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Original Research

Predicting Risk of Malignancy in Adnexal
Masses
John M. McDonald, MD, Stacey Doran, BS, Christopher P. DeSimone, MD, Fred R. Ueland, MD,
Paul D. DePriest, MD, Rachel A. Ware, MD, Brook A. Saunders, MD, Edward J. Pavlik, PhD,
Scott Goodrich, MD, Richard J. Kryscio, PhD, and John R. van Nagell Jr, MD

OBJECTIVE: To estimate the accuracy of preoperative                            cancer and 98.6% of patients with stage III and stage IV
ultrasonography, serum CA 125, and patient demograph-                          ovarian cancer.
ics as a means of predicting risk of malignancy in women                       CONCLUSION: Patients with solid or complex ovarian
with a ultrasonographically confirmed adnexal mass.                            tumors and an elevated serum CA 125 level (greater than
METHODS: Tumor morphology derived from ultrasono-                              35 units/mL) are at high risk of ovarian malignancy.
graphic images, tumor size, tumor bilaterality, serum CA                       (Obstet Gynecol 2010;115:687–94)
125, and patient demographics were evaluated preoper-                          LEVEL OF EVIDENCE: II
atively in 395 patients undergoing surgery from 2001 to
2008. Tumor morphology was classified as complex,
solid, or cystic. Preoperative findings were compared
with tumor histologic findings at the time of surgery.
Multivariable classification and regression tree analysis
                                                                               O      varian cancer remains the leading cause of
                                                                                      death from gynecologic cancers in the United
                                                                               States. It was estimated that in 2009 there would be
were used to identify a group of patients at high risk of                      21,554 new cases of ovarian cancer, and that 14,600
ovarian malignancy.                                                            women would die as a result of disease.1 Case– control
RESULTS: One hundred eighteen patients had ovarian                             studies have indicated that women with ovarian can-
cancer, 13 patients had ovarian tumors of borderline                           cer commonly experience a pattern of symptoms that
malignancy, and 264 had benign ovarian tumors. Multi-                          include bloating, pelvic/abdominal pain, difficulty
variable classification and regression tree analysis defined                   eating/feeling full quickly, and urinary urgency or
women at high risk of ovarian malignancy as those with
                                                                               frequency.2,3 These symptoms were found to be more
an adnexal mass having complex or solid morphology
and a serum CA 125 value greater than 35 units/mL. This
                                                                               commonly associated with ovarian cancer, when they
definition had a positive predictive value of 84.7% and a                      were newly experienced, and occurred more that 12
negative predictive value of 92.4% and correctly identi-                       times per month.4 Recently, consensus groups have
fied 77.3% of patients with stage I and stage II ovarian                       recommended that women who experience symp-
                                                                               toms suggestive of ovarian cancer should undergo a
                      See related editorial on page 680.                       complete physical examination, and in certain cases,
                                                                               transvaginal ultrasonography and CA 125 testing.
From the Division of Gynecologic Oncology, Department of Obstetrics and        Although the majority of patients with these symp-
Gynecology, and Departments of Statistics and Biostatistics, University of     toms will not have ovarian cancer, those who do will
Kentucky Chandler Medical Center–Markey Cancer Center, Lexington,
Kentucky.
                                                                               require complete surgical staging and aggressive tu-
Supported by research grants from the Kentucky Department of Health and
                                                                               mor debulking to maximize their chances of surviv-
Human Services and the Telford Foundation.                                     al.5–7 In this regard, it is important to establish risk
Corresponding author: John Rensselaer van Nagell Jr, MD, Division of           profiles of patients with ultrasonographically con-
Gynecologic Oncology, Department of Obstetrics and Gynecology, University      firmed adnexal tumors so that they can receive ap-
of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536; e-mail:      propriate treatment and, when necessary, referral for
jrvann2@email.uky.edu.
                                                                               specialty cancer care. The authors postulate that the
Financial Disclosure
The authors did not report any potential conflicts of interest.
                                                                               addition of ultrasonographically generated tumor
                                                                               morphology to patient demographics and serum bi-
© 2010 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.                                              omarker profiles could improve prediction of malig-
ISSN: 0029-7844/10                                                             nancy in a clinically detectable adnexal mass. This



VOL. 115, NO. 4, APRIL 2010                                                                        OBSTETRICS & GYNECOLOGY         687
investigation was undertaken to estimate the accuracy      tional Federation of Gynecology and Obstetrics sys-
of a combination of patient demographics, ultrasono-       tem. Data were entered into a MEDLOG database
graphically generated tumor morphology, and serum          (MEDLOG Systems, Crystal Bay, NV) and exported
CA 125 values in predicting risk of malignancy in          into an Excel (Microsoft Corp., Redmond, WA)
adnexal masses.                                            spreadsheet for analysis using WinSTAT (R. Fitch
                                                           Software, Bad Krozingen, Germany), SPSS (SPSS,
MATERIALS AND METHODS                                      Inc., Chicago, IL), and PC-SAS with the Enterprise
This investigation was undertaken after approval           Miner statistical software (SAS Institute, Inc., Cary, NC).
from the University of Kentucky Human Subjects                  Proportions were compared using ␹2 statistics or
Institutional Review Board. Study participants were        Fisher exact tests. Means were compared using two-
women referred to the University of Kentucky–Mar-          sample t tests. Statistical significance was determined
key Women’s Cancer Center with a diagnosis of an           at the .05 level. Multivariable analyses used the
adnexal mass on pelvic examination who underwent           classification and regression tree procedure, a non-
surgery at this institution from 2001 to 2008.             parametric method that defines or accepts cut points
     The following demographic data were obtained          and uses training and validation sets to optimize rules
for all study patients: age, height, weight, gravidity,    for the analysis.9 The training set is formed by split-
family history of breast or ovarian cancer, personal       ting the entire sample in half after stratification for
history of cancer, and menopausal status. Postmeno-        malignant cases and benign controls.
pausal was defined as the absence of menses for a
minimum of 12 months. Family history was consid-           RESULTS
ered positive if the patient had a first-degree relative   Between July 2001 and December 2008, 399 patients
(ie, mother, sister, or daughter) or a second-degree       referred to the outpatient clinic of the University of
relative (ie, grandmother, granddaughter, aunt, or         Kentucky–Markey Women’s Cancer Center for eval-
niece) with documented ovarian or breast cancer. All       uation of an adnexal mass on pelvic examination
women underwent pelvic examination, transvaginal
ultrasonography, and serum CA 125 determination
within 2 weeks before surgery. Transvaginal ultra-         Table 1. Patient Demographics, Tumor Variables,
sonography was performed using General Electric                     and Biomarker Profiles in Patients
(Milwaukee, WI) Logic 400 or Voluson ProV ultra-                    Studied (N‫)593؍‬
sound units with a 5-mHz vaginal probe as described                                           Mean             Range
previously.8 Tumor dimensions from ultrasono-
graphic images were recorded, and tumor morphol-           Age (y)                        51.6 (Ϯ0.8)         10–86
ogy was classified as cystic, solid, or complex (con-      Height (in)                      64 (Ϯ0.02)        55–72
                                                           Weight (lb)                     173 (Ϯ2.8)         78–384
taining both solid and cystic components). All             Gravidity                       2.4 (Ϯ0.1)          0–21
ultrasonograms were reviewed by at least one of the        Family history
authors. All tumors classified as cystic were unilocu-        Ovarian cancer                48 (12)
lar, whereas cystic tumors with septations were in-           Breast cancer                 64 (16)
cluded in the complex group. Ascites was defined as        Menopausal status
                                                              Premenopausal                176 (45)
free fluid more than 60 mL in the abdomen/pelvis              Postmenopausal               219 (55)
confirmed by ultrasonography. Serum CA 125 deter-          Tumor morphology
minations were performed using a two-site sandwich            Cystic                       123 (31)
paramagnetic particle chemiluminescent immunoen-              Complex                      236 (60)
zymatic assay with a normal value less than 35                Solid                         36 (9)
                                                           Tumor diameter
units/mL. Serum samples with values exceeding                 10 cm or less                291 (74)
5,000 units/mL were diluted to end point for a final          More than 10 cm              104 (26)
result.                                                    Ascites
     After surgical removal, the dimensions of each           Present                       54 (14)
tumor were recorded, and frozen section histologic            Absent                       341 (86)
                                                           CA 125 (units/mL)
evaluation was performed. Tumors were classified              Less than 35                 247 (62)
histologically according to the World Health Organi-          35–59                         38 (10)
zation system. Patients with a histologic diagnosis of        60–120                        23 (6)
ovarian malignancy underwent immediate tumor de-              More than 120                 87 (22)
bulking and surgical staging according to the Interna-     Data are mean (Ϯstandard deviation) or n (%).




