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Metastatic renal cell carcinoma presenting as a gallbladder polyp
INSTRUCTIVE CASE
Metastatic renal cell carcinoma presenting as a gallbladder polyp
polyp. This nodule was originally missed 1 year earlier on CT imaging; however, it was confirmed to be present on review. The patient subsequently underwent laparoscopic cholecystectomy. On gross examination of the specimen, a pink-red polypoid mass was identified at the neck of the gallbladder, near the cystic duct orifice and was not associated with cholelithiasis. It measured 1.4 cm in the greatest dimension. Histological assessment identified a well circumscribed, pedunculated mass with clear cells and a delicate vascular network (see Figure 1). The mass arose from the gallbladder submucosa and showed minimal desmoplasia. Lymphovascular and perineural invasion were not identified. Immunohistochemical staining was positive for PAX-8, vimentin and focally positive for CK7 and CD10. EMA staining was negative. The morphologic and immunohistochemical profile was in keeping with metastatic clear cell renal cell carcinoma. Following histologic confirmation of metastatic ccRCC, repeat CT staging was performed and identified two new pancreatic lesions highly suspicious for renal cell carcinoma. The patient was well and asymptomatic and elected to be closely monitored clinically instead of pursuing ablative therapy. Should the disease progress then surgical resection, systemic therapy, and radiotherapy will be discussed.
Willard Wong Rajkumar Vajpeyi
Abstract Clear cell renal cell carcinoma accounts for approximately 3% of all adult malignancies and 85% of all primary renal malignancies. Clear cell renal cell carcinoma (ccRCC) metastasis to the gallbladder is extremely rare and often presents as a metachronous metastasis following several years of tumour free disease. We report a case of a 78-year-old female with metastatic ccRCC to the gallbladder. During follow-up ultrasound imaging, a polypoid gallbladder mass was discovered incidentally. The previous medical history is significant for total nephrectomy for left-sided ccRCC 6 years ago. A new suspicious intraluminal polypoid gallbladder mass in a patient with a history significant for clear cell renal cell carcinoma should alert the physician to consider metastatic clear cell renal cell carcinoma.
Discussion
Keywords clear cell renal cell carcinoma; gallbladder; metastasis
Renal cell carcinoma accounts for 85% of all adult renal malignancies.2 It has high metastatic potential and metastatic RCC has poor prognosis.3 Although the 5-year survival of stage I (T1N0M0) RCC is approximately 90%, the expected 5-year survival for patients with metastatic disease is approximately 10%.3 It has been reported that the 5-year survival rate following metastatectomy of RCC is 35e50%.4 Patients are usually asymptomatic when the metastasis is discovered, otherwise the most common presentation is that of acute cholecystitis.5 Radiological findings are usually incidental and non-specific, though metastatic RCC in the gallbladder more commonly has a polypoid presentation.6 Further, one third of newly diagnosed RCC cases have synchronous metastases, and a further 25e50% will develop metachronous disease.7 Within the distribution of RCC metastatic sites, more common sites include the lungs, bone, liver, adrenal and brain.8 Of metachronous metastasis, the median time for gallbladder involvement following nephrectomy is 4 years in one study.4 The long period of tumour free disease and the clinical rarity of the entity create a challenge for the diagnostician. In this case, the tumour was missed on prior CT imaging. Secondary malignancies of the gallbladder are uncommon. Of the metastases encountered in the gallbladder, malignant melanoma accounts for greater than 50% of secondary tumours of the gallbladder.5 Less common secondary malignancies of the gallbladder include gastric, pancreatic, ovarian, breast, colorectal and pulmonary.9 Some secondary malignancies of the gallbladder commonly arise in the setting of intraperitoneal metastasis. These include gastric, colorectal, ovarian and pancreatic malignancies. The presumed mode of ccRCC metastases to the gallbladder is, however, haematogenous and not by intraperitoneal spread.10 This is supported by observations that the metastasis invariably presents as an intraluminal mass rather than a serosal mass. The majority of haematogenous metastases of RCC to the gallbladder are believed to begin as small
Introduction Clear cell renal cell carcinoma accounts for approximately 3% of all adult malignancies and 85% of all primary renal malignancies. Gallbladder metastasis of clear cell renal cell carcinoma (ccRCC) is exceedingly rare and often arise several years after primary diagnosis.1 We report a case of metachronous gallbladder metastasis of ccRCC presenting as a gallbladder polyp.
