Evaluation of serum level of CA-125 and HE4 in patients with an adnexal mass for the discrimination of benign

from malignant cases

Ahmet Goumlccedilmen Fatih Şanlıkan Yuumlksel Sayın Fatma Seda Oumlztuumlrk Abduumllhamid Guumller

Uumlmraniye Eğitim ve Araştırma Hastanesi

Epidemiology

225000 new incidence annually worldwide Incidence

stable since 1970s

Median age at diagnosis 63

Fifth most common cause of cancer death in women

worldwide

gt60 of women diagnosed with Stage IIIIV

To date no mortality benefit demonstrated with CA125 and

TVUS screening

Ovarian Cancer bull 171 lifetime risk1

bull 5-year survival rates (by year of diagnosis)2

ndash 1990-1992 425 ndash 1993-1995 435 ndash 1996-2003 45

bull Mortality relatively unchanged but statistically significant improvement in 5-year survival rates

1 SEER (Surveillance Epidemiology and End Results) Program Web site httpseercancergovstatfactshtmlovaryhtml Accessed April 22 2007

2 httpseercancergovcsr1975_2004results_mergedsect_21_ovarypdf Accessed April 22 2007

Ca 125 limitations

bull An insufficient sensitivity in early stage OC

(only 23-50 surgical stage I cases)

bull It increases in cases of different physiological and pathological conditions (menses pregnancy endometriosis pleura or peritoneal inflammatory diseases etc)

HE4

bull Human Epididymis-specific protein (HE4- WFDC2)

bull It is expressed in normal ovarian tissue but over expressed in ovarian cancer especially serous and endometrioid histotype

bull It is also expressed in some pulmonary endometrial and breast adenocarcinomas mesotheliomas and less often gastrointestinal renal and transitional cell carcinomas

Material and Methods bull n=63 patients who had adnexal mass on imaging studies and underwent

surgical intervention

bull The exclusion criteriashistory of adnexal surgery for benign disease the diagnosis of pelvic mass during pregnancy ovarian malignancy

bull Serum Ca-125 and HE4 levels were measured on preoperative samples with the upper limit of normal defines as 150 pmolL and 35 UmL respectively for HE4 and CA-125

bull Serum Ca-125 HE4 and ROMA (Risk of Ovarian Malignancy Algorithm) were evaluated for sensitivity specificity positive predictive value (PPV) and negative predictive value (NPV) ROC curves were constructed to determine the sensitivity and specificity of tumor markers at several cut-off points for clinical parameters

Benign n=54 Malign n=9 p

Med (Min-Max) MeanplusmnSD Med (Min-Max) MeanplusmnSD Age 41 (18-77) 428plusmn131 51 (40-60) 508plusmn57 0077

Parity 3 (0-8) 25plusmn26 4 (1-7) 37plusmn19 0198

Body mass index 27 (19-38) 275plusmn49 30 (23-33) 289plusmn36 0402

Histopathology n ()

Endometriosis 18 (333)

Serous cystadenoma 9 (166)

Mucinous cystadenoma 7 (129)

Fibrotecoma 7 (129)

Hemorrhagic cyst 3 (55)

Struma ovari 2 (37)

Mature teratoma 2 (37)

Abscess 2 37)

Others 1 (18)

Histopathology n ()

Serous Papillary carcinoma 6 (666)

Mixed type adenocarcinoma 1 (111)

Mucinous adenocarcinoma 1 (111)

Granulosa cell carcinoma 1 (111)

CA-125 p

Minimum Maximum Mean SD

Bening 93 568 9996 13726

0010 Malign 149 2049 56828 65347

Endometriozis 147 479 14271 14377

Benign Malign Endometriozis ap Min

Max

Mean plusmnSD

MinMax

Mean plusmnSD

Min Max

Mean plusmnSD

HE4 1

368

5454plusmn 5897

64 1317

41862plusmn 45732

2-92 3962plusmn 2491

0001

ROMA 0

77

1182plusmn 1596

14 100

6230plusmn 3718

0-38 866plusmn 1027

0001

n n n bp

Risk Benign 26 703 1 111 13 765

0002 Malign 11 297 8 889 4 235

aKruskall Wallis bFsiher Freeman Halton plt001

Benign Malign p Odds Ratio (95 CI)

