Ìåäèöèíñêèé Âåñòíèê Ýðåáóíè, 2013, 2(54), 102-108 1 ... · 2016. 10....

102

ÓÄÊ 618 207 002 Clinical evaluation of the liquid-based cytology method in investigation of

patients with malignant epithelial tumors of the ovary

S.R. Babloyan1, G.A. Beglaryan

1, P.P. Karakitsos

2

1Department of Obstetrics and Gynaecology, Yerevan State Medical University, Erebouni Medical

Centre, Yerevan, Armenia 2Department of Cytopathology, University General Hospital Attikon, Athens, Greece

Key words: epithelial ovarian cancer, liquid based cytology, ThinPrep

Êëèíè÷åñêàÿ îöåíêà

ìåòîäà

æèäêîñòíîé

öèòîëîãèè ïðè

èññëåäîâàíèè áîëüíûõ

ñî çëîêà÷åñòâåííûìè

ýïèòåëèàëüíûìè

îïóõîÿìè

ÿè÷íèêîâ

Ð»ÕáõÏ³ÇÝ

µçç³µ³Ý³Ï³Ý

Ñ»ï³½áïáõÃÛ³Ý

ÏÉÇÝÇÏ³Ï³Ý

Ýß³Ý³ÏáõÃÛáõÝÁ

Óí³ñ³ÝÝ»ñÇ ã³ñáñ³Ï

¿åÇÃ»É³ÛÇÝ áõéáõóùÝ»ñáí

ÑÇí³Ý¹Ý»ñÇ

Ñ»ï³½áïÙ³Ý Å³Ù³Ý³Ï

Ñ.Ð. Áàáëîÿí, Ã.À. Áåãëàðÿí,

Ï.Ï. Êàðàêèòñîñ

ê.è. ´³µÉáÛ³Ý, ¶.². ´»·É³ñÛ³Ý,

ä.ä.Î³é³ÏÇïëáë

ThinPrep ïðîöåññîðà (Cytyc Co, Ìàëüáîðî, øòàò Ìàññà÷óñåòñ)

ïðåäñòàâëÿåò ñîáîé ìåòîä òîíêîé ïðåïàðîâêè ïðåïàðàòà è ïîëó÷èë

ïîïóëÿðíîñòü â ïîñëåäíèå ãîäû. Îí èñïîëüçóåòñÿ, ÷òîáû ïîäãîòîâèòü

ñëàéäû èç ñóñïåíçèè êëåòîê, ñîáðàííûõ â êîíñåðâàíòå æèäêîñòè

(Cytolyt ® ðàñòâîð). Ìû èññëåäîâàëè 105 ìàòåðèàëà àñöèòè÷åñêîè,

ñâîáîäíîè ïåðèòîíåàëüíîè æèäêîñòè è ñìûâîâ áðþøíîè ïîëîñòè ó

áîëüíûõ ñî çëîêà÷åñòâåííûìè ýïèòåëèàëüíûìè îïóõîëÿìè ÿè÷íèêîâ.

