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Pathol. Oncol. Res. (2011) 17:605–611
DOI 10.1007/s12253-010-9356-5

RESEARCH

Clinical and Prognostic Value of the Presence of Irregular
Giant Nuclear Cells in pT1 Ovarian Clear Cell Carcinoma
Naoki Matsumoto & Takashi Umezawa & Toru Sasaki &Kuninobu Nakajima & Yukiko Kanetsuna &Hiroshi Sasaki

Received: 19 September 2010 / Accepted: 29 December 2010 / Published online: 28 January 2011
# Arányi Lajos Foundation 2011

Abstract In the early stages of epithelial ovarian cancer,
histopathological grading is important. However, thegrading of ovarian clear cell carcinoma (OCCC) remains
controversial. We aimed to identify irregular giant nuclear
cells (IGNCs) by a simple method in clinical practice, andto evaluate the prognostic value of IGNCs in pT1 OCCC.
Eighty-seven pT1 OCCC patients who underwent initialsurgery at Jikei University Kashiwa Hospital, Chiba, Japan,
were retrospectively assessed. Paraffin-embedded tissue
sections (PTSs) stained with hematoxylin and eosin werereviewed. Giant nuclear cells (GNCs) were defined as cellswith a nuclear length of more than twice the median nuclear
N. Matsumoto (*) : H. Sasaki
Department of Obstetrics and Gynecology,
Jikei University Kashiwa Hospital,
163-1 Kashiwashita,
Kashiwa, Chiba 277-8567, Japane-mail: nmazmoto@my.home.ne.jp
T. Umezawa
Department of Pathology,
Jikei University School of Medicine,Tokyo, Japan
T. Sasaki
Department of Obstetrics and Gynecology,
Tokyo Medical University,
Tokyo, JapanK. Nakajima
Department of Obstetrics and Gynecology,
Jikei University School of Medicine,Tokyo, Japan
Y. Kanetsuna
Department of Clinical Pathology,
Jikei University Kashiwa Hospital,
Chiba, Japan

length. GNCs with irregular nuclear circumferences were
defined as IGNCs. Cases where one or more GNCs existed
and where IGNCs accounted for >10% of the GNCs wereclassified as IGNC-positive. We also attempted to identify
IGNCs on touch imprint cytology smears (TICSs). Amongthe 87 cases, 68 were IGNC-negative and 19 were IGNCpositive. The 5-year disease-free and overall survival rates
were 88.9% and 90.3% in the total patients, 98.3% and100% in the IGNC-negative group, and 59.7% and 62.0%
in the IGNC-positive group, respectively. These survival
rates were significantly lower in the IGNC-positive groupthan in the IGNC-negative group (adjusted hazard ratio=
14, 95% confidence interval=2.7–124 and adjusted hazard
ratio=25, 95% confidence interval=2.9–768, respectively).
Prognostic differences were not identified for other factors.
IGNC identification on 28 available TICSs predicted IGNC
identification on PTSs (sensitivity=50.0%, specificity=
100%, P=0.007). The presence of IGNCs has clinical andprognostic value for pT1 OCCC.
Keywords Intraoperative diagnosis .
Nuclear morphometry . Ovarian cancer . Pathology .
Touch imprint cytology
Abbreviations
CI
confidence interval
DFS
disease-free survival
EOC
epithelial ovarian cancer
GNC
giant nuclear cellHRhazard ratio
IGNC irregular giant nuclear cell
OCCC ovarian clear cell carcinoma
OSoverall survival
PTS
paraffin-embedded tissue section

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Introduction
Ovarian clear cell carcinoma (OCCC), which was definedby the World Health Organization in 1973 [1], is recognized as a distinct subtype of epithelial ovarian cancer(EOC). Some of its characteristics are poor prognosis,
chemoresistance, high incidence of early-stage detection,
relatively high occurrence in younger women and highprevalence in Asians. OCCC accounts for 11% of all EOCs
among Asians but only 5% of all EOCs in general [2]. In
Japan, OCCC occurs at an even higher rate of up to 22%[3]. Although OCCC is often diagnosed early, its prognosis
is frequently worse than those of other histological subtypesof EOC. Moreover, the histopathological grading system
for OCCCs remains controversial in terms of its usefulness,and is therefore not recommended by the World HealthOrganization [4]. OCCC is considered to be a high-risk
cancer, regardless of its grade or pT1 substage. Therefore,
even for stage IA or IB OCCC, adjuvant chemotherapy isindicated. Furthermore, surgeons almost uniformly perform
Fig. 1 Representative histological and cytologicalimages. a An ovarian clear cell
carcinoma (OCCC) without giant nuclear cells (GNCs) (tissue
pathology, hematoxylin andeosin staining [H&E], ×400). b
An OCCC without GNCs
(touch imprint cytology, Papanicolaou staining [Pap], ×400).
c An OCCC with GNCs (tissue
pathology, H&E, ×400). d An
OCCC with GNCs (touch imprint cytology, Pap, ×400). e
An OCCC with irregular giant
nuclear cells (IGNCs) (tissue
pathology, H&E, ×400). f An
OCCC with IGNCs (touch imprint cytology, Pap, ×400)

