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\begin{document}

\title{Diagnostic value of serum tumor markers for epithelial ovarian cancer
stage I-II -- A retrospective analysis}



\author[1]{qiang yi}%
\author[1]{yu ran}%
\author[1]{Cong Li}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 08, 2024}


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\selectlanguage{english}
\begin{abstract}
Objective epithelial ovarian cancer (EOC) in early stage is difficult to
diagnose. Serum indicators for stage I-II of epithelial ovarian cancer
which confined to pelvic cavity were found through retrospective
analysis, possible early detection methods might be found. Methods 165
patients were diagnosed as epithelial ovarian cancer at stage I-II from
January 1st, 2015 to December 31st, 2019. Data was collected including
age, pathological type, serum D-dimer (D-D), neutrophil to lymphocyte
ratio (N/L), the platelet to lymphocyte ratio (P/L), cancer antigen 125
(CA125), human epididymis protein 4 (HE4) and diameter of the ovarian
mass by ultrasound. Result D-D, CA125, HE4, ROMA, diameter, pathological
type and age were significantly different in the different stage, age
showed independent effect after logistical regression (P \textless{}
0.05). D-D, CA125, HE4, ROMA, diameter, age and stage were significantly
different in the different pathological type, and diameter showed
significant independent influence on different pathological type after
binary logistic regression (P \textless{} 0.05). Conclusion CA125, HE4,
ROMA, diameter of tumor, D-dimer and age were found significantly
different between stage I and stage II, with age shows good effect on
the diagnosis for stage II and diameter of tumor shows diagnostic value
for non-serous ovarian cancer. Combined diagnosis may improve the
diagnosis rate of early ovarian cancer.%
\end{abstract}%



\sloppy


\textbf{Introduction}

With a survival rate below 45\% of five-year and 15,000 death caused by
it globally making ovarian cancer the 7\textsuperscript{th} most common
cancer and 8\textsuperscript{th} most common cause of cancer death among
women \textsuperscript{{[}1-2{]}}. The five-year survival rate is 92\%
for women with stage I epithelial ovarian cancers while only around 30\%
for those with advanced-stage \textsuperscript{{[}3{]}}. Therefore,
early detection, early diagnosis and early treatment of ovarian cancer
are very important, which can improve the prognosis of patients
significantly. Though many patients were diagnosed with evaluated CA125
or HE4 value, still there are some patients who were in low level that
they are diagnosed with ovarian cancer. Thus, the present study aimed to
explore if there was a role for these parameters that were simple and
accessible in the preoperative to find the early-stage epithelial
ovarian cancer, especially in these who were in negative CA125 and HE4
value and make a judgement of the characteristic of the tumor.

In the recent years, there are more and more advanced equipment to
detect pelvic mass, such as different kinds of cancer antigen (CA125,
CEA, CA199, AFP), pelvic MRI \textsuperscript{{[}4-5{]}}. When patients
are suspicious for as a malignant tumor, more senior technology and
consumption are truly needed. Completed blood count and ultrasonography
for women are easy to get and relatively at low cost. Chronic
inflammation has been associated with the carcinogenesis of different
types of tumors, including ovarian cancer, and neutrophil, lymphocyte
are common inflammation cells in blood cell. And
neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio are
considered predictive factors for survival in ovarian cancer
\textsuperscript{{[}6-7{]}}.

\textbf{1.Methods:}

From January 1\textsuperscript{st} in 2015 to December
31\textsuperscript{st} in 2019, patients were hospitalized as epithelial
ovarian cancer in the First Affiliated Hospital of Chongqing Medical
University. After comprehensive surgical staging, 165 patients were
diagnosed as epithelial ovarian cancer from stage Ia to stage IIa.
Operations included hysterectomy with bilateral salpingo-oophorectomy,
omentectomy, and lymphadenectomy, when mucinous cancer was confirmed,
appendicectomy should be performed to keep comprehensive staging. Both
abdominal surgery and laparoscopic surgery were acceptable. These who
had adjuvant chemotherapy before surgery were excluded, non-epithelial
and borderline tumors were not included. Patients' data were collected
through HIS 2.5 (hospital information system) including the general
information (patient ID, age, menopause or not, diagnosis), complete
blood counts (PLA-platelet count, NEU-neutrophil count, LYM-lymphocyte
count), coagulation function (D-D, D-dimer), serum tumor maker
(CA125-cancer antigen 125, HE4-human epididymis protein 4), pelvic
ultrasound measurement (D-diameter of tumor, tumor location),
pathological data (degree and type of differentiation).