Ca125_Grup

0-35 (Normal) 21 389 2 222 0467 22 (04-117)

gt35 33 611 7 778

He-4_Grup

1-150 (Normal) 53 981 5 556 0001 424 (39-4560)

gt150 1 19 4 444

Patology

p Malign Benign Total n n n

CA-125

Malign 7 111 33 534 40 635 0001

Benign 2 32 21 333 23 365

Total 9 143 54 857 63 1000

Sensitivity () 7777

Spesificity () 3889

Positive predictive value 175

Negative predictive value 9130

ODDS 222

n n n p

HE4

Malign 8 127 15 238 23 365 0001

Benign 1 16 39 619 40 635

Toplam 9 143 54 857

Sensitivity () 8888

Spesificity () 7222

Positive predictive value 3478

Negative predictive value 9750

ODDS 208

Pathology p Malign Benign Total

n n n

CA-125+ HE4

Malign 7 778 34 630 22 349 0001

Benign 2 222 20 370 41 651

Total 9 143 54 857 63 1000

Sensitivity () 4444 Spesificity () 99 ODDS 206

Cut-off values for Ca-125 and HE4 were set at 152 UmL and 655 pmolL with 761 and 917 diagnostic accuracy respectively

Karlsen MAGynecol Oncol 2012 n=1218

Epidemiology

225000 new incidence annually worldwide Incidence

stable since 1970s

Median age at diagnosis 63

Fifth most common cause of cancer death in women

worldwide

gt60 of women diagnosed with Stage IIIIV

To date no mortality benefit demonstrated with CA125 and

TVUS screening

Ovarian Cancer bull 171 lifetime risk1

bull 5-year survival rates (by year of diagnosis)2

ndash 1990-1992 425 ndash 1993-1995 435 ndash 1996-2003 45

bull Mortality relatively unchanged but statistically significant improvement in 5-year survival rates

1 SEER (Surveillance Epidemiology and End Results) Program Web site httpseercancergovstatfactshtmlovaryhtml Accessed April 22 2007

2 httpseercancergovcsr1975_2004results_mergedsect_21_ovarypdf Accessed April 22 2007

Ca 125 limitations

bull An insufficient sensitivity in early stage OC

(only 23-50 surgical stage I cases)

bull It increases in cases of different physiological and pathological conditions (menses pregnancy endometriosis pleura or peritoneal inflammatory diseases etc)

HE4

bull Human Epididymis-specific protein (HE4- WFDC2)

bull It is expressed in normal ovarian tissue but over expressed in ovarian cancer especially serous and endometrioid histotype

bull It is also expressed in some pulmonary endometrial and breast adenocarcinomas mesotheliomas and less often gastrointestinal renal and transitional cell carcinomas

Material and Methods bull n=63 patients who had adnexal mass on imaging studies and underwent

surgical intervention

bull The exclusion criteriashistory of adnexal surgery for benign disease the diagnosis of pelvic mass during pregnancy ovarian malignancy

bull Serum Ca-125 and HE4 levels were measured on preoperative samples with the upper limit of normal defines as 150 pmolL and 35 UmL respectively for HE4 and CA-125

bull Serum Ca-125 HE4 and ROMA (Risk of Ovarian Malignancy Algorithm) were evaluated for sensitivity specificity positive predictive value (PPV) and negative predictive value (NPV) ROC curves were constructed to determine the sensitivity and specificity of tumor markers at several cut-off points for clinical parameters

Benign n=54 Malign n=9 p

Med (Min-Max) MeanplusmnSD Med (Min-Max) MeanplusmnSD Age 41 (18-77) 428plusmn131 51 (40-60) 508plusmn57 0077

Parity 3 (0-8) 25plusmn26 4 (1-7) 37plusmn19 0198

Body mass index 27 (19-38) 275plusmn49 30 (23-33) 289plusmn36 0402

Histopathology n ()

Endometriosis 18 (333)

Serous cystadenoma 9 (166)

Mucinous cystadenoma 7 (129)

Fibrotecoma 7 (129)

Hemorrhagic cyst 3 (55)

Struma ovari 2 (37)

Mature teratoma 2 (37)

Abscess 2 37)

Others 1 (18)

Histopathology n ()

Serous Papillary carcinoma 6 (666)

Mixed type adenocarcinoma 1 (111)

Mucinous adenocarcinoma 1 (111)

Granulosa cell carcinoma 1 (111)

CA-125 p

Minimum Maximum Mean SD

Bening 93 568 9996 13726

0010 Malign 149 2049 56828 65347

Endometriozis 147 479 14271 14377

Benign Malign Endometriozis ap Min

Max

Mean plusmnSD

MinMax

Mean plusmnSD

Min Max

Mean plusmnSD

HE4 1

368

5454plusmn 5897

64 1317

41862plusmn 45732

2-92 3962plusmn 2491

0001

ROMA 0

77

1182plusmn 1596

14 100

6230plusmn 3718

0-38 866plusmn 1027

0001

n n n bp

Risk Benign 26 703 1 111 13 765

0002 Malign 11 297 8 889 4 235

aKruskall Wallis bFsiher Freeman Halton plt001

Benign Malign p Odds Ratio (95 CI)

