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Significance of lipid-associated sialic acid and CA 19-9 as tumor markers for renal cell carcinoma
SIGNIFICANCE
OF LIPID-ASSOCIATED
SIALIC
ACID AND CA 19-9 AS TUMOR MARKERS FOR RENAL CELL CARCINOMA JORGE
E. ECHENIQUE,
SAM D. GRAHAM,
M.D.
JH., M.D.
From the Department of Surgery, Section of Urology, Emory University School of Medicine, Atlanta, Georgia
ABSTRACTNumerous neoplasms, including colonic, lung, stomach, and prostate, have been found to have increased concentrations of lipid-associated sialic acid (LASA). CA 19-9 is a carbohydrate antigen found on the membrane surface of pancreatic, gastric, and colonic cancers. A prospective study involving 25 patients (15 males, 1Ufemales) with renal cel1 carcinoma (RCC) was undertaken to examine the clinical value of these two markers. Patients’ ages ranged from twentyfive to seventy-seven years (mean 56 years). The group consisted of 9 Stage I, 1 Stage II, 5 Stage III, and 10 Stage IV patients. Twenty three of the 25 had known disease present when tested. Eleven patients with no known tumor were used as an age-matched controi group. Sixteen of the 23 patients with known disease (70 %) had elevated LASA values. Nine of the 11 control patients (82 %) had normal LASA values. Three of 7 patients with values obtained pre- and post-nephrectomy showed levels returned to normal after nephrectomy; 3 had persistent LASA elevation and were found to have either metastatic OT recurrent disease, and 1 had a persistent elevation of bis LASA value without known metastatic OT recurrent disease. When the 23 patients with known disease were compared according to stage, 62 percent of Stages I and II, 80 percent of Stage 111, and 70 percent of Stage IV had elevated LASA values. There was no statistically significant differente between LASA values and tumor stage. CA 19-9 values obtained in 15 of 25 patients with RCC were within normal range.
Cancer cells have been found to have specific components which may distinguish them from normal cells. Among these distinguishing surface components are glycoproteins and glycolipids, which are frequently shed into the circulatory system and therefore may serve as useful marker proteins for the presence (or absente) of the tumor.’ With the increasing interest in tumor markers, two relatively new markers, lipid-associated sialic acid (LASA) and CA 199, have been found to be elevated in a variety of tumors. Sialic acid is a common terminal saccharide found on cel1 surface glycoproteins and
UROLOGY
/
NOVEMBER
1988
/
VOI,tJME
XXXII,
NUMBER
glycolipids.2 CA 19-9 is a sialylated oligosaccharide also found on cel1 surface glycoproteins.3 Elevated LASA values have been found in patients with colonic, stomach, lung, and prostate cancer as wel1 as in chronic myeloblastic leukemia (CML), acute myeloblastic leukemia (AML), and melanoma.2,4 Elevated CA 199 values have been found in patients with colonic, gastric, and pancreatic cancer.3 We report on a prospective study evaluating these two tumor markers, lipid-associated sialic acid (LASA) and CA 19-9, in patients with renal cel1 carcinoma.
.5
397
Material and Methods
LASA
The study group consisted of 25 patients, 15 males and 10 females, with renal cel1 carcinema (RCC). Ages ranged from twenty-five to seventy-seven years (mean 56 years). A second group of 11 patients (6 females, 5 males) with no known tumors but other urologie disease (10 asymptomatic renal stones, 1 renal subcapsular hematoma) served as controls. The tumor group consisted of 9 Stage 1, 1 Stage 11, 5 Stage 111, and 10 Stage IV RCC patients. Thirteen of the 25 patients had radical nephrectomies at our institution. Ten patients were referred with metastasis or recurrent disease. Twenty-three patients had renal cel1 carcinoma at the time of assay, and 2 patients had no evidence of disease post-nephrectomy. LASA values were determined by using the procedure described by Katopodis et ~1.~ CA 19-9 values were measured using techniques described by Del Villano et al5 A total of 20 mg/dL was considered upper limits of normal for LASA as determined by Katopodis et aZ.* in a review of LASA values in 100 normal patients. Thirtyseven UlmL were considered upper limit of normal for CA 19-9 as determined by Del Villano et ~1.~ in a review of values in 323 normal patients. Al1 samples were collected in a uniform manner and values were determined by Dianon Systems, Inc., Stratford, CT. LASA values were obtained pre-nephrectomy on 13 patients. Seven of these patients had samples drawn approximately two to three months after nephrectomy. Samples were obtained on al1 10 patients with known metastatic as wel1 as recurrent disease. Two patients without known metastatic disease had samples checked for LASA values drawn approximately two years after radical nephrectomy. Both peripheral and renal vein samples were tested for LASA in 3 of the 13 patients who underwent radical nephrectomy. Serum samples for CA 19-9 were obtained in 15 of 25 patients with RCC. Results LASA Sixteen of 23 patients with known disease (70 % ) had LASA values greater than 20 mg/ dL. Two patients with a history of RCC without known recurrence had values below 20 mg/dL. Mean LASA value for the group of 23 patients with known disease was 25.4 mg/dL
398
UI
1
st& 1
Control FIGURE
1.
