ATLANTA – Among patients with relapsing-remitting multiple sclerosis, higher body mass index, but not vitamin D status, appears to be related to greater loss of gray matter brain volume over time, results from a 5-year analysis showed.

“We had previously known that obesity is a risk factor for developing MS, and among those who already have the disease, obesity-related comorbidities are associated with increased morbidity and mortality,” lead study author Ellen M. Mowry, MD, said in an interview at the annual meeting of the American Neurological Association. “Loss of brain tissue, especially as measured by reduced volume of gray matter noted on brain MRI, is predictive of long-term disability in MS. While we await the results of confirmatory studies and randomized trials, this study adds to the growing body of evidence suggesting there may be a role for modification of lifestyle factors in mitigating longer-term MS-related disability risk.”

In an effort to determine if body mass index (BMI) or vitamin D status is associated with longer-term MRI measures of neurodegeneration, Dr. Mowry and her colleagues drew from 469 patients participating in a longitudinal MS cohort study at the University of California, San Francisco, known as EPIC. Participants had clinical evaluations, brain MRI, and blood draws annually and were followed for 5 years. The main outcomes of interest were BMI and serum 25-hydroxyvitamin D levels measured over the time period, and their relationship to brain volume.


At baseline, the mean age of patients was 42 years, 70% were female, their mean BMI was 25 kg/m², and their mean serum vitamin D level was 27.8 ng/mL. Dr. Mowry, a neurologist at Johns Hopkins University, Baltimore, and her colleagues found that over time, each 1-kg/m² higher BMI was independently associated with reduced gray matter in multivariate models (–1.1 mL; P = .001). In addition, each 1-kg/m² higher BMI over time was independently associated with greater declines in normalized brain parenchymal brain volume (–1.1 mL; P = .039). Elevated vitamin D levels, however, did not appear to be meaningfully associated with brain volumes.

Dr. Mowry acknowledged certain limitations of the study, including its nonrandomized design. “Such a trial may be warranted but I believe will be challenging to conduct,” she said. “Also, this cohort was designed to assess the association of genes with brain MRI outcomes, and so the people included were racially homogeneous – only Caucasians were included. Since MS risk is especially high among African Americans in recent years, and African Americans appear overall to have a higher risk of long-term disability, it is important to evaluate these and other prognostic factors amongst a more representative group of people with MS.”

The study received funding support from the National Institutes of Health, GlaxoSmithKline, and Biogen. Dr. Mowry disclosed that she has received medication from Teva for use in a clinical trial. In addition, she has been the primary investigator for studies sponsored by Biogen and Sun Pharma, and has conducted investigator-initiated studies sponsored by Genzyme and Biogen.

[email protected]

SOURCE: Ann Neurol. 2018;84[S22]:S206-7. Abstract M250.

ATLANTA – Among patients with relapsing-remitting multiple sclerosis, higher body mass index, but not vitamin D status, appears to be related to greater loss of gray matter brain volume over time, results from a 5-year analysis showed.

“We had previously known that obesity is a risk factor for developing MS, and among those who already have the disease, obesity-related comorbidities are associated with increased morbidity and mortality,” lead study author Ellen M. Mowry, MD, said in an interview at the annual meeting of the American Neurological Association. “Loss of brain tissue, especially as measured by reduced volume of gray matter noted on brain MRI, is predictive of long-term disability in MS. While we await the results of confirmatory studies and randomized trials, this study adds to the growing body of evidence suggesting there may be a role for modification of lifestyle factors in mitigating longer-term MS-related disability risk.”

In an effort to determine if body mass index (BMI) or vitamin D status is associated with longer-term MRI measures of neurodegeneration, Dr. Mowry and her colleagues drew from 469 patients participating in a longitudinal MS cohort study at the University of California, San Francisco, known as EPIC. Participants had clinical evaluations, brain MRI, and blood draws annually and were followed for 5 years. The main outcomes of interest were BMI and serum 25-hydroxyvitamin D levels measured over the time period, and their relationship to brain volume.


At baseline, the mean age of patients was 42 years, 70% were female, their mean BMI was 25 kg/m², and their mean serum vitamin D level was 27.8 ng/mL. Dr. Mowry, a neurologist at Johns Hopkins University, Baltimore, and her colleagues found that over time, each 1-kg/m² higher BMI was independently associated with reduced gray matter in multivariate models (–1.1 mL; P = .001). In addition, each 1-kg/m² higher BMI over time was independently associated with greater declines in normalized brain parenchymal brain volume (–1.1 mL; P = .039). Elevated vitamin D levels, however, did not appear to be meaningfully associated with brain volumes.

Dr. Mowry acknowledged certain limitations of the study, including its nonrandomized design. “Such a trial may be warranted but I believe will be challenging to conduct,” she said. “Also, this cohort was designed to assess the association of genes with brain MRI outcomes, and so the people included were racially homogeneous – only Caucasians were included. Since MS risk is especially high among African Americans in recent years, and African Americans appear overall to have a higher risk of long-term disability, it is important to evaluate these and other prognostic factors amongst a more representative group of people with MS.”

The study received funding support from the National Institutes of Health, GlaxoSmithKline, and Biogen. Dr. Mowry disclosed that she has received medication from Teva for use in a clinical trial. In addition, she has been the primary investigator for studies sponsored by Biogen and Sun Pharma, and has conducted investigator-initiated studies sponsored by Genzyme and Biogen.

[email protected]

SOURCE: Ann Neurol. 2018;84[S22]:S206-7. Abstract M250.

ATLANTA – Among patients with relapsing-remitting multiple sclerosis, higher body mass index, but not vitamin D status, appears to be related to greater loss of gray matter brain volume over time, results from a 5-year analysis showed.

“We had previously known that obesity is a risk factor for developing MS, and among those who already have the disease, obesity-related comorbidities are associated with increased morbidity and mortality,” lead study author Ellen M. Mowry, MD, said in an interview at the annual meeting of the American Neurological Association. “Loss of brain tissue, especially as measured by reduced volume of gray matter noted on brain MRI, is predictive of long-term disability in MS. While we await the results of confirmatory studies and randomized trials, this study adds to the growing body of evidence suggesting there may be a role for modification of lifestyle factors in mitigating longer-term MS-related disability risk.”

In an effort to determine if body mass index (BMI) or vitamin D status is associated with longer-term MRI measures of neurodegeneration, Dr. Mowry and her colleagues drew from 469 patients participating in a longitudinal MS cohort study at the University of California, San Francisco, known as EPIC. Participants had clinical evaluations, brain MRI, and blood draws annually and were followed for 5 years. The main outcomes of interest were BMI and serum 25-hydroxyvitamin D levels measured over the time period, and their relationship to brain volume.


At baseline, the mean age of patients was 42 years, 70% were female, their mean BMI was 25 kg/m², and their mean serum vitamin D level was 27.8 ng/mL. Dr. Mowry, a neurologist at Johns Hopkins University, Baltimore, and her colleagues found that over time, each 1-kg/m² higher BMI was independently associated with reduced gray matter in multivariate models (–1.1 mL; P = .001). In addition, each 1-kg/m² higher BMI over time was independently associated with greater declines in normalized brain parenchymal brain volume (–1.1 mL; P = .039). Elevated vitamin D levels, however, did not appear to be meaningfully associated with brain volumes.

Dr. Mowry acknowledged certain limitations of the study, including its nonrandomized design. “Such a trial may be warranted but I believe will be challenging to conduct,” she said. “Also, this cohort was designed to assess the association of genes with brain MRI outcomes, and so the people included were racially homogeneous – only Caucasians were included. Since MS risk is especially high among African Americans in recent years, and African Americans appear overall to have a higher risk of long-term disability, it is important to evaluate these and other prognostic factors amongst a more representative group of people with MS.”

The study received funding support from the National Institutes of Health, GlaxoSmithKline, and Biogen. Dr. Mowry disclosed that she has received medication from Teva for use in a clinical trial. In addition, she has been the primary investigator for studies sponsored by Biogen and Sun Pharma, and has conducted investigator-initiated studies sponsored by Genzyme and Biogen.

[email protected]

SOURCE: Ann Neurol. 2018;84[S22]:S206-7. Abstract M250.

Short interpregnancy intervals carry an increased risk of adverse pregnancy outcomes for women of all ages and increased adverse fetal and infant outcome risks for women between 20 and 34 years old, according to research published in JAMA Internal Medicine.

“This finding may be reassuring particularly for older women who must weigh the competing risks of increasing maternal age with longer interpregnancy intervals (including infertility and chromosomal anomalies) against the risks of short interpregnancy intervals,” wrote Laura Schummers, SD, of the department of epidemiology at Harvard T. H. Chan School of Public Health, Boston, and her colleagues.

The researchers examined 148,544 pregnancies of women in British Columbia who were younger than 20 years old at the index (5%), 20-34 years at the index birth (83%), and 35 years or older (12%). The women had two or more consecutive singleton pregnancies that resulted in a live birth between 2004 and 2014 and were recorded in the British Columbia Perinatal Data Registry. There was a lower number of short interpregnancy intervals, defined as less than 6 months between the index and second pregnancy, among women in the 35-years-or-older group, compared with the 20- to 34-year-old group (4.4% vs. 5.5%); the 35-years-or-older group instead had a higher number of interpregnancy intervals between 6 and 11 months and between 12 and 17 months, compared with the 20- to 34-year-old group (17.7% vs. 16.6%, and 25.2% vs. 22.5%, respectively).

The risk for maternal mortality or severe morbidity was higher in women who were a minimum 35 years old with 6 months between pregnancies (0.62%), compared with women who had 18 months (0.26%) between pregnancies (adjusted relative risk [aRR], 2.39). There was no significant increase in those aged between 20 and 34 years at 6 months, compared with 18 months (0.23% vs. 0.25%; aRR, 0.92). However, the 20- to 34-year-old group did have an increased risk of fetal and infant adverse outcomes at 6 months, compared with 18 months (2.0% vs. 1.4%; aRR, 1.42) and compared with women in the 35-years-or-older group at 6 months and 18 months (2.1% vs. 1.8%; aRR, 1.15).

There was a 5.3% increased risk at 6 months and a 3.2% increased risk at 18 months of spontaneous preterm delivery in the 20- to 34-year-old group (aRR, 1.65), compared with a 5.0% risk at 6 months and 3.6% at 18 months in the 35-years-or-older group (aRR, 1.40). The researchers noted “modest increases” in newborns who were born small for their gestational age and indicated preterm delivery at short intervals that did not differ by age group.

The authors reported no conflicts of interest. Dr Schummers was supported a National Research Service Award from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and received a grant from the Canadian Institutes for Health Research and the Public Health Agency of Canada Family Planning Public Health Chair Seed Grant. Two of her coauthors were supported by various other awards.

SOURCE: Schummers L et al. JAMA Intern Med. 2018 Oct 29. doi: 10.1001/jamainternmed.2018.4696.

Short interpregnancy intervals carry an increased risk of adverse pregnancy outcomes for women of all ages and increased adverse fetal and infant outcome risks for women between 20 and 34 years old, according to research published in JAMA Internal Medicine.

“This finding may be reassuring particularly for older women who must weigh the competing risks of increasing maternal age with longer interpregnancy intervals (including infertility and chromosomal anomalies) against the risks of short interpregnancy intervals,” wrote Laura Schummers, SD, of the department of epidemiology at Harvard T. H. Chan School of Public Health, Boston, and her colleagues.

The researchers examined 148,544 pregnancies of women in British Columbia who were younger than 20 years old at the index (5%), 20-34 years at the index birth (83%), and 35 years or older (12%). The women had two or more consecutive singleton pregnancies that resulted in a live birth between 2004 and 2014 and were recorded in the British Columbia Perinatal Data Registry. There was a lower number of short interpregnancy intervals, defined as less than 6 months between the index and second pregnancy, among women in the 35-years-or-older group, compared with the 20- to 34-year-old group (4.4% vs. 5.5%); the 35-years-or-older group instead had a higher number of interpregnancy intervals between 6 and 11 months and between 12 and 17 months, compared with the 20- to 34-year-old group (17.7% vs. 16.6%, and 25.2% vs. 22.5%, respectively).

The risk for maternal mortality or severe morbidity was higher in women who were a minimum 35 years old with 6 months between pregnancies (0.62%), compared with women who had 18 months (0.26%) between pregnancies (adjusted relative risk [aRR], 2.39). There was no significant increase in those aged between 20 and 34 years at 6 months, compared with 18 months (0.23% vs. 0.25%; aRR, 0.92). However, the 20- to 34-year-old group did have an increased risk of fetal and infant adverse outcomes at 6 months, compared with 18 months (2.0% vs. 1.4%; aRR, 1.42) and compared with women in the 35-years-or-older group at 6 months and 18 months (2.1% vs. 1.8%; aRR, 1.15).