688   McDonald et al    Risk of Malignancy in an Adnexal Mass                          OBSTETRICS & GYNECOLOGY
were included in this investigation. Four patients had     followed by serous cystadenocarcinoma, mucinous
their first CA 125 determination after surgery and         cystadenocarcinoma, and clear-cell carcinoma.
were excluded from further evaluation. Demographic              The relationship of demographic, biomarker, and
data, biomarker profiles, and tumor characteristics of     tumor variables to risk of malignancy in patients with
the patients evaluated are listed in Table 1. Fifty-five   an adnexal mass is presented in Table 2. Variables
percent of patients were postmenopausal and 40%            statistically related to risk of malignancy were tumor
were aged 55 years or older. Sixty-four patients (16%)     morphology, ascites, serum CA 125 level, tumor size,
had a family history of breast cancer, 48 patients         tumor bilaterality, menopausal status, and age.
(12%) had a family history of ovarian cancer, and one           Tumor morphology from ultrasonographically
patient was BRCA1 positive. Two hundred thirty-six         generated images was related directly to risk of ma-
masses (60%) were ultrasonographically complex             lignancy. There were 236 complex adnexal masses,
(Fig. 1A), 123 (31%) were cystic (Fig. 1B), and 36 (9%)    and 120 (51%) were malignant. None of the five
were solid (Fig. 1C). Five of the 236 complex adnexal      complex masses with septal morphology without solid
masses (2.1%) were cystic ovarian tumors with thick        areas were malignant. There were 36 solid adnexal
septa but no solid areas. Radiologic evidence of           masses, and 11 (32%) were malignant. In contrast,
ascites was present in 54 patients (14%). Serum CA         there were 123 cystic adnexal masses, and none were
125 level was elevated (more than 35 units/mL) in          ovarian tumors of borderline malignancy or invasive
148 patients (38%) and was more than 120 units/mL          ovarian cancers (PϽ.001). The finding of purely cystic
in 87 patients (22%).                                      morphology in an adnexal mass was associated with a
     At the time of surgery, 264 patients (67%) were       negative predictive value (NPV) for malignancy of 100%.
found to have benign ovarian tumors, 118 patients               Fifty-four patients with an adnexal mass had
(30%) had ovarian cancer, and 13 patients (3%) had         radiologically confirmed ascites, and all of these pa-
ovarian tumors of borderline malignancy. The stage         tients had invasive epithelial ovarian cancer (stage IC,
distribution of the patients with ovarian tumors of        nϭ2; stage IIC, nϭ1; stage IIIC, nϭ49; and stage IV,
borderline malignancy and ovarian cancer was as            nϭ2). Therefore, the finding of documented ascites
follows: stage I, nϭ38; stage II, nϭ17; stage III,         in a patient with a complex or solid adnexal mass
nϭ74; and stage IV, nϭ2. The most common cell              had a positive predictive value (PPV) for malig-
types of ovarian malignancy were adenocarcinoma,           nancy of 100%.




                                                                                  Fig. 1. Patterns of adnexal mor-
                                                                                  phology. A. Complex adnexal
                                                                                  mass, 12 cm in diameter; the cys-
                                                                                  tic periphery is marked with clear
                                                                                  arrows and the internal solid
                                                                                  component is marked with solid
                                                                                  arrows (histology: clear-cell carci-
                                                                                  noma). B. Cystic adnexal mass,
                                                                                  9.4 cm in diameter, periphery is
                                                                                  marked with clear arrows (histol-
                                                                                  ogy: ovarian serous cystade-
                                                                                  noma). C. Solid adnexal mass, 5
                                                                                  cm in diameter; the periphery is
                                                                                  marked with clear arrows (histol-
                                                                                  ogy: ovarian adenocarcinoma).
                                                                                  McDonald. Risk of Malignancy in an
                                                                                  Adnexal Mass. Obstet Gynecol
                                                                                  2010.