Case report We present a case of a 78-year-old female who was initially diagnosed and treated for clear cell renal carcinoma by total nephrectomy. 6 years later, a gallbladder polyp was discovered on follow-up ultrasound imaging. Overall, the patient was well. She denied symptoms of fever, abdominal pain, nausea, vomiting, or changes to her bowel habits. Her abdomen was nontender and non-distended on physical exam. Her full blood count was unremarkable with a white blood cell count of 5.7 109/L. Screening ultrasound demonstrated an echogenic 1.4 cm, solid and vascular nodule, most likely representing a gallbladder
Willard Wong MBBS Resident in Anatomical Pathology, Department of Pathology, Toronto General Hospital, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. Conflicts of interest: none. Rajkumar Vajpeyi MBBS MD FRCPC FCAP Consultant Pathologist, Department of Pathology, Toronto General Hospital, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. Conflicts of interest: none.
DIAGNOSTIC HISTOPATHOLOGY 23:7
331
Ó 2017 Published by Elsevier Ltd.
INSTRUCTIVE CASE
Figure 1 Intraluminal gallbladder metastasis of clear cell renal cell carcinoma. (a, b) H&E section at 25 and 100 magnification of the intraluminal polypoid mass, respectively. (c) PAX8 immunohistochemistry with positive expression in tumour. (d) CK7 with weak focal immunohistochemical staining in the tumour and strong, diffuse staining in the biliary epithelium. (e) CD10 with focal immunohistochemical staining in the tumour. Vimentin is negative in the biliary epithelium, while staining positive in the mass (f).
nuclear atypia and scant mitoses.12 Immunohistochemistry will stain positively for neuroendocrine markers. In addition, carcinoid tumours associated with von HippeleLindau syndrome show clear cell morphology and will stain positively for inhibin. Primary clear cell adenocarcinoma is also a differential to consider and is an exceedingly uncommon malignancy in the gallbladder. The architecture can exhibit sheets, nests, trabeculae, glands and small papillary structures and is also separated by sinusoidal vessels.12,13 Primary clear cell adenocarcinoma will be strongly positive for CEA and CK7, and negative for vimentin. In contrast, metastatic clear cell RCC is positive for vimentin and
submucosal flat nodules and then grow as a pedunculated or polypoid masses.7,11 This contrasts with primary gallbladder cancer which has more variable gross appearances including diffuse thickening of gallbladder wall or as a nodular mass.7 RCC metastasis to the gallbladder is most often the clear cell type and it is important to consider other differentials with similar morphologies such as clear cell variant of carcinoid tumour and clear cell adenocarcinoma of the gallbladder.7 Clear cell variant of carcinoid tumour typically form nodular or polypoid lesions.12 It exhibits an insular or tubular pattern of growth and typically has inconspicuous nucleoli, minimal
DIAGNOSTIC HISTOPATHOLOGY 23:7
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Ó 2017 Published by Elsevier Ltd.
INSTRUCTIVE CASE
negative for CEA and CK7.14 Although, the tumour in our case demonstrated focal positive staining for CK7, this may be seen encountered in higher grade tumours.15 The overall morphological and immunohistochemical phenotype is of metastatic clear cell renal cell carcinoma.
7 Costa Neves M, Neofytou K, Giakoustidis A, et al. Two cases of gallbladder metastasis from renal cell carcinoma and review of literature. World J Surg Oncol 2016; 14. 8 Bianchi M, Sun M, Jeldres C, et al. Distribution of metastatic sites in renal cell carcinoma: a population-based analysis. Ann Oncol e Off J Eur Soc Med Oncol/ESMO 2012; 23: 973e80. 9 Abrams HL, Spiro R, Goldstein N. Metastases in carcinoma; analysis of 1000 autopsied cases. Cancer 1950; 3: 74e85. 10 Nojima H, Cho A, Yamamoto H, et al. Renal cell carcinoma with unusual metastasis to the gallbladder. J Hepato-Biliary-Pancreatic Surg 2008; 15: 209e12. 11 Celebi I, Guzelsoy M, Yorukoglu K, Kirkali Z. Renal cell carcinoma with gallbladder metastasis. Int J Urol e Off J Jpn Urol Assoc 1998; 5: 288e90. 12 Robert D, Odze JRG. Odze and Goldblum, Surgical pathology of the GI tract, liver, biliary tract, and pancreas. 3rd edn. Philadelphia, PA: Saunders/Elsevier, 2015. 13 Vardaman C, Albores-Saavedra J. Clear cell carcinomas of the gallbladder and extrahepatic bile ducts. Am J Surg Pathol 1995; 19: 91e9. 14 Liang Cheng DGB. Essentials of anatomic pathology. New York: Springer-Verlag, 2011. 15 Truong LD, Shen SS. Immunohistochemical diagnosis of renal neoplasms. Arch Pathol Lab Med 2011; 135: 92e109.