There was a 5.3% increased risk at 6 months and a 3.2% increased risk at 18 months of spontaneous preterm delivery in the 20- to 34-year-old group (aRR, 1.65), compared with a 5.0% risk at 6 months and 3.6% at 18 months in the 35-years-or-older group (aRR, 1.40). The researchers noted “modest increases” in newborns who were born small for their gestational age and indicated preterm delivery at short intervals that did not differ by age group.

The authors reported no conflicts of interest. Dr Schummers was supported a National Research Service Award from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and received a grant from the Canadian Institutes for Health Research and the Public Health Agency of Canada Family Planning Public Health Chair Seed Grant. Two of her coauthors were supported by various other awards.

SOURCE: Schummers L et al. JAMA Intern Med. 2018 Oct 29. doi: 10.1001/jamainternmed.2018.4696.

Short interpregnancy intervals carry an increased risk of adverse pregnancy outcomes for women of all ages and increased adverse fetal and infant outcome risks for women between 20 and 34 years old, according to research published in JAMA Internal Medicine.

“This finding may be reassuring particularly for older women who must weigh the competing risks of increasing maternal age with longer interpregnancy intervals (including infertility and chromosomal anomalies) against the risks of short interpregnancy intervals,” wrote Laura Schummers, SD, of the department of epidemiology at Harvard T. H. Chan School of Public Health, Boston, and her colleagues.

The researchers examined 148,544 pregnancies of women in British Columbia who were younger than 20 years old at the index (5%), 20-34 years at the index birth (83%), and 35 years or older (12%). The women had two or more consecutive singleton pregnancies that resulted in a live birth between 2004 and 2014 and were recorded in the British Columbia Perinatal Data Registry. There was a lower number of short interpregnancy intervals, defined as less than 6 months between the index and second pregnancy, among women in the 35-years-or-older group, compared with the 20- to 34-year-old group (4.4% vs. 5.5%); the 35-years-or-older group instead had a higher number of interpregnancy intervals between 6 and 11 months and between 12 and 17 months, compared with the 20- to 34-year-old group (17.7% vs. 16.6%, and 25.2% vs. 22.5%, respectively).

The risk for maternal mortality or severe morbidity was higher in women who were a minimum 35 years old with 6 months between pregnancies (0.62%), compared with women who had 18 months (0.26%) between pregnancies (adjusted relative risk [aRR], 2.39). There was no significant increase in those aged between 20 and 34 years at 6 months, compared with 18 months (0.23% vs. 0.25%; aRR, 0.92). However, the 20- to 34-year-old group did have an increased risk of fetal and infant adverse outcomes at 6 months, compared with 18 months (2.0% vs. 1.4%; aRR, 1.42) and compared with women in the 35-years-or-older group at 6 months and 18 months (2.1% vs. 1.8%; aRR, 1.15).

There was a 5.3% increased risk at 6 months and a 3.2% increased risk at 18 months of spontaneous preterm delivery in the 20- to 34-year-old group (aRR, 1.65), compared with a 5.0% risk at 6 months and 3.6% at 18 months in the 35-years-or-older group (aRR, 1.40). The researchers noted “modest increases” in newborns who were born small for their gestational age and indicated preterm delivery at short intervals that did not differ by age group.

The authors reported no conflicts of interest. Dr Schummers was supported a National Research Service Award from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and received a grant from the Canadian Institutes for Health Research and the Public Health Agency of Canada Family Planning Public Health Chair Seed Grant. Two of her coauthors were supported by various other awards.

SOURCE: Schummers L et al. JAMA Intern Med. 2018 Oct 29. doi: 10.1001/jamainternmed.2018.4696.

The concept that cell transplantation is the answer to the treatment of heart failure may have suffered a major setback as a result of a research scam perpetrated at Harvard University’s Brigham and Women’s Hospital in Boston.

The fraudulent cardiac research at that institution was from the lab of Piero Anversa, MD, which falsified or fabricated data. Dr. Anversa was one of the leaders in pursuing the concept that adult cardiomyocytes can not only regenerate by cell division but can also be transplanted from one animal to another, in his case a mouse.

The original reports over a decade ago caused a major stir in heart failure research. They also were met with considerable skepticism in the research field and have not been reproduced in other laboratories. Numerous small trials in humans have been unsuccessful in demonstrating the survival of autologous cells transplanted in both animal and humans. Dr. Anversa’s research has been under scrutiny by Harvard and Brigham and Women’s since 2013, ultimately resulting in the call to retract 31 published studies in mid-October. In the meantime, admission of fraud in regard to the original Anversa papers resulted in a fine of $10 million paid by the institutions to the National Institutes of Health in a 2017 settlement. Dr. Anversa left Harvard in 2015.

Nevertheless Dr. Anversa’s concepts led to the initiation of an NIH-supported multicenter trial in humans of the implantation of autologous bone marrow cells using endocardial devices to transplant cells in 144 patients with heart failure. The Combination of Autologous Bone Marrow Derived Mesenchymal and C-Kit+ Cardiac Stem Cells as Regenerative Therapy for Heart Failure (CONCERT-HF) was started in 2015 and was still recruiting until Oct. 29, when the National Heart, Lung, and Blood Institute announced that a pause in recruitment was called in order to review the fraudulent data that led to the trial’s initiation. Patients were to be followed over a 1-year period using delayed-enhanced magnetic resonance imaging (DEMRI) scans to assess scar size and left ventricular function and structure at baseline and at 6 and 12 months post study product ad-ministration. For the purpose of the endpoint analysis and safety evaluations, the investigators planned to use an intention-to-treat study population evaluating a number of clinical parameters.

Anatomists and physiologists have long been of the opinion that adult human and mammalian cardiomyocytes are terminally differentiated and do not undergo cell division. However, over time, cardiomyocytes can undergo hypertrophy as a result of increased workload. Cells can die as a result of ischemia, infarction, or stress mediated through unchecked inflammatory processes. It also has been shown that cells can die as a result of apoptosis, particularly in areas in proximity to myocardial scars. It is generally believed that these three methods of cell depletion contribute to the progression of heart failure. Dr. Anversa also proposed that there is some degree of replication of cardiomyocytes but not to a degree that can have a meaningful replacement value.

The concept of cell transplantation in medicine certainly has been in the forefront of clinical research in medicine for the last decade based in part on research by Dr. Anversa and others in cardiology and numerous investigators in other medical disciplines. With few exceptions, there has been little support for the clinical benefit of these clinical studies. We are unfortunately now faced with the release of the tainted fraudulent research that led to CONCERT-HF. Whether there is anything of scientific value to come of the trial is highly unlikely.
 

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

This article was updated Oct. 30, 2018.

The concept that cell transplantation is the answer to the treatment of heart failure may have suffered a major setback as a result of a research scam perpetrated at Harvard University’s Brigham and Women’s Hospital in Boston.

The fraudulent cardiac research at that institution was from the lab of Piero Anversa, MD, which falsified or fabricated data. Dr. Anversa was one of the leaders in pursuing the concept that adult cardiomyocytes can not only regenerate by cell division but can also be transplanted from one animal to another, in his case a mouse.

The original reports over a decade ago caused a major stir in heart failure research. They also were met with considerable skepticism in the research field and have not been reproduced in other laboratories. Numerous small trials in humans have been unsuccessful in demonstrating the survival of autologous cells transplanted in both animal and humans. Dr. Anversa’s research has been under scrutiny by Harvard and Brigham and Women’s since 2013, ultimately resulting in the call to retract 31 published studies in mid-October. In the meantime, admission of fraud in regard to the original Anversa papers resulted in a fine of $10 million paid by the institutions to the National Institutes of Health in a 2017 settlement. Dr. Anversa left Harvard in 2015.

Nevertheless Dr. Anversa’s concepts led to the initiation of an NIH-supported multicenter trial in humans of the implantation of autologous bone marrow cells using endocardial devices to transplant cells in 144 patients with heart failure. The Combination of Autologous Bone Marrow Derived Mesenchymal and C-Kit+ Cardiac Stem Cells as Regenerative Therapy for Heart Failure (CONCERT-HF) was started in 2015 and was still recruiting until Oct. 29, when the National Heart, Lung, and Blood Institute announced that a pause in recruitment was called in order to review the fraudulent data that led to the trial’s initiation. Patients were to be followed over a 1-year period using delayed-enhanced magnetic resonance imaging (DEMRI) scans to assess scar size and left ventricular function and structure at baseline and at 6 and 12 months post study product ad-ministration. For the purpose of the endpoint analysis and safety evaluations, the investigators planned to use an intention-to-treat study population evaluating a number of clinical parameters.

Anatomists and physiologists have long been of the opinion that adult human and mammalian cardiomyocytes are terminally differentiated and do not undergo cell division. However, over time, cardiomyocytes can undergo hypertrophy as a result of increased workload. Cells can die as a result of ischemia, infarction, or stress mediated through unchecked inflammatory processes. It also has been shown that cells can die as a result of apoptosis, particularly in areas in proximity to myocardial scars. It is generally believed that these three methods of cell depletion contribute to the progression of heart failure. Dr. Anversa also proposed that there is some degree of replication of cardiomyocytes but not to a degree that can have a meaningful replacement value.

The concept of cell transplantation in medicine certainly has been in the forefront of clinical research in medicine for the last decade based in part on research by Dr. Anversa and others in cardiology and numerous investigators in other medical disciplines. With few exceptions, there has been little support for the clinical benefit of these clinical studies. We are unfortunately now faced with the release of the tainted fraudulent research that led to CONCERT-HF. Whether there is anything of scientific value to come of the trial is highly unlikely.
 

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

This article was updated Oct. 30, 2018.

The concept that cell transplantation is the answer to the treatment of heart failure may have suffered a major setback as a result of a research scam perpetrated at Harvard University’s Brigham and Women’s Hospital in Boston.

The fraudulent cardiac research at that institution was from the lab of Piero Anversa, MD, which falsified or fabricated data. Dr. Anversa was one of the leaders in pursuing the concept that adult cardiomyocytes can not only regenerate by cell division but can also be transplanted from one animal to another, in his case a mouse.

The original reports over a decade ago caused a major stir in heart failure research. They also were met with considerable skepticism in the research field and have not been reproduced in other laboratories. Numerous small trials in humans have been unsuccessful in demonstrating the survival of autologous cells transplanted in both animal and humans. Dr. Anversa’s research has been under scrutiny by Harvard and Brigham and Women’s since 2013, ultimately resulting in the call to retract 31 published studies in mid-October. In the meantime, admission of fraud in regard to the original Anversa papers resulted in a fine of $10 million paid by the institutions to the National Institutes of Health in a 2017 settlement. Dr. Anversa left Harvard in 2015.

Nevertheless Dr. Anversa’s concepts led to the initiation of an NIH-supported multicenter trial in humans of the implantation of autologous bone marrow cells using endocardial devices to transplant cells in 144 patients with heart failure. The Combination of Autologous Bone Marrow Derived Mesenchymal and C-Kit+ Cardiac Stem Cells as Regenerative Therapy for Heart Failure (CONCERT-HF) was started in 2015 and was still recruiting until Oct. 29, when the National Heart, Lung, and Blood Institute announced that a pause in recruitment was called in order to review the fraudulent data that led to the trial’s initiation. Patients were to be followed over a 1-year period using delayed-enhanced magnetic resonance imaging (DEMRI) scans to assess scar size and left ventricular function and structure at baseline and at 6 and 12 months post study product ad-ministration. For the purpose of the endpoint analysis and safety evaluations, the investigators planned to use an intention-to-treat study population evaluating a number of clinical parameters.

Anatomists and physiologists have long been of the opinion that adult human and mammalian cardiomyocytes are terminally differentiated and do not undergo cell division. However, over time, cardiomyocytes can undergo hypertrophy as a result of increased workload. Cells can die as a result of ischemia, infarction, or stress mediated through unchecked inflammatory processes. It also has been shown that cells can die as a result of apoptosis, particularly in areas in proximity to myocardial scars. It is generally believed that these three methods of cell depletion contribute to the progression of heart failure. Dr. Anversa also proposed that there is some degree of replication of cardiomyocytes but not to a degree that can have a meaningful replacement value.

The concept of cell transplantation in medicine certainly has been in the forefront of clinical research in medicine for the last decade based in part on research by Dr. Anversa and others in cardiology and numerous investigators in other medical disciplines. With few exceptions, there has been little support for the clinical benefit of these clinical studies. We are unfortunately now faced with the release of the tainted fraudulent research that led to CONCERT-HF. Whether there is anything of scientific value to come of the trial is highly unlikely.
 

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

This article was updated Oct. 30, 2018.

The Society for Vascular Surgery Community Practice Committee announces the Excellence in Community Service Award, honoring a member who has made contributions not only to the profession but to the community as well. Applications are due Feb. 1, 2019. The recipient will be announced and recognized at the 2019 Vascular Annual Meeting in June. Nominees must have practiced vascular surgery for at least 20 years and been an SVS member for at least five. They also must present evidence of impact on vascular care or community health.