\textbf{1.1 Samples}

All the blood sample date was obtained before surgery and the nearest to
surgery if there were more than one for analysis. The complete blood
count (CBC) was obtained through the automated hematology analyzer
Sysmex XE-2100, X-800, According to our receiver operating
characteristic (ROC) curve analyses, the optimal cut off point for
elevated PLT was considered if higher than 320, elevated NEU was
considered if higher than 6.3, and elevated LYM was considered if higher
than 3.2 (All the CBC count values were expressed in
10\textsuperscript{9}/L) . In the meanwhile, we calculated the ratio of
neutrophils to lymphocytes (N/L) and ratio of platelets to lymphocytes
(P/L). Sysmex CA1500, CA7000, CS5100 were used to detect the D-D value,
which was presented in milligram per liter (mg/l) and if more than 0.55
mg/L was regard as elevated.

Serum CA125 and HE4 concentration were determined through the
electrochemiluminescence technique in the Cobas e602 automatic analyzer.
All CA125 values were expressed in units per milliliter (u/ml), and HE4
were expressed in picomole per liter (pmol/l). The levels of CA125 were
considered elevated if higher than 35 u/ml. The HE4 value was thought
elevated if higher than 70 pmol/l for premenopausal women while higher
than 140 pmol/l was considered elevated for postmenopausal women. In the
meanwhile, ROMA index was calculated through the Sysmex system according
to menopause or not. Ovary cancer prediction value was low If the ROMA
lower than 7.4\% for premenopausal women and lower than 25.3\% for
postmenopausal women.

Diameter, location (in the left, right, or bilateral) and resistance
index (RI) were recorded by pelvic ultrasound. The diameter of the
ovarian mass was expressed in centimeter (cm). If more than one mass was
detected on the ovarian, the diameter of the largest mass was chosen as
the ovarian cancer's diameter.

Pathological type, differentiation degree and clinical stage was
collected as specific as possible. And the ovarian cancer staging was
complied with surgical and pathological staging system of ovarian
malignant tumor (FIGO, 2014)\textsuperscript{{[}8{]}}. All the
Pathological diagnosis report were given by the Pathology department,
medical testing center, Chongqing Medical University.

\textbf{1.2 Statistical Analysis}

The data were analyzed using Statistical Product and Service Solutions
25.0 (SPSS 25.0, IBM). Logistic regression was used to explore the risk
factors of the early ovarian cancer, and predict the probability of
ovarian cancer according to the risk factors, and p
values\textless{}0.05 was considered as significant. Ovarian tumors were
classified into stage I and stage II, serous and non-serous, with and
without CA125 elevated group (CA125+, CA125-). The measurement data in
accordance with normal distribution were expressed as mean \selectlanguage{ngerman}± standard
deviation, and the comparison between the two groups was conducted by
two independent sample t-test. The measurement data of non-normal
distribution were expressed as median (interquartile interval). Rank sum
test was used to compare the two groups. The count data were expressed
as percentage, and the comparison between groups was performed by chi
square (x\textsuperscript{2}) test. Then we used factors that were
significant different between two groups to do the logistic regression
analysis.

\textbf{2.Results}

\textbf{2.1 General information and clinical features of EOC with stage
I and stage II}

Totally 165 cases were collected. All EOC patients diagnosed as stage I
and stage II were located in pelvic, while patients with stage I
candidate early stage, and with staged II means patients in advanced
stage but limited in pelvic. More patients with stage II were found (103
vs 62).

