CASE REPORT
Xp11.2 translocation tumor: A rare cause of gross hematuria Howard E. Asaki, PA-C; Gianni Moshero, PA-C; Melissa L. Stanton, MD; Mitchell R. Humphreys, MD
ABSTRACT Xp11.2 translocation tumor is a rare but aggressive form of renal cell carcinoma that predominantly occurs in children but also may be found in young adults. Because this type of cancer is diagnosed via histologic and chromosomal analysis, clinicians should consider translocation tumor in the differential diagnosis of patients with renal lesions and gross hematuria. Keywords: Xp11.2 translocation tumor, renal cell carcinoma, chromosomal abnormalities, fluorescence in situ hybridization, transcription factor E3, TFE3
CASE A 41-year-old woman in good health experienced right flank pain and noticed gross hematuria on micturition. She presented to the ED for evaluation. History The patient denied any trauma, anticoagulation therapy, atrial fibrillation, or prior history of urinary stones or microscopic or gross hematuria. Her past medical history and family history were noncontributory. Her social history was negative for smoking. Vital signs were within normal limits. Urinalysis demonstrated greater than 180 red blood cells and 137 white blood cells per high-power field. Her urine was not nitrate positive, and the urine culture was negative for any microorganisms. All other laboratory tests, including hemoglobin, creatinine, and coagulation studies, were within normal limits. A CT scan of the abdomen and pelvis revealed an infarcted region in the medial aspect of the upper pole of the right kidney, as well as hyperdense areas on the precontrast images, consistent with acute renal bleeding (Figure 1). This initial study had no arterial phase because Howard E. Asaki and Gianni Moshero practice in the Department of Urology at the Mayo Clinic Hospital in Phoenix, Ariz. Melissa L. Stanton practices in the Division of Anatomic Pathology at the Mayo Clinic in Scottsdale, Ariz. Mitchell R. Humphreys practices in the Department of Urology at the Mayo Clinic Hospital in Phoenix, Ariz. The authors have indicated no relationships to disclose relating to the content of this article. DOI: 10.1097/01.JAA.0000442700.87975.0b Copyright © 2014 American Academy of Physician Assistants
24
www.JAAPA.com
A
B
FIGURE 1. CT of the right renal lesion at time of patient presen-
tation to the ED. A hyperintense area of the medial right renal parenchyma includes the collecting system and is consistent with acute hemorrhage (A, circled). A limited contrast study with partial renal obstruction, as evident by the delayed excretion of the contrast agent and the renal defect that was interpreted as a renal infarct (B, circled). Volume 27 • Number 2 • February 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Xp11.2 translocation tumor: A rare cause of gross hematuria
Key points Keep an open mind when evaluating a patient: The problem might not be what was initially presented. Obtain the diagnostic study that you need, rather than settling for a similar study that has already been done. When the pathology of a renal tumor reveals renal cell carcinoma, consider the diagnosis of translocation carcinoma.
the radiologist decided to minimize the patient’s radiation exposure. At this point, the urology department was contacted to evaluate and manage the patient’s gross hematuria. Physical examination revealed no renal bruit, no abdominal tenderness, and no palpable abdominal mass. Deep palpation at the costovertebral angle reproduced the flank pain. A three-way urinary catheter was placed in the patient’s bladder, clots were irrigated out by hand, and continuous bladder irrigation with saline was started. The internal medicine service was contacted regarding the presumed finding of renal infarction. The patient was admitted to the urology service for monitoring and hydration and further evaluation and treatment. The patient received overnight hydration. The next morning, the urology staff ordered a CT angiogram with arterial phase to better evaluate the renal arteries and to see the arterial phase of the kidneys. The new images showed no findings consistent with renal arterial injury, dissection, or thrombus. However, the images now clearly showed a contrast-enhancing mass in the medial aspect of the right kidney (Figure 2). An MRI showed no tumor involvement in the right renal vein.