VOL. 115, NO. 4, APRIL 2010                           McDonald et al   Risk of Malignancy in an Adnexal Mass      689
Table 2. Demographic, Tumor, and Biomarker                      patients with complex and solid adnexal masses are
         Variables Related to Risk of Malignancy                listed in Table 3. The only benign histologic finding
         (N‫)593؍‬                                                consistently associated with an elevated serum CA
Variable                       Total   Malignant       P        125 value was ovarian endometriosis. Thirteen (48%)
                                                                of 27 women with an ovarian endometrioma had an
Age (y)                                                         elevated serum CA 125 value (more than 35 units/
   55 or younger               239      58 (24.3)   Ͻ.001
   Older than 55               156      73 (46.8)
                                                                mL), and 5 (18%) had a serum CA 125 value more
Gravidity                                                       than 60 units/mL. There were 114 women with other
   1 or less                   125      41 (32.8)     .92       benign complex or solid adnexal masses, and only 1
   More than 1                 270      90 (33.3)               patient (with an ovarian fibroma) had a CA 125 level
Menopausal status                                               more than 60 units/mL. As expected, serum CA 125
   Premenopausal               176      43 (24.4)   Ͻ.001
   Postmenopausal              219      88 (40.2)
                                                                values were related directly to stage of disease in
Weight (lb)                                                     patients with ovarian malignancies. Serum CA 125
   200 or less                 314     116 (36.9)   Ͻ.02        values were elevated (more than 35 units/mL) in
   More than 200                81      15 (18.5)               30.7% of patients with an ovarian tumor of borderline
Family history of ovarian                                       malignancy, 77.2% of patients with stage I and stage II
       cancer
   Yes                          48      16 (33.3)     .98
                                                                ovarian cancer, and 98.6% of patients with stage IIIC
   No                          347     115 (33.1)               and IV ovarian cancer. All 54 patients with ascites
Family history of breast                                        had an elevated (more than 35 units/mL) serum CA
       cancer                                                   125 level, and 52 (96.2%) had a CA 125 level more
   Yes                          64      20 (31.3)     .72       than 60 units/mL.
   No                          331     111 (33.5)
Tumor morphology
                                                                     Risk of malignancy in an adnexal mass was signif-
   Cystic                      123       0 (0)      Ͻ.001*      icantly higher in women older than 55 years than in
   Complex                     236     120 (50.8)               younger women (PϽ.001), in postmenopausal women
   Solid                        36      11 (30.6)               compared with premenopausal women (PϽ.001), in
Ascites                                                         women with bilateral compared with unilateral ovarian
   Negative                    341      77 (22.6)   Ͻ.001
   Positive                     54      54 (100)
                                                                tumors (PϽ.01), and in women whose adnexal masses
Tumor laterality                                                were more than 10 cm in diameter compared with
   Unilateral                  375     119 (22.6)   Ͻ.01        smaller tumors (PϽ.001). A family history of ovarian
   Bilateral                    20      12 (60)                 cancer or breast cancer in a woman with an adnexal
Tumor diameter                                                  mass was not associated statistically with an increased
   10 cm or less               291      67 (23)     Ͻ.001
   More than 10 cm             104      64 (61.5)
                                                                risk of malignancy in the population studied.
CA 125 (units/mL)                                                    Although many variables were correlated with ma-
                                                    Ͻ.001       lignancy, only a small number had acceptable positive
                                                            †
   Less than 35                247      19 (7.7)
   35–59                        38      13 (34.2)               or NPVs (Table 4). Classification and regression tree
   60–120                       23      17 (73.9)               multivariable analysis considered age, gravidity, post-
   More than 120                87      82 (94.2)
                                                                menopausal status, weight, family history of ovarian
Data are n or n (%).                                            cancer or breast cancer, tumor morphology, ascites,
* Cystic compared with complex or solid tumor morphology.
†
  CA 125 less than 35 units/mL compared with 35–59, 60 –120,    tumor bilaterality, maximum tumor diameter, and CA
   or more than 120 units/mL.                                   125 value. This analysis found the most accurate signif-
                                                                icance of interactions to declare a high risk of malig-
                                                                nancy if a patient had an adnexal mass with complex or
    Serum CA 125 values were related directly to risk           solid morphology and a serum CA 125 value more than
of malignancy in women with an adnexal mass. Only               35 units/mL. The statistics for the training and validation
19 (7.7%) of 247 patients with a normal serum CA 125            sets indicated uniformly high performances for sensitiv-
value (less than 35 units/mL) had ovarian cancer.               ity, specificity, and predictive values across both the
Conversely, 13 of 83 patients (34.2%) with a serum              training and validation sets.
CA 125 value of 35–59 units/mL, 17 of 23 patients                    Statistical parameters associated with the high-risk
(73.9%) with a serum CA 125 value of 60 –120                    definition are listed in Table 5. Using the stated high-risk
units/mL, and 82 of 87 patients (86.8%) with a CA 125           parameters resulted in a sensitivity of 30.8% for ovarian
value more than 120 units/mL had borderline or                  tumors of borderline malignancy, 77.3% for early
malignant ovarian tumors (PϽ.001). Serum CA 125                 stage (I and II) ovarian cancer, and 98.6% for ad-
values related to specific histologic diagnoses in all          vanced stage (III and IV) ovarian cancer. Increasing


690   McDonald et al        Risk of Malignancy in an Adnexal Mass                         OBSTETRICS & GYNECOLOGY
Table 3. CA 125 Related to Histology in Ultrasonographically Complex or Solid Adnexal Tumors
         (n‫)272؍‬
                                                                              CA 125
                                               Less Than            35–59               60–120         More Than
Histology                           n         35 Units/mL          Units/mL            Units/mL       120 Units/mL

Fibroma                             15             12                  2                  1                  0
Cystadenofibroma                    27             25                  2                  0                  0
Endometrioma                        27             14                  8                  1                  4
Serous cystadenoma                  22             22                  0                  0                  0
Cystic teratoma                     20             20                  0                  0                  0
Mucinous cystadenoma                15             15                  0                  0                  0
Granulosa cell tumor                 4              3                  1                  0                  0
Pedunculated myoma                   7              6                  1                  0                  0
Sertoli-Leydig cell tumor            1              0                  1                  0                  0
Brenner tumor                        3              3                  0                  0                  0
Mucinous LMP                         5              3                  1                  0                  1
Serous LMP                           8              5                  1                  1                  0
Clear-cell carcinoma                 8              3                  2                  3                  0
Carcinosarcoma                       4              0                  0                  0                  4
Mucinous cystadenocarcinoma          5              2                  0                  1                  1
Serous cystadenocarcinoma            8              1                  0                  0                  7
Adenocarcinoma                      93              5                  8                 12                 68
LMP, low malignant potential.
Data are n.



the cutoff value of CA 125 from 35 units/mL to 60           tumor morphology obtained from ultrasonographic
units/mL and keeping the other parts of the definition      images, and serum CA 125 levels is useful in estimat-
the same increased specificity from 92.4% to 96.6%          ing the risk of malignancy in women with an adnexal
but lowered sensitivity from 84.7% to 80.9% and             mass. For example, the risk of neoplasia in unilocular
missed 13 patients with stage I or stage II ovarian         cystic ovarian tumors is very low. This morphologic
cancer. Therefore, a cutoff value of 35 units/mL for        pattern was present in 123 (31%) of 395 adnexal
CA 125 was used in the final high-risk definition. This     tumors, and no patient had either a borderline or an
definition correctly identified 34 of 44 patients with      invasive ovarian malignancy. This confirms the ob-
stage I and stage II ovarian cancer and 93 of 94            servation by Roman and colleagues10 who, in a sum-
patients with stage III and stage IV ovarian cancer.        mary of the literature, reported a 0.7% rate of malig-
Also, it correctly excluded 244 of the 264 patients         nancy in 569 unilocular cystic ovarian tumors 10 cm
with benign ovarian tumors.                                 or less in diameter. Similarly, Modesitt and col-
                                                            leagues11 followed more than 3,200 women with
DISCUSSION                                                  unilocular cystic ovarian tumors less than 10 cm in
The observation that the occurrence of certain symp-        diameter for an average of 6 years without operative
toms may precede the clinical diagnosis of ovarian          intervention. No patient developed ovarian cancer,
cancer has resulted in the recommendation that              and 69% of these tumors resolved spontaneously over
women experiencing the recent onset of bloating,            the period of observation. There is no doubt that
pelvic/abdominal pain, feeling full quickly after eat-      some unilocular cystic ovarian tumors grow to signif-
ing, or urinary urgency/frequency should consult a          icant size and require surgical removal. However, the
physician and undergo a complete physical examina-          risk of malignancy even in larger cystic lesions is low,
tion. Women having a clinically palpable abnormality        particularly in women with a normal CA 125 level. In
in the pelvis or those with persisting symptoms in the      the present study, there were 27 unilocular cystic
presence of a normal pelvic examination are advised         ovarian tumors more than 10 cm diameter, and all
to undergo transvaginal ultrasonography and CA 125          were benign.
testing.                                                         In contrast, adnexal masses with complex or solid
     The findings of this investigation indicate that       morphology are associated with a significant risk of
analysis of data concerning patient demographics,           malignancy. There were 272 patients with a complex



