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Renal Cell Carcinoma Associated With Sarcoidlike Tissue Reaction
KEVIN G. MODER, M.D., Department of Internal Medicine; SCOTT C. LITIN, M.D., Division ofArea Medicine; THOMAS A. GAFFEY, M.D., Division of Pathology A 60-year-old man was referred to our institution with the diagnosis of sarcoidosis. Because of several months' complaint of right flank pain and weight loss, the patient had consulted his local physician. After an extensive workup revealed only cholelithiasis, he· underwent a cholecystectomy for presumed chronic cholecystitis. At the time of operation, biopsy of several liver nodules and peripancreatic nodes revealed noncaseating granulomas, consistent with sarcoidosis. On initial examination at our institution, the patient had microhematuria. A chest roentgenogram demonstrated multiple pulmonary nodules, an abdominal computed tomographic scan showed an indeterminate left renal mass, and magnetic resonance imaging of the spine revealed abnormal signals in the body ofT-12. Open-lung biopsy showed an adenocarcinoma with clear cell features, likely of renal origin. The patient was diagnosed as having a metastatic renal carcinoma associated with a sarcoidlike tissue reaction. Although noncaseating granulomas have been reported in association with other malignant lesions, to our knowledge this is the first report of such an association with renal carcinoma. In addition, this case illustrates several points. First, sarcoidosis is a multisystem disorder with protean extrapulmonary manifestations. In fact, all our patient's findings could have been attributed to sarcoidosis. Second, noncaseating granulomas occur with many types of processes, including infections, chemical exposures, and, as in this case, neoplasms. Thus, noncaseating granulomas are not pathognomonic for sarcoidosis. Third, sarcoidosis is a clinical diagnosis that cannot be based on histologic findings alone.
Sarcoidosis is a multisystem disorder of unknown cause that is characterized histologically by noncaseating granulomas. It most commonly affects young adults and usually manifests with bilateral hilar adenopathy or pulmonary infiltrates. This disorder, however, can have protean extrapulmonary manifestations, and many other organs can be involved. The diagnosis is established by a compatible clinical picture, biopsy evidence of noncaseating granulomas, Address reprint requests to Dr. S. C. Litin, Division of Area Medicine, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 65:1498-1501, 1990
and exclusion of other causes of granulomatous disease. The clinical course of sarcoidosis is variable: many patients have spontaneous remission, others respond to corticosteroid therapy, and a minority may have a fatal course. Herein we report a case that illustrates that histologic findings alone are insufficient to make the diagnosis.
REPORT OF CASE A 60-year-old man was referred to our institution with the diagnosis of sarcoidosis. During the preceding 5 months, he had experienced
1498
Mayo Clin Proc, November 1990, Vol 65
RENAL CELL CARCINOMA AND SARCOIDLIKE REACTION 1499
right flank pain, a 13.6-kg weight loss, night sweats, and low-grade fever. Important past medical history included hypertension for 15 years, which was well controlled with lisinopril, 10 mg/day, and adult-onset diabetes mellitus for 5 years, which was treated with tolazamide, 250 mg/day. Assessment by his local physician, including a hematology profile, chemistry panel, and roentgenograms of the spine and colon, had been unrevealing. An abdominal ultrasound examination, however, showed gallstones, and he underwent a cholecystectomy for presumed chronic cholecystitis; the discomfort was not relieved. At the time of the operation, the surgeon noted several large peripancreatic nodes and liver nodules and obtained biopsy specimens. Histologically, noncaseating granulomas were demonstrated; thus, sarcoidosis was diagnosed (Fig. 1). Subsequently, this diagnosis was seemingly further confirmed by the finding of chest roentgenographic abnormalities. The patient was transferred to our facility for further assessment and treatment. On admission, he was normotensive and afebrile. Physical examination was remarkable for only a healing abdominal scar and some tenderness to palpation over the right sacroiliac joint. Laboratory findings, including a complete blood cell count, chemistry panel, prothrombin time, blood cultures, and an electrocardiogram, were all negative or within normal limits. Urinalysis revealed 4 to 10 erythrocytes per high-power field. A chest roentgenogram confirmed the presence of multiple pulmonary nodules in both lungs (Fig. 2). Abdominal, spine, and pelvic roentgenograms showed normal findings. Biopsy tissue specimens obtained elsewhere were reviewed by pathologists at our institution, who agreed that the tissue was consistent with sarcoidosis. An abdominal computed tomographic scan showed an indeterminate left renal mass and also suggested some thickening of the right paravertebral soft tissue at the level of T-12 (Fig. 3). A magnetic resonance image of the spine demonstrated several areas of abnormal Tl and T2 signals in the vertebral column, most notably at T-12. Because these areas were
Fig. 1. Noncaseating granuloma from liver biopsy. (Hematoxylin-eosin; x400.)