Ca125_Grup

0-35 (Normal) 21 389 2 222 0467 22 (04-117)

gt35 33 611 7 778

He-4_Grup

1-150 (Normal) 53 981 5 556 0001 424 (39-4560)

gt150 1 19 4 444

Patology

p Malign Benign Total n n n

CA-125

Malign 7 111 33 534 40 635 0001

Benign 2 32 21 333 23 365

Total 9 143 54 857 63 1000

Sensitivity () 7777

Spesificity () 3889

Positive predictive value 175

Negative predictive value 9130

ODDS 222

n n n p

HE4

Malign 8 127 15 238 23 365 0001

Benign 1 16 39 619 40 635

Toplam 9 143 54 857

Sensitivity () 8888

Spesificity () 7222

Positive predictive value 3478

Negative predictive value 9750

ODDS 208

Pathology p Malign Benign Total

n n n

CA-125+ HE4

Malign 7 778 34 630 22 349 0001

Benign 2 222 20 370 41 651

Total 9 143 54 857 63 1000

Sensitivity () 4444 Spesificity () 99 ODDS 206

Cut-off values for Ca-125 and HE4 were set at 152 UmL and 655 pmolL with 761 and 917 diagnostic accuracy respectively

Karlsen MAGynecol Oncol 2012 n=1218

Ovarian Cancer bull 171 lifetime risk1

bull 5-year survival rates (by year of diagnosis)2

ndash 1990-1992 425 ndash 1993-1995 435 ndash 1996-2003 45

bull Mortality relatively unchanged but statistically significant improvement in 5-year survival rates

1 SEER (Surveillance Epidemiology and End Results) Program Web site httpseercancergovstatfactshtmlovaryhtml Accessed April 22 2007

2 httpseercancergovcsr1975_2004results_mergedsect_21_ovarypdf Accessed April 22 2007

Ca 125 limitations

bull An insufficient sensitivity in early stage OC

(only 23-50 surgical stage I cases)

bull It increases in cases of different physiological and pathological conditions (menses pregnancy endometriosis pleura or peritoneal inflammatory diseases etc)

HE4

bull Human Epididymis-specific protein (HE4- WFDC2)

bull It is expressed in normal ovarian tissue but over expressed in ovarian cancer especially serous and endometrioid histotype

bull It is also expressed in some pulmonary endometrial and breast adenocarcinomas mesotheliomas and less often gastrointestinal renal and transitional cell carcinomas

Material and Methods bull n=63 patients who had adnexal mass on imaging studies and underwent

surgical intervention

bull The exclusion criteriashistory of adnexal surgery for benign disease the diagnosis of pelvic mass during pregnancy ovarian malignancy

bull Serum Ca-125 and HE4 levels were measured on preoperative samples with the upper limit of normal defines as 150 pmolL and 35 UmL respectively for HE4 and CA-125

bull Serum Ca-125 HE4 and ROMA (Risk of Ovarian Malignancy Algorithm) were evaluated for sensitivity specificity positive predictive value (PPV) and negative predictive value (NPV) ROC curves were constructed to determine the sensitivity and specificity of tumor markers at several cut-off points for clinical parameters

Benign n=54 Malign n=9 p

Med (Min-Max) MeanplusmnSD Med (Min-Max) MeanplusmnSD Age 41 (18-77) 428plusmn131 51 (40-60) 508plusmn57 0077

Parity 3 (0-8) 25plusmn26 4 (1-7) 37plusmn19 0198

Body mass index 27 (19-38) 275plusmn49 30 (23-33) 289plusmn36 0402

Histopathology n ()

Endometriosis 18 (333)

Serous cystadenoma 9 (166)

Mucinous cystadenoma 7 (129)

Fibrotecoma 7 (129)

Hemorrhagic cyst 3 (55)

Struma ovari 2 (37)

Mature teratoma 2 (37)

Abscess 2 37)

Others 1 (18)

Histopathology n ()

Serous Papillary carcinoma 6 (666)

Mixed type adenocarcinoma 1 (111)

Mucinous adenocarcinoma 1 (111)

Granulosa cell carcinoma 1 (111)

CA-125 p

Minimum Maximum Mean SD

Bening 93 568 9996 13726

0010 Malign 149 2049 56828 65347

Endometriozis 147 479 14271 14377

Benign Malign Endometriozis ap Min

Max

Mean plusmnSD

MinMax

Mean plusmnSD

Min Max

Mean plusmnSD

HE4 1

368

5454plusmn 5897

64 1317

41862plusmn 45732

2-92 3962plusmn 2491

0001

ROMA 0

77

1182plusmn 1596

14 100

6230plusmn 3718

0-38 866plusmn 1027

0001

n n n bp

Risk Benign 26 703 1 111 13 765

0002 Malign 11 297 8 889 4 235

aKruskall Wallis bFsiher Freeman Halton plt001

Benign Malign p Odds Ratio (95 CI)