Conclusion Metastatic clear cell renal cell carcinoma to the gallbladder is rare and often presents following a prolonged period of tumour free disease. Metastatic ccRCC to the gallbladder is often an incidental finding found on radiology, but may also present with an acute cholecystitis picture. Diagnostic consideration should be raised whenever any new suspicious findings are found. Radiological findings commonly identify an intraluminal polypoid mass, however it is non-specific and in this case it was initially missed on CT abdominal imaging. Definitive diagnosis is determined after cholecystectomy and immunohistochemical phenotype invariably matches that of the primary diagnosis. A REFERENCES 1 Weiss L, Harlos JP, Torhorst J, et al. Metastatic patterns of renal carcinoma: an analysis of 687 necropsies. J Cancer Res Clin Oncol 1988; 114: 605e12. 2 Robbins SL, Kumar V, Cotran RS. Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Saunders/Elsevier, 2010. 3 Klapper JA, Downey SG, Smith FO, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma. Cancer 2008; 113: 293e301. 4 Chung PH, Srinivasan R, Linehan WM, Pinto PA, Bratslavsky G. Renal cell carcinoma with metastases to the gallbladder: four cases from the National Cancer Institute (NCI) and review of the literature. Urol Oncol 2012; 30: 476e81. 5 Hamilton SR, Aaltonen LA, Organization WH, Cancer IAfRo. Pathology and genetics of tumours of the digestive system. IARC Press, 2000. 6 Choi WS, Kim SH, Lee ES, et al. CT findings of gallbladder metastases: emphasis on differences according to primary tumors. Korean J Radiol 2014; 15: 334e45.
DIAGNOSTIC HISTOPATHOLOGY 23:7
Practice points C
C
C
C
333
Metastatic clear cell renal cell carcinoma presenting as a polyp in the gallbladder is exceedingly rare. Metachronous clear cell renal cell carcinoma often arises after many years of tumour free disease. Immunohistochemical phenotype matches that of the primary clear cell renal cell carcinoma diagnosis. Any new and suspicious clinicopathological findings should raise diagnostic consideration of metastases in a patient with history significant for clear cell renal cell carcinoma.
Ó 2017 Published by Elsevier Ltd.
Metastatic renal cell carcinoma presenting as a gallbladder polyp
polyp. This nodule was originally missed 1 year earlier on CT imaging; however, it was confirmed to be present on review. The patient subsequently underwent laparoscopic cholecystectomy. On gross examination of the specimen, a pink-red polypoid mass was identified at the neck of the gallbladder, near the cystic duct orifice and was not associated with cholelithiasis. It measured 1.4 cm in the greatest dimension. Histological assessment identified a well circumscribed, pedunculated mass with clear cells and a delicate vascular network (see Figure 1). The mass arose from the gallbladder submucosa and showed minimal desmoplasia. Lymphovascular and perineural invasion were not identified. Immunohistochemical staining was positive for PAX-8, vimentin and focally positive for CK7 and CD10. EMA staining was negative. The morphologic and immunohistochemical profile was in keeping with metastatic clear cell renal cell carcinoma. Following histologic confirmation of metastatic ccRCC, repeat CT staging was performed and identified two new pancreatic lesions highly suspicious for renal cell carcinoma. The patient was well and asymptomatic and elected to be closely monitored clinically instead of pursuing ablative therapy. Should the disease progress then surgical resection, systemic therapy, and radiotherapy will be discussed.
Willard Wong Rajkumar Vajpeyi
Abstract Clear cell renal cell carcinoma accounts for approximately 3% of all adult malignancies and 85% of all primary renal malignancies. Clear cell renal cell carcinoma (ccRCC) metastasis to the gallbladder is extremely rare and often presents as a metachronous metastasis following several years of tumour free disease. We report a case of a 78-year-old female with metastatic ccRCC to the gallbladder. During follow-up ultrasound imaging, a polypoid gallbladder mass was discovered incidentally. The previous medical history is significant for total nephrectomy for left-sided ccRCC 6 years ago. A new suspicious intraluminal polypoid gallbladder mass in a patient with a history significant for clear cell renal cell carcinoma should alert the physician to consider metastatic clear cell renal cell carcinoma.