Ðåçóëüòàòû äîêàçàëè, ÷òî òðàäèöèîííûé ìåòîä ÿâëÿåòñÿ íàäåæíûì, òàê

êàê äèàãíîñòè÷åñêàÿ òî÷íîñòü áûëà 85,71%, à ïîëîæèòåëüíàÿ ïðîã-

íîñòè÷åñêàÿ öåííîñòü ñîñòàâèëà 100%, íî âàæíàÿ ïðîáëåìà âîçíèêàåò

â îòíîøåíèè îöåíêè îòðèöàòåëüíûõ ðåçóëüòàòîâ, ïîñêîëüêó îòðèöà-

òåëüíàÿ ïðîãíîñòè÷åñêàÿ öåííîñòü ñîîòâåòñòâîâàëà 58,33%. Óëó÷øåíèå

êà÷åñòâà öèòîìîðôîëîãè÷åñêèõ õàðàêòåðèñòèê â ìåòîäå ThinPrep âåäåò

ê óìåíüøåíèþ ëîæíî-îòðèöàòåëüíûõ ðåçóëüòàòîâ äî 8 ñëó÷àåâ áåç

íàëè÷èÿ êàêèõ-ëèáî ëîæíî-ïîëîæèòåëüíûõ ðåçóëüòàòîâ. Ýòî ïðèâîäèò

ê ñòàòèñòè÷åñêè çíà÷èìûì ðàçëè÷èÿì äèàãíîñòè÷åñêîé òî÷íîñòè ìåæäó

äâóìÿ ìåòîäàìè (x2=10,35, ð<0,05). Êðîìå òîãî, ÷óâñòâèòåëüíîñòü

óâåëè÷èëàñü ñ 82,14 äî 90,47%, îòðèöàòåëüíàÿ ïðîãíîñòè÷åñêàÿ

öåííîñòü îò 58,33 äî 72,43% è, íàêîíåö, äèàãíîñòè÷åñêàÿ òî÷íîñòü îò

85,71 äî 92,37%. Ýòè äàííûå íàõîäÿòñÿ â îòëè÷íîì ñîîòíîøåíèè ñ

îêîí÷àòåëüíûì êëèíè÷åñêèì äèàãíîçîì (õ2 =3,27, ð> 0,05).

Òàêèì îáðàçîì, ìåòîä ThinPrep çíà÷èòåëüíî óëó÷øàåò äèàãíîñòè-

÷åñêóþ òî÷íîñòü öèòîëîãè÷åñêîé äèàãíîñòèêè, ïîçâîëÿåò ñîçäàâàòü

íåñêîëüêî ñëàéäîâ ñ ïðåäñòàâëåíèåì êëåòî÷íîãî ìàòåðèàëà äëÿ öåëåé

èììóíîöèòîõèìèè è ìîëåêóëÿðíîé öèòîëîãèè.

Ð»ï³½áïáõÃÛ³Ý »Ý »Ý-

Ã³ñÏí»É Óí³ñ³ÝÝ»ñÇ ã³ñá-

ñ³Ï ¿åÇÃ»É³ÛÇÝ áõéáõóùÝ»-

ñáí 105 ÑÇí³Ý¹Ý»ñÇó

í»ñóí³Í µçç³µ³Ý³Ï³Ý

ÝÛáõÃ»ñÁ, áñáÝù Ñ»ï³½áïí»É

»Ý ³í³Ý¹³Ï³Ý ¨ Ñ»ÕáõÏ³ÇÝ

µçç³µ³Ý³Ï³Ý ùÝÝáõÃÛ³Ý

»Õ³Ý³Ïáí: ²ÛÝáõÑ»ï¨ ·Ý³-

Ñ³ïí»É »Ý ëï³óí³Í ïíÛ³É-

Ý»ñÁ ¨ »ñÏáõ Ñ»ï³-

½áïáõÃÛ³Ý ³ñ¹ÛáõÝùÝ»ñÁ

Ñ³Ù»Ù³ïí»É »Ý: Ð»ï³½á-

ïáõÃÛ³Ý ïíÛ³ÉÝ»ñÁ ÷³ë-

ïáõÙ »Ý, áñ Ñ»ÕáõÏÇ íñ³

ÑÇÙÝí³Í µçç³µ³Ý³Ï³Ý

ùÝÝáõÃÛáõÝÁ ½·³ÉÇáñ»Ý

µ³ñ»É³íáõÙ ¿ ³ËïáñáßÇã

×ß·ñïáõÃÛáõÝÁ, Ýí³½»óÝ»Éáí

³å³ÏÇÝ»ñÇ óáõó³¹ñáõÃÛ³Ý

Å³Ù³Ý³ÏÁ, µ³ñÓñ³óÝ»Éáí

Ýñ³Ýó áñ³ÏÁ, ¨ ÃáõÛÉ ¿

ï³ÉÇë ÏÇé³ñ»É ³ñÅ»ù³íáñ

¨ Ýáñ³·áõÛÝ ëï³ïÇÏ

óÇïáÙ»ïñÇ³ÛÇ Ù»Ãá¹Á:

Ìåäèöèíñêèé Âåñòíèê Ýðåáóíè, 2013, 2(54), 102-108

103

Introduction: The ThinPrep Processor (Cytyc

Co., Marlborough, MA) is a thin layer

preparation device that has been gaining in

popularity in the recent years. It is used to

prepare slides from cell suspensions collected in

a preservative liquid (Cytolyt® solution). In

gynaecological and non gynaecological

specimens, the ThinPrep® method appeared to

improve the diagnostic accuracy and the quality

of the smear, reducing the obscuring effects of

blood and inflammation and to offer the

possibility making more than one slides with

homogenized representative material useful for

immunocytochemistry and molecular cytology

(1-4 from 2a, 5-7 from 2a and 1-10 to1a).

Microscopic peritoneal seeding with tumor

cells by ovarian tumors predates the formation

of ascites and its detection by peritoneal

cytology may provide valuable staging and

prognostic information. The technique of

intraoperative peritoneal washing cytology was

introduced in 1958 by Keetle [2-4]. In 1975

FIGO incorporated diagnoses of peritoneal

washings into the staging classification for

ovarian carcinoma [5,6].

This study discusses the role of liquid-based

cytology with ThinPrep® technique, in the

investigation of patients with malignant common

epithelial tumors of the ovary. Consequently we

have investigated the potential role of DNA

ploidy as an indicator of improvement of

diagnostic accuracy for the ovarian cancers.

Materials and Methods

Our study was carried out on 105 consecutive

body cavity fluids of women which were

hospitalized in the 1st Gynaecological Clinic of

Medical School of Athens’ University, in

Alexandra Hospital for ovarian cancer. The

patients were from 22 to 70 years old with a

mean age 45.2 years (SD=18.35 years).

Thirty-two (32) ascitic fluids, 42 free

peritoneal fluids and 31 peritoneal washings

were examined cytologically. For the diagnosis,

WHO classification scheme was used. All

material was processed by the conventional and

the ThinPrep® methods (Cytyc, Co.,

Boxborough, MA.). Five slides were prepared

by the conventional method for each case. Three

slides were stained by Papanicolaou stain and

the other two by Giemsa stain.

For the ThinPrep® method, the fluid was

initially centrifuged. Consequently the

supernatant fluid was discarded and the pellet

was suspended in the fixative solution

(Cytolyt®, Cytyc, Co, Boxborough, MA). Then

the sample in Cytolyt® solution was centrifuged

again and resuspended in cytopreservative

solution (PreservCyt® solution, Cytyc, Co,

Boxborough, MA) which mildly fixed the cells

within 10-15 minutes and then the material was

ready to be prepared by the ThinPrep 2000

Automated Slide Processor (Cytyc, Co,

Boxborough, MA). In cases of bloody samples,

additional Cytolyt® solution washes may be

necessary, until the sample becomes clear.

Finally, two ThinPrep® (TP) slides were

prepared for each case. The one TP® slide was

stained by Papanicolaou stain for cytological

diagnosis and the other was stained by Feulgen

stain suitable for DNA ploidy. DNA ploidy

analysis was performed with a SAMBA 2005

Image Analysis System (Alkatel™, Grenoble,

France) according to the standard protocol, using

a Zeiss Axioplan microscope (Cöttingen,

Germany) with a 40:1 planachromatic lens, 3-

color CCD camera (Tokyo, Japan) and Compaq

computer (Houston, Texas, U.S.A.). In each case

(slide) at least 200 randomly selected nuclei

were measured.

Both ThinPrep and conventional smears were

diagnosed by cytopathologists. All negative

diagnoses, by both methods, were reviewed

independently by two at least cytopathologists

without knowledge of the previous cytological

diagnosis.