The Society for Vascular Surgery Community Practice Committee announces the Excellence in Community Service Award, honoring a member who has made contributions not only to the profession but to the community as well. Applications are due Feb. 1, 2019. The recipient will be announced and recognized at the 2019 Vascular Annual Meeting in June. Nominees must have practiced vascular surgery for at least 20 years and been an SVS member for at least five. They also must present evidence of impact on vascular care or community health.

The Society for Vascular Surgery Community Practice Committee announces the Excellence in Community Service Award, honoring a member who has made contributions not only to the profession but to the community as well. Applications are due Feb. 1, 2019. The recipient will be announced and recognized at the 2019 Vascular Annual Meeting in June. Nominees must have practiced vascular surgery for at least 20 years and been an SVS member for at least five. They also must present evidence of impact on vascular care or community health.

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The SVS Foundation’s 2018 Annual Report has just been published online. The report highlights the Foundation’s work, the money raised, and money spent. It tells why people give and the profound difference SVS members make, not only in their research labs but also in their communities. The Foundation offers a number of ways to give and a number of funds – the general fund, disaster relief, research and more – to which donations may be directed. This is the season for the SVS annual Giving Campaign. Please read the report and give today.
 

Download Below

The SVS Foundation’s 2018 Annual Report has just been published online. The report highlights the Foundation’s work, the money raised, and money spent. It tells why people give and the profound difference SVS members make, not only in their research labs but also in their communities. The Foundation offers a number of ways to give and a number of funds – the general fund, disaster relief, research and more – to which donations may be directed. This is the season for the SVS annual Giving Campaign. Please read the report and give today.
 

Download Below

The SVS Foundation’s 2018 Annual Report has just been published online. The report highlights the Foundation’s work, the money raised, and money spent. It tells why people give and the profound difference SVS members make, not only in their research labs but also in their communities. The Foundation offers a number of ways to give and a number of funds – the general fund, disaster relief, research and more – to which donations may be directed. This is the season for the SVS annual Giving Campaign. Please read the report and give today.
 

Hospitalized patients who developed acute kidney injury and fully recovered faced triple the risk of dementia compared with other patients. ACIP votes unanimously in favor of immunization schedule updated and redesign, could daptomycin/fosfomycin be a new standard for MRSA bacteremia? Plus, expert analysis on Justice Kavanaugh’s lasting healthcare impact.

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Hospitalized patients who developed acute kidney injury and fully recovered faced triple the risk of dementia compared with other patients. ACIP votes unanimously in favor of immunization schedule updated and redesign, could daptomycin/fosfomycin be a new standard for MRSA bacteremia? Plus, expert analysis on Justice Kavanaugh’s lasting healthcare impact.

Amazon Alexa
Apple Podcasts
Spotify

Hospitalized patients who developed acute kidney injury and fully recovered faced triple the risk of dementia compared with other patients. ACIP votes unanimously in favor of immunization schedule updated and redesign, could daptomycin/fosfomycin be a new standard for MRSA bacteremia? Plus, expert analysis on Justice Kavanaugh’s lasting healthcare impact.

Amazon Alexa
Apple Podcasts
Spotify

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that involves multiple organs and appears as syndromes that were once thought to be unrelated. This disease leads to mass lesions, fibrosis, and subsequent organ failure if allowed to progress untreated.¹ Involvement of gastrointestinal (GI) organs, salivary glands, lacrimal glands, lymph, prostate, pulmonary, and vascular system have all been reported.² Elevated IgG4 serum levels are common, but about one-third of patients with biopsy-proven IgG4-RD do not manifest this characteristic.^3,4

Diagnostic confirmation is with biopsy, and all patients with symptomatic, active IgG4-RD require treatment. Glucocorticoids are first-line treatment and are utilized for relapse of symptoms. In addition to glucocorticoids, steroid-sparing medications, including rituximab, azathioprine, mycophenolate mofetil, tacrolimus, and cyclophosphamide have all been used with successful remission.^5,6 Here, the authors discuss a case of IgG4-RD that presented with intrahepatic biliary obstruction (mimicking cholangiocarcinoma) and subsequent development of coronary arteritis despite treatment.

Case Presentation

In June 2015, a 57-year-old Air Force veteran presented to Eglin AFB Hospital with pruritic jaundice and acute abdominal pain. He was found to have elevated bilirubin levels (total bilirubin 10 mg/dL [normal range 0.2-1.3 mg/dL], direct bilirubin 6.6 mg/dL [normal range 0.1-0.4 mg/dL]). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) also were moderately elevated (147 U/L and 337 U/L, respectively). 

Prior to this presentation, the patient had been in his usual state of health. His past medical history was notable only for minimal change kidney disease (MCD). MCD is defined as effacement of the podocyte seen on electron microscopy, which allows the passage of large amounts of protein. 

A cholangiogram showed abnormal filling into the left main intrahepatic duct and obvious obstruction at the bifurcation of the bile duct. A biliary drainage catheter was placed, and a repeat cholangiogram 2 days later showed involvement of both right and left intrahepatic ducts. The distal common bile duct appeared uninvolved as did the pancreas. Lymphadenopathy was noted at the liver hilum. Klatskin cholangiocarcinoma (type IIIB) was the presumed diagnosis. Based on these findings, tumor resection was performed 3 weeks later, including left hepatectomy, caudate lobe resection, complete bile duct resection, cholecystectomy, with reconstruction by Roux-en-Y intrahepaticojejunostomy. In addition, portal and hepatic artery lymph node dissection was completed.

Surgical specimens were sent for pathologic evaluation and were found negative for malignancy. Patchy areas of storiform fibrosis, obliterative phlebitis, and lymphoplasmacytic infiltrate were noted. IgG4 immunostain highlighted the presence of IgG4 positive plasma cells with a peak count of 145 IgG4 positive plasma cells/hpf. About 80% of the plasma cells were positive for IgG4. Unusually dense eosinophilic infiltrate with plasma cells and regions of dense fibrosis that strongly contributed to the masslike appearance on CT imaging also were noted. Final histology confirmed the diagnosis of IgG4-RD. Elevated levels of total IgG in the serum were observed without elevation in serum IgG4 (Table).

The patient was started on prednisone 40 mg and azathioprine 150 mg daily, with subsequent taper of prednisone over the next 6 months. After prednisone was discontinued, the patient reported new symptoms of lower extremity pain, neuropathy, and swelling of his face. Laboratory results were notable for elevated erythrocyte sedimentation rate. The patient was restarted on prednisone 40 mg daily. Azathioprine was replaced with a regimen of 4 doses every 6 months of IV rituximab 700 mg q week and mycophenolate mofetil (1,000 mg bid). After remission was induced, the patient was slowly weaned off prednisone again.

Following 6 months of successful discontinuation of prednisone and continued rituximab and mycophenolate mofetil therapy, the patient presented to the emergency department with new onset chest pain and shortness of breath. A CT angiography of the chest showed right upper and middle lobe infiltrate, and he was treated for community acquired pneumonia. Additionally, he was noted to have elevated troponin levels suggestive of myocardial infarction (MI). Initial troponin was 1.23 ng/mL (normal range < 0.015 ng/mL), which trended down over the next 18 hours. A bedside echocardiogram showed a normal left ventricular ejection fraction without wall motion abnormalities. Etiology for his acute MI was presumed to be demand ischemia from fixed atherosclerotic plaque. Further inpatient cardiac risk stratification was changed to the outpatient setting, and he was started on medical management for coronary artery disease with a beta blocker, a statin, and aspirin. He was discharged home on 10 mg prednisone daily, which was subsequently tapered over several weeks.

In follow-up, a Lexiscan myocardial perfusion imaging was conducted that demonstrated an inferolateral defect and associated wall motion abnormalities (Figures 2 and 3). 

Discussion

IgG4-related disease has been found to be a systemic disorder. Typical characteristics include predominance in men aged > 50 years, elevated IgG4 levels, and findings on histology.¹ It has been reported to involve many organs, including pancreas, liver, gallbladder, salivary glands, thyroid, and pleura of the lung.^2,5

This case report begins with a presumptive diagnosis of cholangiocarcinoma, which was treated aggressively with extensive surgery. Several case reports of complex tumefactive lesions in the GI area (mostly pancreatic and biliary) have detailed IgG4-RD as both a risk factor for subsequent development of cholangiocarcinoma and as a separate entity of IgG4-related sclerosing cholangitis.^7-9 It is hypothesized that the induction of IgG4- positive plasma cells has been intertwined with the development of cholangiocarcinoma. Differentiation between IgG4 reaction that is scattered around cancerous nests and IgG4 sclerosing cholangitis without malignancy is challenging. It has been documented that both elevated IgG4 levels and hilar hepatic lesions that resemble cholangiocarcinoma frequently accompany those cases of IgG4 sclerosing chlolangitis without pancreatic involvement.⁹ The histologic features of IgG4-RD need to be identified with multiple biopsies and cytology, and superficial biopsy from biliary mucosa cannot reliably exclude cholangiocarcinoma.

Lymphoplasmacytic aortitis and arteritis have been documented in IgG4-RD. In 2017, Barbu and colleagues described how one such case of coronary arteritis presented with typical angina and coronary catheterization revealing coronary artery stenosis.¹⁰ However, during coronary artery bypass surgery, the aorta and coronary vessels were noted to be abnormally stiff. A diffuse fibrotic tissue was identified to be causing the significant stenosis without evidence of atherosclerosis. Pathology showed typical findings of IgG4-RD, and there was a rapid response to immunosuppressive therapy. Involvement of coronary arteries has been described in a small number of cases at this time and is associated with progressive fibrotic changes resulting in an MI, aneurysms, and sudden cardiac death.^2,10,11

IgG4-RD can be an extensively systemic disease. All presentations of fibrosis or vasculitis should be viewed with heightened suspicion in the future as being a facet of his IgG4-RD. Pleural involvement has been reported in 12% of cases presenting with systemic presentation, kidney involvement in 13%.^2,12

Unfortunately, there is no standard laboratory parameter to date that is diagnostic for IgG4-RD. The gold standard remains confirmation of histologic findings with biopsy. According to an international consensus from 2015, 2 out of the 3 major findings need to be present: (1) dense lymphoplasmacytic infiltrate; (2) storiform fibrosis; and (3) obliterative phlebitis in veins and arteries.^1,5 Most patients present with symptoms related to either tumefaction or fibrosis of an organ system.¹ Peripheral eosinophilia and elevated serum IgE are often present in IgG4-RD.¹³ Although IgG4 values are elevated in 51% of biopsy-proven cases, flow cytometry of CD19^lowCD38⁺CD20^-CD27⁺ plasmablasts has been explored recently as a correlation with disease flare.^3,14 These particular plasmablasts mark a stage between B cells and plasma cells and have been reported to have a sensitivity of 95% and a specificity of 82% in association with actual IgG4-RD.¹⁴ Furthermore, blood plasmablast concentrations decrease in response to glucocorticoid treatment, thereby providing a possible quantifiable value by which to measure success of IgG4 treatment.^5,12

Treatment for this disease consists of immunosuppressive therapy. There is documentation of successful remission with rituximab and azathioprine, as well as methotrexate.^1,5 Both 2015 consensus guidelines and a recent small single-center retrospective study support addition of second-line steroid sparing agents such as mycophenolate mofetil.^5,6 For acute flairs, however, glucocorticoids with slow taper are usually utilized. In these cases, they should be tapered as soon as clinically feasible to avoid long-term adverse effects. Untreated IgG4-RD, even asymptomatic, has been shown to progress to fibrosis.⁵

Conclusion

IgG4-RD is a complicated disease process that requires a high index of suspicion to diagnose. In addition, for patients who are diagnosed with this condition, its ability to mimic other pathologic conditions should be taken into account with manifestation of any new illness. This case emphasizes the ability of this disease to localize in multiple organs over time and the need for lifetime surveillance in patients with IgG4-RD disease.

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that involves multiple organs and appears as syndromes that were once thought to be unrelated. This disease leads to mass lesions, fibrosis, and subsequent organ failure if allowed to progress untreated.¹ Involvement of gastrointestinal (GI) organs, salivary glands, lacrimal glands, lymph, prostate, pulmonary, and vascular system have all been reported.² Elevated IgG4 serum levels are common, but about one-third of patients with biopsy-proven IgG4-RD do not manifest this characteristic.^3,4

Diagnostic confirmation is with biopsy, and all patients with symptomatic, active IgG4-RD require treatment. Glucocorticoids are first-line treatment and are utilized for relapse of symptoms. In addition to glucocorticoids, steroid-sparing medications, including rituximab, azathioprine, mycophenolate mofetil, tacrolimus, and cyclophosphamide have all been used with successful remission.^5,6 Here, the authors discuss a case of IgG4-RD that presented with intrahepatic biliary obstruction (mimicking cholangiocarcinoma) and subsequent development of coronary arteritis despite treatment.

Case Presentation

In June 2015, a 57-year-old Air Force veteran presented to Eglin AFB Hospital with pruritic jaundice and acute abdominal pain. He was found to have elevated bilirubin levels (total bilirubin 10 mg/dL [normal range 0.2-1.3 mg/dL], direct bilirubin 6.6 mg/dL [normal range 0.1-0.4 mg/dL]). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) also were moderately elevated (147 U/L and 337 U/L, respectively). 