Ca125_Grup

0-35 (Normal) 21 389 2 222 0467 22 (04-117)

gt35 33 611 7 778

He-4_Grup

1-150 (Normal) 53 981 5 556 0001 424 (39-4560)

gt150 1 19 4 444

Patology

p Malign Benign Total n n n

CA-125

Malign 7 111 33 534 40 635 0001

Benign 2 32 21 333 23 365

Total 9 143 54 857 63 1000

Sensitivity () 7777

Spesificity () 3889

Positive predictive value 175

Negative predictive value 9130

ODDS 222

n n n p

HE4

Malign 8 127 15 238 23 365 0001

Benign 1 16 39 619 40 635

Toplam 9 143 54 857

Sensitivity () 8888

Spesificity () 7222

Positive predictive value 3478

Negative predictive value 9750

ODDS 208

Pathology p Malign Benign Total

n n n

CA-125+ HE4

Malign 7 778 34 630 22 349 0001

Benign 2 222 20 370 41 651

Total 9 143 54 857 63 1000

Sensitivity () 4444 Spesificity () 99 ODDS 206

Cut-off values for Ca-125 and HE4 were set at 152 UmL and 655 pmolL with 761 and 917 diagnostic accuracy respectively

Karlsen MAGynecol Oncol 2012 n=1218

Ca 125 limitations

bull An insufficient sensitivity in early stage OC

(only 23-50 surgical stage I cases)

bull It increases in cases of different physiological and pathological conditions (menses pregnancy endometriosis pleura or peritoneal inflammatory diseases etc)

HE4

bull Human Epididymis-specific protein (HE4- WFDC2)

bull It is expressed in normal ovarian tissue but over expressed in ovarian cancer especially serous and endometrioid histotype

bull It is also expressed in some pulmonary endometrial and breast adenocarcinomas mesotheliomas and less often gastrointestinal renal and transitional cell carcinomas

Material and Methods bull n=63 patients who had adnexal mass on imaging studies and underwent

surgical intervention

bull The exclusion criteriashistory of adnexal surgery for benign disease the diagnosis of pelvic mass during pregnancy ovarian malignancy

bull Serum Ca-125 and HE4 levels were measured on preoperative samples with the upper limit of normal defines as 150 pmolL and 35 UmL respectively for HE4 and CA-125

bull Serum Ca-125 HE4 and ROMA (Risk of Ovarian Malignancy Algorithm) were evaluated for sensitivity specificity positive predictive value (PPV) and negative predictive value (NPV) ROC curves were constructed to determine the sensitivity and specificity of tumor markers at several cut-off points for clinical parameters

Benign n=54 Malign n=9 p

Med (Min-Max) MeanplusmnSD Med (Min-Max) MeanplusmnSD Age 41 (18-77) 428plusmn131 51 (40-60) 508plusmn57 0077

Parity 3 (0-8) 25plusmn26 4 (1-7) 37plusmn19 0198

Body mass index 27 (19-38) 275plusmn49 30 (23-33) 289plusmn36 0402

Histopathology n ()

Endometriosis 18 (333)

Serous cystadenoma 9 (166)

Mucinous cystadenoma 7 (129)

Fibrotecoma 7 (129)

Hemorrhagic cyst 3 (55)

Struma ovari 2 (37)

Mature teratoma 2 (37)

Abscess 2 37)

Others 1 (18)

Histopathology n ()

Serous Papillary carcinoma 6 (666)

Mixed type adenocarcinoma 1 (111)

Mucinous adenocarcinoma 1 (111)

Granulosa cell carcinoma 1 (111)

CA-125 p

Minimum Maximum Mean SD

Bening 93 568 9996 13726

0010 Malign 149 2049 56828 65347

Endometriozis 147 479 14271 14377

Benign Malign Endometriozis ap Min

Max

Mean plusmnSD

MinMax

Mean plusmnSD

Min Max

Mean plusmnSD

HE4 1

368

5454plusmn 5897

64 1317

41862plusmn 45732

2-92 3962plusmn 2491

0001

ROMA 0

77

1182plusmn 1596

14 100

6230plusmn 3718

0-38 866plusmn 1027

0001

n n n bp

Risk Benign 26 703 1 111 13 765

0002 Malign 11 297 8 889 4 235

aKruskall Wallis bFsiher Freeman Halton plt001

Benign Malign p Odds Ratio (95 CI)