N. Matsumoto et al.

retroperitoneal lymphadenectomy and hesitate to conduct
less-invasive operations like fertility-sparing surgery.
Liu et al. [5] analyzed the nuclear shapes in pathologicaltissue specimens obtained from 40 OCCC patients using
image measurement software. In addition, they evaluatedthe prognostic value of the presence of giant nuclei andnuclear irregularities in OCCC and found that these factors
were related to a poor prognosis. In the present study, we
aimed to identify irregular giant nuclear cells (IGNCs) byemploying a simple method that is easily applicable inclinical practice and to evaluate the clinical and prognostic
value of IGNCs in pT1 OCCC.

Methods
Among the primary EOC patients who initially underwent
surgery between 1995 and 2008 at Jikei University
Kashiwa Hospital, Chiba, Japan, 151 were diagnosed with
OCCC. The pathological diagnoses were determined by

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Irregular Giant Nuclear Cells Predict Poor Prognosis

pathologists of the Department of Clinical Pathology at thehospital. Among the 151 patients, 87 had pT1 tumors, andtheir cases were retrospectively analyzed. For all cases,
paraffin-embedded hematoxylin and eosin-stained tissue
sections were archived and available for pathologicalreview. These sections were reviewed by two independent
pathologists and the pathological diagnoses were verified(see the Acknowledgments). For morphometric assessment,
the paraffin-embedded tissue sections (PTSs) were examined under a double-headed microscope by two of theauthors who were blinded to the patients’ clinical data. Allavailable sections that included cancer cells were reviewed
for each patient. Giant nuclear cells (GNCs) were definedas cells with a nuclear length of more than twice the mediannuclear length. Moreover, GNCs with irregular nuclear
circumferences, bizarre nuclear forms or obviously distorted nuclear membranes were defined as IGNCs. Cases
where one or more GNCs existed and where IGNCs
accounted for more than 10% of the GNCs were classified
as IGNC-positive. All the other cases were classified as
IGNC-negative. If the initial opinions of the authors wereconflicting in the classification of a case, a consensus
decision was taken. The prognosis was evaluated on thebasis of the IGNC grouping and other factors.
In addition, we attempted to identify IGNCs by touch
imprint cytology in cases where touch imprint cytology smear
Table 1 Characteristics of the
87 patients who received initial
operations and were diagnosed
with pT1 ovarian clear cell
carcinoma

607(TICS) specimens were available. These smears, which wereprepared ex vivo by touching the cut surface of the excised
tumors, were stained by the Papanicolaou method.
The associations between the IGNC grouping or characteristic factors and the outcomes were analyzed using Student’s
t-test, Fisher’s exact test and the chi-square test. To assess the
prognosis, the disease-free survival (DFS) and overall survival(OS) rates were analyzed using the Kaplan-Meier method,log-rank test and multivariate Cox proportional hazards
model. Hazard ratios (HRs) were calculated in multivariate
analyses adjusted for patient age, pT1 substage, retroperitoneal
lymphadenectomy, first-line chemotherapy regimen and
IGNC grouping. All the tests were two-tailed and values ofP<0.05 were considered statistically significant.

Results
Representative photographs of PTSs and TICSs for caseswith no GNCs, with GNCs, and with IGNCs are shown in
Fig. 1. The patients’ characteristics are listed in Table 1 andthe profiles of nine relapse cases are shown in Table 2.
GNCs and IGNCs were seen most frequently in the sixth
case shown in Table 2. For this case, we counted total
tumor cells, GNCs, and IGNCs on prints of 20 vision fields(×200 magnification) for each of the PTSs and the TICSs.

Characteristics

Total

Total (%)
Age (y)Mean ± standard deviation
Range
pT1 substage
pT1a
pT1c

a

Calculated using Student’s t-testb

Calculated using Fisher’s exact
testcCalculated using the chi-squaretestdCalculated using Fisher’s exact
test to compare the groupthat received taxane and carboplatin with the group that received
the conventional cisplatin-based
regimen

IGNC, irregular giant nuclear
cell

No. of patients

Lymph node involvement
N0
Nx
N1
Retroperitoneal lymphadenectomy
Performed
Not performed
First-line chemotherapy regimen
Taxane and carboplatin
Conventional cisplatin-based regimen
Irinotecan hydrochloride and cisplatin
Not performed
Unknown

87

(%)

(100)

54.0±10.5
27–84

P

IGNC grouping
Negative

Positive

68 (78.2)

19 (21.8)54.5±10.2
33–75

52.4±11.5
27–84

0.44a

20
67

(23.0)(77.0)

16
52

4
15

1.0b

74
10
3

(85.1)(11.5)
(3.4)

60
7
1

14
3
2

0.12c

69
18

(79.3)(20.7)

57
11

12
7

0.061b

67
12
1
6
1

(77.0)(13.8)
(1.1)
(6.9)
(1.1)

56
9
0
2
1

11
3
1
4
0

0.44d

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N. Matsumoto et al.