Prior to this presentation, the patient had been in his usual state of health. His past medical history was notable only for minimal change kidney disease (MCD). MCD is defined as effacement of the podocyte seen on electron microscopy, which allows the passage of large amounts of protein. 

A cholangiogram showed abnormal filling into the left main intrahepatic duct and obvious obstruction at the bifurcation of the bile duct. A biliary drainage catheter was placed, and a repeat cholangiogram 2 days later showed involvement of both right and left intrahepatic ducts. The distal common bile duct appeared uninvolved as did the pancreas. Lymphadenopathy was noted at the liver hilum. Klatskin cholangiocarcinoma (type IIIB) was the presumed diagnosis. Based on these findings, tumor resection was performed 3 weeks later, including left hepatectomy, caudate lobe resection, complete bile duct resection, cholecystectomy, with reconstruction by Roux-en-Y intrahepaticojejunostomy. In addition, portal and hepatic artery lymph node dissection was completed.

Surgical specimens were sent for pathologic evaluation and were found negative for malignancy. Patchy areas of storiform fibrosis, obliterative phlebitis, and lymphoplasmacytic infiltrate were noted. IgG4 immunostain highlighted the presence of IgG4 positive plasma cells with a peak count of 145 IgG4 positive plasma cells/hpf. About 80% of the plasma cells were positive for IgG4. Unusually dense eosinophilic infiltrate with plasma cells and regions of dense fibrosis that strongly contributed to the masslike appearance on CT imaging also were noted. Final histology confirmed the diagnosis of IgG4-RD. Elevated levels of total IgG in the serum were observed without elevation in serum IgG4 (Table).

The patient was started on prednisone 40 mg and azathioprine 150 mg daily, with subsequent taper of prednisone over the next 6 months. After prednisone was discontinued, the patient reported new symptoms of lower extremity pain, neuropathy, and swelling of his face. Laboratory results were notable for elevated erythrocyte sedimentation rate. The patient was restarted on prednisone 40 mg daily. Azathioprine was replaced with a regimen of 4 doses every 6 months of IV rituximab 700 mg q week and mycophenolate mofetil (1,000 mg bid). After remission was induced, the patient was slowly weaned off prednisone again.

Following 6 months of successful discontinuation of prednisone and continued rituximab and mycophenolate mofetil therapy, the patient presented to the emergency department with new onset chest pain and shortness of breath. A CT angiography of the chest showed right upper and middle lobe infiltrate, and he was treated for community acquired pneumonia. Additionally, he was noted to have elevated troponin levels suggestive of myocardial infarction (MI). Initial troponin was 1.23 ng/mL (normal range < 0.015 ng/mL), which trended down over the next 18 hours. A bedside echocardiogram showed a normal left ventricular ejection fraction without wall motion abnormalities. Etiology for his acute MI was presumed to be demand ischemia from fixed atherosclerotic plaque. Further inpatient cardiac risk stratification was changed to the outpatient setting, and he was started on medical management for coronary artery disease with a beta blocker, a statin, and aspirin. He was discharged home on 10 mg prednisone daily, which was subsequently tapered over several weeks.

In follow-up, a Lexiscan myocardial perfusion imaging was conducted that demonstrated an inferolateral defect and associated wall motion abnormalities (Figures 2 and 3). 

Discussion

IgG4-related disease has been found to be a systemic disorder. Typical characteristics include predominance in men aged > 50 years, elevated IgG4 levels, and findings on histology.¹ It has been reported to involve many organs, including pancreas, liver, gallbladder, salivary glands, thyroid, and pleura of the lung.^2,5

This case report begins with a presumptive diagnosis of cholangiocarcinoma, which was treated aggressively with extensive surgery. Several case reports of complex tumefactive lesions in the GI area (mostly pancreatic and biliary) have detailed IgG4-RD as both a risk factor for subsequent development of cholangiocarcinoma and as a separate entity of IgG4-related sclerosing cholangitis.^7-9 It is hypothesized that the induction of IgG4- positive plasma cells has been intertwined with the development of cholangiocarcinoma. Differentiation between IgG4 reaction that is scattered around cancerous nests and IgG4 sclerosing cholangitis without malignancy is challenging. It has been documented that both elevated IgG4 levels and hilar hepatic lesions that resemble cholangiocarcinoma frequently accompany those cases of IgG4 sclerosing chlolangitis without pancreatic involvement.⁹ The histologic features of IgG4-RD need to be identified with multiple biopsies and cytology, and superficial biopsy from biliary mucosa cannot reliably exclude cholangiocarcinoma.

Lymphoplasmacytic aortitis and arteritis have been documented in IgG4-RD. In 2017, Barbu and colleagues described how one such case of coronary arteritis presented with typical angina and coronary catheterization revealing coronary artery stenosis.¹⁰ However, during coronary artery bypass surgery, the aorta and coronary vessels were noted to be abnormally stiff. A diffuse fibrotic tissue was identified to be causing the significant stenosis without evidence of atherosclerosis. Pathology showed typical findings of IgG4-RD, and there was a rapid response to immunosuppressive therapy. Involvement of coronary arteries has been described in a small number of cases at this time and is associated with progressive fibrotic changes resulting in an MI, aneurysms, and sudden cardiac death.^2,10,11

IgG4-RD can be an extensively systemic disease. All presentations of fibrosis or vasculitis should be viewed with heightened suspicion in the future as being a facet of his IgG4-RD. Pleural involvement has been reported in 12% of cases presenting with systemic presentation, kidney involvement in 13%.^2,12

Unfortunately, there is no standard laboratory parameter to date that is diagnostic for IgG4-RD. The gold standard remains confirmation of histologic findings with biopsy. According to an international consensus from 2015, 2 out of the 3 major findings need to be present: (1) dense lymphoplasmacytic infiltrate; (2) storiform fibrosis; and (3) obliterative phlebitis in veins and arteries.^1,5 Most patients present with symptoms related to either tumefaction or fibrosis of an organ system.¹ Peripheral eosinophilia and elevated serum IgE are often present in IgG4-RD.¹³ Although IgG4 values are elevated in 51% of biopsy-proven cases, flow cytometry of CD19^lowCD38⁺CD20^-CD27⁺ plasmablasts has been explored recently as a correlation with disease flare.^3,14 These particular plasmablasts mark a stage between B cells and plasma cells and have been reported to have a sensitivity of 95% and a specificity of 82% in association with actual IgG4-RD.¹⁴ Furthermore, blood plasmablast concentrations decrease in response to glucocorticoid treatment, thereby providing a possible quantifiable value by which to measure success of IgG4 treatment.^5,12

Treatment for this disease consists of immunosuppressive therapy. There is documentation of successful remission with rituximab and azathioprine, as well as methotrexate.^1,5 Both 2015 consensus guidelines and a recent small single-center retrospective study support addition of second-line steroid sparing agents such as mycophenolate mofetil.^5,6 For acute flairs, however, glucocorticoids with slow taper are usually utilized. In these cases, they should be tapered as soon as clinically feasible to avoid long-term adverse effects. Untreated IgG4-RD, even asymptomatic, has been shown to progress to fibrosis.⁵

Conclusion

IgG4-RD is a complicated disease process that requires a high index of suspicion to diagnose. In addition, for patients who are diagnosed with this condition, its ability to mimic other pathologic conditions should be taken into account with manifestation of any new illness. This case emphasizes the ability of this disease to localize in multiple organs over time and the need for lifetime surveillance in patients with IgG4-RD disease.

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that involves multiple organs and appears as syndromes that were once thought to be unrelated. This disease leads to mass lesions, fibrosis, and subsequent organ failure if allowed to progress untreated.¹ Involvement of gastrointestinal (GI) organs, salivary glands, lacrimal glands, lymph, prostate, pulmonary, and vascular system have all been reported.² Elevated IgG4 serum levels are common, but about one-third of patients with biopsy-proven IgG4-RD do not manifest this characteristic.^3,4

Diagnostic confirmation is with biopsy, and all patients with symptomatic, active IgG4-RD require treatment. Glucocorticoids are first-line treatment and are utilized for relapse of symptoms. In addition to glucocorticoids, steroid-sparing medications, including rituximab, azathioprine, mycophenolate mofetil, tacrolimus, and cyclophosphamide have all been used with successful remission.^5,6 Here, the authors discuss a case of IgG4-RD that presented with intrahepatic biliary obstruction (mimicking cholangiocarcinoma) and subsequent development of coronary arteritis despite treatment.

Case Presentation

In June 2015, a 57-year-old Air Force veteran presented to Eglin AFB Hospital with pruritic jaundice and acute abdominal pain. He was found to have elevated bilirubin levels (total bilirubin 10 mg/dL [normal range 0.2-1.3 mg/dL], direct bilirubin 6.6 mg/dL [normal range 0.1-0.4 mg/dL]). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) also were moderately elevated (147 U/L and 337 U/L, respectively). 

Prior to this presentation, the patient had been in his usual state of health. His past medical history was notable only for minimal change kidney disease (MCD). MCD is defined as effacement of the podocyte seen on electron microscopy, which allows the passage of large amounts of protein. 

A cholangiogram showed abnormal filling into the left main intrahepatic duct and obvious obstruction at the bifurcation of the bile duct. A biliary drainage catheter was placed, and a repeat cholangiogram 2 days later showed involvement of both right and left intrahepatic ducts. The distal common bile duct appeared uninvolved as did the pancreas. Lymphadenopathy was noted at the liver hilum. Klatskin cholangiocarcinoma (type IIIB) was the presumed diagnosis. Based on these findings, tumor resection was performed 3 weeks later, including left hepatectomy, caudate lobe resection, complete bile duct resection, cholecystectomy, with reconstruction by Roux-en-Y intrahepaticojejunostomy. In addition, portal and hepatic artery lymph node dissection was completed.

Surgical specimens were sent for pathologic evaluation and were found negative for malignancy. Patchy areas of storiform fibrosis, obliterative phlebitis, and lymphoplasmacytic infiltrate were noted. IgG4 immunostain highlighted the presence of IgG4 positive plasma cells with a peak count of 145 IgG4 positive plasma cells/hpf. About 80% of the plasma cells were positive for IgG4. Unusually dense eosinophilic infiltrate with plasma cells and regions of dense fibrosis that strongly contributed to the masslike appearance on CT imaging also were noted. Final histology confirmed the diagnosis of IgG4-RD. Elevated levels of total IgG in the serum were observed without elevation in serum IgG4 (Table).

The patient was started on prednisone 40 mg and azathioprine 150 mg daily, with subsequent taper of prednisone over the next 6 months. After prednisone was discontinued, the patient reported new symptoms of lower extremity pain, neuropathy, and swelling of his face. Laboratory results were notable for elevated erythrocyte sedimentation rate. The patient was restarted on prednisone 40 mg daily. Azathioprine was replaced with a regimen of 4 doses every 6 months of IV rituximab 700 mg q week and mycophenolate mofetil (1,000 mg bid). After remission was induced, the patient was slowly weaned off prednisone again.

Following 6 months of successful discontinuation of prednisone and continued rituximab and mycophenolate mofetil therapy, the patient presented to the emergency department with new onset chest pain and shortness of breath. A CT angiography of the chest showed right upper and middle lobe infiltrate, and he was treated for community acquired pneumonia. Additionally, he was noted to have elevated troponin levels suggestive of myocardial infarction (MI). Initial troponin was 1.23 ng/mL (normal range < 0.015 ng/mL), which trended down over the next 18 hours. A bedside echocardiogram showed a normal left ventricular ejection fraction without wall motion abnormalities. Etiology for his acute MI was presumed to be demand ischemia from fixed atherosclerotic plaque. Further inpatient cardiac risk stratification was changed to the outpatient setting, and he was started on medical management for coronary artery disease with a beta blocker, a statin, and aspirin. He was discharged home on 10 mg prednisone daily, which was subsequently tapered over several weeks.

In follow-up, a Lexiscan myocardial perfusion imaging was conducted that demonstrated an inferolateral defect and associated wall motion abnormalities (Figures 2 and 3). 

Discussion

IgG4-related disease has been found to be a systemic disorder. Typical characteristics include predominance in men aged > 50 years, elevated IgG4 levels, and findings on histology.¹ It has been reported to involve many organs, including pancreas, liver, gallbladder, salivary glands, thyroid, and pleura of the lung.^2,5

This case report begins with a presumptive diagnosis of cholangiocarcinoma, which was treated aggressively with extensive surgery. Several case reports of complex tumefactive lesions in the GI area (mostly pancreatic and biliary) have detailed IgG4-RD as both a risk factor for subsequent development of cholangiocarcinoma and as a separate entity of IgG4-related sclerosing cholangitis.^7-9 It is hypothesized that the induction of IgG4- positive plasma cells has been intertwined with the development of cholangiocarcinoma. Differentiation between IgG4 reaction that is scattered around cancerous nests and IgG4 sclerosing cholangitis without malignancy is challenging. It has been documented that both elevated IgG4 levels and hilar hepatic lesions that resemble cholangiocarcinoma frequently accompany those cases of IgG4 sclerosing chlolangitis without pancreatic involvement.⁹ The histologic features of IgG4-RD need to be identified with multiple biopsies and cytology, and superficial biopsy from biliary mucosa cannot reliably exclude cholangiocarcinoma.