Ca125_Grup

0-35 (Normal) 21 389 2 222 0467 22 (04-117)

gt35 33 611 7 778

He-4_Grup

1-150 (Normal) 53 981 5 556 0001 424 (39-4560)

gt150 1 19 4 444

Patology

p Malign Benign Total n n n

CA-125

Malign 7 111 33 534 40 635 0001

Benign 2 32 21 333 23 365

Total 9 143 54 857 63 1000

Sensitivity () 7777

Spesificity () 3889

Positive predictive value 175

Negative predictive value 9130

ODDS 222

n n n p

HE4

Malign 8 127 15 238 23 365 0001

Benign 1 16 39 619 40 635

Toplam 9 143 54 857

Sensitivity () 8888

Spesificity () 7222

Positive predictive value 3478

Negative predictive value 9750

ODDS 208

Pathology p Malign Benign Total

n n n

CA-125+ HE4

Malign 7 778 34 630 22 349 0001

Benign 2 222 20 370 41 651

Total 9 143 54 857 63 1000

Sensitivity () 4444 Spesificity () 99 ODDS 206

Cut-off values for Ca-125 and HE4 were set at 152 UmL and 655 pmolL with 761 and 917 diagnostic accuracy respectively

Karlsen MAGynecol Oncol 2012 n=1218

HE4

bull Human Epididymis-specific protein (HE4- WFDC2)

bull It is expressed in normal ovarian tissue but over expressed in ovarian cancer especially serous and endometrioid histotype

bull It is also expressed in some pulmonary endometrial and breast adenocarcinomas mesotheliomas and less often gastrointestinal renal and transitional cell carcinomas

Material and Methods bull n=63 patients who had adnexal mass on imaging studies and underwent

surgical intervention

bull The exclusion criteriashistory of adnexal surgery for benign disease the diagnosis of pelvic mass during pregnancy ovarian malignancy

bull Serum Ca-125 and HE4 levels were measured on preoperative samples with the upper limit of normal defines as 150 pmolL and 35 UmL respectively for HE4 and CA-125

bull Serum Ca-125 HE4 and ROMA (Risk of Ovarian Malignancy Algorithm) were evaluated for sensitivity specificity positive predictive value (PPV) and negative predictive value (NPV) ROC curves were constructed to determine the sensitivity and specificity of tumor markers at several cut-off points for clinical parameters

Benign n=54 Malign n=9 p

Med (Min-Max) MeanplusmnSD Med (Min-Max) MeanplusmnSD Age 41 (18-77) 428plusmn131 51 (40-60) 508plusmn57 0077

Parity 3 (0-8) 25plusmn26 4 (1-7) 37plusmn19 0198

Body mass index 27 (19-38) 275plusmn49 30 (23-33) 289plusmn36 0402

Histopathology n ()

Endometriosis 18 (333)

Serous cystadenoma 9 (166)

Mucinous cystadenoma 7 (129)

Fibrotecoma 7 (129)

Hemorrhagic cyst 3 (55)

Struma ovari 2 (37)

Mature teratoma 2 (37)

Abscess 2 37)

Others 1 (18)

Histopathology n ()

Serous Papillary carcinoma 6 (666)

Mixed type adenocarcinoma 1 (111)

Mucinous adenocarcinoma 1 (111)

Granulosa cell carcinoma 1 (111)

CA-125 p

Minimum Maximum Mean SD

Bening 93 568 9996 13726

0010 Malign 149 2049 56828 65347

Endometriozis 147 479 14271 14377

Benign Malign Endometriozis ap Min

Max

Mean plusmnSD

MinMax

Mean plusmnSD

Min Max

Mean plusmnSD

HE4 1

368

5454plusmn 5897

64 1317

41862plusmn 45732

2-92 3962plusmn 2491

0001

ROMA 0

77

1182plusmn 1596

14 100

6230plusmn 3718

0-38 866plusmn 1027

0001

n n n bp

Risk Benign 26 703 1 111 13 765

0002 Malign 11 297 8 889 4 235

aKruskall Wallis bFsiher Freeman Halton plt001

Benign Malign p Odds Ratio (95 CI)

Ca125_Grup

0-35 (Normal) 21 389 2 222 0467 22 (04-117)

gt35 33 611 7 778

He-4_Grup

1-150 (Normal) 53 981 5 556 0001 424 (39-4560)

gt150 1 19 4 444

Patology

p Malign Benign Total n n n

CA-125

Malign 7 111 33 534 40 635 0001

Benign 2 32 21 333 23 365

Total 9 143 54 857 63 1000

Sensitivity () 7777

Spesificity () 3889

Positive predictive value 175

Negative predictive value 9130

ODDS 222

n n n p

HE4

Malign 8 127 15 238 23 365 0001

Benign 1 16 39 619 40 635

Toplam 9 143 54 857

Sensitivity () 8888

Spesificity () 7222

Positive predictive value 3478

Negative predictive value 9750

ODDS 208

Pathology p Malign Benign Total

n n n

CA-125+ HE4

Malign 7 778 34 630 22 349 0001

Benign 2 222 20 370 41 651

Total 9 143 54 857 63 1000

Sensitivity () 4444 Spesificity () 99 ODDS 206

Cut-off values for Ca-125 and HE4 were set at 152 UmL and 655 pmolL with 761 and 917 diagnostic accuracy respectively