suggestive of metastatic lesions, a computed tomographic-guided needle biopsy of T-12 and the surrounding thickened paravertebral tissues was attempted. Unfortunately, the biopsies yielded only fibrous tissue. Because some question existed about the diagnosis of sarcoidosis, obtaining more tissue was thought to be necessary to rule out a malignant lesion. Therefore, an open-lung biopsy was performed with the plan to explore the renal mass at the same surgical procedure if feasible. The biopsy revealed numerous 1- to 5-mm pulmonary nodules. On microscopic examination, these lesions were grade 3 adenocarcinoma, and clear cells, likely of renal origin, were present. Because of the location of the tumor on the kidney, the surgeon thought that a renal biopsy was not
1500 RENAL CELL CARCINOMA AND SARCOIDLIKE REACTION
Fig. 2. Chest roentgenogram, demonstrating multiple small pulmonary nodules.
possible without a complete nephrectomy; consequently, no renal biopsy was done. Postoperatively, myelography revealed an epidural mass at the level of T-ll that compressed the spinal cord. Although neurologically intact, the patient received radiation therapy (3,000 rad) to that area. A bone scan demonstrated multiple areas of uptake in the pelvis, sacrum, ribs, femur, and spine. The patient died of progressive pulmonary disease 2 months after the metastatic cancer was diagnosed.
DISCUSSION Of importance, most of the findings in the patient described in detail in our case report, including his constitutional symptoms of weight loss (reported in 28% of patients with sarcoidosis') and fever (reported in 17%1), could be attributed to sarcoidosis. Common extrapulmonary manifestations of sarcoidosis include lymphadenopathy in 73% and involvement of the skin in 32%, liver in 21%, eye in 21%, and spleen in 18%.1 Bony involve-
Mayo elin Proc, November 1990, Vol 65
ment occurs in 14% of patients and may include osteolytic lesions that resemble metastatic tumors." Such changes have been detected in the vertebral column. 3 Our patient had several unusual aspects for sarcoidosis. Although multiple pulmonary nodules have been reported in sarcoidosis," this pulmonary manifestation is uncommon. 5 Hematuria occurs in only about 2%.1 Furthermore, the constellation of an indeterminate renal mass, microhematuria, back pain, and the suggestion of changes in the vertebrae on magnetic resonance imaging raised our index of suspicion for a metastatic malignant lesion. Other tests that were considered to help distinguish sarcoidosis from a malignant lesion included a serum angiotensin-converting enzyme level and a bone scan. Because the patient was taking an angiotensin-converting enzyme inhibitor (lisinopril) for control of blood pressure, this test was not done. These medications lower the serum angiotensin-converting enzyme level in patients with sarcoidosis and would complicate the interpretation of the result. 6 Additionally, only about 60% of patients with sarcoidosis have an increased serum angiotensin-converting enzyme level, and the test has a false-positive rate of more than 10%.7 Likewise, a bone scan was concluded not to be helpful in distinguishingmetastatic malignant lesions from sarcoidosis because bones affected by sarcoidosis also take up the bone scanning agent. 8 Therefore, more tissue was needed for a definitive diagnosis, and the patient underwent openlung biopsy. Our case illustrates that noncaseating granulomas can occur in numerous settings and are not pathognomonic for sarcoidosis. Causes of noncaseating granulomas include infections, neoplasms, and exposure to beryllium." Review of the literature revealed that tumor-related tissue reactions resulting in noncaseating granulomas have been reported with many types of malignant lesions, including cutaneous and pulmonary squamous cell carcinomas and cervical, bladder, gastric, lung, and breast cancers." To our knowledge, this case is the first report of such a reaction in renal carcinoma. Overall,
Mayo Clin Proc, November 1990, Vo165
RENAL CELL CARCINOMA AND SARCOIDLIKE REACTION 1501