Lymphoplasmacytic aortitis and arteritis have been documented in IgG4-RD. In 2017, Barbu and colleagues described how one such case of coronary arteritis presented with typical angina and coronary catheterization revealing coronary artery stenosis.¹⁰ However, during coronary artery bypass surgery, the aorta and coronary vessels were noted to be abnormally stiff. A diffuse fibrotic tissue was identified to be causing the significant stenosis without evidence of atherosclerosis. Pathology showed typical findings of IgG4-RD, and there was a rapid response to immunosuppressive therapy. Involvement of coronary arteries has been described in a small number of cases at this time and is associated with progressive fibrotic changes resulting in an MI, aneurysms, and sudden cardiac death.^2,10,11

IgG4-RD can be an extensively systemic disease. All presentations of fibrosis or vasculitis should be viewed with heightened suspicion in the future as being a facet of his IgG4-RD. Pleural involvement has been reported in 12% of cases presenting with systemic presentation, kidney involvement in 13%.^2,12

Unfortunately, there is no standard laboratory parameter to date that is diagnostic for IgG4-RD. The gold standard remains confirmation of histologic findings with biopsy. According to an international consensus from 2015, 2 out of the 3 major findings need to be present: (1) dense lymphoplasmacytic infiltrate; (2) storiform fibrosis; and (3) obliterative phlebitis in veins and arteries.^1,5 Most patients present with symptoms related to either tumefaction or fibrosis of an organ system.¹ Peripheral eosinophilia and elevated serum IgE are often present in IgG4-RD.¹³ Although IgG4 values are elevated in 51% of biopsy-proven cases, flow cytometry of CD19^lowCD38⁺CD20^-CD27⁺ plasmablasts has been explored recently as a correlation with disease flare.^3,14 These particular plasmablasts mark a stage between B cells and plasma cells and have been reported to have a sensitivity of 95% and a specificity of 82% in association with actual IgG4-RD.¹⁴ Furthermore, blood plasmablast concentrations decrease in response to glucocorticoid treatment, thereby providing a possible quantifiable value by which to measure success of IgG4 treatment.^5,12

Treatment for this disease consists of immunosuppressive therapy. There is documentation of successful remission with rituximab and azathioprine, as well as methotrexate.^1,5 Both 2015 consensus guidelines and a recent small single-center retrospective study support addition of second-line steroid sparing agents such as mycophenolate mofetil.^5,6 For acute flairs, however, glucocorticoids with slow taper are usually utilized. In these cases, they should be tapered as soon as clinically feasible to avoid long-term adverse effects. Untreated IgG4-RD, even asymptomatic, has been shown to progress to fibrosis.⁵

Conclusion

IgG4-RD is a complicated disease process that requires a high index of suspicion to diagnose. In addition, for patients who are diagnosed with this condition, its ability to mimic other pathologic conditions should be taken into account with manifestation of any new illness. This case emphasizes the ability of this disease to localize in multiple organs over time and the need for lifetime surveillance in patients with IgG4-RD disease.

Coffee drinking has been linked to the reduced risk of fibrosis progression, liver cirrhosis, and hepatocellular carcinoma in some patients, including those with hepatitis C virus (HCV) infection, but the results of studies in patients with hepatitis B virus (HBV) infection have been inconsistent. Given the “global impact of HBV infection and the wide consumption of coffee,” researchers from Tzu Chi University in Taiwan, wanted to find out more.

They analyzed data from 328 patients with chronic HBV infection who were enrolled in a population-based gastroesophageal reflux disease study. Of those, 155 patients also entered into a 5-year follow-up study. 

Among the patients with chronic HBV, 137 did not drink coffee. Of the 191 who did, 61 drank it on < 4 days a week, and 130 drank it ≥ 4 days.

Initially, the researchers observed an inverse association between coffee drinking and serum aspartate aminotransferase (AST) levels, as well as predicting indices of liver fibrosis in patients with HBV infection. Patients who drank ≥ 4 cups of coffee per day had a 70% decrease of serum AST, a 70% decrease of the AST to platelet ratio index, and a 70% decrease of fibrosis-4 index values. 

Those findings indicated that coffee might have a “generally beneficial” effect on liver inflammation and fibrosis progression in patients with chronic liver disease, the researchers say. However, at the end of the 5-year follow-up, the incidences of liver cirrhosis complications and changes of serum predicting indices of liver fibrosis were comparable between HBV coffee drinkers and nondrinkers. That indicated, the researchers believe, that the beneficial effect “seems to be outweighed” in patients with chronic HBV infection.

The researchers suggest that the protective effects of coffee consumption on liver inflammation and insulin resistance may not be able to surpass the direct carcinogenic effect of HBV, and even the HBV virus replication.

Coffee drinking has been linked to the reduced risk of fibrosis progression, liver cirrhosis, and hepatocellular carcinoma in some patients, including those with hepatitis C virus (HCV) infection, but the results of studies in patients with hepatitis B virus (HBV) infection have been inconsistent. Given the “global impact of HBV infection and the wide consumption of coffee,” researchers from Tzu Chi University in Taiwan, wanted to find out more.

They analyzed data from 328 patients with chronic HBV infection who were enrolled in a population-based gastroesophageal reflux disease study. Of those, 155 patients also entered into a 5-year follow-up study. 

Among the patients with chronic HBV, 137 did not drink coffee. Of the 191 who did, 61 drank it on < 4 days a week, and 130 drank it ≥ 4 days.

Initially, the researchers observed an inverse association between coffee drinking and serum aspartate aminotransferase (AST) levels, as well as predicting indices of liver fibrosis in patients with HBV infection. Patients who drank ≥ 4 cups of coffee per day had a 70% decrease of serum AST, a 70% decrease of the AST to platelet ratio index, and a 70% decrease of fibrosis-4 index values. 

Those findings indicated that coffee might have a “generally beneficial” effect on liver inflammation and fibrosis progression in patients with chronic liver disease, the researchers say. However, at the end of the 5-year follow-up, the incidences of liver cirrhosis complications and changes of serum predicting indices of liver fibrosis were comparable between HBV coffee drinkers and nondrinkers. That indicated, the researchers believe, that the beneficial effect “seems to be outweighed” in patients with chronic HBV infection.

The researchers suggest that the protective effects of coffee consumption on liver inflammation and insulin resistance may not be able to surpass the direct carcinogenic effect of HBV, and even the HBV virus replication.

Coffee drinking has been linked to the reduced risk of fibrosis progression, liver cirrhosis, and hepatocellular carcinoma in some patients, including those with hepatitis C virus (HCV) infection, but the results of studies in patients with hepatitis B virus (HBV) infection have been inconsistent. Given the “global impact of HBV infection and the wide consumption of coffee,” researchers from Tzu Chi University in Taiwan, wanted to find out more.

They analyzed data from 328 patients with chronic HBV infection who were enrolled in a population-based gastroesophageal reflux disease study. Of those, 155 patients also entered into a 5-year follow-up study. 

Among the patients with chronic HBV, 137 did not drink coffee. Of the 191 who did, 61 drank it on < 4 days a week, and 130 drank it ≥ 4 days.

Initially, the researchers observed an inverse association between coffee drinking and serum aspartate aminotransferase (AST) levels, as well as predicting indices of liver fibrosis in patients with HBV infection. Patients who drank ≥ 4 cups of coffee per day had a 70% decrease of serum AST, a 70% decrease of the AST to platelet ratio index, and a 70% decrease of fibrosis-4 index values. 

Those findings indicated that coffee might have a “generally beneficial” effect on liver inflammation and fibrosis progression in patients with chronic liver disease, the researchers say. However, at the end of the 5-year follow-up, the incidences of liver cirrhosis complications and changes of serum predicting indices of liver fibrosis were comparable between HBV coffee drinkers and nondrinkers. That indicated, the researchers believe, that the beneficial effect “seems to be outweighed” in patients with chronic HBV infection.

The researchers suggest that the protective effects of coffee consumption on liver inflammation and insulin resistance may not be able to surpass the direct carcinogenic effect of HBV, and even the HBV virus replication.

Photo from St. Jude Children’s Research Hospital

New research suggests several factors may be associated with the risk of short stature and excess weight gain in children with acute lymphoblastic leukemia (ALL).

Researchers found that patients who were younger at ALL diagnosis had an increased risk of becoming overweight or obese both during and after therapy.

Patients had an increased risk of short stature after therapy if they were older at diagnosis or had standard or high-risk disease, higher white blood cell counts at diagnosis, and central nervous system disease.

The researchers reported these findings in Cancer.

The team looked at 372 children with ALL, reviewing changes in their body mass index (BMI), weight, and height from diagnosis to 5 years after treatment ended.

The patients were treated with the Total XV protocol between 2000 and 2007 (NCT00137111). They received 6 weeks of induction therapy, 8 weeks of consolidation, and continuation for 120 weeks in females and 146 weeks in males.

BMI changes

Roughly a quarter of patients were overweight or obese at diagnosis, but that increased to roughly half of patients by the time they had been off therapy for 5 years.

“Over the whole population that was studied, we found statistically significant weight gain even during remission-induction therapy,” said study author Hiroto Inaba, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Patients’ median BMI z scores increased significantly during induction (P<0.001) and reinduction (P=0.001) with glucocorticoid therapy as well as in the first year after therapy ended (P=0.006).

At various points during treatment, there were significant differences in BMI z scores according to sex, race, and disease risk group. However, these differences were not present after therapy.

On the other hand, there were significant differences in BMI z scores according to age both during and after therapy.

Between week 21 of treatment and 3 years after therapy ended, patients who were ages 2 to 9 at diagnosis had median BMI z scores that were significantly higher than scores of patients who were age 10 or older at diagnosis (P≤0.033 for all time points).

The researchers also found that patients who were of a healthy weight or underweight at the time of diagnosis had a significantly higher risk of becoming overweight or obese during or after therapy if they were ages 2 to 9 at diagnosis, compared to the older patients (P=0.001).

Height changes

The researchers found that height z scores declined during treatment and improved after it ended, although z scores “never improved to the levels noted at the time of diagnosis.”

Median height z scores at the end of induction and in continuation weeks 1 to 21 were significantly higher in patients age 10 or older at diagnosis than in patients ages to 2 to 9 at diagnosis (P≤0.038 for all time points).

However, the median height z scores at 5 years off therapy were significantly higher for the younger patients than for the older patients (P=0.011).

The median height z scores were higher for patients with low-risk disease than for standard- or high-risk patients in weeks 17, 21, 48, and 146 of treatment and at 1 to 3 years after therapy ended (P≤0.024 for all time points).

At 3 years to 5 years after treatment ended, the median height z scores were significantly higher among patients with white blood cell counts below 50 × 10⁹/L at diagnosis (P≤0.018 for all time points).

Patients without central nervous system disease had significantly higher median height z scores at 3 years after treatment ended (P=0.029).

Males had significantly higher median height z scores than females in weeks 96 and 120 of therapy (P≤0.009 for both time points).

And white patients had higher median height z scores than black patients at 2 to 4 years after treatment ended (P≤0.027 for all time points).

Implications

To address the issue of excess weight gain in ALL patients, the researchers suggested early interventions, such as education about proper diet and exercise.

“When you look at the literature of childhood obesity prevention for the general population, there are interventions that could also help ALL patients,” said study author Emily Browne, of St. Jude.

“But we need to adapt those recommendations to take the cancer therapy into account.”

For the issue of height, the researchers recommended evaluating certain patients for growth hormone deficiency.

The team also noted that further study is needed to determine whether emerging therapeutic approaches can reduce toxicities without compromising antileukemic effects.

“We are hoping new therapeutic options can decrease intensity of chemotherapy and keep normal tissues intact,” Dr. Inaba said. “But until then, we’re collaborating with multiple clinical departments to help ensure a good, quality cure and a good quality of life in survivorship.”

This research was supported by grants from the National Institutes of Health and ALSAC, the fundraising and awareness organization of St. Jude.

Photo from St. Jude Children’s Research Hospital

New research suggests several factors may be associated with the risk of short stature and excess weight gain in children with acute lymphoblastic leukemia (ALL).

Researchers found that patients who were younger at ALL diagnosis had an increased risk of becoming overweight or obese both during and after therapy.

Patients had an increased risk of short stature after therapy if they were older at diagnosis or had standard or high-risk disease, higher white blood cell counts at diagnosis, and central nervous system disease.

The researchers reported these findings in Cancer.

The team looked at 372 children with ALL, reviewing changes in their body mass index (BMI), weight, and height from diagnosis to 5 years after treatment ended.