Karlsen MAGynecol Oncol 2012 n=1218

Material and Methods bull n=63 patients who had adnexal mass on imaging studies and underwent

surgical intervention

bull The exclusion criteriashistory of adnexal surgery for benign disease the diagnosis of pelvic mass during pregnancy ovarian malignancy

bull Serum Ca-125 and HE4 levels were measured on preoperative samples with the upper limit of normal defines as 150 pmolL and 35 UmL respectively for HE4 and CA-125

bull Serum Ca-125 HE4 and ROMA (Risk of Ovarian Malignancy Algorithm) were evaluated for sensitivity specificity positive predictive value (PPV) and negative predictive value (NPV) ROC curves were constructed to determine the sensitivity and specificity of tumor markers at several cut-off points for clinical parameters

Benign n=54 Malign n=9 p

Med (Min-Max) MeanplusmnSD Med (Min-Max) MeanplusmnSD Age 41 (18-77) 428plusmn131 51 (40-60) 508plusmn57 0077

Parity 3 (0-8) 25plusmn26 4 (1-7) 37plusmn19 0198

Body mass index 27 (19-38) 275plusmn49 30 (23-33) 289plusmn36 0402

Histopathology n ()

Endometriosis 18 (333)

Serous cystadenoma 9 (166)

Mucinous cystadenoma 7 (129)

Fibrotecoma 7 (129)

Hemorrhagic cyst 3 (55)

Struma ovari 2 (37)

Mature teratoma 2 (37)

Abscess 2 37)

Others 1 (18)

Histopathology n ()

Serous Papillary carcinoma 6 (666)

Mixed type adenocarcinoma 1 (111)

Mucinous adenocarcinoma 1 (111)

Granulosa cell carcinoma 1 (111)

CA-125 p

Minimum Maximum Mean SD

Bening 93 568 9996 13726

0010 Malign 149 2049 56828 65347

Endometriozis 147 479 14271 14377

Benign Malign Endometriozis ap Min

Max

Mean plusmnSD

MinMax

Mean plusmnSD

Min Max

Mean plusmnSD

HE4 1

368

5454plusmn 5897

64 1317

41862plusmn 45732

2-92 3962plusmn 2491

0001

ROMA 0

77

1182plusmn 1596

14 100

6230plusmn 3718

0-38 866plusmn 1027

0001

n n n bp

Risk Benign 26 703 1 111 13 765

0002 Malign 11 297 8 889 4 235

aKruskall Wallis bFsiher Freeman Halton plt001

Benign Malign p Odds Ratio (95 CI)

Ca125_Grup

0-35 (Normal) 21 389 2 222 0467 22 (04-117)

gt35 33 611 7 778

He-4_Grup

1-150 (Normal) 53 981 5 556 0001 424 (39-4560)

gt150 1 19 4 444

Patology

p Malign Benign Total n n n

CA-125

Malign 7 111 33 534 40 635 0001

Benign 2 32 21 333 23 365

Total 9 143 54 857 63 1000

Sensitivity () 7777

Spesificity () 3889

Positive predictive value 175

Negative predictive value 9130

ODDS 222

n n n p

HE4

Malign 8 127 15 238 23 365 0001

Benign 1 16 39 619 40 635

Toplam 9 143 54 857

Sensitivity () 8888

Spesificity () 7222

Positive predictive value 3478

Negative predictive value 9750

ODDS 208

Pathology p Malign Benign Total

n n n

CA-125+ HE4

Malign 7 778 34 630 22 349 0001

Benign 2 222 20 370 41 651

Total 9 143 54 857 63 1000

Sensitivity () 4444 Spesificity () 99 ODDS 206

Cut-off values for Ca-125 and HE4 were set at 152 UmL and 655 pmolL with 761 and 917 diagnostic accuracy respectively

Karlsen MAGynecol Oncol 2012 n=1218

Benign n=54 Malign n=9 p

Med (Min-Max) MeanplusmnSD Med (Min-Max) MeanplusmnSD Age 41 (18-77) 428plusmn131 51 (40-60) 508plusmn57 0077

Parity 3 (0-8) 25plusmn26 4 (1-7) 37plusmn19 0198

Body mass index 27 (19-38) 275plusmn49 30 (23-33) 289plusmn36 0402

Histopathology n ()

Endometriosis 18 (333)

Serous cystadenoma 9 (166)

Mucinous cystadenoma 7 (129)

Fibrotecoma 7 (129)

Hemorrhagic cyst 3 (55)

Struma ovari 2 (37)

Mature teratoma 2 (37)

Abscess 2 37)

Others 1 (18)