sarcoidlike tissue reactions have been reported with many other types of malignant tumors. Additionally, one of the cardinal principles of medicine is to evaluate a patient's findings and, whenever possible, make one diagnosis that explains the entire picture. The diagnosis of metastatic renal carcinoma with sarcoidlike tissue reaction best explains the findings in this patient. For clinicians, the important point to remember is that malignant tumors can cause sarcoidlike tissue reactions. Therefore, other diagnostic methods must be used in conjunction with histologic analysis if the clinical picture is not Fig. 3. Abdominal computed tomographic scan, showing characteristic of sarcoidosis.
indeterminate left renal mass (arrow) and other bilateral simple renal cyst's.
REFERENCES
sarcoid reactions occur in 4.4% of carcinomas, 13.8% of Hodgkin's lymphoma, and 7.3% of nonHodgkin's lymphomas and rarely in sarcomas. 9 Such reactions can occur in lymph nodes draining an area in which a malignant lesion is located, in the tumor itself, and even in nonregional tissues. Possibly, the sarcoid reactions are caused by antigenic factors derived from the tumor, which elicit an immunologic hypersensitivity reaction and lead to the formation of noncaseating granulomas.
CONCLUSION We believe that our patient had metastatic renal carcinoma and an associated sarcoidlike tissue reaction but did not, in fact, have sarcoidosis. Several factors oppose the presence of both diseases, including the unusual initial manifestations for sarcoidosis mentioned earlier, the fact that he was asymptomatic before the development of the malignant lesion, and the fact that
1. Mayock RL, BertrandP, Morrison CE, Scott JH: Manifestations of sarcoidosis: analysis of 145 patients, with a review of nine series selected from the literature. Am J Med 35:67-89,1963 2. Cinti DC, Hawkins HB, Slavin JD Jr: Radioisotope bone scanning in a case of sarcoidosis. Clin Nucl Med 10:192-194, 1985 3. Dinerstein SL, Kovarsky J: Vertebral sarcoidosis: demonstration of bone involvement by computerized axial tomography. South Med J 77:1060-1061, 1984 4. Vidal F, Oliver JA, Campanya E, Baguer A, Carrera M, Richart C: Sarcoidosis presenting as multiple pulmonary nodules and nephrotic syndrome. Postgrad Med J 62:1147-1149, 1986 5. Bascom R, Johns CJ: The natural history and management of sarcoidosis. Adv Intern Med 31:213-241,1986 6. Mizuno K, Gotoh M, Matsui J, Nagasawa S, Fukuchi S: Acute effects of captopril on serum angiotensin-converting enzyme activity, the renin-aldosterone system and blood pressure in patients with sarcoidosis. Tohoku J Exp Med 140:107-108, 1983 7. DeRemee RA, Rohrbach MS: Serum angiotensin-converting enzyme activity in evaluating the clinical course of sarcoidosis. Ann Intern Med 92:361-365, 1980 8. Zelitch SR, Israel HL: Sarcoidosis. Am Fam Physician 38:127-139, August 1988 9. Brincker H: Sarcoid reactions in malignant tumours. Cancer Treat Rev 13:147-156,1986
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Renal Cell Carcinoma Associated With Sarcoidlike Tissue Reaction
KEVIN G. MODER, M.D., Department of Internal Medicine; SCOTT C. LITIN, M.D., Division ofArea Medicine; THOMAS A. GAFFEY, M.D., Division of Pathology A 60-year-old man was referred to our institution with the diagnosis of sarcoidosis. Because of several months' complaint of right flank pain and weight loss, the patient had consulted his local physician. After an extensive workup revealed only cholelithiasis, he· underwent a cholecystectomy for presumed chronic cholecystitis. At the time of operation, biopsy of several liver nodules and peripancreatic nodes revealed noncaseating granulomas, consistent with sarcoidosis. On initial examination at our institution, the patient had microhematuria. A chest roentgenogram demonstrated multiple pulmonary nodules, an abdominal computed tomographic scan showed an indeterminate left renal mass, and magnetic resonance imaging of the spine revealed abnormal signals in the body ofT-12. Open-lung biopsy showed an adenocarcinoma with clear cell features, likely of renal origin. The patient was diagnosed as having a metastatic renal carcinoma associated with