stage2
stage3
sta&!4
T
LASA values versus stage of disease.
with a range from 14.5 to 39.10 mg/dL. Seven of the 10 patients with documented metastatic disease (70.0 %) had values greater than 20 mg/ dL. The mean LASA value for the 11 control patients was 17.6 mg/dL. Nine of the 11 control patients (82 % ) had LASA values equal to or less than 20.0 mg/dL. This was significantly different from the tumor group (p = 3. 11m3). When the 23 patients were compared according to stage of disease, 5 of 8 patients (62.5 % ) with Stages 1 and 11 disease, 4 of 5 patients (80%) with Stage 111 disease, and 7 of 10 patients (70%) with Stage IV disease had LASA values greater than the norm of 20 mg/dL (Fig. 1). The mean LASA value for patients with known Stages 1 and 11 disease was 24.9 mg/dL. The mean values for patients with known Stages 111 and IV disease were 25.4 mg/dL and 25.8 mg/dL, respectively (Fig. 2). The differences in these values are not statistically significant . Seven patients had LASA values obtained approximately two months after nephrectomy. Values had returned to normal levels in 3 of the 7, al1 of whom had no evidente of disease. Three of the 7 had persistent elevation of their post-nephrectomy LASA values and were proved to have metastatic or recurrent disease. One patient with an elevated post-nephrectomy value had no evidente of recurrence or metastasis. Renal vein samples were obtained in 3 of the 13 patients undergoing radical nephrectomy. Al1 had renal vein LASA values greater than peripheral vein values, and al1 3 renal vein levels were above the norm of 20 mg/dL (Table 1).
UROLOGY
i
NOVEMBER
1988
/ VOLUME XxX11, NUMBER 5
CONTROL
MEAN
LASA
VALUE
RANGE
STAGE 1
17.6
11.7
-
PERCEN’l ELEVATION ABOVE NOREl
STAGE 2
23.5
27.0
16.6
-
STAGE 3
34.3
37.0
18.1
STAGE 4
25.4
___-
15.3
62.5
-
80.0
25.8
34.5
14.5
-
39.1
70.0
I FIGURE
2.
Comparison
CA 19-9 CA 19-9 values for the 15 patients with known disease were below the upper limit of normal (37 U/mL). The mean CA 19-9 value for this group was 10.2 UlmL. Comment This study shows that LASA appears to be a good tumor marker for renal cel1 carcinoma with a sensitivity of 70 percent and a specificity of 82 percent. Seventy percent of al1 23 patients with known disease had elevated LASA values. Two patients with a history of renal cel1 carcinema without known metastasis had normal values. One patient with a previously normal LASA value had a marked elevation with a pulmonary metastasis. Three of 7 patients with pre- and post-nephrectomy LASA levels showed a decrease in LASA to normal. Three of the 7 patients tested had persistent elevation of LASA and were found to have either recurrent or metastatic disease. The seventh patient had a persistent elevation of LASA with no evidente of disease. Seventy percent of patients with known metastatic disease had values above nor-
T~131.1:
1.
Peripheral
renal
vein
LASA
-LASA Value (mg/dL)--Renal Vein Peripheral Vein
Pt. No.
30.8 28.3 20.4
15.3 21.1 18.9
1 2 3
UROLOGY
vein and values
/
NOVEMBER
1988
i
VOLUME
XxX11,
of LASA
values.