Histopathology n ()

Serous Papillary carcinoma 6 (666)

Mixed type adenocarcinoma 1 (111)

Mucinous adenocarcinoma 1 (111)

Granulosa cell carcinoma 1 (111)

CA-125 p

Minimum Maximum Mean SD

Bening 93 568 9996 13726

0010 Malign 149 2049 56828 65347

Endometriozis 147 479 14271 14377

Benign Malign Endometriozis ap Min

Max

Mean plusmnSD

MinMax

Mean plusmnSD

Min Max

Mean plusmnSD

HE4 1

368

5454plusmn 5897

64 1317

41862plusmn 45732

2-92 3962plusmn 2491

0001

ROMA 0

77

1182plusmn 1596

14 100

6230plusmn 3718

0-38 866plusmn 1027

0001

n n n bp

Risk Benign 26 703 1 111 13 765

0002 Malign 11 297 8 889 4 235

aKruskall Wallis bFsiher Freeman Halton plt001

Benign Malign p Odds Ratio (95 CI)

Ca125_Grup

0-35 (Normal) 21 389 2 222 0467 22 (04-117)

gt35 33 611 7 778

He-4_Grup

1-150 (Normal) 53 981 5 556 0001 424 (39-4560)

gt150 1 19 4 444

Patology

p Malign Benign Total n n n

CA-125

Malign 7 111 33 534 40 635 0001

Benign 2 32 21 333 23 365

Total 9 143 54 857 63 1000

Sensitivity () 7777

Spesificity () 3889

Positive predictive value 175

Negative predictive value 9130

ODDS 222

n n n p

HE4

Malign 8 127 15 238 23 365 0001

Benign 1 16 39 619 40 635

Toplam 9 143 54 857

Sensitivity () 8888

Spesificity () 7222

Positive predictive value 3478

Negative predictive value 9750

ODDS 208

Pathology p Malign Benign Total

n n n

CA-125+ HE4

Malign 7 778 34 630 22 349 0001

Benign 2 222 20 370 41 651

Total 9 143 54 857 63 1000

Sensitivity () 4444 Spesificity () 99 ODDS 206

Cut-off values for Ca-125 and HE4 were set at 152 UmL and 655 pmolL with 761 and 917 diagnostic accuracy respectively

Karlsen MAGynecol Oncol 2012 n=1218

CA-125 p

Minimum Maximum Mean SD

Bening 93 568 9996 13726

0010 Malign 149 2049 56828 65347

Endometriozis 147 479 14271 14377

Benign Malign Endometriozis ap Min

Max

Mean plusmnSD

MinMax

Mean plusmnSD

Min Max

Mean plusmnSD

HE4 1

368

5454plusmn 5897

64 1317

41862plusmn 45732

2-92 3962plusmn 2491

0001

ROMA 0

77

1182plusmn 1596

14 100

6230plusmn 3718

0-38 866plusmn 1027

0001

n n n bp

Risk Benign 26 703 1 111 13 765

0002 Malign 11 297 8 889 4 235

aKruskall Wallis bFsiher Freeman Halton plt001

Benign Malign p Odds Ratio (95 CI)

Ca125_Grup

0-35 (Normal) 21 389 2 222 0467 22 (04-117)

gt35 33 611 7 778

He-4_Grup

1-150 (Normal) 53 981 5 556 0001 424 (39-4560)

gt150 1 19 4 444

Patology

p Malign Benign Total n n n

CA-125

Malign 7 111 33 534 40 635 0001

Benign 2 32 21 333 23 365

Total 9 143 54 857 63 1000

Sensitivity () 7777

Spesificity () 3889

Positive predictive value 175

Negative predictive value 9130

ODDS 222

n n n p

HE4

Malign 8 127 15 238 23 365 0001

Benign 1 16 39 619 40 635

Toplam 9 143 54 857

Sensitivity () 8888

Spesificity () 7222

Positive predictive value 3478

Negative predictive value 9750

ODDS 208

Pathology p Malign Benign Total

n n n

CA-125+ HE4

Malign 7 778 34 630 22 349 0001

Benign 2 222 20 370 41 651

Total 9 143 54 857 63 1000

Sensitivity () 4444 Spesificity () 99 ODDS 206

Cut-off values for Ca-125 and HE4 were set at 152 UmL and 655 pmolL with 761 and 917 diagnostic accuracy respectively

Karlsen MAGynecol Oncol 2012 n=1218

Benign Malign p Odds Ratio (95 CI)

