Clinical And Computed Tomography Imaging Features Of Renal Medullary Carcinoma: A Report Of Six Cases
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Renal medullary carcinoma is a rare subtype ofrenal cell carcinoma that most commonly occurs in adolescents andyoung adults with sickle cell hemoglobinopathies . According to the World HealthOrganization classification of renal tumors, RMC is adistinct entity with unique biological behavior and distinctivepathological and morphogenetic characteristics . The mostcommon symptoms of RMC are hematuria and flank or abdominal pain,which may lead to a misdiagnosis of urinary tract infection orrenal abscess in certain patients, prior to a neoplasm beingsuspected .
A number of cases of RMC in non-African Americanswithout sickle cell anemia or sickle cell trait were reportedwithin a series of 33 highly aggressive RMC first described in 1995. The histopathological featuresof RMC include epithelial cells with reticular, adenoid cysticplasia, and prominent inflammation .
Patients and methods
Multi-slice CT examinations
Antibodies used forimmunohistochemical analysis.
Antibodies used forimmunohistochemical analysis.
Learn More About Renal Medullary Carcinoma
Renal medullary carcinoma, also known as RMC, is a rare cancer of the kidney that mainly afflicts young people of African descent who carry the sickle cell trait, sickle cell disease, or other sickle hemoglobinopathies that can cause sickling of the red blood cells. Renal cell carcinoma, unclassified with medullary phenotype is a very rare subtype of RMC that occurs in people who do not carry any sickle hemoglobinopathies.
Glycerol Gradients Followed By Sds
Nuclear extracts and gradients were performed as previously published . Briefly, 500 micrograms of nuclear extract from approximately 30 million cells were resuspended in 0% glycerol HEMG buffer containing 1 mM DTT, cOmplete protease inhibitors and PhosStop . This was placed on a 1030% glycerol gradient and ultracentrifuged at 40 k RPM for 16 hr at 4C. Following centrifugation, fractions of 550 µL were collected. Samples were then prepared with 1x LDS Sample Buffer . Samples were run on a 412% Bis-Tris gel and then transferred by immunoblotting in tris-glycine-SDS buffer with methanol. Immunoblots were subsequently blocked with Licor Blocking Buffer and then incubated with antibodies as noted in the methods section. Immunoblots shown are representative of at least two biological replicates.
Malignant Rhabdoid Tumor Of The Kidney
Malignant rhabdoid tumor of the kidney can have a very similar morphologic presentation to RMC however, the former occurs in patients younger than 3 years. Both tumors show loss of INI1 expression. Although rhabdoid tumors mostly show SMARCB1 deletions or mutations, RMC harbors hemizygous SMARCB1 deletions with concurrent translocations or homozygous deletions.
Renal Medullary Carcinoma In An Adolescent With Sickle Cell Trait
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Katherine E. Warren, Vinod Gidvani-Diaz, Bertrand Duval-Arnould Renal Medullary Carcinoma in an Adolescent With Sickle Cell Trait. Pediatrics February 1999 103 : e22. 10.1542/peds.103.2.e22
We describe the complex presentation of a patient with renal medullary carcinoma, a newly described entity primarily affecting young patients with sickle cell trait. Renal medullary carcinoma is an aggressive, rapidly destructive tumor associated with a delayed diagnosis and a poor outcome. The most common presenting signs and symptoms include hematuria, abdominal or flank pain, and weight loss. Sickle cell trait as the sole cause of hematuria in young black patients is a diagnosis of exclusion. Hemoglobin electrophoresis, intravenous pyelography, and computed tomography scans should be the minimal studies performed in young black patients with hematuria.
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What Is Medullary Nephrocalcinosis
Medullary Nephrocalcinosis is a disorder of the kidneys in which there is accumulation of excess calcium within the medulla of the kidney. The medulla of the kidney, also known as renal medulla, is the innermost part of the kidney. It is splint into different parts called pyramids. The function of the renal medulla is to maintain a balance between salt and water in the blood. It also acts as filter for ions such as sodium, chloride, potassium, and calcium.