mal. These results show that LASA values appear to correlate with the presence or absente of residual or metastatic disease. There appears to be a significant differente between LASA value in each of the four stages of renal cel1 carcinema when compared with the control group. When the LASA values within the stage group were compared with each other, there was no significant differente. The increase in renal vein values in the patients tested suggest that renal cel1 carcinoma is the source of the elevated sialic acid markers, though more renal vein samples need testing. Our results compare favorably with those of Erbil et aE.l who determined LASA values in 15 patients with renal cel1 carcinoma. Sensitivity and specificity values of this study compare with Erbil’s study of 73.3 percent and 90 percent, respectively. The studies differ in patient group size as wel1 as the LASA value considered to be the upper limit of normal. This may explain why Erbil’s l results show 100 percent correlation between abnormal LASA values and Stage IV disease when this study’s results show a 70 percent correlation. CA 19-9 is not a good tumor marker for renal cel1 carcinoma. Al1 patients tested had values below the upper limit of normal. These results are similar to those of Souchon et ~1.~ who studied 11 patients with renal cel1 carcinoma and showed elevated CA 19-9 levels in only 1 patient. In conclusion, LASA appears to be a good tumor marker for the presence of renal cel1 carcinema with a sensitivity of 70 percent and a specificity of 82 percent. A significant difference between LASA values in each stage of
NUMBER
5
399
RCC and control patients was demonstrated. When the LASA values of patients within the different stage groups were compared, there was no statistically significant differente therefore showing a poor correlation between LASA and staging. Future studies should attempt to show better correlation between LASA values and stage as wel1 as the volume of tumor present. CA 19-9 is not a good tumor marker for renal cel1 carcinoma. 2931 Coral Way Miami, Florida 33145 (DR. ECHENIQUE)
400
References 1. Erbil KM, Sen SE, Zincke H, and Jones JD: Significante of serum protein and lipid-bound sialic acid as a marker for genitourinary malignancies, Cancer 57: 1389 (1986). 2. Ritts RE, et al: Initial clinical evaluation of an immunoradiometric assay for CA 19-9 using the NCI serum bank, Int J Cancer 33: 339 (1984). 3. Khadapkar SV, Sheth NA, and Bhide SV: Independente of sialic acid levels in normal and malignant growth, Cancer Res 35: 1120 (1975). 4. Katopodis N, Hirshaut Y, Geller NL, and Stock CC: Lipid associated sialic acid test for the detection of human cancer, Cancer Res 42: 5270 (1982). 5. Del Villano BC, et al: Radioimmunometric assay for a monoclonal antibody-defined tumor marker, CA 19-9. Clin Chem 29: 549 (1983). 6. Souchon R. et al: Clinical experience with the tumor marker CA 19-9 in an unselected group of more than 300 tumor patients, Cancer Det Prev 8: 101 (1985).
UROLOGY
/
NOVEMBER
1988
/
VOLUME
XxX11. NUMBER
5
OF LIPID-ASSOCIATED
SIALIC
ACID AND CA 19-9 AS TUMOR MARKERS FOR RENAL CELL CARCINOMA JORGE
E. ECHENIQUE,
SAM D. GRAHAM,
M.D.
JH., M.D.
From the Department of Surgery, Section of Urology, Emory University School of Medicine, Atlanta, Georgia
ABSTRACTNumerous neoplasms, including colonic, lung, stomach, and prostate, have been found to have increased concentrations of lipid-associated sialic acid (LASA). CA 19-9 is a carbohydrate antigen found on the membrane surface of pancreatic, gastric, and colonic cancers. A prospective study involving 25 patients (15 males, 1Ufemales) with renal cel1 carcinoma (RCC) was undertaken to examine the clinical value of these two markers. Patients’ ages ranged from twentyfive to seventy-seven years (mean 56 years). The group consisted of 9 Stage I, 1 Stage II, 5 Stage III, and 10 Stage IV patients. Twenty three of the 25 had known disease present when tested. Eleven patients with no known tumor were used as an age-matched controi group. Sixteen of the 23 patients with known disease (70 %) had elevated LASA values. Nine of the 11 control patients (82 %) had normal LASA values. Three of 7 patients with values obtained pre- and post-nephrectomy showed levels returned to normal after nephrectomy; 3 had persistent LASA elevation and were found to have either metastatic OT recurrent disease, and 1 had a persistent elevation of bis LASA value without known metastatic OT recurrent disease. When the 23 patients with known disease were compared according to stage, 62 percent of Stages I and II, 80 percent of Stage 111, and 70 percent of Stage IV had elevated LASA values. There was no statistically significant differente between LASA values and tumor stage. CA 19-9 values obtained in 15 of 25 patients with RCC were within normal range.