Variants of renal cell carcinoma carry a more ominous prognosis. A solid renal mass that enhances on CT and MRI has a high likelihood for malignancy. Given the tumor size, location, and proximity to the renal hilum and collecting system, a nephron-sparing approach was not possible, and after consultation with the urology team, the patient agreed to a right laparoscopic nephrectomy. Nephrectomy is the standard of care at our institution when a nephronsparing approach is not feasible. Cystoscopy and urine cytology were performed to complete the hematuria evaluation and were unremarkable. Nephrectomy was performed and the patient’s postoperative recovery was
FIGURE 2. CT of the right renal lesion the following day, with
the arterial phase provided and showing delayed excretion of the contrast agent from the right collecting system and clear enhancement of the lesion (circled).
FIGURE 3. Gross specimen showing the area involved by tumor
(arrows)
uneventful. She has been disease-free since the surgery, with no recurrence or complications. The gross specimen of the removed kidney showed the area involved by tumor (Figure 3). The preliminary pathology report revealed a renal cell carcinoma of advanced grade, stage pT1N0M0. The pathologist performed additional studies because the morphologic features and immunohistochemical stain results were suggestive of renal cell carcinoma associated with the Xp11.2 translocation. These studies included testing for chromosomal anomalies and fluorescence in situ hybridization (FISH) to look for rearrangement of the transcription factor E3 (TFE3) locus with probes for the 5' and 3' regions of the TFE3 gene at Xp11.2 (Figure 4). This testing confirmed the strong suspicion of translocation renal cell carcinoma.
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
www.JAAPA.com
25
CASE REPORT
FIGURE 4. FISH assay using TFE3 break-apart probe to detect
Xp11.2 translocation. Image shows abnormal 1R1G1F pattern (one red, one green, and one fusion signal), indicating a disruption in the normal fusion signal and the presence of the translocation.
DISCUSSION About 90% of all renal tumors are renal cell carcinoma.1 As the most common and most lethal adult renal epithelial cancer, renal cell carcinoma is a cause of substantial morbidity and mortality. According to 2012 statistics, about 65,000 new cancers of the kidney and renal pelvis and about 13,500 deaths from these cancers occur each year in the United States.2 The 2004 World Health Organization classification for renal neoplasms recognizes several distinct histologic subtypes of renal cell carcinoma, pointing out that the translocation carcinoma subtype accounts for less than 1% of all renal cell carcinomas.1
Personally reviewing CT images for accuracy may lead to a different diagnosis. Renal cell carcinoma associated with Xp11.2 translocation was first reported by de Jong in 1986 and may be considered a relatively new entity.3 Translocation renal cell carcinoma has been shown to contain a translocation involving a member of the microphthalmia transcription factor gene family.4 These translocations most commonly involve the TFE3 gene on locus Xp11.2. These variants of renal cell carcinoma carry a more ominous prognosis and typically present at a more advanced stage, making most treatments palliative. For the past several years, case reports have shown that this unique subtype occurs predominantly in children and young adults. The mean age in the published cases is 25 26
www.JAAPA.com
years; the median age is 20 years.5 An article published in 2007 reported that carcinoma associated with Xp11.2 translocation is increasingly being documented in patients older than 40 years and in women.6,7 Now that this subtype is being recognized, awareness may increase the diagnosis in adults, especially those with clinically aggressive forms of renal cell carcinoma. The molecular aspects of this disease may provide a future target for specific therapy or intervention. The importance in defining the features of these translocation tumors is that they are more clinically aggressive than other subtypes of renal cell carcinomas, present in younger patients, and are associated with a worse prognosis. These tumors may require more aggressive treatment and closer follow-up. However, to date they have been underreported, which makes definitive recommendations difficult because of the lack of clinical experience. The discovery that this patient’s tumor was a translocation renal cell carcinoma would