Medullary Nephrocalcinosis is normally a result of some other medical condition which results in the inability of the renal medulla to filter out the calcium ions causing an accumulation of calcium with the medulla of the kidney causing Medullary Nephrocalcinosis. This condition in itself is normally asymptomatic but the affected individual may experience symptoms of the underlying medical condition that is responsible for the development of Medullary Nephrocalcinosis.
In most of the cases, kidney stones are believed to be responsible for Medullary Nephrocalcinosis and in such cases the affected individual will experience blood in the urine, nausea and vomiting, abdominal pain along with pain in the flank area.
Some of the other causes for Medullary Nephrocalcinosis are certain medication which increases the levels of calcium in the blood, infections, medical conditions like hyperparathyroidism and renal tubular acidosis. In some cases, there has been a genetic link to the development of Medullary Nephrocalcinosis.
Effects Of Proteasome Inhibition In Vivo
These studies identify a lethal interaction between suppressing the UPS and SMARCB1-deficient cancers in vitro. The doses used in this study were based on in vitro studies of multiple myeloma or lymphoma cell lines . For patients with primary or refractory multiple myeloma, use of proteasome inhibitors has led to significant clinical responses . We reasoned that if our SMARCB1 deficient cancers were susceptible to proteasome inhibitors at similar in vitro dosing, we would also see similar in vivo responses. We first determined whether these doses led to proteasome inhibition by assessing the ability of these cell lines to cleave Suc-LLVY-aminoluciferin. We found that treatment of the SMARCB1 deficient cell lines with either bortezomib or MLN2238 led to inhibition of the proteasome to a similar extent observed when the multiple myeloma cell line RPMI8226 was treated . We also simulated the pharmacodynamics of proteasome inhibitors in vivo by treating cells in vitro with a pulse dose of proteasome inhibitors as has been performed in multiple myeloma and chronic myeloid leukemia cell lines . We found that upon treatment with MLN2238, SMARCB1 deficient cells arrested in G2/M, which led to cell death as measured by Annexin V/PI staining and led to accumulation of cyclin B1 similar to treatment with a continuous dose of MLN2238 .
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Breakapart Fluorescent In Situ Hybridization
We developed a custom dual-color breakapart FISH probe, using BAC probes surrounding SMARCB1 at 22q11.23: RP11-662F7 and RP11-1112A23 . The probe set was hybridized to a normal control to confirm chromosomal locations and to determine the frequency of expected fusion signals in normal cells. 50 nuclei were scored by two independent observers in the CLF_PEDS0005 and CLF_PEDS9001 models.
How Does It Spread
If a cancerous tumor is discovered in one of your kidneys, the usual treatment is to surgically remove part or all of the affected kidney.
If the tumor is not removed, its more likely that the cancer will spread to either your lymph nodes or other organs. The spread of cancer is called metastasis.
In the case of RCC, the tumor can invade a large vein leading out of the kidney. It can also spread to the lymph system and other organs. The lungs are especially vulnerable.
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How Is Medullary Nephrocalcinosis Treated
Preventing further deposition of calcium in the medullary region of the kidney is the primary concern for the treating physician. This will prevent worsening of the condition. The next step towards treatment of Medullary Nephrocalcinosis is to identify the cause of the excess calcium deposits. Once a cause is identified then treatment for that cause is begun immediately to treat Medullary Nephrocalcinosis.
Bringing down the levels of calcium is another challenge for the physician which is done by administration of isotonic sodium chloride which helps in bringing down the levels of calcium in the blood. Potassium and magnesium supplementation along with diuretics and restriction of salt is yet another way to bring down the levels of calcium in the blood and treat Medullary Nephrocalcinosis.
In some cases, with the identification of the cause of Medullary Nephrocalcinosis and prompt treatment, the levels of calcium comes down by themselves thereby treating Medullary Nephrocalcinosis. In some cases where Medullary Nephrocalcinosis is caused by renal tubular acidosis the damage done to the kidneys is basically irreversible.
Thus, it is highly recommended that an individual needs to start immediate treatment once a cause is identified and the diagnosis is confirmed of Medullary Nephrocalcinosis.