VOL. 115, NO. 4, APRIL 2010                          McDonald et al     Risk of Malignancy in an Adnexal Mass    691
Table 4. Sensitivity, Specificity, Positive and Negative Predictive Values, and 95% Confidence Limits of
         Each Variable Identifying or Ruling Out Ovarian Malignancy
                                                                       Sensitivity                                       Specificity
                                                                       (95% CL)                                          (95% CL)
Variable                                       Sensitivity         Lower         Upper       Specificity            Lower        Upper
Age older than 55 y                                55.7            47.2            64.2            68.6              63.0          74.2
Gravidity more than 1                              68.7            60.8            76.6            31.8              26.2          37.4
Postmenopausal                                     67.2            59.1            75.2            50.4              44.3          56.4
Weight more than 200 lb                            11.5             6.0            16.9            75.0              69.8          80.2
Family history
   Ovarian cancer                                  12.2              6.6           17.8            87.9              83.9          91.8
   Breast cancer                                   15.3              9.1           21.4            83.3              78.8          87.8
Tumor morphology
   Cystic                                         100.0            97.7          100.0           46.6                40.6          52.6
   Complex                                         91.6            86.9           96.4           56.1                50.1          62.0
Ascites                                            41.2            32.8           49.7          100.0                98.9         100.0
Tumor bilaterality                                  9.2             4.2           14.1           97.0                94.9          99.0
Tumor diameter
   More than 10 cm                                 48.9            40.3            57.4            84.8              80.5          89.2
CA 125 level more than 35 units/mL                 85.5            79.5            91.5            86.4              82.2          90.5
CL, confidence limit; PPV, positive predictive value; NPV, negative predictive value.


or solid adnexal mass, and 131 (48%) had an ovarian                   tricians and Gynecologists and the Society of Gyne-
malignancy. These women form the basis of a high-                     cologic Oncologists.13 This report stated that 69.8% of
risk group for ovarian cancer. In the present investi-                postmenopausal women with an adnexal mass and a
gation, documented ascites in a woman with a com-                     serum CA 125 value more than 35 units/mL had an
plex or solid adnexal mass was uniformly predictive                   ovarian malignancy and that an elevated serum CA
of ovarian cancer. There were 54 patients with this                   125 value in a patient with a clinically detectable
finding, and all had epithelial ovarian cancer. These                 pelvic mass could be used as one indication for
results are consistent with the findings of Im and                    patient referral for subspecialty care. In the present
colleagues12 who, in a multiinstitutional review, re-                 investigation, more than three fourths of women with
ported that 79% of postmenopausal women with a                        a complex or solid adnexal mass and a CA 125 value
clinically detectable pelvic mass and ascites had an                  more than 35 units/mL had either borderline or
ovarian malignancy.                                                   invasive ovarian cancer.
     The use of serum CA 125 as a method of                                When evaluating a number of variables, includ-
predicting risk of malignancy in patients with a clin-                ing patient demographics, tumor morphology, and
ically detectable pelvic mass was suggested in 2002 by                CA 125 levels, as predictors of malignancy, multiva-
a joint publication of the American College of Obste-                 riable classification and regression tree analysis de-

Table 5. Statistical Parameters Associated with a High-Risk* Group for Ovarian Cancer as Defined by
         Multivariable Classification and Regression Tree Analysis
Criteria                                TP        FP         TN       FN         PPV       NPV            Sensitivity†      Specificity‡

Total malignancies (nϭ131)             111        20         244       20       0.847      0.924            0.847§             0.924§
Borderline malignancy (nϭ13)             4        20         244        9       0.167      0.964            0.308              0.924
Stages I and II ovarian                 34        20         244       10       0.630      0.961            0.773              0.924
  malignancy (nϭ44)
Stages III and IV ovarian                73       20         244        1       0.785      0.996            0.986              0.924
  malignancy (nϭ74)
TP, true positive; FP, false positive; TN, true negative; FN, false negative; PPV, positive predictive value (TP/TPϩFP); NPV, negative
    predictive value (TN/TNϩFN).
* High-risk defined as a complex or solid adnexal mass with a CA 125 value more than 35 units/mL.
†
  Sensitivity, (TP/TPϩFN).
‡
  Specificity, (TN/TNϩFN).
§
  These figures vary within 1 standard error (Ϯ3.1% for sensitivity and Ϯ1.6% for specificity) when the sample is randomly split into
    training and validation sets.




692   McDonald et al        Risk of Malignancy in an Adnexal Mass                                  OBSTETRICS & GYNECOLOGY
PPV                                                                     PPV
                                (95% CL)                                                                (95% CL)
PPV                   Lower                  Upper                  NPV                      Lower                     Upper
 46.8                  39.0                    54.6                  75.7                     70.3                       81.2
 33.3                  27.7                    39.0                  67.2                     59.0                       75.4
 40.2                  33.7                    46.7                  75.6                     69.2                       81.9
 18.5                  10.1                    27.0                  63.1                     57.7                       68.4

 33.3                  20.0                    46.7                  66.9                     61.9                       71.8
 31.3                  19.9                    42.6                  66.5                     61.4                       71.6

 48.2                  42.2                   54.1                 100.0                      97.6                      100.0
 50.8                  44.5                   57.2                  93.1                      89.1                       97.0
100.0                  94.4                  100.0                  77.4                      73.0                       81.9
 60.0                  38.5                   81.5                  68.3                      63.6                       73.0

 61.5                  52.2                    70.9                  77.0                     72.1                       81.8
 75.7                  68.8                    82.6                  92.3                     89.0                       95.6



fined high risk as women with a complex or solid             netic testing,17 and this information should be taken into
adnexal mass and a serum CA 125 value of more than           consideration in determining optimal treatment for a
35 units/mL. In the population studied, this definition      patient with an adnexal mass.
of high risk was associated with a PPV of 84.7% and               As an increasing number of women who have
a NPV of 92.4% and correctly identified 34 (77.3%) of        symptoms suggestive of ovarian cancer are evaluated,
44 patients with stage I or stage II ovarian cancer as       clinicians will be asked to determine which patients
well as 73 of 74 patients (98.6%) with stage III or stage    are at significant risk for ovarian cancer. Data from
IV ovarian cancer. Thus, including tumor morphol-            the present investigation suggest that the combination
ogy significantly increases predictive values beyond         of ultrasonographic tumor morphology and serum
the PPV of 24.3% for stage I or II ovarian cancer and        CA 125 value improves the discrimination of women
56.8% for stage III or IV ovarian cancer associated          at risk of ovarian cancer from those with benign
with the original American College of Obstetricians          adnexal lesions. These findings should be helpful in
and Gynecologists/Society of Gynecologic Oncolo-             determining which patients can be followed without
gists high-risk criteria.14 In the present study, raising    surgery, which patients are likely to have a benign
the cutoff value of CA 125 from 35 units/mL to 60            ovarian tumor, and which patients are at high risk of
units/mL in the definition of high risk would have           ovarian malignancy and should be referred for sub-
increased specificity for identifying ovarian cancer         specialty care.
cases but would have lowered sensitivity and resulted
in missing a significant number of patients with             REFERENCES
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694   McDonald et al        Risk of Malignancy in an Adnexal Mass                                 OBSTETRICS & GYNECOLOGY