The patients were treated with the Total XV protocol between 2000 and 2007 (NCT00137111). They received 6 weeks of induction therapy, 8 weeks of consolidation, and continuation for 120 weeks in females and 146 weeks in males.

BMI changes

Roughly a quarter of patients were overweight or obese at diagnosis, but that increased to roughly half of patients by the time they had been off therapy for 5 years.

“Over the whole population that was studied, we found statistically significant weight gain even during remission-induction therapy,” said study author Hiroto Inaba, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Patients’ median BMI z scores increased significantly during induction (P<0.001) and reinduction (P=0.001) with glucocorticoid therapy as well as in the first year after therapy ended (P=0.006).

At various points during treatment, there were significant differences in BMI z scores according to sex, race, and disease risk group. However, these differences were not present after therapy.

On the other hand, there were significant differences in BMI z scores according to age both during and after therapy.

Between week 21 of treatment and 3 years after therapy ended, patients who were ages 2 to 9 at diagnosis had median BMI z scores that were significantly higher than scores of patients who were age 10 or older at diagnosis (P≤0.033 for all time points).

The researchers also found that patients who were of a healthy weight or underweight at the time of diagnosis had a significantly higher risk of becoming overweight or obese during or after therapy if they were ages 2 to 9 at diagnosis, compared to the older patients (P=0.001).

Height changes

The researchers found that height z scores declined during treatment and improved after it ended, although z scores “never improved to the levels noted at the time of diagnosis.”

Median height z scores at the end of induction and in continuation weeks 1 to 21 were significantly higher in patients age 10 or older at diagnosis than in patients ages to 2 to 9 at diagnosis (P≤0.038 for all time points).

However, the median height z scores at 5 years off therapy were significantly higher for the younger patients than for the older patients (P=0.011).

The median height z scores were higher for patients with low-risk disease than for standard- or high-risk patients in weeks 17, 21, 48, and 146 of treatment and at 1 to 3 years after therapy ended (P≤0.024 for all time points).

At 3 years to 5 years after treatment ended, the median height z scores were significantly higher among patients with white blood cell counts below 50 × 10⁹/L at diagnosis (P≤0.018 for all time points).

Patients without central nervous system disease had significantly higher median height z scores at 3 years after treatment ended (P=0.029).

Males had significantly higher median height z scores than females in weeks 96 and 120 of therapy (P≤0.009 for both time points).

And white patients had higher median height z scores than black patients at 2 to 4 years after treatment ended (P≤0.027 for all time points).

Implications

To address the issue of excess weight gain in ALL patients, the researchers suggested early interventions, such as education about proper diet and exercise.

“When you look at the literature of childhood obesity prevention for the general population, there are interventions that could also help ALL patients,” said study author Emily Browne, of St. Jude.

“But we need to adapt those recommendations to take the cancer therapy into account.”

For the issue of height, the researchers recommended evaluating certain patients for growth hormone deficiency.

The team also noted that further study is needed to determine whether emerging therapeutic approaches can reduce toxicities without compromising antileukemic effects.

“We are hoping new therapeutic options can decrease intensity of chemotherapy and keep normal tissues intact,” Dr. Inaba said. “But until then, we’re collaborating with multiple clinical departments to help ensure a good, quality cure and a good quality of life in survivorship.”

This research was supported by grants from the National Institutes of Health and ALSAC, the fundraising and awareness organization of St. Jude.

Photo from St. Jude Children’s Research Hospital

New research suggests several factors may be associated with the risk of short stature and excess weight gain in children with acute lymphoblastic leukemia (ALL).

Researchers found that patients who were younger at ALL diagnosis had an increased risk of becoming overweight or obese both during and after therapy.

Patients had an increased risk of short stature after therapy if they were older at diagnosis or had standard or high-risk disease, higher white blood cell counts at diagnosis, and central nervous system disease.

The researchers reported these findings in Cancer.

The team looked at 372 children with ALL, reviewing changes in their body mass index (BMI), weight, and height from diagnosis to 5 years after treatment ended.

The patients were treated with the Total XV protocol between 2000 and 2007 (NCT00137111). They received 6 weeks of induction therapy, 8 weeks of consolidation, and continuation for 120 weeks in females and 146 weeks in males.

BMI changes

Roughly a quarter of patients were overweight or obese at diagnosis, but that increased to roughly half of patients by the time they had been off therapy for 5 years.

“Over the whole population that was studied, we found statistically significant weight gain even during remission-induction therapy,” said study author Hiroto Inaba, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Patients’ median BMI z scores increased significantly during induction (P<0.001) and reinduction (P=0.001) with glucocorticoid therapy as well as in the first year after therapy ended (P=0.006).

At various points during treatment, there were significant differences in BMI z scores according to sex, race, and disease risk group. However, these differences were not present after therapy.

On the other hand, there were significant differences in BMI z scores according to age both during and after therapy.

Between week 21 of treatment and 3 years after therapy ended, patients who were ages 2 to 9 at diagnosis had median BMI z scores that were significantly higher than scores of patients who were age 10 or older at diagnosis (P≤0.033 for all time points).

The researchers also found that patients who were of a healthy weight or underweight at the time of diagnosis had a significantly higher risk of becoming overweight or obese during or after therapy if they were ages 2 to 9 at diagnosis, compared to the older patients (P=0.001).

Height changes

The researchers found that height z scores declined during treatment and improved after it ended, although z scores “never improved to the levels noted at the time of diagnosis.”

Median height z scores at the end of induction and in continuation weeks 1 to 21 were significantly higher in patients age 10 or older at diagnosis than in patients ages to 2 to 9 at diagnosis (P≤0.038 for all time points).

However, the median height z scores at 5 years off therapy were significantly higher for the younger patients than for the older patients (P=0.011).

The median height z scores were higher for patients with low-risk disease than for standard- or high-risk patients in weeks 17, 21, 48, and 146 of treatment and at 1 to 3 years after therapy ended (P≤0.024 for all time points).

At 3 years to 5 years after treatment ended, the median height z scores were significantly higher among patients with white blood cell counts below 50 × 10⁹/L at diagnosis (P≤0.018 for all time points).

Patients without central nervous system disease had significantly higher median height z scores at 3 years after treatment ended (P=0.029).

Males had significantly higher median height z scores than females in weeks 96 and 120 of therapy (P≤0.009 for both time points).

And white patients had higher median height z scores than black patients at 2 to 4 years after treatment ended (P≤0.027 for all time points).

Implications

To address the issue of excess weight gain in ALL patients, the researchers suggested early interventions, such as education about proper diet and exercise.

“When you look at the literature of childhood obesity prevention for the general population, there are interventions that could also help ALL patients,” said study author Emily Browne, of St. Jude.

“But we need to adapt those recommendations to take the cancer therapy into account.”

For the issue of height, the researchers recommended evaluating certain patients for growth hormone deficiency.

The team also noted that further study is needed to determine whether emerging therapeutic approaches can reduce toxicities without compromising antileukemic effects.

“We are hoping new therapeutic options can decrease intensity of chemotherapy and keep normal tissues intact,” Dr. Inaba said. “But until then, we’re collaborating with multiple clinical departments to help ensure a good, quality cure and a good quality of life in survivorship.”

This research was supported by grants from the National Institutes of Health and ALSAC, the fundraising and awareness organization of St. Jude.

Soft tissue sarcomas are rare mesenchymal tumors that comprise 1% of all malignancies. Synovial sarcoma accounts for 5% to 10% of adult soft tissue sarcomas and usually occurs in close association with joint capsules, tendon sheaths, and bursa in the extremities of young and middle-aged adults.¹ Synovial sarcomas have been reported in other unusual sites, including the head and neck, thoracic and abdominal wall, retroperitoneum, bone, pleura, and visceral organs such as the lung, prostate, or kidney.² Primary renal synovial sarcoma is an extremely rare tumor accounting for <2% of all malignant renal tumors.³ To the best of our knowledge, fewer than 50 cases of primary renal synovial sarcoma have been described in the English literature.⁴ It presents as a diagnostic dilemma because of the dearth of specific clinical and imaging findings and is often confused with benign and malignant tumors. The differential diagnosis includes angiomyolipoma, renal cell carcinoma with sarcomatoid differentiation, metastatic sarcoma, hemangiopericytoma, malignant solitary fibrous tumor, Wilms tumor, and malignant peripheral nerve sheath tumor. Hence, a combination of histomorphologic, immunohistochemical, cytogenetic, and molecular studies that show a unique chromosomal translocation t(X;18) (p11;q11) is imperative in the diagnosis of primary renal synovial sarcoma.⁴ In the present report, we present the case of a 38-year-old man who was diagnosed with primary renal synovial sarcoma.

Case presentation and summary

A 38-year-old man with a medical history of gastroesophageal reflux disease and Barrett’s esophagus presented to our hospital for the first time with persistent and progressive right-sided flank and abdominal pain that was aggravated after a minor trauma to the back. There was no associated hematuria or dysuria.

Of note is that he had experienced intermittent flank pain for 2 years before this transfer. He had initially been diagnosed at his local hospital close to his home by ultrasound with an angiomyolipoma of 2 × 3 cm arising from the upper pole of his right kidney, which remained stable on repeat sonograms. About 22 months after his initial presentation at his local hospital, the flank pain increased, and a computed-tomographic (CT) scan revealed a perinephric hematoma that was thought to originate from a ruptured angiomyolipoma. He subsequently underwent embolization, but his symptoms recurred soon after. He presented again to his local hospital where CT imaging revealed a significant increase in the size of the retroperitoneal mass, and findings were suggestive of a hematoma. Subsequent angiogram did not reveal active extravasation, so a biopsy was performed.

Before confirmatory pathologic evaluation could be completed, the patient presented to his local hospital again in excruciating pain. A CT scan of his abdomen and pelvis demonstrated a massive subacute on chronic hematoma in the right retroperitoneum measuring 22 × 19 × 18 cm, with calcifications originating from an upper pole right renal neoplasm. The right kidney was displaced antero-inferiorly, and the inferior vena cava was displaced anteriorly and to the left. The preliminary pathology returned with findings suggestive of sarcoma (Figures 1 and 2).

Discussion

Synovial sarcoma is the fourth most common type of soft tissue sarcoma, accounting for 2.5% to 10.5% of all primary soft tissue malignancies worldwide. It occurs most frequently in adolescents and young adults, with most patients presenting between the ages of 15 and 40 years. Median age of presentation is 36 years. Despite the nomenclature, synovial sarcoma does not arise in intra-articular locations but typically occurs in proximity to joints in the extremities. Synovial sarcomas are less commonly described in other sites, including the head and neck, mediastinum, intraperitoneum, retroperitoneum, lung, pleura, and kidney.^4,5 Renal synovial sarcoma was first described in a published article by Argani and colleagues in 2000.⁵

Adult renal mesenchymal tumors are classified into benign and malignant tumors on the basis of the histologic features and clinicobiologic behavior.^6,7 The benign esenchymal renal tumors include angiomyolipoma, leiomyoma, hemangioma, lymphangioma, juxtaglomerular cell tumor, renomedullary interstitial cell tumor (medullary fibroma), lipoma, solitary fibrous tumor, and schwannoma. Malignant renal tumors of mesenchymal origin include leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, solitary fibrous tumor, and synovial sarcoma.

Most of these tumor types cause the same nonspecific symptoms in patients – abdominal pain, flank pain, abdominal fullness, a palpable mass, and hematuria – although they can be clinically silent. The average duration of symptoms in synovial sarcoma is 2 to 4 years.⁸ The long duration of symptoms and initial slow growth of synovial sarcomas may give a false impression of a benign process.

A preoperative radiological diagnosis of primary renal synovial sarcoma may be suspected by analyzing the tumor’s growth patterns on CT scans.⁹ Renal synovial sarcomas often appear as large, well-defined soft tissue masses that can extend into the renal pelvis or into the perinephric region.⁹ A CT scan may identify soft tissue calcifications, especially subtle ones in areas where the tumor anatomy is complex. A CT scan may also reveal areas of hemorrhage, necrosis, or cyst formation within the tumor, and can easily confirm bone involvement. Intravenous contrast may help in differentiating the mass from adjacent muscle and neurovascular complex.^9,10 On MRI, renal synovial sarcomas are often described as nonspecific heterogeneous masses, although they may also exhibit heterogeneous enhancement of hemorrhagic areas, calcifications, and air-fluid levels (known as “triple sign”) as well as septae. The triple sign may be identified as areas of low, intermediate, and high signal intensity, correlating with areas of hemorrhage, calcification, and air-fluid level.^9,10 Signal intensity is about equal to that of skeletal muscle on T1-weighted MRI and higher than that of subcutaneous fat on T2-weighted MRI.