not have been possible without the clinical acumen of the pathologist. Pathologists can identify and characterize cancers not only through histologic examination using the microscope, but also through chromosomal analysis, which lets them look for genetic alterations that are the fingerprint for translocation renal cell carcinoma. Renal translocation carcinomas are typically large tumors that often present at a high stage with regional lymph node involvement or metastasis. Grossly, these tumors commonly have a variegated coloration with prominent necrosis. Microscopically, they are often recognized for the variety of growth patterns. The tumor cells typically have abundant clear, eosinophilic, or granular cytoplasm. Histologic features that are clues to the diagnosis are extensive papillary or solid architecture and large, clear cells with voluminous cytoplasm and readily apparent nucleoli. With immunohistochemistry, the translocation carcinomas typically underexpress epithelial markers and have variable positivity for vimentin. Cytogenetic or molecular testing steps include sending fresh tissue for chromosome analysis or performing FISH or polymerase chain reaction studies on formalin-fixed, paraffin-embedded sections of tumor. Most of these tumors involve the TFE3 gene on Xp11.2, and the most common fusion partner is the ASPL gene on chromosome 17. Although the translocation Xp11.2 subtype accounts for less than 1% of renal cell carcinomas, clinicians should be aware of its existence and consider this tumor subtype in the differential diagnosis of renal lesions and gross hematuria. Initially, this patient was presented to the urology team as having a renal infarct. However, a critical step for the clinicians was to personally review the CT images for accuracy and confirmation and to bring to bear the experience of the urology field. During this step, the Volume 27 • Number 2 • February 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Xp11.2 translocation tumor: A rare cause of gross hematuria
provider noted that images of the arterial phase were lacking. Rather than simply accept this shortcoming, the urology team ordered a triphase CT angiogram of the abdomen, which includes the arterial phase. This study exposed the patient to additional radiation, but was justified because it provided the critical information that led to a different diagnosis and changed the patient’s treatment. The needed surgery may have been delayed had the diagnosis of renal infarction been accepted. Although keeping the radiation dose as low as can be reasonably expected is a laudable goal, sometimes a more critical eye is needed to ensure the appropriate diagnostic yield. A good working relationship among all members of the healthcare team is a critical component to ensure the best possible outcomes for patients. CONCLUSION Translocation carcinoma is a relatively new, rare, and aggressive subset of renal cell carcinoma. Clinicians need to diagnose, identify, and report patients who have these translocation tumors. A collaborative approach between clinicians and scientists will lead to a proper analysis of data and the characterization of these cancers at the molecular level. This partnership will contribute to the
collective understanding of Xp11.2 translocation renal cell carcinoma and lead to proper therapy and follow-up for patients in the future. JAAPA
REFERENCES 1. Eble JN, Sauter G, Epstein JI, Sesterhenn IA. International Agency for Research on Cancer. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon, France: World Health Organization; 2004. 2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10-29. 3. de Jong B, Molenaar IM, Leeuw JA, et al. Cytogenetics of renal adenocarcinoma in a 2-year-old child. Cancer Genet Cytogenet. 1986;21(2):165-169. 4. Wu AJ. Pathology of translocation carcinoma. http://www. emedicine.medscape.com/article/1611937-overview. Accessed March 15, 2013. 5. Camparo P, Vasiliu V, Molinie V, et al. Renal translocation carcinomas: clinicopathologic, immunohistochemical, and gene expression profiling analysis of 31 cases with a review of the literature. Am J Surg Pathol. 2008;32(5):656-670. 6. Argani P, Olgac S, Tickoo SK, et al. Xp11 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum. Am J Surg Pathol. 2007;31(8):1149-1160. 7. Choueiri TK, Lim ZD, Hirsch MS, et al. Vascular endothelial growth factor-targeted therapy for the treatment of adult metastatic Xp11.2 translocation renal cell carcinoma. Cancer. 2010;116(22):5219-5225.