a sarcoidlike tissue reaction. Although noncaseating granulomas have been reported in association with other malignant lesions, to our knowledge this is the first report of such an association with renal carcinoma. In addition, this case illustrates several points. First, sarcoidosis is a multisystem disorder with protean extrapulmonary manifestations. In fact, all our patient's findings could have been attributed to sarcoidosis. Second, noncaseating granulomas occur with many types of processes, including infections, chemical exposures, and, as in this case, neoplasms. Thus, noncaseating granulomas are not pathognomonic for sarcoidosis. Third, sarcoidosis is a clinical diagnosis that cannot be based on histologic findings alone.
Sarcoidosis is a multisystem disorder of unknown cause that is characterized histologically by noncaseating granulomas. It most commonly affects young adults and usually manifests with bilateral hilar adenopathy or pulmonary infiltrates. This disorder, however, can have protean extrapulmonary manifestations, and many other organs can be involved. The diagnosis is established by a compatible clinical picture, biopsy evidence of noncaseating granulomas, Address reprint requests to Dr. S. C. Litin, Division of Area Medicine, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 65:1498-1501, 1990
and exclusion of other causes of granulomatous disease. The clinical course of sarcoidosis is variable: many patients have spontaneous remission, others respond to corticosteroid therapy, and a minority may have a fatal course. Herein we report a case that illustrates that histologic findings alone are insufficient to make the diagnosis.
REPORT OF CASE A 60-year-old man was referred to our institution with the diagnosis of sarcoidosis. During the preceding 5 months, he had experienced
1498
Mayo Clin Proc, November 1990, Vol 65
RENAL CELL CARCINOMA AND SARCOIDLIKE REACTION 1499
right flank pain, a 13.6-kg weight loss, night sweats, and low-grade fever. Important past medical history included hypertension for 15 years, which was well controlled with lisinopril, 10 mg/day, and adult-onset diabetes mellitus for 5 years, which was treated with tolazamide, 250 mg/day. Assessment by his local physician, including a hematology profile, chemistry panel, and roentgenograms of the spine and colon, had been unrevealing. An abdominal ultrasound examination, however, showed gallstones, and he underwent a cholecystectomy for presumed chronic cholecystitis; the discomfort was not relieved. At the time of the operation, the surgeon noted several large peripancreatic nodes and liver nodules and obtained biopsy specimens. Histologically, noncaseating granulomas were demonstrated; thus, sarcoidosis was diagnosed (Fig. 1). Subsequently, this diagnosis was seemingly further confirmed by the finding of chest roentgenographic abnormalities. The patient was transferred to our facility for further assessment and treatment. On admission, he was normotensive and afebrile. Physical examination was remarkable for only a healing abdominal scar and some tenderness to palpation over the right sacroiliac joint. Laboratory findings, including a complete blood cell count, chemistry panel, prothrombin time, blood cultures, and an electrocardiogram, were all negative or within normal limits. Urinalysis revealed 4 to 10 erythrocytes per high-power field. A chest roentgenogram confirmed the presence of multiple pulmonary nodules in both lungs (Fig. 2). Abdominal, spine, and pelvic roentgenograms showed normal findings. Biopsy tissue specimens obtained elsewhere were reviewed by pathologists at our institution, who agreed that the tissue was consistent with sarcoidosis. An abdominal computed tomographic scan showed an indeterminate left renal mass and also suggested some thickening of the right paravertebral soft tissue at the level of T-12 (Fig. 3). A magnetic resonance image of the spine demonstrated several areas of abnormal Tl and T2 signals in the vertebral column, most notably at T-12. Because these areas were
Fig. 1. Noncaseating granuloma from liver biopsy. (Hematoxylin-eosin; x400.)