The final cytological diagnoses, after

reviewing the negative ones, were classified as:

within normal limits (WNL), malignant and

insufficient (no cellular material other than

blood).

Statistical analysis was performed using the

Mc Neamar test for the correlation of the results

Êëèíè÷åñêàÿ îöåíêà ìåòîäà æèäêîñòíîé öèòîëîãèè ïðè èññëåäîâàíèè áîëüíûõ ñî çëîêà÷åñòâåííûìè ýïèòåëèàëüíûìè îïóõîÿìè

ÿè÷íèêîâ

104

by the conventional method and the ThinPrep

one. The chi-squared method was used in

ordinary contingency tables.

Results and Discussion

Our material included 110 cases of body

cavity fluids. From the total of the cases the five

were excluded for the purposes of this study, as

the material was insufficient for cytological

diagnosis by both methods.

Of 105 cases, the 21 were ovarian cancers Ia-

IIb stage, where the presence of tumor cells in

the cytological diagnosis was not expected and

the remaining 84 cases corresponded to ovarian

cancers stage IIc-IV.

Through the conventional method, false

positive results were not observed, whereas in 15

of 84 cases which were expected to be

cytologically positive, tumor cells were not

identified in the smears (Table 1). Based on

these results, sensitivity, specificity, positive

predictive value, negative predictive value and

diagnostic accuracy of diagnosis by

conventional method were 82.14%, 100%,

100%, 58.33% and 85.71% respectively.

Table 1

Correlation of the conventional cytological

diagnosis with the final diagnosis

Conven-

tional

cytological

diagnosis

Stage

Ia- IIb* IIc -IV TOTAL

Negative 21 15 36

Positive 0 69 69

TOTAL 21 84 105

Χ2=64.32, DF=1, p<0.001, φ=0.69

* Tumor cells did not observed at stage Ic

According to the ThinPrep method, false

positive results were not observed either,

whereas in 8 of 84 cases, which were expected

to be cytologically positive, tumor cells were not

identified in the smears (Table 2). Based on

these data, sensitivity, specificity, positive

predictive value, negative predictive value and

diagnostic accuracy of diagnosis by ThinPrep

method were 90.47%, 100%, 100%, 72.41% and

92.37% respectively.

Table 2

Correlation of the ThinPrep diagnosis with

the final diagnosis

ThinPrep Stage

Ia- IIb* IIc -IV TOTAL

Negative 21 8 29

Positive 0 76 76

TOTAL 21 84 105

Χ2=3.27, DF=1, p>0.05, φ=0.81


Out of the eight false negative cases

diagnosed by the ThinPrep method, four cases

were correctly diagnosed as positive by the

conventional method. Finally, according to the

final cytological diagnosis, only four cases were

the real false negative by both ThinPrep and

conventional method (Table 3). Based on these

data, sensitivity, specificity, positive predictive

value, negative predictive value and diagnostic

accuracy of final cytological diagnosis of our

material were 95.24%, 100%, 100%, 84% and

96.19% respectively.

Table 3

Corelation of the final cytological diagnosis

with final diagnosis

Final cytological

diagnosis

Stage

Ia- IIb* IIc -IV TOTA

L

Negative 21 4 25

Positive 0 80 80

TOTAL 21 84 105

Χ2=2.25, DF=1, p>0.05, φ=0.89


Statistically no significant difference was

observed between the final cytological diagnosis

and the final clinical one (x2 = 2.25, p>0.05),

whereas a statistically significant difference was

observed between the conventional cytological

diagnosis and the final clinical one (x2 = 64.32,

p<0.001). On the contrary, no statistically

significant difference was observed between the

Ñ.Ð. Áàáëîÿí, Ã.À. Áåãëàðÿí, Ï.Ï. Êàðàêèòñîñ

105

ThinPrep cytological diagnosis and the final

clinical one (x2 = 3.27, p>0.05). The comparison

of the diagnosis between the conventional and

the ThinPrep method is presented in Table 4 (x2

= 10.35, p<0.05).