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
www.JAAPA.com
27
Xp11.2 translocation tumor: A rare cause of gross hematuria Howard E. Asaki, PA-C; Gianni Moshero, PA-C; Melissa L. Stanton, MD; Mitchell R. Humphreys, MD
ABSTRACT Xp11.2 translocation tumor is a rare but aggressive form of renal cell carcinoma that predominantly occurs in children but also may be found in young adults. Because this type of cancer is diagnosed via histologic and chromosomal analysis, clinicians should consider translocation tumor in the differential diagnosis of patients with renal lesions and gross hematuria. Keywords: Xp11.2 translocation tumor, renal cell carcinoma, chromosomal abnormalities, fluorescence in situ hybridization, transcription factor E3, TFE3
CASE A 41-year-old woman in good health experienced right flank pain and noticed gross hematuria on micturition. She presented to the ED for evaluation. History The patient denied any trauma, anticoagulation therapy, atrial fibrillation, or prior history of urinary stones or microscopic or gross hematuria. Her past medical history and family history were noncontributory. Her social history was negative for smoking. Vital signs were within normal limits. Urinalysis demonstrated greater than 180 red blood cells and 137 white blood cells per high-power field. Her urine was not nitrate positive, and the urine culture was negative for any microorganisms. All other laboratory tests, including hemoglobin, creatinine, and coagulation studies, were within normal limits. A CT scan of the abdomen and pelvis revealed an infarcted region in the medial aspect of the upper pole of the right kidney, as well as hyperdense areas on the precontrast images, consistent with acute renal bleeding (Figure 1). This initial study had no arterial phase because Howard E. Asaki and Gianni Moshero practice in the Department of Urology at the Mayo Clinic Hospital in Phoenix, Ariz. Melissa L. Stanton practices in the Division of Anatomic Pathology at the Mayo Clinic in Scottsdale, Ariz. Mitchell R. Humphreys practices in the Department of Urology at the Mayo Clinic Hospital in Phoenix, Ariz. The authors have indicated no relationships to disclose relating to the content of this article. DOI: 10.1097/01.JAA.0000442700.87975.0b Copyright © 2014 American Academy of Physician Assistants
24
www.JAAPA.com
A
B
FIGURE 1. CT of the right renal lesion at time of patient presen-
tation to the ED. A hyperintense area of the medial right renal parenchyma includes the collecting system and is consistent with acute hemorrhage (A, circled). A limited contrast study with partial renal obstruction, as evident by the delayed excretion of the contrast agent and the renal defect that was interpreted as a renal infarct (B, circled). Volume 27 • Number 2 • February 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Xp11.2 translocation tumor: A rare cause of gross hematuria
Key points Keep an open mind when evaluating a patient: The problem might not be what was initially presented. Obtain the diagnostic study that you need, rather than settling for a similar study that has already been done. When the pathology of a renal tumor reveals renal cell carcinoma, consider the diagnosis of translocation carcinoma.
the radiologist decided to minimize the patient’s radiation exposure. At this point, the urology department was contacted to evaluate and manage the patient’s gross hematuria. Physical examination revealed no renal bruit, no abdominal tenderness, and no palpable abdominal mass. Deep palpation at the costovertebral angle reproduced the flank pain. A three-way urinary catheter was placed in the patient’s bladder, clots were irrigated out by hand, and continuous bladder irrigation with saline was started. The internal medicine service was contacted regarding the presumed finding of renal infarction. The patient was admitted to the urology service for monitoring and hydration and further evaluation and treatment. The patient received overnight hydration. The next morning, the urology staff ordered a CT angiogram with arterial phase to better evaluate the renal arteries and to see the arterial phase of the kidneys. The new images showed no findings consistent with renal arterial injury, dissection, or thrombus. However, the images now clearly showed a contrast-enhancing mass in the medial aspect of the right kidney (Figure 2). An MRI showed no tumor involvement in the right renal vein.