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Predicting risk of_malignancy_in_adnexal_masses.4

  • 1. Original Research Predicting Risk of Malignancy in Adnexal Masses John M. McDonald, MD, Stacey Doran, BS, Christopher P. DeSimone, MD, Fred R. Ueland, MD, Paul D. DePriest, MD, Rachel A. Ware, MD, Brook A. Saunders, MD, Edward J. Pavlik, PhD, Scott Goodrich, MD, Richard J. Kryscio, PhD, and John R. van Nagell Jr, MD OBJECTIVE: To estimate the accuracy of preoperative cancer and 98.6% of patients with stage III and stage IV ultrasonography, serum CA 125, and patient demograph- ovarian cancer. ics as a means of predicting risk of malignancy in women CONCLUSION: Patients with solid or complex ovarian with a ultrasonographically confirmed adnexal mass. tumors and an elevated serum CA 125 level (greater than METHODS: Tumor morphology derived from ultrasono- 35 units/mL) are at high risk of ovarian malignancy. graphic images, tumor size, tumor bilaterality, serum CA (Obstet Gynecol 2010;115:687–94) 125, and patient demographics were evaluated preoper- LEVEL OF EVIDENCE: II atively in 395 patients undergoing surgery from 2001 to 2008. Tumor morphology was classified as complex, solid, or cystic. Preoperative findings were compared with tumor histologic findings at the time of surgery. Multivariable classification and regression tree analysis O varian cancer remains the leading cause of death from gynecologic cancers in the United States. It was estimated that in 2009 there would be were used to identify a group of patients at high risk of 21,554 new cases of ovarian cancer, and that 14,600 ovarian malignancy. women would die as a result of disease.1 Case– control RESULTS: One hundred eighteen patients had ovarian studies have indicated that women with ovarian can- cancer, 13 patients had ovarian tumors of borderline cer commonly experience a pattern of symptoms that malignancy, and 264 had benign ovarian tumors. Multi- include bloating, pelvic/abdominal pain, difficulty variable classification and regression tree analysis defined eating/feeling full quickly, and urinary urgency or women at high risk of ovarian malignancy as those with frequency.2,3 These symptoms were found to be more an adnexal mass having complex or solid morphology and a serum CA 125 value greater than 35 units/mL. This commonly associated with ovarian cancer, when they definition had a positive predictive value of 84.7% and a were newly experienced, and occurred more that 12 negative predictive value of 92.4% and correctly identi- times per month.4 Recently, consensus groups have fied 77.3% of patients with stage I and stage II ovarian recommended that women who experience symp- toms suggestive of ovarian cancer should undergo a See related editorial on page 680. complete physical examination, and in certain cases, transvaginal ultrasonography and CA 125 testing. From the Division of Gynecologic Oncology, Department of Obstetrics and Although the majority of patients with these symp- Gynecology, and Departments of Statistics and Biostatistics, University of toms will not have ovarian cancer, those who do will Kentucky Chandler Medical Center–Markey Cancer Center, Lexington, Kentucky. require complete surgical staging and aggressive tu- Supported by research grants from the Kentucky Department of Health and mor debulking to maximize their chances of surviv- Human Services and the Telford Foundation. al.5–7 In this regard, it is important to establish risk Corresponding author: John Rensselaer van Nagell Jr, MD, Division of profiles of patients with ultrasonographically con- Gynecologic Oncology, Department of Obstetrics and Gynecology, University firmed adnexal tumors so that they can receive ap- of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536; e-mail: propriate treatment and, when necessary, referral for jrvann2@email.uky.edu. specialty cancer care. The authors postulate that the Financial Disclosure The authors did not report any potential conflicts of interest. addition of ultrasonographically generated tumor morphology to patient demographics and serum bi- © 2010 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. omarker profiles could improve prediction of malig- ISSN: 0029-7844/10 nancy in a clinically detectable adnexal mass. This VOL. 115, NO. 4, APRIL 2010 OBSTETRICS & GYNECOLOGY 687
  • 2. investigation was undertaken to estimate the accuracy tional Federation of Gynecology and Obstetrics sys- of a combination of patient demographics, ultrasono- tem. Data were entered into a MEDLOG database graphically generated tumor morphology, and serum (MEDLOG Systems, Crystal Bay, NV) and exported CA 125 values in predicting risk of malignancy in into an Excel (Microsoft Corp., Redmond, WA) adnexal masses. spreadsheet for analysis using WinSTAT (R. Fitch Software, Bad Krozingen, Germany), SPSS (SPSS, MATERIALS AND METHODS Inc., Chicago, IL), and PC-SAS with the Enterprise This investigation was undertaken after approval Miner statistical software (SAS Institute, Inc., Cary, NC). from the University of Kentucky Human Subjects Proportions were compared using ␹2 statistics or Institutional Review Board. Study participants were Fisher exact tests. Means were compared using two- women referred to the University of Kentucky–Mar- sample t tests. Statistical significance was determined key Women’s Cancer Center with a diagnosis of an at the .05 level. Multivariable analyses used the adnexal mass on pelvic examination who underwent classification and regression tree procedure, a non- surgery at this institution from 2001 to 2008. parametric method that defines or accepts cut points The following demographic data were obtained and uses training and validation sets to optimize rules for all study patients: age, height, weight, gravidity, for the analysis.9 The training set is formed by split- family history of breast or ovarian cancer, personal ting the entire sample in half after stratification for history of cancer, and menopausal status. Postmeno- malignant cases and benign controls. pausal was defined as the absence of menses for a minimum of 12 months. Family history was consid- RESULTS ered positive if the patient had a first-degree relative Between July 2001 and December 2008, 399 patients (ie, mother, sister, or daughter) or a second-degree referred to the outpatient clinic of the University of relative (ie, grandmother, granddaughter, aunt, or Kentucky–Markey Women’s Cancer Center for eval- niece) with documented ovarian or breast cancer. All uation of an adnexal mass on pelvic examination women underwent pelvic examination, transvaginal ultrasonography, and serum CA 125 determination within 2 weeks before surgery. Transvaginal ultra- Table 1. Patient Demographics, Tumor Variables, sonography was performed using General Electric and Biomarker Profiles in Patients (Milwaukee, WI) Logic 400 