In the present case, the tumor was initially misdiagnosed as an angiomyolipoma, the most common benign tumor of the kidney. Angiomyolipomas are usually solid triphasic tumors arising from the renal cortex and are composed of 3 major elements: dysmorphic blood vessels, smooth muscle components, and adipose tissue. When angiomyolipomas are large enough, they are readily recognized by the identification of macroscopic fat within the tumor, either by CT scan or MRI.¹¹ When they are small, they may be difficult to distinguish from a small cyst on CT because of volume averaging.

On pathology, synovial sarcoma has dual epithelial and mesenchymal differentiation. They are frequently multi-lobulated, and areas of necrosis, hemorrhage, and cyst formation are also common. There are 3 main histologic subtypes of synovial sarcoma: biphasic (20%-30%), monophasic (50%-60%), and poorly differentiated (15%-25%). Poorly differentiated synovial sarcomas are generally epithelioid in morphology, have high mitotic activity (usually 10-20 mitoses/10 high-power field; range is <5 for well differentiated, low-grade tumors), and can be confused with round cell tumors such as Ewing sarcoma. Poorly differentiated synovial sarcomas are high-grade tumors.

Immunohistochemical studies can confirm the pathological diagnosis. Synovial sarcomas usually stain positive for Bcl2, CD99/Mic2, CD56, Vim, and focally for EMA but negatively for desmin, actin, WT1, S-100, CD34, and CD31.⁵ Currently, the gold standard for diagnosis and hallmark for synovial sarcomas are the t (X;18) translocation and SYT-SSX gene fusion products (SYT-SSX1 in 67% and SYT-SSX2 in 33% of cases). These can be detected either by FISH or reverse-transcription polymerase chain reaction. This genetic alteration is identified in more than 90% of synovial sarcomas and is highly specific.

The role of SYT-SSX gene fusion in the pathogenesis of synovial sarcoma is an active area of investigation. The fusion of SYT with SSX translates into a fusion protein that binds to the transcription activator SMARCA4 that is involved in chromatin remodeling, thus displacing both the wildtype SYT and the tumor suppressor gene SMARCB1. The modified protein complex then binds at several super-enhancer loci, unlocking suppressed genes such as Sox2, which is known to be necessary for synovial sarcoma proliferation. Alterations in SMARCB1 are involved in several cancer types, implicating this event as a driver of these malignancies.¹² This results in a global alteration in chromatin remodeling that needs to be better understood to design targeted therapies.

The clinical course of synovial sarcoma, regardless of the tissue of origin, is typically poor. Multiple clinical and pathologic factors, including tumor size, location, patient age, and presence of poorly differentiated areas, are thought to have prognostic significance. A tumor size of more than 5 cm at presentation has the greatest impact on prognosis, with studies showing 5-year survival rates of 64% for patients with tumors smaller than 5 cm and 26% for patients with masses greater than 5 cm.^13,14 High-grade synovial sarcoma is favored in tumors that have cystic components, hemorrhage, and fluid levels and the triple sign.

Patients with tumors in the extremities have a more favorable prognosis than those with lesions in the head and neck area or axially, a feature that likely reflects better surgical control available for extremity lesions. Patient age of less than 15 to 20 years is also associated with a better long-term prognosis.^15,16 Varela-Duran and Enzinger¹⁷ reported that the presence of extensive calcifications suggests improved long-term survival, with 5-year survival rates of 82% and decreased rates of local recurrence (32%) and metastatic disease (29%). The poorly differentiated subtype is associated with a worsened prognosis, with a 5-year survival rate of 20% through 30%.^18,19 Other pathologic factors associated with worsened prognosis include presence of rhabdoid cells, extensive tumor necrosis, high nuclear grade, p53 mutations, and high mitotic rate (>10 mitoses/10 high-power field). More recently, the gene fusion type SYT-SSX2 (more common in monophasic lesions) has been associated with an improved prognosis, compared with that for SYT-SSX1, and an 89% metastasis-free survival.²⁰

Although there are no guidelines for the treatment of primary renal synovial sarcoma because of the limited number of cases reported, surgery is considered the first choice. Adjuvant chemotherapy with an anthracycline (doxorubicin or epirubicin) combined with ifosfamide has been the most frequently used regimen in published cases, especially in those in which patients have poor prognostic factors as mentioned above.

Overall, the 5-year survival rate ranges from 36% to 76%.¹⁴ The clinical course of synovial sarcoma is characterized by a high rate of local recurrence (30%-50%) and metastatic disease (41%). Most metastases occur within the first 2 to 5 years after treatment cessation. Metastases are present in 16% to 25% of patients at their initial presentation, with the most frequent metastatic site being the lung, followed by the lymph nodes (4%-18%) and bone (8%-11%).
 

Conclusion

Primary renal synovial sarcoma is extremely rare, and preoperative diagnosis is difficult in the absence of specific clinical or imaging findings. A high index of suspicion combined with pathologic, immunohistochemical, cytogenetic, and molecular studies is essential for accurate diagnosis and subsequent treatment planning. The differential diagnosis of renal synovial sarcoma can be extensive, and our experience with this patient illustrates the diagnostic dilemma associated with renal synovial sarcoma.

Soft tissue sarcomas are rare mesenchymal tumors that comprise 1% of all malignancies. Synovial sarcoma accounts for 5% to 10% of adult soft tissue sarcomas and usually occurs in close association with joint capsules, tendon sheaths, and bursa in the extremities of young and middle-aged adults.¹ Synovial sarcomas have been reported in other unusual sites, including the head and neck, thoracic and abdominal wall, retroperitoneum, bone, pleura, and visceral organs such as the lung, prostate, or kidney.² Primary renal synovial sarcoma is an extremely rare tumor accounting for <2% of all malignant renal tumors.³ To the best of our knowledge, fewer than 50 cases of primary renal synovial sarcoma have been described in the English literature.⁴ It presents as a diagnostic dilemma because of the dearth of specific clinical and imaging findings and is often confused with benign and malignant tumors. The differential diagnosis includes angiomyolipoma, renal cell carcinoma with sarcomatoid differentiation, metastatic sarcoma, hemangiopericytoma, malignant solitary fibrous tumor, Wilms tumor, and malignant peripheral nerve sheath tumor. Hence, a combination of histomorphologic, immunohistochemical, cytogenetic, and molecular studies that show a unique chromosomal translocation t(X;18) (p11;q11) is imperative in the diagnosis of primary renal synovial sarcoma.⁴ In the present report, we present the case of a 38-year-old man who was diagnosed with primary renal synovial sarcoma.

Case presentation and summary

A 38-year-old man with a medical history of gastroesophageal reflux disease and Barrett’s esophagus presented to our hospital for the first time with persistent and progressive right-sided flank and abdominal pain that was aggravated after a minor trauma to the back. There was no associated hematuria or dysuria.

Of note is that he had experienced intermittent flank pain for 2 years before this transfer. He had initially been diagnosed at his local hospital close to his home by ultrasound with an angiomyolipoma of 2 × 3 cm arising from the upper pole of his right kidney, which remained stable on repeat sonograms. About 22 months after his initial presentation at his local hospital, the flank pain increased, and a computed-tomographic (CT) scan revealed a perinephric hematoma that was thought to originate from a ruptured angiomyolipoma. He subsequently underwent embolization, but his symptoms recurred soon after. He presented again to his local hospital where CT imaging revealed a significant increase in the size of the retroperitoneal mass, and findings were suggestive of a hematoma. Subsequent angiogram did not reveal active extravasation, so a biopsy was performed.

Before confirmatory pathologic evaluation could be completed, the patient presented to his local hospital again in excruciating pain. A CT scan of his abdomen and pelvis demonstrated a massive subacute on chronic hematoma in the right retroperitoneum measuring 22 × 19 × 18 cm, with calcifications originating from an upper pole right renal neoplasm. The right kidney was displaced antero-inferiorly, and the inferior vena cava was displaced anteriorly and to the left. The preliminary pathology returned with findings suggestive of sarcoma (Figures 1 and 2).

Discussion

Synovial sarcoma is the fourth most common type of soft tissue sarcoma, accounting for 2.5% to 10.5% of all primary soft tissue malignancies worldwide. It occurs most frequently in adolescents and young adults, with most patients presenting between the ages of 15 and 40 years. Median age of presentation is 36 years. Despite the nomenclature, synovial sarcoma does not arise in intra-articular locations but typically occurs in proximity to joints in the extremities. Synovial sarcomas are less commonly described in other sites, including the head and neck, mediastinum, intraperitoneum, retroperitoneum, lung, pleura, and kidney.^4,5 Renal synovial sarcoma was first described in a published article by Argani and colleagues in 2000.⁵

Adult renal mesenchymal tumors are classified into benign and malignant tumors on the basis of the histologic features and clinicobiologic behavior.^6,7 The benign esenchymal renal tumors include angiomyolipoma, leiomyoma, hemangioma, lymphangioma, juxtaglomerular cell tumor, renomedullary interstitial cell tumor (medullary fibroma), lipoma, solitary fibrous tumor, and schwannoma. Malignant renal tumors of mesenchymal origin include leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, solitary fibrous tumor, and synovial sarcoma.

Most of these tumor types cause the same nonspecific symptoms in patients – abdominal pain, flank pain, abdominal fullness, a palpable mass, and hematuria – although they can be clinically silent. The average duration of symptoms in synovial sarcoma is 2 to 4 years.⁸ The long duration of symptoms and initial slow growth of synovial sarcomas may give a false impression of a benign process.

A preoperative radiological diagnosis of primary renal synovial sarcoma may be suspected by analyzing the tumor’s growth patterns on CT scans.⁹ Renal synovial sarcomas often appear as large, well-defined soft tissue masses that can extend into the renal pelvis or into the perinephric region.⁹ A CT scan may identify soft tissue calcifications, especially subtle ones in areas where the tumor anatomy is complex. A CT scan may also reveal areas of hemorrhage, necrosis, or cyst formation within the tumor, and can easily confirm bone involvement. Intravenous contrast may help in differentiating the mass from adjacent muscle and neurovascular complex.^9,10 On MRI, renal synovial sarcomas are often described as nonspecific heterogeneous masses, although they may also exhibit heterogeneous enhancement of hemorrhagic areas, calcifications, and air-fluid levels (known as “triple sign”) as well as septae. The triple sign may be identified as areas of low, intermediate, and high signal intensity, correlating with areas of hemorrhage, calcification, and air-fluid level.^9,10 Signal intensity is about equal to that of skeletal muscle on T1-weighted MRI and higher than that of subcutaneous fat on T2-weighted MRI.

In the present case, the tumor was initially misdiagnosed as an angiomyolipoma, the most common benign tumor of the kidney. Angiomyolipomas are usually solid triphasic tumors arising from the renal cortex and are composed of 3 major elements: dysmorphic blood vessels, smooth muscle components, and adipose tissue. When angiomyolipomas are large enough, they are readily recognized by the identification of macroscopic fat within the tumor, either by CT scan or MRI.¹¹ When they are small, they may be difficult to distinguish from a small cyst on CT because of volume averaging.

On pathology, synovial sarcoma has dual epithelial and mesenchymal differentiation. They are frequently multi-lobulated, and areas of necrosis, hemorrhage, and cyst formation are also common. There are 3 main histologic subtypes of synovial sarcoma: biphasic (20%-30%), monophasic (50%-60%), and poorly differentiated (15%-25%). Poorly differentiated synovial sarcomas are generally epithelioid in morphology, have high mitotic activity (usually 10-20 mitoses/10 high-power field; range is <5 for well differentiated, low-grade tumors), and can be confused with round cell tumors such as Ewing sarcoma. Poorly differentiated synovial sarcomas are high-grade tumors.

Immunohistochemical studies can confirm the pathological diagnosis. Synovial sarcomas usually stain positive for Bcl2, CD99/Mic2, CD56, Vim, and focally for EMA but negatively for desmin, actin, WT1, S-100, CD34, and CD31.⁵ Currently, the gold standard for diagnosis and hallmark for synovial sarcomas are the t (X;18) translocation and SYT-SSX gene fusion products (SYT-SSX1 in 67% and SYT-SSX2 in 33% of cases). These can be detected either by FISH or reverse-transcription polymerase chain reaction. This genetic alteration is identified in more than 90% of synovial sarcomas and is highly specific.

The role of SYT-SSX gene fusion in the pathogenesis of synovial sarcoma is an active area of investigation. The fusion of SYT with SSX translates into a fusion protein that binds to the transcription activator SMARCA4 that is involved in chromatin remodeling, thus displacing both the wildtype SYT and the tumor suppressor gene SMARCB1. The modified protein complex then binds at several super-enhancer loci, unlocking suppressed genes such as Sox2, which is known to be necessary for synovial sarcoma proliferation. Alterations in SMARCB1 are involved in several cancer types, implicating this event as a driver of these malignancies.¹² This results in a global alteration in chromatin remodeling that needs to be better understood to design targeted therapies.