After normality test it can be found that D-D, CA125, HE4, ROMA, N/L,
P/L, D-diameter and age do not comply to normal distribution (P
\textless{} 0.05), so rank sum test is used and LYM complies to normal
distribution, then t test is used. The rank sum test showed that D-D,
CA125, HE4, ROMA, D-diameter and age are significantly different in the
stage (P \textless{} 0.05), while N/L, P/L show no significant
difference in the stage (P\textgreater{}0.05). Independent sample t test
showed that there was no significant difference in LYM in the stage (P
\textgreater{} 0.05). x2 test showed that there were significant
differences in different pathological type (P \textless{} 0.05). Among
them, the proportion of patients classified as non-serous in stage I was
relatively high (64.52\%), and the proportion in stage II was relatively
low. Chi square test showed that there was no significant difference
between left and right in the stage (P \textgreater{} 0.05) (in table
1).

For the parameters with statistical differences including D-D, CA125,
HE4, ROMA, D-diameter, age and type, they were tested by logistic
regression as the risk factors. Age showed significant independent
effect on the occurrence of stage (P \textless{} 0.05). So, if patient
detects with ovarian tumor, the aged is older than 50-year-old, serum
CA125 is higher than 100u/ml, HE4 is in positive level, D-D is high,
more possibility is found to be advanced stage as malignant cancer. The
ratio of the elder subgroup to the younger subgroup was 1.061(table 1).

According the two results of logistic regression analysis, we draw a
Receiver Operating Characteristic (ROC) curve of the age to stage
(Figure 1a) and diameter to pathologic type (Figure 1b). And area under
the curve (AUC) of a) is 0.803 and b) is 0.647. In the case of AUC
higher than 0.5, the closer the AUC to 1 is, the better the diagnostic
effect is. It proves there is a good effect on the diagnosis for stage
II of age and diameter for non-serous ovarian cancer.

\textbf{2.2 Clinical features of EOC with CA125 level positive or not}

Patients selected with CA125 value \textless{} 35 was regarded as
negative value. For ovarian epithelial malignant tumors confined to
pelvic cavity, the number of CA125+ was more than twice the number of
cases that in CA125-. In CA125 negative group, serum HE4, Roma, D-D were
not significantly increased, indicating that the above serological
indicators for supplement of CA125 for the diagnosis of early ovarian
cancer is limited. The other clinical features of the stage showed that
the location of ovarian cancer in CA125 negative group was more common
on the right side, more than 50\%, and the number of clear cell
carcinoma in pathological type was significantly increased, reaching
36\%, which was significantly higher than that in CA125 positive group.
There was no significant difference in age and tumor diameter (tab 2).

\textbf{2.3 Clinical features of EOC with different pathological type}

According to the origin and differentiation of ovarian tumors, the
different pathological types can be divided into serous and non-serous
cancer. Thus, these parameters were analyzed by different pathological
types (serous and non-serous). D-D, CA125, HE4, ROMA, location and
diameter were significantly different in different pathological type
after rank sum test (P \textless{} 0.05), while N/L, P/L shows no
significant difference in different type (P \textgreater{} 0.05).
According to x\textsuperscript{2} test, there were significant
differences among different stage (P \textless{} 0.05). In the location,
the proportion of patients in the non-serous group was relatively high,
and the proportion was 52.12\% (86/165) (Tab 3). There was no
significant difference in the classification of menopause (P
\textgreater{} 0.05).

\textbf{3.Discussion}

According to this five-year history, the number of advanced epithelial
ovarian cancer was significantly more than that of early ovarian cancer.
Between the stage I and stage II of epithelial ovarian cancer,
significant difference was observed in D-dimer, CA125, HE4, ROMA index.
Diameter and age while ratio of neutrophils to lymphocytes (N/L) and
ratio of platelets to lymphocytes (P/L) didn't showed Statistical
difference. It indicated that EOC with early stage and advanced stage
may have different serum indicators which included in CBC and
coagulation.