or Voluson ProV ultra- Studied (N‫)593؍‬ sound units with a 5-mHz vaginal probe as described Mean Range previously.8 Tumor dimensions from ultrasono- graphic images were recorded, and tumor morphol- Age (y) 51.6 (Ϯ0.8) 10–86 ogy was classified as cystic, solid, or complex (con- Height (in) 64 (Ϯ0.02) 55–72 Weight (lb) 173 (Ϯ2.8) 78–384 taining both solid and cystic components). All Gravidity 2.4 (Ϯ0.1) 0–21 ultrasonograms were reviewed by at least one of the Family history authors. All tumors classified as cystic were unilocu- Ovarian cancer 48 (12) lar, whereas cystic tumors with septations were in- Breast cancer 64 (16) cluded in the complex group. Ascites was defined as Menopausal status Premenopausal 176 (45) free fluid more than 60 mL in the abdomen/pelvis Postmenopausal 219 (55) confirmed by ultrasonography. Serum CA 125 deter- Tumor morphology minations were performed using a two-site sandwich Cystic 123 (31) paramagnetic particle chemiluminescent immunoen- Complex 236 (60) zymatic assay with a normal value less than 35 Solid 36 (9) Tumor diameter units/mL. Serum samples with values exceeding 10 cm or less 291 (74) 5,000 units/mL were diluted to end point for a final More than 10 cm 104 (26) result. Ascites After surgical removal, the dimensions of each Present 54 (14) tumor were recorded, and frozen section histologic Absent 341 (86) CA 125 (units/mL) evaluation was performed. Tumors were classified Less than 35 247 (62) histologically according to the World Health Organi- 35–59 38 (10) zation system. Patients with a histologic diagnosis of 60–120 23 (6) ovarian malignancy underwent immediate tumor de- More than 120 87 (22) bulking and surgical staging according to the Interna- Data are mean (Ϯstandard deviation) or n (%). 688 McDonald et al Risk of Malignancy in an Adnexal Mass OBSTETRICS & GYNECOLOGY
  • 3. were included in this investigation. Four patients had followed by serous cystadenocarcinoma, mucinous their first CA 125 determination after surgery and cystadenocarcinoma, and clear-cell carcinoma. were excluded from further evaluation. Demographic The relationship of demographic, biomarker, and data, biomarker profiles, and tumor characteristics of tumor variables to risk of malignancy in patients with the patients evaluated are listed in Table 1. Fifty-five an adnexal mass is presented in Table 2. Variables percent of patients were postmenopausal and 40% statistically related to risk of malignancy were tumor were aged 55 years or older. Sixty-four patients (16%) morphology, ascites, serum CA 125 level, tumor size, had a family history of breast cancer, 48 patients tumor bilaterality, menopausal status, and age. (12%) had a family history of ovarian cancer, and one Tumor morphology from ultrasonographically patient was BRCA1 positive. Two hundred thirty-six generated images was related directly to risk of ma- masses (60%) were ultrasonographically complex lignancy. There were 236 complex adnexal masses, (Fig. 1A), 123 (31%) were cystic (Fig. 1B), and 36 (9%) and 120 (51%) were malignant. None of the five were solid (Fig. 1C). Five of the 236 complex adnexal complex masses with septal morphology without solid masses (2.1%) were cystic ovarian tumors with thick areas were malignant. There were 36 solid adnexal septa but no solid areas. Radiologic evidence of masses, and 11 (32%) were malignant. In contrast, ascites was present in 54 patients (14%). Serum CA there were 123 cystic adnexal masses, and none were 125 level was elevated (more than 35 units/mL) in ovarian tumors of borderline malignancy or invasive 148 patients (38%) and was more than 120 units/mL ovarian cancers (PϽ.001). The finding of purely cystic in 87 patients (22%). morphology in an adnexal mass was associated with a At the time of surgery, 264 patients (67%) were negative predictive value (NPV) for malignancy of 100%. found to have benign ovarian tumors, 118 patients Fifty-four patients with an adnexal mass had (30%) had ovarian cancer, and 13 patients (3%) had radiologically confirmed ascites, and all of these pa- ovarian tumors of borderline malignancy. The stage tients had invasive epithelial ovarian cancer (stage IC, distribution of the patients with ovarian tumors of nϭ2; stage IIC, nϭ1; stage IIIC, nϭ49; and stage IV, borderline malignancy and ovarian cancer was as nϭ2). Therefore, the finding of documented ascites follows: stage I, nϭ38; stage II, nϭ17; stage III, in a patient with a complex or solid adnexal mass nϭ74; and stage IV, nϭ2. The most common cell had a positive predictive value (PPV) for malig- types of ovarian malignancy were adenocarcinoma, nancy of 100%. Fig. 1. Patterns of adnexal mor- phology. A. Complex adnexal mass, 12 cm in diameter; the cys- tic periphery is marked with clear arrows and the internal solid component is marked with solid arrows (histology: clear-cell carci- noma). B. Cystic adnexal mass, 9.4 cm in diameter, periphery is marked with clear arrows (histol- ogy: ovarian serous cystade- noma). C. Solid adnexal mass, 5 cm in diameter; the periphery is marked with clear arrows (histol- ogy: ovarian adenocarcinoma). McDonald. Risk of Malignancy in an Adnexal Mass. Obstet Gynecol 2010. VOL. 115, NO. 4, APRIL 2010 McDonald et al Risk of Malignancy in an Adnexal Mass 689
  • 4. Table 2. Demographic, Tumor, and Biomarker patients with complex and solid adnexal masses are Variables Related to Risk of Malignancy listed in Table 3. The only benign histologic finding (N‫)593؍‬ consistently associated with an elevated serum CA Variable Total Malignant P 125 value was ovarian endometriosis. Thirteen (48%) of 27 women with an ovarian endometrioma had an Age (y) elevated serum CA 125 value (more than 35 units/ 55 or younger 239 58 (24.3) Ͻ.001 Older than 55 156 73 (46.8) mL), and 5 (18%) had a serum CA 125 value more Gravidity than 60 units/mL. There were 114 women with other 1 or less 125 41 (32.8) .92 benign complex or solid adnexal masses, and only 1 More than 1 270 90 (33.3) patient (with an ovarian fibroma) had a CA 125 level Menopausal status more than 60 units/mL. As expected, serum CA 125 Premenopausal 176 43 (24.4) Ͻ.001 Postmenopausal 219 88 (40.2) values were related directly to stage of disease in Weight (lb) patients with ovarian malignancies. Serum CA 125 200 or less 314 116 (36.9) Ͻ.02 values were elevated (more than 35 units/mL) in More than 200 81 15 (18.5) 30.7% of patients with an ovarian tumor of borderline Family history of ovarian malignancy, 77.2% of patients with stage I and stage II cancer Yes 48 16 (33.3) .98 ovarian cancer, and 98.6% of patients with stage IIIC No 347 115 (33.1) and IV ovarian cancer. All 54 patients with ascites Family history of breast had an elevated (more than 35 units/mL) serum CA cancer 125 level, and 52 (96.2%) had a CA 125 level more Yes 64 20 (31.3) .72 than 60 units/mL. No 331 111 (33.5) Tumor morphology Risk of