suggestive of metastatic lesions, a computed tomographic-guided needle biopsy of T-12 and the surrounding thickened paravertebral tissues was attempted. Unfortunately, the biopsies yielded only fibrous tissue. Because some question existed about the diagnosis of sarcoidosis, obtaining more tissue was thought to be necessary to rule out a malignant lesion. Therefore, an open-lung biopsy was performed with the plan to explore the renal mass at the same surgical procedure if feasible. The biopsy revealed numerous 1- to 5-mm pulmonary nodules. On microscopic examination, these lesions were grade 3 adenocarcinoma, and clear cells, likely of renal origin, were present. Because of the location of the tumor on the kidney, the surgeon thought that a renal biopsy was not
1500 RENAL CELL CARCINOMA AND SARCOIDLIKE REACTION
Fig. 2. Chest roentgenogram, demonstrating multiple small pulmonary nodules.
possible without a complete nephrectomy; consequently, no renal biopsy was done. Postoperatively, myelography revealed an epidural mass at the level of T-ll that compressed the spinal cord. Although neurologically intact, the patient received radiation therapy (3,000 rad) to that area. A bone scan demonstrated multiple areas of uptake in the pelvis, sacrum, ribs, femur, and spine. The patient died of progressive pulmonary disease 2 months after the metastatic cancer was diagnosed.
DISCUSSION Of importance, most of the findings in the patient described in detail in our case report, including his constitutional symptoms of weight loss (reported in 28% of patients with sarcoidosis') and fever (reported in 17%1), could be attributed to sarcoidosis. Common extrapulmonary manifestations of sarcoidosis include lymphadenopathy in 73% and involvement of the skin in 32%, liver in 21%, eye in 21%, and spleen in 18%.1 Bony involve-
Mayo elin Proc, November 1990, Vol 65
ment occurs in 14% of patients and may include osteolytic lesions that resemble metastatic tumors." Such changes have been detected in the vertebral column. 3 Our patient had several unusual aspects for sarcoidosis. Although multiple pulmonary nodules have been reported in sarcoidosis," this pulmonary manifestation is uncommon. 5 Hematuria occurs in only about 2%.1 Furthermore, the constellation of an indeterminate renal mass, microhematuria, back pain, and the suggestion of changes in the vertebrae on magnetic resonance imaging raised our index of suspicion for a metastatic malignant lesion. Other tests that were considered to help distinguish sarcoidosis from a malignant lesion included a serum angiotensin-converting enzyme level and a bone scan. Because the patient was taking an angiotensin-converting enzyme inhibitor (lisinopril) for control of blood pressure, this test was not done. These medications lower the serum angiotensin-converting enzyme level in patients with sarcoidosis and would complicate the interpretation of the result. 6 Additionally, only about 60% of patients with sarcoidosis have an increased serum angiotensin-converting enzyme level, and the test has a false-positive rate of more than 10%.7 Likewise, a bone scan was concluded not to be helpful in distinguishingmetastatic malignant lesions from sarcoidosis because bones affected by sarcoidosis also take up the bone scanning agent. 8 Therefore, more tissue was needed for a definitive diagnosis, and the patient underwent openlung biopsy. Our case illustrates that noncaseating granulomas can occur in numerous settings and are not pathognomonic for sarcoidosis. Causes of noncaseating granulomas include infections, neoplasms, and exposure to beryllium." Review of the literature revealed that tumor-related tissue reactions resulting in noncaseating granulomas have been reported with many types of malignant lesions, including cutaneous and pulmonary squamous cell carcinomas and cervical, bladder, gastric, lung, and breast cancers." To our knowledge, this case is the first report of such a reaction in renal carcinoma. Overall,