Cancer cells have been found to have specific components which may distinguish them from normal cells. Among these distinguishing surface components are glycoproteins and glycolipids, which are frequently shed into the circulatory system and therefore may serve as useful marker proteins for the presence (or absente) of the tumor.’ With the increasing interest in tumor markers, two relatively new markers, lipid-associated sialic acid (LASA) and CA 199, have been found to be elevated in a variety of tumors. Sialic acid is a common terminal saccharide found on cel1 surface glycoproteins and
UROLOGY
/
NOVEMBER
1988
/
VOI,tJME
XXXII,
NUMBER
glycolipids.2 CA 19-9 is a sialylated oligosaccharide also found on cel1 surface glycoproteins.3 Elevated LASA values have been found in patients with colonic, stomach, lung, and prostate cancer as wel1 as in chronic myeloblastic leukemia (CML), acute myeloblastic leukemia (AML), and melanoma.2,4 Elevated CA 199 values have been found in patients with colonic, gastric, and pancreatic cancer.3 We report on a prospective study evaluating these two tumor markers, lipid-associated sialic acid (LASA) and CA 19-9, in patients with renal cel1 carcinoma.
.5
397
Material and Methods
LASA
The study group consisted of 25 patients, 15 males and 10 females, with renal cel1 carcinema (RCC). Ages ranged from twenty-five to seventy-seven years (mean 56 years). A second group of 11 patients (6 females, 5 males) with no known tumors but other urologie disease (10 asymptomatic renal stones, 1 renal subcapsular hematoma) served as controls. The tumor group consisted of 9 Stage 1, 1 Stage 11, 5 Stage 111, and 10 Stage IV RCC patients. Thirteen of the 25 patients had radical nephrectomies at our institution. Ten patients were referred with metastasis or recurrent disease. Twenty-three patients had renal cel1 carcinoma at the time of assay, and 2 patients had no evidence of disease post-nephrectomy. LASA values were determined by using the procedure described by Katopodis et ~1.~ CA 19-9 values were measured using techniques described by Del Villano et al5 A total of 20 mg/dL was considered upper limits of normal for LASA as determined by Katopodis et aZ.* in a review of LASA values in 100 normal patients. Thirtyseven UlmL were considered upper limit of normal for CA 19-9 as determined by Del Villano et ~1.~ in a review of values in 323 normal patients. Al1 samples were collected in a uniform manner and values were determined by Dianon Systems, Inc., Stratford, CT. LASA values were obtained pre-nephrectomy on 13 patients. Seven of these patients had samples drawn approximately two to three months after nephrectomy. Samples were obtained on al1 10 patients with known metastatic as wel1 as recurrent disease. Two patients without known metastatic disease had samples checked for LASA values drawn approximately two years after radical nephrectomy. Both peripheral and renal vein samples were tested for LASA in 3 of the 13 patients who underwent radical nephrectomy. Serum samples for CA 19-9 were obtained in 15 of 25 patients with RCC. Results LASA Sixteen of 23 patients with known disease (70 % ) had LASA values greater than 20 mg/ dL. Two patients with a history of RCC without known recurrence had values below 20 mg/dL. Mean LASA value for the group of 23 patients with known disease was 25.4 mg/dL
398
UI
1
st& 1
Control FIGURE
1.
stage2
stage3
sta&!4
T
LASA values versus stage of disease.
with a range from 14.5 to 39.10 mg/dL. Seven of the 10 patients with documented metastatic disease (70.0 %) had values greater than 20 mg/ dL. The mean LASA value for the 11 control patients was 17.6 mg/dL. Nine of the 11 control patients (82 % ) had LASA values equal to or less than 20.0 mg/dL. This was significantly different from the tumor group (p = 3. 11m3). When the 23 patients were compared according to stage of disease, 5 of 8 patients (62.5 % ) with Stages 1 and 11 disease, 4 of 5 patients (80%) with Stage 111 disease, and 7 of 10 patients (70%) with Stage IV disease had LASA values greater than the norm of 20 mg/dL (Fig. 1). The mean LASA value for patients with known Stages 1 and 11 disease was 24.9 mg/dL. The mean values for patients with known Stages 111 and IV disease were 25.4 mg/dL and 25.8 mg/dL, respectively (Fig. 2). The differences in these values are not statistically significant . Seven patients had LASA values obtained approximately two months after nephrectomy. Values had returned to normal levels in 3 of the 7, al1 of whom had no evidente of disease. Three of the 7 had persistent elevation of their post-nephrectomy LASA values and were proved to have metastatic or recurrent disease. One patient with an elevated post-nephrectomy value had no evidente of recurrence or metastasis. Renal vein samples were obtained in 3 of the 13 patients undergoing radical nephrectomy. Al1 had renal vein LASA values greater than peripheral vein values, and al1 3 renal vein levels were above the norm of 20 mg/dL (Table 1).