The clinical course of synovial sarcoma, regardless of the tissue of origin, is typically poor. Multiple clinical and pathologic factors, including tumor size, location, patient age, and presence of poorly differentiated areas, are thought to have prognostic significance. A tumor size of more than 5 cm at presentation has the greatest impact on prognosis, with studies showing 5-year survival rates of 64% for patients with tumors smaller than 5 cm and 26% for patients with masses greater than 5 cm.^13,14 High-grade synovial sarcoma is favored in tumors that have cystic components, hemorrhage, and fluid levels and the triple sign.

Patients with tumors in the extremities have a more favorable prognosis than those with lesions in the head and neck area or axially, a feature that likely reflects better surgical control available for extremity lesions. Patient age of less than 15 to 20 years is also associated with a better long-term prognosis.^15,16 Varela-Duran and Enzinger¹⁷ reported that the presence of extensive calcifications suggests improved long-term survival, with 5-year survival rates of 82% and decreased rates of local recurrence (32%) and metastatic disease (29%). The poorly differentiated subtype is associated with a worsened prognosis, with a 5-year survival rate of 20% through 30%.^18,19 Other pathologic factors associated with worsened prognosis include presence of rhabdoid cells, extensive tumor necrosis, high nuclear grade, p53 mutations, and high mitotic rate (>10 mitoses/10 high-power field). More recently, the gene fusion type SYT-SSX2 (more common in monophasic lesions) has been associated with an improved prognosis, compared with that for SYT-SSX1, and an 89% metastasis-free survival.²⁰

Although there are no guidelines for the treatment of primary renal synovial sarcoma because of the limited number of cases reported, surgery is considered the first choice. Adjuvant chemotherapy with an anthracycline (doxorubicin or epirubicin) combined with ifosfamide has been the most frequently used regimen in published cases, especially in those in which patients have poor prognostic factors as mentioned above.

Overall, the 5-year survival rate ranges from 36% to 76%.¹⁴ The clinical course of synovial sarcoma is characterized by a high rate of local recurrence (30%-50%) and metastatic disease (41%). Most metastases occur within the first 2 to 5 years after treatment cessation. Metastases are present in 16% to 25% of patients at their initial presentation, with the most frequent metastatic site being the lung, followed by the lymph nodes (4%-18%) and bone (8%-11%).
 

Conclusion

Primary renal synovial sarcoma is extremely rare, and preoperative diagnosis is difficult in the absence of specific clinical or imaging findings. A high index of suspicion combined with pathologic, immunohistochemical, cytogenetic, and molecular studies is essential for accurate diagnosis and subsequent treatment planning. The differential diagnosis of renal synovial sarcoma can be extensive, and our experience with this patient illustrates the diagnostic dilemma associated with renal synovial sarcoma.

Soft tissue sarcomas are rare mesenchymal tumors that comprise 1% of all malignancies. Synovial sarcoma accounts for 5% to 10% of adult soft tissue sarcomas and usually occurs in close association with joint capsules, tendon sheaths, and bursa in the extremities of young and middle-aged adults.¹ Synovial sarcomas have been reported in other unusual sites, including the head and neck, thoracic and abdominal wall, retroperitoneum, bone, pleura, and visceral organs such as the lung, prostate, or kidney.² Primary renal synovial sarcoma is an extremely rare tumor accounting for <2% of all malignant renal tumors.³ To the best of our knowledge, fewer than 50 cases of primary renal synovial sarcoma have been described in the English literature.⁴ It presents as a diagnostic dilemma because of the dearth of specific clinical and imaging findings and is often confused with benign and malignant tumors. The differential diagnosis includes angiomyolipoma, renal cell carcinoma with sarcomatoid differentiation, metastatic sarcoma, hemangiopericytoma, malignant solitary fibrous tumor, Wilms tumor, and malignant peripheral nerve sheath tumor. Hence, a combination of histomorphologic, immunohistochemical, cytogenetic, and molecular studies that show a unique chromosomal translocation t(X;18) (p11;q11) is imperative in the diagnosis of primary renal synovial sarcoma.⁴ In the present report, we present the case of a 38-year-old man who was diagnosed with primary renal synovial sarcoma.

Case presentation and summary

A 38-year-old man with a medical history of gastroesophageal reflux disease and Barrett’s esophagus presented to our hospital for the first time with persistent and progressive right-sided flank and abdominal pain that was aggravated after a minor trauma to the back. There was no associated hematuria or dysuria.

Of note is that he had experienced intermittent flank pain for 2 years before this transfer. He had initially been diagnosed at his local hospital close to his home by ultrasound with an angiomyolipoma of 2 × 3 cm arising from the upper pole of his right kidney, which remained stable on repeat sonograms. About 22 months after his initial presentation at his local hospital, the flank pain increased, and a computed-tomographic (CT) scan revealed a perinephric hematoma that was thought to originate from a ruptured angiomyolipoma. He subsequently underwent embolization, but his symptoms recurred soon after. He presented again to his local hospital where CT imaging revealed a significant increase in the size of the retroperitoneal mass, and findings were suggestive of a hematoma. Subsequent angiogram did not reveal active extravasation, so a biopsy was performed.

Before confirmatory pathologic evaluation could be completed, the patient presented to his local hospital again in excruciating pain. A CT scan of his abdomen and pelvis demonstrated a massive subacute on chronic hematoma in the right retroperitoneum measuring 22 × 19 × 18 cm, with calcifications originating from an upper pole right renal neoplasm. The right kidney was displaced antero-inferiorly, and the inferior vena cava was displaced anteriorly and to the left. The preliminary pathology returned with findings suggestive of sarcoma (Figures 1 and 2).

Discussion

Synovial sarcoma is the fourth most common type of soft tissue sarcoma, accounting for 2.5% to 10.5% of all primary soft tissue malignancies worldwide. It occurs most frequently in adolescents and young adults, with most patients presenting between the ages of 15 and 40 years. Median age of presentation is 36 years. Despite the nomenclature, synovial sarcoma does not arise in intra-articular locations but typically occurs in proximity to joints in the extremities. Synovial sarcomas are less commonly described in other sites, including the head and neck, mediastinum, intraperitoneum, retroperitoneum, lung, pleura, and kidney.^4,5 Renal synovial sarcoma was first described in a published article by Argani and colleagues in 2000.⁵

Adult renal mesenchymal tumors are classified into benign and malignant tumors on the basis of the histologic features and clinicobiologic behavior.^6,7 The benign esenchymal renal tumors include angiomyolipoma, leiomyoma, hemangioma, lymphangioma, juxtaglomerular cell tumor, renomedullary interstitial cell tumor (medullary fibroma), lipoma, solitary fibrous tumor, and schwannoma. Malignant renal tumors of mesenchymal origin include leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, solitary fibrous tumor, and synovial sarcoma.

Most of these tumor types cause the same nonspecific symptoms in patients – abdominal pain, flank pain, abdominal fullness, a palpable mass, and hematuria – although they can be clinically silent. The average duration of symptoms in synovial sarcoma is 2 to 4 years.⁸ The long duration of symptoms and initial slow growth of synovial sarcomas may give a false impression of a benign process.

A preoperative radiological diagnosis of primary renal synovial sarcoma may be suspected by analyzing the tumor’s growth patterns on CT scans.⁹ Renal synovial sarcomas often appear as large, well-defined soft tissue masses that can extend into the renal pelvis or into the perinephric region.⁹ A CT scan may identify soft tissue calcifications, especially subtle ones in areas where the tumor anatomy is complex. A CT scan may also reveal areas of hemorrhage, necrosis, or cyst formation within the tumor, and can easily confirm bone involvement. Intravenous contrast may help in differentiating the mass from adjacent muscle and neurovascular complex.^9,10 On MRI, renal synovial sarcomas are often described as nonspecific heterogeneous masses, although they may also exhibit heterogeneous enhancement of hemorrhagic areas, calcifications, and air-fluid levels (known as “triple sign”) as well as septae. The triple sign may be identified as areas of low, intermediate, and high signal intensity, correlating with areas of hemorrhage, calcification, and air-fluid level.^9,10 Signal intensity is about equal to that of skeletal muscle on T1-weighted MRI and higher than that of subcutaneous fat on T2-weighted MRI.

In the present case, the tumor was initially misdiagnosed as an angiomyolipoma, the most common benign tumor of the kidney. Angiomyolipomas are usually solid triphasic tumors arising from the renal cortex and are composed of 3 major elements: dysmorphic blood vessels, smooth muscle components, and adipose tissue. When angiomyolipomas are large enough, they are readily recognized by the identification of macroscopic fat within the tumor, either by CT scan or MRI.¹¹ When they are small, they may be difficult to distinguish from a small cyst on CT because of volume averaging.

On pathology, synovial sarcoma has dual epithelial and mesenchymal differentiation. They are frequently multi-lobulated, and areas of necrosis, hemorrhage, and cyst formation are also common. There are 3 main histologic subtypes of synovial sarcoma: biphasic (20%-30%), monophasic (50%-60%), and poorly differentiated (15%-25%). Poorly differentiated synovial sarcomas are generally epithelioid in morphology, have high mitotic activity (usually 10-20 mitoses/10 high-power field; range is <5 for well differentiated, low-grade tumors), and can be confused with round cell tumors such as Ewing sarcoma. Poorly differentiated synovial sarcomas are high-grade tumors.

Immunohistochemical studies can confirm the pathological diagnosis. Synovial sarcomas usually stain positive for Bcl2, CD99/Mic2, CD56, Vim, and focally for EMA but negatively for desmin, actin, WT1, S-100, CD34, and CD31.⁵ Currently, the gold standard for diagnosis and hallmark for synovial sarcomas are the t (X;18) translocation and SYT-SSX gene fusion products (SYT-SSX1 in 67% and SYT-SSX2 in 33% of cases). These can be detected either by FISH or reverse-transcription polymerase chain reaction. This genetic alteration is identified in more than 90% of synovial sarcomas and is highly specific.

The role of SYT-SSX gene fusion in the pathogenesis of synovial sarcoma is an active area of investigation. The fusion of SYT with SSX translates into a fusion protein that binds to the transcription activator SMARCA4 that is involved in chromatin remodeling, thus displacing both the wildtype SYT and the tumor suppressor gene SMARCB1. The modified protein complex then binds at several super-enhancer loci, unlocking suppressed genes such as Sox2, which is known to be necessary for synovial sarcoma proliferation. Alterations in SMARCB1 are involved in several cancer types, implicating this event as a driver of these malignancies.¹² This results in a global alteration in chromatin remodeling that needs to be better understood to design targeted therapies.

The clinical course of synovial sarcoma, regardless of the tissue of origin, is typically poor. Multiple clinical and pathologic factors, including tumor size, location, patient age, and presence of poorly differentiated areas, are thought to have prognostic significance. A tumor size of more than 5 cm at presentation has the greatest impact on prognosis, with studies showing 5-year survival rates of 64% for patients with tumors smaller than 5 cm and 26% for patients with masses greater than 5 cm.^13,14 High-grade synovial sarcoma is favored in tumors that have cystic components, hemorrhage, and fluid levels and the triple sign.

Patients with tumors in the extremities have a more favorable prognosis than those with lesions in the head and neck area or axially, a feature that likely reflects better surgical control available for extremity lesions. Patient age of less than 15 to 20 years is also associated with a better long-term prognosis.^15,16 Varela-Duran and Enzinger¹⁷ reported that the presence of extensive calcifications suggests improved long-term survival, with 5-year survival rates of 82% and decreased rates of local recurrence (32%) and metastatic disease (29%). The poorly differentiated subtype is associated with a worsened prognosis, with a 5-year survival rate of 20% through 30%.^18,19 Other pathologic factors associated with worsened prognosis include presence of rhabdoid cells, extensive tumor necrosis, high nuclear grade, p53 mutations, and high mitotic rate (>10 mitoses/10 high-power field). More recently, the gene fusion type SYT-SSX2 (more common in monophasic lesions) has been associated with an improved prognosis, compared with that for SYT-SSX1, and an 89% metastasis-free survival.²⁰

Although there are no guidelines for the treatment of primary renal synovial sarcoma because of the limited number of cases reported, surgery is considered the first choice. Adjuvant chemotherapy with an anthracycline (doxorubicin or epirubicin) combined with ifosfamide has been the most frequently used regimen in published cases, especially in those in which patients have poor prognostic factors as mentioned above.

Overall, the 5-year survival rate ranges from 36% to 76%.¹⁴ The clinical course of synovial sarcoma is characterized by a high rate of local recurrence (30%-50%) and metastatic disease (41%). Most metastases occur within the first 2 to 5 years after treatment cessation. Metastases are present in 16% to 25% of patients at their initial presentation, with the most frequent metastatic site being the lung, followed by the lymph nodes (4%-18%) and bone (8%-11%).
 

Conclusion

Primary renal synovial sarcoma is extremely rare, and preoperative diagnosis is difficult in the absence of specific clinical or imaging findings. A high index of suspicion combined with pathologic, immunohistochemical, cytogenetic, and molecular studies is essential for accurate diagnosis and subsequent treatment planning. The differential diagnosis of renal synovial sarcoma can be extensive, and our experience with this patient illustrates the diagnostic dilemma associated with renal synovial sarcoma.