malignancy in an adnexal mass was signif- Cystic 123 0 (0) Ͻ.001* icantly higher in women older than 55 years than in Complex 236 120 (50.8) younger women (PϽ.001), in postmenopausal women Solid 36 11 (30.6) compared with premenopausal women (PϽ.001), in Ascites women with bilateral compared with unilateral ovarian Negative 341 77 (22.6) Ͻ.001 Positive 54 54 (100) tumors (PϽ.01), and in women whose adnexal masses Tumor laterality were more than 10 cm in diameter compared with Unilateral 375 119 (22.6) Ͻ.01 smaller tumors (PϽ.001). A family history of ovarian Bilateral 20 12 (60) cancer or breast cancer in a woman with an adnexal Tumor diameter mass was not associated statistically with an increased 10 cm or less 291 67 (23) Ͻ.001 More than 10 cm 104 64 (61.5) risk of malignancy in the population studied. CA 125 (units/mL) Although many variables were correlated with ma- Ͻ.001 lignancy, only a small number had acceptable positive † Less than 35 247 19 (7.7) 35–59 38 13 (34.2) or NPVs (Table 4). Classification and regression tree 60–120 23 17 (73.9) multivariable analysis considered age, gravidity, post- More than 120 87 82 (94.2) menopausal status, weight, family history of ovarian Data are n or n (%). cancer or breast cancer, tumor morphology, ascites, * Cystic compared with complex or solid tumor morphology. † CA 125 less than 35 units/mL compared with 35–59, 60 –120, tumor bilaterality, maximum tumor diameter, and CA or more than 120 units/mL. 125 value. This analysis found the most accurate signif- icance of interactions to declare a high risk of malig- nancy if a patient had an adnexal mass with complex or Serum CA 125 values were related directly to risk solid morphology and a serum CA 125 value more than of malignancy in women with an adnexal mass. Only 35 units/mL. The statistics for the training and validation 19 (7.7%) of 247 patients with a normal serum CA 125 sets indicated uniformly high performances for sensitiv- value (less than 35 units/mL) had ovarian cancer. ity, specificity, and predictive values across both the Conversely, 13 of 83 patients (34.2%) with a serum training and validation sets. CA 125 value of 35–59 units/mL, 17 of 23 patients Statistical parameters associated with the high-risk (73.9%) with a serum CA 125 value of 60 –120 definition are listed in Table 5. Using the stated high-risk units/mL, and 82 of 87 patients (86.8%) with a CA 125 parameters resulted in a sensitivity of 30.8% for ovarian value more than 120 units/mL had borderline or tumors of borderline malignancy, 77.3% for early malignant ovarian tumors (PϽ.001). Serum CA 125 stage (I and II) ovarian cancer, and 98.6% for ad- values related to specific histologic diagnoses in all vanced stage (III and IV) ovarian cancer. Increasing 690 McDonald et al Risk of Malignancy in an Adnexal Mass OBSTETRICS & GYNECOLOGY
  • 5. Table 3. CA 125 Related to Histology in Ultrasonographically Complex or Solid Adnexal Tumors (n‫)272؍‬ CA 125 Less Than 35–59 60–120 More Than Histology n 35 Units/mL Units/mL Units/mL 120 Units/mL Fibroma 15 12 2 1 0 Cystadenofibroma 27 25 2 0 0 Endometrioma 27 14 8 1 4 Serous cystadenoma 22 22 0 0 0 Cystic teratoma 20 20 0 0 0 Mucinous cystadenoma 15 15 0 0 0 Granulosa cell tumor 4 3 1 0 0 Pedunculated myoma 7 6 1 0 0 Sertoli-Leydig cell tumor 1 0 1 0 0 Brenner tumor 3 3 0 0 0 Mucinous LMP 5 3 1 0 1 Serous LMP 8 5 1 1 0 Clear-cell carcinoma 8 3 2 3 0 Carcinosarcoma 4 0 0 0 4 Mucinous cystadenocarcinoma 5 2 0 1 1 Serous cystadenocarcinoma 8 1 0 0 7 Adenocarcinoma 93 5 8 12 68 LMP, low malignant potential. Data are n. the cutoff value of CA 125 from 35 units/mL to 60 tumor morphology obtained from ultrasonographic units/mL and keeping the other parts of the definition images, and serum CA 125 levels is useful in estimat- the same increased specificity from 92.4% to 96.6% ing the risk of malignancy in women with an adnexal but lowered sensitivity from 84.7% to 80.9% and mass. For example, the risk of neoplasia in unilocular missed 13 patients with stage I or stage II ovarian cystic ovarian tumors is very low. This morphologic cancer. Therefore, a cutoff value of 35 units/mL for pattern was present in 123 (31%) of 395 adnexal CA 125 was used in the final high-risk definition. This tumors, and no patient had either a borderline or an definition correctly identified 34 of 44 patients with invasive ovarian malignancy. This confirms the ob- stage I and stage II ovarian cancer and 93 of 94 servation by Roman and colleagues10 who, in a sum- patients with stage III and stage IV ovarian cancer. mary of the literature, reported a 0.7% rate of malig- Also, it correctly excluded 244 of the 264 patients nancy in 569 unilocular cystic ovarian tumors 10 cm with benign ovarian tumors. or less in diameter. Similarly, Modesitt and col- leagues11 followed more than 3,200 women with DISCUSSION unilocular cystic ovarian tumors less than 10 cm in The observation that the occurrence of certain symp- diameter for an average of 6 years without operative toms may precede the clinical diagnosis of ovarian intervention. No patient developed ovarian cancer, cancer has resulted in the recommendation that and 69% of these tumors resolved spontaneously over women experiencing the recent onset of bloating, the period of observation. There is no doubt that pelvic/abdominal pain, feeling full quickly after eat- some unilocular cystic ovarian tumors grow to signif- ing, or urinary urgency/frequency should consult a icant size and require surgical removal. However, the physician and undergo a complete physical examina- risk of malignancy even in larger cystic lesions is low, tion. Women having a clinically palpable abnormality particularly in women with a normal CA 125 level. In in the pelvis or those with persisting symptoms in the the present study, there were 27 unilocular cystic presence of a normal pelvic examination are advised ovarian tumors more than 10 cm diameter, and all to undergo transvaginal ultrasonography and CA 125 were benign. testing. In contrast, adnexal masses with complex or solid The findings of this investigation indicate that morphology are associated with a significant risk of analysis of data concerning patient demographics, malignancy. There were 272 patients with a complex VOL. 115, NO. 4, APRIL 2010 McDonald et al Risk of Malignancy in an Adnexal Mass 691