\textbf{3.1} \textbf{CA125, HE4, ROMA index and D-dimer may be Possible
serum tumor markers in EOC early stage}

Serum CA125 concentration test is the most widely studied biochemical
method for screening ovarian cancer. About 50\% of women with early
ovarian cancer and more than 80\% of women with advanced ovarian cancer
have elevated serum CA125 value \textsuperscript{{[}9{]}}. CA125 is the
most common marker of epithelial ovarian cancer. The level of CA125 in
these patients with stage II is higher than the normal range, and the
average value is more than 200 u/ml, which is significantly higher than
that in stage I, it indicated the sensitivity of CA125 in advanced
epithelial ovarian cancer, which can be thought as good predict factor.
But the research objects of serum CA125 test for ovarian cancer mainly
focus on postmenopausal women, because the variation of CA125 with
menstrual cycle\textsuperscript{{[}10-11{]}} and the prevalence of
benign gynecological diseases like
endometriosis\textsuperscript{{[}12{]}}, pelvic inflammatory
disease\textsuperscript{{[}13-14{]}} in premenopausal women will lead to
a significantly higher probability of false-positive results. There is
evidence suggests that for postmenopausal women at general risk,
screening only by annual CA125 measurement is not sufficiently specific,
more specific indicators need to be combined.

HE4 and ROMA index ere possible parameters for ovarian cancer early
diagnosis \textsuperscript{{[}15-16{]}}. In this study, HE4 level
reached to 113.00 pmol/l in stage II, because the above results denied
the impact of menopause on early ovarian cancer, so high level of HE4
and ROMA indicating that their values largely which reflecting the
malignant behavior of tumor. there were 115 of 165 patients (69.7\%)
showing elevated CA125 levels in this study, 63.2\% of which in staging
I represented positive value, while positive rate was significantly
increased into 76.9\% when combined CA125 with HE4, as a good testimony
that combined diagnosis can improve diagnostic accuracy.

D-dimer is a major degradation product of polymerized fibrin after blood
coagulation and plasmin processing. In this study, D-dimer in patients
with stage II was significantly higher than that in patients with stage
I, indicating that hyper-coagulation in patients with malignant tumors
can indicate the degree of malignancy of tumors. Elevated plasma D-dimer
levels usually indicate active fibrinolysis and are observed in several
disorders, including arterial and venous thromboembolic disease,
malignancy, and renal and liver disease \textsuperscript{{[}18{]}}.
Serum D-dimer has been reported as a useful diagnosis and prognosis
parameter for several malignancies including ovarian
cancer\textsuperscript{{[}19-21{]}}. In addition, elevated platelet
counts and thrombocytosis have been shown to actively affect tumor
growth and metastasis in ovarian cancer. In this early ovarian cancer,
D-dimer did show significant difference between stage I and stage II,
which indicates a worse prognosis. Learning coagulation related
examination results before comprehensive staging operation can provide a
better judgment of the disease.

Many much studies show that the neutrophil-to-lymphocyte ratio has been
recognized as a potent prognosticator for PFS and OS in ovarian
cancer\textsuperscript{{[}22-24{]}}. In addition,
neutrophil-to-lymphocyte ratio has been suggested to predict the immune
status of women in ovarian cancer \textsuperscript{{[}25{]}}. however,
in this study, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte
ratio didn't presented significant difference whether in different stage
or in different pathological type. Most of them were focusing on the
predictive value of P/L and N/L in distinguishing benign masses and
malignant tumors\textsuperscript{{[}26-27{]}}, There was no significant
difference in the ratio of N/L and P/L: blood cell count in the patients
with stage I/II, suggesting that the related indicators of malignant
tumor in blood cells are of limited value in the early diagnosis of
epithelial ovarian cancer.

\textbf{3.2 Different pathological types, different ages and different
sites of ovarian tumors may be clinical indications to consider the
benign and malignant ovarian, but it has no value for early diagnosis of
EOC}

According to the analysis of histopathology, immunohistochemistry and
molecular genetics, there are five subtypes of epithelial ovarian
cancer, including high grade serous carcinoma (HGSC), low grade serous
carcinoma (LGSC), endometrial carcinoma, clear cell carcinoma and
mucinous cancer. HGSC and LGSC present different molecular pathogenesis
and are two types of tumors with essential difference. However, it is
believed that both tumors may originate from the precursor lesions of
fallopian tube \textsuperscript{{[}28{]}}. They were classified as
serious cancer, and the rest were classified as no non-serous cancer.
According to our study, non-serous cancer presented great diameter, this
is because clear cell carcinoma is usually a large mass, and mucinous
carcinoma can vary from 8 to 20cm in size, but can also be
larger\textsuperscript{{[}29{]}}.

