 3Department of Public Health Sciences, University of Miami, Miami, Florida; 4Division of Pediatric Hematology-Oncology, Children’s Hospital of Michigan, Detroit, Michigan Grant sponsor: University of Miami Conflict of interest: Nothing to declare Correspondence to: Ofelia Alvarez, Division of Pediatric HematologyOncology, University of Miami, 1601 NW 12th Avenue, Mailman Center for Child Development, Room 5048, Miami, FL 33136. E-mail: [email protected]
Received 27 May 2014; Accepted 3 April 2015
Renal Medullary Carcinoma following data were extracted and analyzed from the literature: age in years, gender, hemoglobinopathy status, symptoms at presentation, kidney tumor laterality, primary tumor diameter, metastatic sites, treatment received, survival status, and survival time.
RESULTS Review of Renal Medullary Carcinoma Beginning in 1995, 64 articles[11–74] have been published in the world medical literature describing cases of RMC for a total of 213 cases. There are now 217 including our four cases summarized on Table I. Two of our cases had diagnosis of either SCT or sickle cell anemia, and two did not. Supplemental Figure 1 shows the PRISMA flow diagram of the articles included in this review. Eighteen articles were series of three cases or more (3–40).[11–28] Davis described the initial series of 34 patients.[11] Swartz et al. reviewed 40 cases from the files of the National Wilms’ Tumor Study Group Pathology Center between the years 1973 and 1998. [12] The rest were isolated single cases or two-case reports.[29–74] Four references appeared to have included the same patients; [16,19,57,69] thus these patients were counted once. There are no randomized controlled trials reported.
1695
Clinical Presentation and Diagnostic Evaluation RMC cases were young with a mean age of 24.3 23.6 years (median 22, range 5–69 years) at presentation; 96% of the cases were younger than 40 years of age. Fifty percent were children (21 years or younger). Male gender was predominant (151 males and 62 females; four unknown gender) with a male to female ratio of 2.4:1. Table II presents the hemoglobin genotypes from the known cases (N ¼ 176). Eighty eight percent of the cases occurred in people with SCT. Table III presents the signs and symptoms at the time of diagnosis. Contrary to the most common location for benign hematuria (left kidney), 70% of the tumors arose in the right kidney. Sixty six percent of the patients presented with either hematuria or abdominal or flank pain or a combination of hematuria and pain, occasionally associated with weight loss (16%). Frequently, hematuria was present for weeks or months prior to diagnosis. The primary tumor diameter at diagnosis was available for 90 tumors; mean diameter 6.8 3.0 cm (range 1.1–15 cm). Most cases had tumors measuring 4 cm or larger, with only nine cases being smaller. Many tumors had local lymphatic node involvement and extension to peri-renal soft tissue. Metastatic disease occurred very frequently, and the sites of metastasis were described in 158
TABLE I. New Reported Cases of Renal Medullary Carcinoma Age (Years) Gender
Hb type
24
M
AS
13
F
17
F
Beta Incidental ultrasound thal finding of mass in trait the upper pole of the left kidney. Ultrasound was obtained for enuresis work-up SS LUQ mass, microscopic hematuria
14
F
NA
Clinical presentation Abdominal pain and mass, dyspnea
Abdominal pain, nausea, and vomiting for 2 months
Metastatic Kidney Size sites laterality (cm)
Treatment
Follow-up (weeks)
Outcome
Lungs, adrenal, BM, lymph nodes, opposite kidney None
Right
4.5
None
4 weeks
Died from disease
Left