Mayo Clin Proc, November 1990, Vo165
RENAL CELL CARCINOMA AND SARCOIDLIKE REACTION 1501
sarcoidlike tissue reactions have been reported with many other types of malignant tumors. Additionally, one of the cardinal principles of medicine is to evaluate a patient's findings and, whenever possible, make one diagnosis that explains the entire picture. The diagnosis of metastatic renal carcinoma with sarcoidlike tissue reaction best explains the findings in this patient. For clinicians, the important point to remember is that malignant tumors can cause sarcoidlike tissue reactions. Therefore, other diagnostic methods must be used in conjunction with histologic analysis if the clinical picture is not Fig. 3. Abdominal computed tomographic scan, showing characteristic of sarcoidosis.
indeterminate left renal mass (arrow) and other bilateral simple renal cyst's.
REFERENCES
sarcoid reactions occur in 4.4% of carcinomas, 13.8% of Hodgkin's lymphoma, and 7.3% of nonHodgkin's lymphomas and rarely in sarcomas. 9 Such reactions can occur in lymph nodes draining an area in which a malignant lesion is located, in the tumor itself, and even in nonregional tissues. Possibly, the sarcoid reactions are caused by antigenic factors derived from the tumor, which elicit an immunologic hypersensitivity reaction and lead to the formation of noncaseating granulomas.
CONCLUSION We believe that our patient had metastatic renal carcinoma and an associated sarcoidlike tissue reaction but did not, in fact, have sarcoidosis. Several factors oppose the presence of both diseases, including the unusual initial manifestations for sarcoidosis mentioned earlier, the fact that he was asymptomatic before the development of the malignant lesion, and the fact that
1. Mayock RL, BertrandP, Morrison CE, Scott JH: Manifestations of sarcoidosis: analysis of 145 patients, with a review of nine series selected from the literature. Am J Med 35:67-89,1963 2. Cinti DC, Hawkins HB, Slavin JD Jr: Radioisotope bone scanning in a case of sarcoidosis. Clin Nucl Med 10:192-194, 1985 3. Dinerstein SL, Kovarsky J: Vertebral sarcoidosis: demonstration of bone involvement by computerized axial tomography. South Med J 77:1060-1061, 1984 4. Vidal F, Oliver JA, Campanya E, Baguer A, Carrera M, Richart C: Sarcoidosis presenting as multiple pulmonary nodules and nephrotic syndrome. Postgrad Med J 62:1147-1149, 1986 5. Bascom R, Johns CJ: The natural history and management of sarcoidosis. Adv Intern Med 31:213-241,1986 6. Mizuno K, Gotoh M, Matsui J, Nagasawa S, Fukuchi S: Acute effects of captopril on serum angiotensin-converting enzyme activity, the renin-aldosterone system and blood pressure in patients with sarcoidosis. Tohoku J Exp Med 140:107-108, 1983 7. DeRemee RA, Rohrbach MS: Serum angiotensin-converting enzyme activity in evaluating the clinical course of sarcoidosis. Ann Intern Med 92:361-365, 1980 8. Zelitch SR, Israel HL: Sarcoidosis. Am Fam Physician 38:127-139, August 1988 9. Brincker H: Sarcoid reactions in malignant tumours. Cancer Treat Rev 13:147-156,1986