In this study serous carcinoma was more than other types in stage I and
II, which was more significant in stage II, reaching 55.34\%. The second
type is mucinous carcinoma. The proportion of patients in stage I was
significantly higher than that in stage II. While HGSC is the most
common type of ovarian cancer, accounting for 70\% - 80\% of all ovarian
malignant tumors, but the tumor volume is often not in big
size\textsuperscript{{[}30{]}}. Therefore, when the ovarian mass is
found giant, it is particularly important to do a good job in practice
of tumor free principle.

For CA125 negative patients, we should be alert to the occurrence of
ovarian clear cell carcinoma. Therefore, for high-risk groups, such as
recurrent ovarian endometriosis cyst, deep invasive endometriosis
patients, it is necessary to further prevent the occurrence of
endometriosis associated ovarian cancer (EAOC).

Age revealed independent influence on the ovarian stage. the average age
of patients with early ovarian cancer was lower than that of patients in
stage II. The incidence rate of epithelial ovarian cancer increased with
age. But there was no significant difference in menopause. An analysis
of data from the ''nurse health study'' found that the risk of
epithelial ovarian cancer increased by about 2\% for women under 50
years old and 11\% for women aged 50 and above \textsuperscript{{[}3,
17{]}}. The median age at diagnosis of ovarian cancer was 63
years\textsuperscript{{[}1{]}}. Thus, referring with our study-age can
be an independent influence factor--when CA125 elevated is observed in
an elder woman with pelvic mass, there is reason to believe she is
suffering an ovarian cancer at least in early stage. Patients younger
than 50 years old and with tumor diameter larger than 10 cm are more
likely to be early epithelial ovarian cancer than advanced ovarian
cancer.

Tumor location: ovarian cancer took placed in left or right side,
unilateral or bilateral. There was no significant difference between
stage I and stage II. Tumor diameter: the diameter of ovarian cancer in
stage I is larger than that in stage II, indicating that the invasive
ability of ovarian cancer tissue in advanced patients was better than
that of ovarian tissue growth alone. At the same time, we found that if
epithelial ovarian cancer patients have normal level of CA125, more
incidence was taken placed in the right ovarian, which is statistically
different.

\textbf{3.3 limitations}

Whether these clinical phenomena are related to the origin of ovarian
blood vessels in different parts, further research was needed. The
diagnosis rate may be improved after combination of the above factors of
early ovarian cancer, and there will be more references for clinical
diagnosis and treatment.

\textbf{Conclusion}

In this retrospective analysis, CA125, HE4, ROMA, diameter of tumor,
D-dimer and age were found significantly different between in early
stage and in advanced stage which located in pelvic. CA125 is still the
most specific tumor marker for early ovarian cancer and advanced stage
II epithelial ovarian cancer. The serum levels of HE4, Roma and D-D may
assist with CA125 level in early diagnosis if CA125 in normal level. The
diagnostic value of N/L and P/L for ovarian cancer was not found. What's
more, age shows good independent effect on the diagnosis for stage II
and diameter of tumor shows independent diagnostic value for non-serous
ovarian cancer.

\textbf{Author contributions}

Qiang Yi: data collecting and analyzing, manuscript writing; Yu Ran:
data collecting and analyzing; Cong Li: project development, manuscript
revise. All authors read and approved the final manuscript.

\textbf{Funding support} :

NO

\textbf{Conflict of interest:}

The authors declare that they have no conflict of interest.

\textbf{Ethic approval} :

All patients were consent to participate in the study like this: ``I
have read this informed consent form, and my doctor has explained the
purpose, content, risks and benefits of this clinical trial to me in
detail, and answered all the questions I asked. I have already
understood this clinical study, and I am willing to participate in this
study''.The study was approved by the Ethics Committee of the First
Affiliated Hospital of Chongqing Medical University (2020-636).

\selectlanguage{english}\textbf{Appendix:Tables and figures:}

Table 1 General information and clinical features in stage

Table 2 Subgroup analysis for CA125

Table 3 Subgroup analysis for different pathologic type

Figures:

Figure 1a) ROC curve of the age to stage

Figure 1b) ROC curve of diameter to pathologic type\selectlanguage{english}
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695-700.\selectlanguage{english}
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