Table 4

Correlation of convetional cytological and

ThinPrep results

ThinPrep

method

Conventional cytological method

Negative Positive TOTAL

Negative 25 4 29

Positive 11 65 76

TOTAL 36 69 105

Χ2=10.35, DF=1, p<0.05, φ=0.67

For the purposes of this study, the neoplasms

were divided in euploid and aneuploid. Euploid

neoplasms were those with DNA value from 0.9

to 1.1 and/or from 1.8 to 2.2, while hyperploid

neoplasms were those with degree of

hyperploidy lower than 3. The remaining cases

were aneuploid.

According to our results, 64 (60.95%) cases

were aneuploid while 41 (39.04%) cases were

euploid (x2 = 11.25, p<0.001). Euploid only

neoplasms were observed in the cases of ovarian

cancer stage Ia-IIb, which were diagnosed,

positive cytologically, while out of the 84 cases

of ovarian cancers stage IIc-IV, aneuploidy was

detected in 64. In two cases of neoplasms with

aneuploidy the cytological diagnosis

misdiagnosed the presence of tumor cells by

both methods (Table 5).

Table 5

Correlation of the final cytological

diagnosis with the DNA ploidy

Cytological

diagnosis

DNA ploidy

Ddiploindy aneuploidy total

Negative 23 2 25

Positive 18 62 80

TOTAL 41 64 105

X2 = 11.25, p<0.001

Based on these data, sensitivity, specificity,

positive predictive value, negative predictive

value and diagnostic accuracy adding the DNA

ploidy in our material were 97.62%, 100%,

100%, 91.3% and 98.09% respectively.

Finally in Table 6 the correlation between the

final cytological diagnosis including the DNA

ploidy results, with the final clinical one is

presented (x2 = 2.02, p > 0.05).

Table 6

Correlation between the cytological

diagnosis adding the DNA ploidy and the

clinical one

Cytological

diagnosis and

DNA ploidy

Staging

Ia – IIb* IIc - IV TOTAL

Negative 21 2 23

Positive 0 82 82

TOTAL 21 84 105

X2 = 2.02, p>0.05, * Tumor cells did not observed at

stage Ic

Epithelial ovarian carcinoma is a relatively

frequent cancer in women, and results the main

reason of death by gynecological cancer [1]. The

lack of effective screening methods dictates the

need of determination of better prognostic

factors for the estimation of the survival of these

patients [1,7,8].

Thus, the cytological examination of the

ascitic fluid, the free peritoneal fluid and the

peritoneal washing is a well-accepted method for

the investigation of patients with epithelial

ovarian cancer [4]. In 1975 the International

Federation of Gynaecologists and Obstetricians

(FIGO) incorporated results of peritoneal

washing cytology into the staging classification

for ovarian carcinomas. The adequacy of the

smear is important issue in the evaluation of

cytological specimens. From 1970 until

nowadays, 3000 cases have been reported in the

literature without reference to insufficient

smears, which is characteristic of absence of

criteria. Although there are some cases with the

cytological diagnosis no malignant cells are observed it would be more appropriate if those

cases were referred like cytological elements are not observed [9,10]. In our material all five cases


ÿè÷íèêîâ

106

with insufficient material by both methods were

observed only in peritoneal washings specimens.

Previous studies have shown that the

diagnostic accuracy for the conventional

cytology ranged from 54% to 96%25 (9,10).

However, several investigators reported false

negative cytological diagnoses of ovarian

cancers with histological confirmation of the

peritoneum dissemination ranging from 20% to

70% and most of those were concerned

peritoneal washings [12-14].