Renal Medullary Carcinomas Depend Upon Smarcb1 Loss And Are Sensitive To Proteasome Inhibition
- Open annotations. The current annotation count on this page is being calculated.
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Derivation And Genomic Characterization Of Rmc Models
Sequencing and cytogenetic efforts have identified deletion of one allele of SMARCB1 along with fusion events in the second allele of SMARCB1 in RMC patients . We performed WES or whole genome sequencing on the primary kidney tumor tissues. In both patients, we confirmed the presence of sickle cell trait but also found tumor purity was < 20%, which, like prior studies, prevented the identification of the fusion events . This low tumor purity is attributable to the stromal desmoplasia seen in RMC .
We then performed WES on the normal cell line or whole blood and compared it to the primary tumor cell lines and metastatic cell lines . We found a low mutation frequency in the tumor cell lines similar to that of other pediatric cancers and cell lines such as MRT, ATRT and Ewing sarcoma . We found that only the metastatic cell lines harbored mutations in TP53 and TPR . Using copy number analysis, we confirmed the heterozygous loss of SMARCB1. In agreement with prior studies, we failed to find an identifiable mutation or deletion to account for the loss of the second SMARCB1 allele with WES.
Patient-derived models of RMC have quiet genomes and are driven by intronic translocations.
What Is Renal Cell Carcinoma
It’s the most common type of kidney cancer. Although itâs a serious disease, finding and treating it early makes it more likely that youâll be cured. No matter when youâre diagnosed, you can do certain things to ease your symptoms and feel better during your treatment.
Most people who have renal cell carcinoma are older, usually between ages 50 and 70. It often starts as just one tumor in a kidney, but sometimes it begins as several tumors, or itâs found in both kidneys at once. You might also hear it called renal cell cancer.
Doctors have different ways to treat renal cell carcinoma, and scientists are testing new ones, too. Youâll want to learn as much about your disease as you can and work with your doctor so you can choose the best treatment.
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Renal Medullary Cancer In A Patient With Sickle Cell Trait
Achuta K. Guddati
1Division of Pulmonary and Critical Care Medicine, Montefiore Hospital, Albert Einstein College of Medicine, Yeshiva University, New York, NY, USA
2Department of Internal Medicine, University of Iowa Hospital, University of Iowa, Iowa, IA, USA
3Department of Pathology, Montefiore Hospital, Albert Einstein College of Medicine, Yeshiva University, New York, NY, USA
4Department of Internal Medicine, Massachusetts General Hospital, Harvard Medical School, Harvard University, 50 Fruit Street, Boston, MA, USA
2. Case Description
Proteasome Inhibitor Induced G2/m Arrest Is Mediated In Part By Inappropriate Cyclin B1 Degradation Driven By A Dependency On Ube2c
We subsequently searched for genes related to the ubiquitin-proteasome system and SMARCB1 function. We defined a set of 204 genes that were upregulated when comparing the log2 fold change between SMARCB1 deficient cells and SMARCB1 re-expressed cells in RMC and MRT cell lines . We then took this set of 204 genes and examined the Project Achilles DepMap Public 18Q3 dataset to determine whether any SMARCB1 deficient cell lines required expression of these genes for survival. This dataset included loss of function screens from 485 cancer cell lines and included three ATRT SMARCB1-deficient cancer cell lines: COGAR359, CHLA06ATRT and CHLA266. We found that SMARCB1 deficient cancer cell lines required UBE2C, an ubiquitin-conjugating enzyme, for survival. We noted that these cell lines were in the top 5% of cell lines that required UBE2C for survival . These observations suggested that cancer cell lines that lack SMARCB1 were also dependent on UBE2C.
Cell cycle arrest secondary to proteasome inhibition acts via UBE2C/cyclin B1 dysregulation and proteasome inhibition with MLN2238 is effective in vivo.
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The Renal Medulla Is A Hypoxic And Hypertonic Environment
In addition to sickle cell trait/disease, RMC has been described in other sickle hemoglobinopathies such as sickle beta thalassemia and sickle cell hemoglobin C disease , but never in hemoglobinopathies not associated with RBC sickling. This raises the question: What is it about RBC sickling that predisposes to RMC?