Discussion
Keywords clear cell renal cell carcinoma; gallbladder; metastasis
Renal cell carcinoma accounts for 85% of all adult renal malignancies.2 It has high metastatic potential and metastatic RCC has poor prognosis.3 Although the 5-year survival of stage I (T1N0M0) RCC is approximately 90%, the expected 5-year survival for patients with metastatic disease is approximately 10%.3 It has been reported that the 5-year survival rate following metastatectomy of RCC is 35e50%.4 Patients are usually asymptomatic when the metastasis is discovered, otherwise the most common presentation is that of acute cholecystitis.5 Radiological findings are usually incidental and non-specific, though metastatic RCC in the gallbladder more commonly has a polypoid presentation.6 Further, one third of newly diagnosed RCC cases have synchronous metastases, and a further 25e50% will develop metachronous disease.7 Within the distribution of RCC metastatic sites, more common sites include the lungs, bone, liver, adrenal and brain.8 Of metachronous metastasis, the median time for gallbladder involvement following nephrectomy is 4 years in one study.4 The long period of tumour free disease and the clinical rarity of the entity create a challenge for the diagnostician. In this case, the tumour was missed on prior CT imaging. Secondary malignancies of the gallbladder are uncommon. Of the metastases encountered in the gallbladder, malignant melanoma accounts for greater than 50% of secondary tumours of the gallbladder.5 Less common secondary malignancies of the gallbladder include gastric, pancreatic, ovarian, breast, colorectal and pulmonary.9 Some secondary malignancies of the gallbladder commonly arise in the setting of intraperitoneal metastasis. These include gastric, colorectal, ovarian and pancreatic malignancies. The presumed mode of ccRCC metastases to the gallbladder is, however, haematogenous and not by intraperitoneal spread.10 This is supported by observations that the metastasis invariably presents as an intraluminal mass rather than a serosal mass. The majority of haematogenous metastases of RCC to the gallbladder are believed to begin as small
Introduction Clear cell renal cell carcinoma accounts for approximately 3% of all adult malignancies and 85% of all primary renal malignancies. Gallbladder metastasis of clear cell renal cell carcinoma (ccRCC) is exceedingly rare and often arise several years after primary diagnosis.1 We report a case of metachronous gallbladder metastasis of ccRCC presenting as a gallbladder polyp.
Case report We present a case of a 78-year-old female who was initially diagnosed and treated for clear cell renal carcinoma by total nephrectomy. 6 years later, a gallbladder polyp was discovered on follow-up ultrasound imaging. Overall, the patient was well. She denied symptoms of fever, abdominal pain, nausea, vomiting, or changes to her bowel habits. Her abdomen was nontender and non-distended on physical exam. Her full blood count was unremarkable with a white blood cell count of 5.7 109/L. Screening ultrasound demonstrated an echogenic 1.4 cm, solid and vascular nodule, most likely representing a gallbladder
Willard Wong MBBS Resident in Anatomical Pathology, Department of Pathology, Toronto General Hospital, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. Conflicts of interest: none. Rajkumar Vajpeyi MBBS MD FRCPC FCAP Consultant Pathologist, Department of Pathology, Toronto General Hospital, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. Conflicts of interest: none.
DIAGNOSTIC HISTOPATHOLOGY 23:7
331
Ó 2017 Published by Elsevier Ltd.
INSTRUCTIVE CASE
Figure 1 Intraluminal gallbladder metastasis of clear cell renal cell carcinoma. (a, b) H&E section at 25 and 100 magnification of the intraluminal polypoid mass, respectively. (c) PAX8 immunohistochemistry with positive expression in tumour. (d) CK7 with weak focal immunohistochemical staining in the tumour and strong, diffuse staining in the biliary epithelium. (e) CD10 with focal immunohistochemical staining in the tumour. Vimentin is negative in the biliary epithelium, while staining positive in the mass (f).
nuclear atypia and scant mitoses.12 Immunohistochemistry will stain positively for neuroendocrine markers. In addition, carcinoid tumours associated with von HippeleLindau syndrome show clear cell morphology and will stain positively for inhibin. Primary clear cell adenocarcinoma is also a differential to consider and is an exceedingly uncommon malignancy in the gallbladder. The architecture can exhibit sheets, nests, trabeculae, glands and small papillary structures and is also separated by sinusoidal vessels.12,13 Primary clear cell adenocarcinoma will be strongly positive for CEA and CK7, and negative for vimentin. In contrast, metastatic clear cell RCC is positive for vimentin and
submucosal flat nodules and then grow as a pedunculated or polypoid masses.7,11 This contrasts with primary gallbladder cancer which has more variable gross appearances including diffuse thickening of gallbladder wall or as a nodular mass.7 RCC metastasis to the gallbladder is most often the clear cell type and it is important to consider other differentials with similar morphologies such as clear cell variant of carcinoid tumour and clear cell adenocarcinoma of the gallbladder.7 Clear cell variant of carcinoid tumour typically form nodular or polypoid lesions.12 It exhibits an insular or tubular pattern of growth and typically has inconspicuous nucleoli, minimal
DIAGNOSTIC HISTOPATHOLOGY 23:7
332
Ó 2017 Published by Elsevier Ltd.