Ca125_Grup

0-35 (Normal) 21 389 2 222 0467 22 (04-117)

gt35 33 611 7 778

He-4_Grup

1-150 (Normal) 53 981 5 556 0001 424 (39-4560)

gt150 1 19 4 444

Patology

p Malign Benign Total n n n

CA-125

Malign 7 111 33 534 40 635 0001

Benign 2 32 21 333 23 365

Total 9 143 54 857 63 1000

Sensitivity () 7777

Spesificity () 3889

Positive predictive value 175

Negative predictive value 9130

ODDS 222

n n n p

HE4

Malign 8 127 15 238 23 365 0001

Benign 1 16 39 619 40 635

Toplam 9 143 54 857

Sensitivity () 8888

Spesificity () 7222

Positive predictive value 3478

Negative predictive value 9750

ODDS 208

Pathology p Malign Benign Total

n n n

CA-125+ HE4

Malign 7 778 34 630 22 349 0001

Benign 2 222 20 370 41 651

Total 9 143 54 857 63 1000

Sensitivity () 4444 Spesificity () 99 ODDS 206

Cut-off values for Ca-125 and HE4 were set at 152 UmL and 655 pmolL with 761 and 917 diagnostic accuracy respectively

Karlsen MAGynecol Oncol 2012 n=1218

Patology

p Malign Benign Total n n n

CA-125

Malign 7 111 33 534 40 635 0001

Benign 2 32 21 333 23 365

Total 9 143 54 857 63 1000

Sensitivity () 7777

Spesificity () 3889

Positive predictive value 175

Negative predictive value 9130

ODDS 222

n n n p

HE4

Malign 8 127 15 238 23 365 0001

Benign 1 16 39 619 40 635

Toplam 9 143 54 857

Sensitivity () 8888

Spesificity () 7222

Positive predictive value 3478

Negative predictive value 9750

ODDS 208

Pathology p Malign Benign Total

n n n

CA-125+ HE4

Malign 7 778 34 630 22 349 0001

Benign 2 222 20 370 41 651

Total 9 143 54 857 63 1000

Sensitivity () 4444 Spesificity () 99 ODDS 206

Cut-off values for Ca-125 and HE4 were set at 152 UmL and 655 pmolL with 761 and 917 diagnostic accuracy respectively

Karlsen MAGynecol Oncol 2012 n=1218

Pathology p Malign Benign Total

n n n

CA-125+ HE4

Malign 7 778 34 630 22 349 0001

Benign 2 222 20 370 41 651

Total 9 143 54 857 63 1000

Sensitivity () 4444 Spesificity () 99 ODDS 206

Cut-off values for Ca-125 and HE4 were set at 152 UmL and 655 pmolL with 761 and 917 diagnostic accuracy respectively

Karlsen MAGynecol Oncol 2012 n=1218

Cut-off values for Ca-125 and HE4 were set at 152 UmL and 655 pmolL with 761 and 917 diagnostic accuracy respectively

Karlsen MAGynecol Oncol 2012 n=1218

Karlsen MAGynecol Oncol 2012 n=1218

Comparison of HE4 CA125 and ROMA algorithm in women with a pelvic mass Correlation with pathological outcome

Sandri MT1Gynecol Oncol 2013

N= 7792 tests (11 studies) ROMA for EOC sensitivity 89 specificity 83 and AUC 93 Comparison of EOC predictive value specificity HE4 (93) gt CA125 (84) AUC CA125 88 gt HE4 82 Comparison of OC predictive value AUC CA125 (89) gt HE4 (79) Comparison among the three tests for EOC prediction sensitivity ROMA (86) gtHE4 (80) specificity HE4 (95) gt ROMA (84) gt CA125 (78)

Li2012

n= 6269 (31 trials) bull HE4 Sensitivity 73 (95 CI 071ndash075)

Specificity 89 (95 CI 088ndash090)

Positive likelihood ratio 730 (95 CI 542ndash984)

Negative likelihood ratio 015 (95 CI 010ndash023)

Yang et al2013

Conclusion

bull The combination of CA-125 and HE4 may improve the diagnostic accuracy for the discrimination of benign adnexal mass from malignant cases

bull Further studies into the molecular basis of tumor biology might contribute the current understanding of the nature of the ovarian cancer and tumor markers

n= 6269 (31 trials) bull HE4 Sensitivity 73 (95 CI 071ndash075)

Specificity 89 (95 CI 088ndash090)

Positive likelihood ratio 730 (95 CI 542ndash984)

Negative likelihood ratio 015 (95 CI 010ndash023)

Yang et al2013

Conclusion

bull The combination of CA-125 and HE4 may improve the diagnostic accuracy for the discrimination of benign adnexal mass from malignant cases

bull Further studies into the molecular basis of tumor biology might contribute the current understanding of the nature of the ovarian cancer and tumor markers

Conclusion

bull The combination of CA-125 and HE4 may improve the diagnostic accuracy for the discrimination of benign adnexal mass from malignant cases

bull Further studies into the molecular basis of tumor biology might contribute the current understanding of the nature of the ovarian cancer and tumor markers