UROLOGY
i
NOVEMBER
1988
/ VOLUME XxX11, NUMBER 5
CONTROL
MEAN
LASA
VALUE
RANGE
STAGE 1
17.6
11.7
-
PERCEN’l ELEVATION ABOVE NOREl
STAGE 2
23.5
27.0
16.6
-
STAGE 3
34.3
37.0
18.1
STAGE 4
25.4
___-
15.3
62.5
-
80.0
25.8
34.5
14.5
-
39.1
70.0
I FIGURE
2.
Comparison
CA 19-9 CA 19-9 values for the 15 patients with known disease were below the upper limit of normal (37 U/mL). The mean CA 19-9 value for this group was 10.2 UlmL. Comment This study shows that LASA appears to be a good tumor marker for renal cel1 carcinoma with a sensitivity of 70 percent and a specificity of 82 percent. Seventy percent of al1 23 patients with known disease had elevated LASA values. Two patients with a history of renal cel1 carcinema without known metastasis had normal values. One patient with a previously normal LASA value had a marked elevation with a pulmonary metastasis. Three of 7 patients with pre- and post-nephrectomy LASA levels showed a decrease in LASA to normal. Three of the 7 patients tested had persistent elevation of LASA and were found to have either recurrent or metastatic disease. The seventh patient had a persistent elevation of LASA with no evidente of disease. Seventy percent of patients with known metastatic disease had values above nor-
T~131.1:
1.
Peripheral
renal
vein
LASA
-LASA Value (mg/dL)--Renal Vein Peripheral Vein
Pt. No.
30.8 28.3 20.4
15.3 21.1 18.9
1 2 3
UROLOGY
vein and values
/
NOVEMBER
1988
i
VOLUME
XxX11,
of LASA
values.
mal. These results show that LASA values appear to correlate with the presence or absente of residual or metastatic disease. There appears to be a significant differente between LASA value in each of the four stages of renal cel1 carcinema when compared with the control group. When the LASA values within the stage group were compared with each other, there was no significant differente. The increase in renal vein values in the patients tested suggest that renal cel1 carcinoma is the source of the elevated sialic acid markers, though more renal vein samples need testing. Our results compare favorably with those of Erbil et aE.l who determined LASA values in 15 patients with renal cel1 carcinoma. Sensitivity and specificity values of this study compare with Erbil’s study of 73.3 percent and 90 percent, respectively. The studies differ in patient group size as wel1 as the LASA value considered to be the upper limit of normal. This may explain why Erbil’s l results show 100 percent correlation between abnormal LASA values and Stage IV disease when this study’s results show a 70 percent correlation. CA 19-9 is not a good tumor marker for renal cel1 carcinoma. Al1 patients tested had values below the upper limit of normal. These results are similar to those of Souchon et ~1.~ who studied 11 patients with renal cel1 carcinoma and showed elevated CA 19-9 levels in only 1 patient. In conclusion, LASA appears to be a good tumor marker for the presence of renal cel1 carcinema with a sensitivity of 70 percent and a specificity of 82 percent. A significant difference between LASA values in each stage of
NUMBER
5
399
RCC and control patients was demonstrated. When the LASA values of patients within the different stage groups were compared, there was no statistically significant differente therefore showing a poor correlation between LASA and staging. Future studies should attempt to show better correlation between LASA values and stage as wel1 as the volume of tumor present. CA 19-9 is not a good tumor marker for renal cel1 carcinoma. 2931 Coral Way Miami, Florida 33145 (DR. ECHENIQUE)
400
References 1. Erbil KM, Sen SE, Zincke H, and Jones JD: Significante of serum protein and lipid-bound sialic acid as a marker for genitourinary malignancies, Cancer 57: 1389 (1986). 2. Ritts RE, et al: Initial clinical evaluation of an immunoradiometric assay for CA 19-9 using the NCI serum bank, Int J Cancer 33: 339 (1984). 3. Khadapkar SV, Sheth NA, and Bhide SV: Independente of sialic acid levels in normal and malignant growth, Cancer Res 35: 1120 (1975). 4. Katopodis N, Hirshaut Y, Geller NL, and Stock CC: Lipid associated sialic acid test for the detection of human cancer, Cancer Res 42: 5270 (1982). 5. Del Villano BC, et al: Radioimmunometric assay for a monoclonal antibody-defined tumor marker, CA 19-9. Clin Chem 29: 549 (1983). 6. Souchon R. et al: Clinical experience with the tumor marker CA 19-9 in an unselected group of more than 300 tumor patients, Cancer Det Prev 8: 101 (1985).
UROLOGY
/
NOVEMBER
1988
/
VOLUME
XxX11. NUMBER
5