Variants of renal cell carcinoma carry a more ominous prognosis. A solid renal mass that enhances on CT and MRI has a high likelihood for malignancy. Given the tumor size, location, and proximity to the renal hilum and collecting system, a nephron-sparing approach was not possible, and after consultation with the urology team, the patient agreed to a right laparoscopic nephrectomy. Nephrectomy is the standard of care at our institution when a nephronsparing approach is not feasible. Cystoscopy and urine cytology were performed to complete the hematuria evaluation and were unremarkable. Nephrectomy was performed and the patient’s postoperative recovery was
FIGURE 2. CT of the right renal lesion the following day, with
the arterial phase provided and showing delayed excretion of the contrast agent from the right collecting system and clear enhancement of the lesion (circled).
FIGURE 3. Gross specimen showing the area involved by tumor
(arrows)
uneventful. She has been disease-free since the surgery, with no recurrence or complications. The gross specimen of the removed kidney showed the area involved by tumor (Figure 3). The preliminary pathology report revealed a renal cell carcinoma of advanced grade, stage pT1N0M0. The pathologist performed additional studies because the morphologic features and immunohistochemical stain results were suggestive of renal cell carcinoma associated with the Xp11.2 translocation. These studies included testing for chromosomal anomalies and fluorescence in situ hybridization (FISH) to look for rearrangement of the transcription factor E3 (TFE3) locus with probes for the 5' and 3' regions of the TFE3 gene at Xp11.2 (Figure 4). This testing confirmed the strong suspicion of translocation renal cell carcinoma.
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
www.JAAPA.com
25
CASE REPORT
FIGURE 4. FISH assay using TFE3 break-apart probe to detect
Xp11.2 translocation. Image shows abnormal 1R1G1F pattern (one red, one green, and one fusion signal), indicating a disruption in the normal fusion signal and the presence of the translocation.
DISCUSSION About 90% of all renal tumors are renal cell carcinoma.1 As the most common and most lethal adult renal epithelial cancer, renal cell carcinoma is a cause of substantial morbidity and mortality. According to 2012 statistics, about 65,000 new cancers of the kidney and renal pelvis and about 13,500 deaths from these cancers occur each year in the United States.2 The 2004 World Health Organization classification for renal neoplasms recognizes several distinct histologic subtypes of renal cell carcinoma, pointing out that the translocation carcinoma subtype accounts for less than 1% of all renal cell carcinomas.1
Personally reviewing CT images for accuracy may lead to a different diagnosis. Renal cell carcinoma associated with Xp11.2 translocation was first reported by de Jong in 1986 and may be considered a relatively new entity.3 Translocation renal cell carcinoma has been shown to contain a translocation involving a member of the microphthalmia transcription factor gene family.4 These translocations most commonly involve the TFE3 gene on locus Xp11.2. These variants of renal cell carcinoma carry a more ominous prognosis and typically present at a more advanced stage, making most treatments palliative. For the past several years, case reports have shown that this unique subtype occurs predominantly in children and young adults. The mean age in the published cases is 25 26
www.JAAPA.com
years; the median age is 20 years.5 An article published in 2007 reported that carcinoma associated with Xp11.2 translocation is increasingly being documented in patients older than 40 years and in women.6,7 Now that this subtype is being recognized, awareness may increase the diagnosis in adults, especially those with clinically aggressive forms of renal cell carcinoma. The molecular aspects of this disease may provide a future target for specific therapy or intervention. The importance in defining the features of these translocation tumors is that they are more clinically aggressive than other subtypes of renal cell carcinomas, present in younger patients, and are associated with a worse prognosis. These tumors may require more aggressive treatment and closer follow-up. However, to date they have been underreported, which makes definitive recommendations difficult because of the lack of clinical experience. The discovery that this patient’s tumor was a translocation renal cell carcinoma would not have been possible without the