According to our findings, 15 false negative

cases and none false positive were observed in

the conventional slides (Τable 1). These findings

prove that the conventional method is reliable, as

the diagnostic accuracy was 85.71% and the

positive predictive value was 100%, but an

important problem arised regarding the

evaluation of negative results, as the negative

predictive value was 58.33%. The negative

predictive value is affected by the fact that out of

the 10 cases with peritoneal metastases but

without the presence of ascitic fluid or free

peritoneal fluid during the surgery, only in 3

cases neoplastic peritoneal washings detected

cells. This is due to the low cellularity of the

observed material as also to the fact that the

smears were bloody so the background obscured

the diagnostic cells.

Five peritoneal washings with insufficient

material and 7 false negative cases out of the 10

with peritoneal metastases were observed, but

without the presence of ascitic or free peritoneal

fluid during the surgery. The remaining false

negative cases consisted of 6 free peritoneal

fluids out of the total of 42 cases and 2 ascitic

fluids out of the total of 32.

The purpose of this study is the evaluation of

liquid- based cytology in the investigation of

peritoneal dissemination to patients with ovarian

epithelial cancer and the potential role of the

DNA ploidy as an indicator of improvement of

diagnostic accuracy of the ovarian cancers.

The application of liquid-based cytology and

especially the ThinPrep method in

gynaecological smears started in mid 90’s both

in USA and Europe and later this method was

applied in non-gynaecological material which

was examined in cytological laboratories

[1,13,14].

It has been proven in gynaecological smears,

that the ThinPrep method permits the

concentration and immediate fixation of the

examined specimens and its homogenization.

Thus making possible the Thin preparation of

more slides with the same representative cellular

material. Furthermore, the nuclear and

cytoplasmic details are better preserved than

those of the conventional method. In addition,

through the ThinPrep method, the cytological

diagnosis is possible in one only slide, while in

the conventional method five at least slides were

necessary [15,16].

The improvement of the quality of

cytomorphological characteristics in the

ThinPrep method results in the reduction of false

negative rate at 8 cases without the presence of

any false positive result (Table 2). This results in

a statistically significant difference of the

diagnostic accuracy between the two methods

(x2=10.35, p<0.05). Furthermore, sensitivity

improved from 82.14% to 90.47%, negative

predictive value from 58.33% to 72.43% and

finally diagnostic accuracy from 85.71% to

92.37%. These findings are in excellent

correlation with the final clinical diagnosis

(x2=3.27, p>0.05).

Furthermore, the final cytological diagnosis

resulted in the reduction of false negative

diagnoses in 4 peritoneal washings during the

second look surgery, consisting by one serous

papillary adenocarcinoma stage IIIc, one serous

papillary adenocarcinoma stage IIc and two

serous papillary adenocarcinoma stage IIIc. The

correlation of the final cytological diagnosis

with the final clinical one did not show a

statistically significant difference (x2= 2.25,

p>0.05).

Based on these findings it appears that despite

its additional cost, the ThinPrep method

improves the diagnostic accuracy of cytological

diagnosis. We were initially cautious of using


107

this new cytopreparatory technique, since it

added substantial cost to already existing

cytodiagnostic procedures, because of high cost

of the reagents. Despite of that, the ThinPrep

method offers certain advantages over the

conventional method; the most important being

the rapid screening, through the reduction of the

time of microscopy at least to 1/5 as it needs

only one slide for the diagnosis in comparison

with the five used by the conventional method.

Furthermore, the ThinPrep method allows the

creation of more slides with representative

cellular material for the purposes of

immunocytochemistry and molecular cytology

[17,18].

In summary, the liquid-based cytology

improved significantly the diagnostic accuracy

of the cytological diagnosis, reduced the

screening time and permitted the valuable

application of current techniques of static DNA

cytometry.

In spite of the fact that the further reduction

of the false negative diagnoses is not possible to

improve the diagnostic accuracy significantly,

the application of the static DNA cytometry

confirms the fact that the are changes in

submicroscopical level which are difficult to be

recognized with the simple microscopical

examination. Based on the findings of automatic

cytology, it is possible to improve our diagnostic

criteria.

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ÿè÷íèêîâ

108

16. Bernstein S.J., Sanchez-ramos L., Ndubisi B.

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