  • 6. Table 4. Sensitivity, Specificity, Positive and Negative Predictive Values, and 95% Confidence Limits of Each Variable Identifying or Ruling Out Ovarian Malignancy Sensitivity Specificity (95% CL) (95% CL) Variable Sensitivity Lower Upper Specificity Lower Upper Age older than 55 y 55.7 47.2 64.2 68.6 63.0 74.2 Gravidity more than 1 68.7 60.8 76.6 31.8 26.2 37.4 Postmenopausal 67.2 59.1 75.2 50.4 44.3 56.4 Weight more than 200 lb 11.5 6.0 16.9 75.0 69.8 80.2 Family history Ovarian cancer 12.2 6.6 17.8 87.9 83.9 91.8 Breast cancer 15.3 9.1 21.4 83.3 78.8 87.8 Tumor morphology Cystic 100.0 97.7 100.0 46.6 40.6 52.6 Complex 91.6 86.9 96.4 56.1 50.1 62.0 Ascites 41.2 32.8 49.7 100.0 98.9 100.0 Tumor bilaterality 9.2 4.2 14.1 97.0 94.9 99.0 Tumor diameter More than 10 cm 48.9 40.3 57.4 84.8 80.5 89.2 CA 125 level more than 35 units/mL 85.5 79.5 91.5 86.4 82.2 90.5 CL, confidence limit; PPV, positive predictive value; NPV, negative predictive value. or solid adnexal mass, and 131 (48%) had an ovarian tricians and Gynecologists and the Society of Gyne- malignancy. These women form the basis of a high- cologic Oncologists.13 This report stated that 69.8% of risk group for ovarian cancer. In the present investi- postmenopausal women with an adnexal mass and a gation, documented ascites in a woman with a com- serum CA 125 value more than 35 units/mL had an plex or solid adnexal mass was uniformly predictive ovarian malignancy and that an elevated serum CA of ovarian cancer. There were 54 patients with this 125 value in a patient with a clinically detectable finding, and all had epithelial ovarian cancer. These pelvic mass could be used as one indication for results are consistent with the findings of Im and patient referral for subspecialty care. In the present colleagues12 who, in a multiinstitutional review, re- investigation, more than three fourths of women with ported that 79% of postmenopausal women with a a complex or solid adnexal mass and a CA 125 value clinically detectable pelvic mass and ascites had an more than 35 units/mL had either borderline or ovarian malignancy. invasive ovarian cancer. The use of serum CA 125 as a method of When evaluating a number of variables, includ- predicting risk of malignancy in patients with a clin- ing patient demographics, tumor morphology, and ically detectable pelvic mass was suggested in 2002 by CA 125 levels, as predictors of malignancy, multiva- a joint publication of the American College of Obste- riable classification and regression tree analysis de- Table 5. Statistical Parameters Associated with a High-Risk* Group for Ovarian Cancer as Defined by Multivariable Classification and Regression Tree Analysis Criteria TP FP TN FN PPV NPV Sensitivity† Specificity‡ Total malignancies (nϭ131) 111 20 244 20 0.847 0.924 0.847§ 0.924§ Borderline malignancy (nϭ13) 4 20 244 9 0.167 0.964 0.308 0.924 Stages I and II ovarian 34 20 244 10 0.630 0.961 0.773 0.924 malignancy (nϭ44) Stages III and IV ovarian 73 20 244 1 0.785 0.996 0.986 0.924 malignancy (nϭ74) TP, true positive; FP, false positive; TN, true negative; FN, false negative; PPV, positive predictive value (TP/TPϩFP); NPV, negative predictive value (TN/TNϩFN). * High-risk defined as a complex or solid adnexal mass with a CA 125 value more than 35 units/mL. † Sensitivity, (TP/TPϩFN). ‡ Specificity, (TN/TNϩFN). § These figures vary within 1 standard error (Ϯ3.1% for sensitivity and Ϯ1.6% for specificity) when the sample is randomly split into training and validation sets. 692 McDonald et al Risk of Malignancy in an Adnexal Mass OBSTETRICS & GYNECOLOGY
  • 7. PPV PPV (95% CL) (95% CL) PPV Lower Upper NPV Lower Upper 46.8 39.0 54.6 75.7 70.3 81.2 33.3 27.7 39.0 67.2 59.0 75.4 40.2 33.7 46.7 75.6 69.2 81.9 18.5 10.1 27.0 63.1 57.7 68.4 33.3 20.0 46.7 66.9 61.9 71.8 31.3 19.9 42.6 66.5 61.4 71.6 48.2 42.2 54.1 100.0 97.6 100.0 50.8 44.5 57.2 93.1 89.1 97.0 100.0 94.4 100.0 77.4 73.0 81.9 60.0 38.5 81.5 68.3 63.6 73.0 61.5 52.2 70.9 77.0 72.1 81.8 75.7 68.8 82.6 92.3 89.0 95.6 fined high risk as women with a complex or solid netic testing,17 and this information should be taken into adnexal mass and a serum CA 125 value of more than consideration in determining optimal treatment for a 35 units/mL. In the population studied, this definition patient with an adnexal mass. of high risk was associated with a PPV of 84.7% and As an increasing number of women who have a NPV of 92.4% and correctly identified 34 (77.3%) of symptoms suggestive of ovarian cancer are evaluated, 44 patients with stage I or stage II ovarian cancer as clinicians will be asked to determine which patients well as 73 of 74 patients (98.6%) with stage III or stage are at significant risk for ovarian cancer. Data from IV ovarian cancer. Thus, including tumor morphol- the present investigation suggest that the combination ogy significantly increases predictive values beyond of ultrasonographic tumor morphology and serum the PPV of 24.3% for stage I or II ovarian cancer and CA 125 value improves the discrimination of women 56.8% for stage III or IV ovarian cancer associated at risk of ovarian cancer from those with benign with the original American College of Obstetricians adnexal lesions. These findings should be helpful in and Gynecologists/Society of Gynecologic Oncolo- determining which patients can be followed without gists high-risk criteria.14 In the present study, raising surgery, which patients are likely to have a benign the cutoff value of CA 125 from 35 units/mL to 60 ovarian tumor, and which patients are at high risk of units/mL in the definition of high risk would have ovarian malignancy and should be referred for sub- increased specificity for identifying ovarian cancer specialty care. cases but would have lowered sensitivity and resulted in missing a significant number of patients with REFERENCES early-stage disease. This is important because several 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun M. Cancer studies have reported as high as a 24% survival statistics 2009. CA Cancer J Clin 2009;59:225– 49. advantage for patients with early-stage ovarian cancer 2. Goff BA, Mandel LS, Melancon CH, Muntz HG. Frequency of who received comprehensive surgical staging and symptoms of ovarian cancer in women presenting to primary care clinics. JAMA 2004;291:2705–12. treatment by a gynecologic oncologist.15,16 3. Smith LH, Morris CR, Yasmeen S, Parikh-Patel A, Cress RD, Although family history of ovarian cancer or breast Romano PS. Ovarian cancer: can we make the clinical diag- cancer was not statistically associated with an increased nosis earlier? Cancer 2005;104:1398 – 407. risk of ovarian cancer in this investigation, a hereditary 4. Goff BA, Mandel L, Drescher CW, Urban N, Gough S, cancer risk assessment was not routinely performed on Schurman KM, et al. Development of an ovarian cancer every patient enrolled in this study. Clearly, women symptom index. Cancer 2007;109:221–7. with a strong family history of ovarian or breast cancer 5. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for or women who are members of populations with a high advanced ovarian carcinoma during the platinum era: a meta- prevalence of “founder mutations” should undergo ge- analysis. J Clin Oncol 2002;20:1248 –59. VOL. 115, NO. 4, APRIL 2010 McDonald et al Risk of Malignancy in an Adnexal Mass 693
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