clinical acumen of the pathologist. Pathologists can identify and characterize cancers not only through histologic examination using the microscope, but also through chromosomal analysis, which lets them look for genetic alterations that are the fingerprint for translocation renal cell carcinoma. Renal translocation carcinomas are typically large tumors that often present at a high stage with regional lymph node involvement or metastasis. Grossly, these tumors commonly have a variegated coloration with prominent necrosis. Microscopically, they are often recognized for the variety of growth patterns. The tumor cells typically have abundant clear, eosinophilic, or granular cytoplasm. Histologic features that are clues to the diagnosis are extensive papillary or solid architecture and large, clear cells with voluminous cytoplasm and readily apparent nucleoli. With immunohistochemistry, the translocation carcinomas typically underexpress epithelial markers and have variable positivity for vimentin. Cytogenetic or molecular testing steps include sending fresh tissue for chromosome analysis or performing FISH or polymerase chain reaction studies on formalin-fixed, paraffin-embedded sections of tumor. Most of these tumors involve the TFE3 gene on Xp11.2, and the most common fusion partner is the ASPL gene on chromosome 17. Although the translocation Xp11.2 subtype accounts for less than 1% of renal cell carcinomas, clinicians should be aware of its existence and consider this tumor subtype in the differential diagnosis of renal lesions and gross hematuria. Initially, this patient was presented to the urology team as having a renal infarct. However, a critical step for the clinicians was to personally review the CT images for accuracy and confirmation and to bring to bear the experience of the urology field. During this step, the Volume 27 • Number 2 • February 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Xp11.2 translocation tumor: A rare cause of gross hematuria
provider noted that images of the arterial phase were lacking. Rather than simply accept this shortcoming, the urology team ordered a triphase CT angiogram of the abdomen, which includes the arterial phase. This study exposed the patient to additional radiation, but was justified because it provided the critical information that led to a different diagnosis and changed the patient’s treatment. The needed surgery may have been delayed had the diagnosis of renal infarction been accepted. Although keeping the radiation dose as low as can be reasonably expected is a laudable goal, sometimes a more critical eye is needed to ensure the appropriate diagnostic yield. A good working relationship among all members of the healthcare team is a critical component to ensure the best possible outcomes for patients. CONCLUSION Translocation carcinoma is a relatively new, rare, and aggressive subset of renal cell carcinoma. Clinicians need to diagnose, identify, and report patients who have these translocation tumors. A collaborative approach between clinicians and scientists will lead to a proper analysis of data and the characterization of these cancers at the molecular level. This partnership will contribute to the
collective understanding of Xp11.2 translocation renal cell carcinoma and lead to proper therapy and follow-up for patients in the future. JAAPA
REFERENCES 1. Eble JN, Sauter G, Epstein JI, Sesterhenn IA. International Agency for Research on Cancer. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon, France: World Health Organization; 2004. 2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10-29. 3. de Jong B, Molenaar IM, Leeuw JA, et al. Cytogenetics of renal adenocarcinoma in a 2-year-old child. Cancer Genet Cytogenet. 1986;21(2):165-169. 4. Wu AJ. Pathology of translocation carcinoma. http://www. emedicine.medscape.com/article/1611937-overview. Accessed March 15, 2013. 5. Camparo P, Vasiliu V, Molinie V, et al. Renal translocation carcinomas: clinicopathologic, immunohistochemical, and gene expression profiling analysis of 31 cases with a review of the literature. Am J Surg Pathol. 2008;32(5):656-670. 6. Argani P, Olgac S, Tickoo SK, et al. Xp11 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum. Am J Surg Pathol. 2007;31(8):1149-1160. 7. Choueiri TK, Lim ZD, Hirsch MS, et al. Vascular endothelial growth factor-targeted therapy for the treatment of adult metastatic Xp11.2 translocation renal cell carcinoma. Cancer. 2010;116(22):5219-5225.
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
www.JAAPA.com
27