INSTRUCTIVE CASE
negative for CEA and CK7.14 Although, the tumour in our case demonstrated focal positive staining for CK7, this may be seen encountered in higher grade tumours.15 The overall morphological and immunohistochemical phenotype is of metastatic clear cell renal cell carcinoma.
7 Costa Neves M, Neofytou K, Giakoustidis A, et al. Two cases of gallbladder metastasis from renal cell carcinoma and review of literature. World J Surg Oncol 2016; 14. 8 Bianchi M, Sun M, Jeldres C, et al. Distribution of metastatic sites in renal cell carcinoma: a population-based analysis. Ann Oncol e Off J Eur Soc Med Oncol/ESMO 2012; 23: 973e80. 9 Abrams HL, Spiro R, Goldstein N. Metastases in carcinoma; analysis of 1000 autopsied cases. Cancer 1950; 3: 74e85. 10 Nojima H, Cho A, Yamamoto H, et al. Renal cell carcinoma with unusual metastasis to the gallbladder. J Hepato-Biliary-Pancreatic Surg 2008; 15: 209e12. 11 Celebi I, Guzelsoy M, Yorukoglu K, Kirkali Z. Renal cell carcinoma with gallbladder metastasis. Int J Urol e Off J Jpn Urol Assoc 1998; 5: 288e90. 12 Robert D, Odze JRG. Odze and Goldblum, Surgical pathology of the GI tract, liver, biliary tract, and pancreas. 3rd edn. Philadelphia, PA: Saunders/Elsevier, 2015. 13 Vardaman C, Albores-Saavedra J. Clear cell carcinomas of the gallbladder and extrahepatic bile ducts. Am J Surg Pathol 1995; 19: 91e9. 14 Liang Cheng DGB. Essentials of anatomic pathology. New York: Springer-Verlag, 2011. 15 Truong LD, Shen SS. Immunohistochemical diagnosis of renal neoplasms. Arch Pathol Lab Med 2011; 135: 92e109.
Conclusion Metastatic clear cell renal cell carcinoma to the gallbladder is rare and often presents following a prolonged period of tumour free disease. Metastatic ccRCC to the gallbladder is often an incidental finding found on radiology, but may also present with an acute cholecystitis picture. Diagnostic consideration should be raised whenever any new suspicious findings are found. Radiological findings commonly identify an intraluminal polypoid mass, however it is non-specific and in this case it was initially missed on CT abdominal imaging. Definitive diagnosis is determined after cholecystectomy and immunohistochemical phenotype invariably matches that of the primary diagnosis. A REFERENCES 1 Weiss L, Harlos JP, Torhorst J, et al. Metastatic patterns of renal carcinoma: an analysis of 687 necropsies. J Cancer Res Clin Oncol 1988; 114: 605e12. 2 Robbins SL, Kumar V, Cotran RS. Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Saunders/Elsevier, 2010. 3 Klapper JA, Downey SG, Smith FO, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma. Cancer 2008; 113: 293e301. 4 Chung PH, Srinivasan R, Linehan WM, Pinto PA, Bratslavsky G. Renal cell carcinoma with metastases to the gallbladder: four cases from the National Cancer Institute (NCI) and review of the literature. Urol Oncol 2012; 30: 476e81. 5 Hamilton SR, Aaltonen LA, Organization WH, Cancer IAfRo. Pathology and genetics of tumours of the digestive system. IARC Press, 2000. 6 Choi WS, Kim SH, Lee ES, et al. CT findings of gallbladder metastases: emphasis on differences according to primary tumors. Korean J Radiol 2014; 15: 334e45.
DIAGNOSTIC HISTOPATHOLOGY 23:7
Practice points C
C
C
C
333
Metastatic clear cell renal cell carcinoma presenting as a polyp in the gallbladder is exceedingly rare. Metachronous clear cell renal cell carcinoma often arises after many years of tumour free disease. Immunohistochemical phenotype matches that of the primary clear cell renal cell carcinoma diagnosis. Any new and suspicious clinicopathological findings should raise diagnostic consideration of metastases in a patient with history significant for clear cell renal cell carcinoma.
Ó 2017 Published by Elsevier Ltd.