Under normal conditions, the renal inner medulla is the most hypoxic and hypertonic tissue in the human body, with a partial pressure of oxygen in the range of 10 to 20 mm Hg and interstitial osmolarity of 1,200 mOsm/L . Such extreme hypoxia and hypertonicity allow the kidneys to concentrate urine via the countercurrent multiplication process . Within this environment, the RBCs of individuals with sickle hemoglobinopathies, including sickle cell trait, will sickle . As a result, microvascular occlusions occur, further increasing the hypoxic environment and causing concomitant acidosis, which will further exacerbate sickling and increase blood viscosity . Indeed, sickle cells are often found in the renal medulla of individuals with sickle cell trait despite the absence of sickling in the peripheral blood , and sickled RBCs are a frequent finding in RMC nephrectomy specimens from patients with sickle cell trait .
Sanger Sequencing Confirmation Of Wgs Findings
gDNA was extracted using QIAamp DNA mini kit . We performed a mixing study of our RMC cell lines with gDNA isolated from the G401 MRT cell line and then performed PCR amplification. We determined that the lower limits of detection of these fusions with our methods were ~1% of tumor cell line gDNA with a minimum 50 ng of gDNA. We subsequently performed the same PCR reactions with 100 ng of gDNA from the tumor tissue samples. Samples were gel purified and submitted for Sanger sequencing . We found that the sequences from the tumor tissue samples matched those of the cell lines, confirming that the genomic alterations that we found in the cell lines reflect those found in the original tumor. Primers utilized were CLF_PEDS0005 chr1 forward , CLF_PEDS0005 SMARCB1 reverse , CLF_PEDS9001 chr12 forward , CLF_PEDS9001 SMARCB1 reverse .
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Taking Care Of Yourself
You can do things during and after your treatment to feel stronger physically and emotionally.
- Eat well. You need calories and nutrients to stay strong for treatment. If itâs hard for you to eat, try smaller meals every few hours instead of three big meals.
- Keep moving.Exercise is good for your body and your mind. Your treatment may leave you feeling tired, so be sure to balance activity with rest.
- Follow your treatment plan. Keep your doctor in the loop about any changes in how youâre feeling.
- Get support. Itâs important to take care of your emotional health, too. Trained counselors and support groups can offer safe places to talk about how you and your loved ones feel. Also, ask for help from family, friends, and members of your community.
What Causes Medullary Nephrocalcinosis
As stated, the main cause for the development of Medullary Nephrocalcinosis is believed to be renal stones, although there are certain infections which also lead to excess calcium in the blood. There are also other medical conditions that are believed to play a part in the development of Medullary Nephrocalcinosis. These medical conditions are:
- Primary hyperparathyroidism
- Pain in the abdominal and flank regions
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Why I’m Fighting For Renal Medullary Carcinoma Patients
As I entered the fall of 2016, I found myself excited about my brother Hermans cancer-free status. He had returned from MD Anderson at the end of August with continued good news: clear scans.
Four years ago, he was diagnosed with renal medullary carcinoma, an extremely rare type of kidney cancer with a poor prognosis. Hermans been cancer-free for the last two years.
Many people are shocked when they hear Herman is still surviving. When you read the statistics, he shouldnt be here.
But as Ive learned, despite your diagnosis, theres always hope beyond what you see.
Dont be afraid to reach out
When Herman was diagnosed with renal medullary carcinoma in 2012, our family couldnt see a way out. All of the odds seemed stacked against us.
To have a center of excellence like MD Anderson accept us was such a blessing. Hermans story brings hope to everyone who has been diagnosed with renal medullary carcinoma.
However, the statistics are still sobering, and currently there is no cure for renal medullary carcinoma. All of the survivors I meet are desperate for a doctor who is familiar with treating this disease. I feel lucky that we found Nazir Tannir, M.D., Hermans MD Anderson oncologist, who is one of the worlds leaders in treating renal medullary carcinoma.
Building hope through advocacy
I remember feeling so hopeless. I didnt want anyone to feel like this. So I created a community through social media where others can get connected and know that they arent alone.