Table 2 Characteristics of the 9 relapse cases
Age
(y)

pTNM
stage

Initial operation

First-line
chemotherapy(courses)

Area of recurrence

Outcome

Positive84

pT1cNxM0

Nonea

4

7

54

pT1cN1M0

Unknownb

5

More than 9

Negative51

pT1cN0M0

Alive

10

More than 27

Positive52

pT1cN0M0

Peritoneal
dissemination
Virchow’s andmediastinal lymph
nodes
Peritoneal
dissemination
Para-aortic lymph
nodes

Dead

Positive

Dead

11

33

Positive61

pT1cN0M0

Positive49

pT1cN0M0

Positive48

pT1cN1M0

TH + BSO +OM
TH + BSO +OM + PL +PAL
TH + BSO +OM + PL
TH + BSO +OM + lymph
node biopsy
TH + BSO +OM + PL +PAL
TH + BSO +OM + PL
TH + BSO +OM + PL

Positive64

pT1cN0M0

TH + BSO +OM + PL

Negative48

pT1aN0M0

TH + BSO + PLaDC (6)PC (6)PC (6)

Disease-freesurvival(months)

Overallsurvival(months)

IGNC
grouping

DC (6)

Liver parenchyma

Dead

13

33

CAP (5)Peritoneal
dissemination
Para-aortic lymph
nodes

Dead

14

32

Dead

21

25

Liver parenchyma
and para-aortic
lymph nodes
Peritoneal
dissemination

Dead

44

47

Dead

71

82

Irinotecanhydrochloride+ cisplatin (6) c
CAP (5)

CAP (5)

Because of old age (84 y)bNine months after the surgery, the hospital records of the patient were not availablecBecause of taxane allergy

IGNC, irregular giant nuclear cell; pTNM, pathological tumor-nodes-metastasis classification; TH, total hysterectomy; BSO, bilateral salpingooophorectomy; OM, omentectomy; PL, pelvic lymphadenectomy; PAL, para-aortic lymphadenectomy; DC, docetaxel + carboplatin; PC,paclitaxel + carboplatin; CAP, cyclophosphamide + adriamycin + cisplatin

The numbers (percentages) of total tumor cells, GNCs, and
IGNCs in these specimens were 1447, 12 (0.83%), 3(0.21%) and 1253, 31 (2.5%), 4 (0.32%) in the PTSs and
TICSs, respectively. The median observation period was
46 months (range, 3–136 months). Six patients underwent
fertility-sparing surgery, while the remaining patients
underwent standard operations, including total hysterectomy, bilateral salpingo-oophorectomy and omentectomy (orbiopsy), as the initial procedures. Sixty-nine patients
underwent retroperitoneal lymphadenectomy (50 pelvic,
19 both pelvic and para-aortic), and lymph node involvement was observed in three cases. Eight patients underwent
a retroperitoneal lymph node biopsy and lymph node
involvement was not observed. The remaining 10 cases
did not undergo pathological exploration of retroperitoneal
lymph nodes. Postoperative adjuvant chemotherapy wasadministered to 80 patients. No significant differences wereobserved between the IGNC-positive and IGNC-negative
groups with respect to patient age, pT1 substage, lymphadenectomy or first-line chemotherapy regimen.
Table 3 shows the associations between the prognostic
factors of interest and the recurrence or survival rates. In the

total patients, the 5-year DFS and OS rates were 88.9% and90.3%, respectively. The mean ages of the patients withtumor recurrence or death did not differ significantly fromthose of the patients without recurrence or death (P=0.41
and P=0.30, respectively, Student’s t-test). Multivariate
analyses with the Cox proportional hazards model revealed
that patient age was not related to the rates of recurrence ordeath (HR for a one-unit [1-year] increase in age [one-unit
HR]=1.01, 95% confidence interval [CI]=0.90–1.13 andone-unit HR =1.02, 95% CI =0.88–1.19, respectively).
Tumor recurrence and death were more common in the
IGNC-positive group than in the IGNC-negative group(relative risk=12.5, 95% CI=2.8–56 and relative risk=
21.5, 95% CI=2.7–168, respectively). The DFS and OS
rates were significantly lower in the IGNC-positive groupthan in the IGNC-negative group (Fig. 2). There were no
prognostic differences in terms of the pT1 substage (pT1avs. pT1c) or whether lymphadenectomy was performed.
The DFS and OS rates tended to be lower in the group
receiving a conventional cisplatin-based regimen as thefirst-line chemotherapy than in the group receiving taxane
and carboplatin. However, multivariate analyses with theAuthor's personal copy
Irregular Giant Nuclear Cells Predict Poor Prognosis

609

Table 3 Univariate and multivariate analyses of prognostic factors using the Kaplan-Meier method and Cox proportional hazards model
Factorsn

EventsDFS

OS

Kaplan-Meier

Coxa

Kaplan-Meier

5-yearpT1 substage
pT1a
pT1c

5-yearRecurrence

Death

DFS
(%)

Pb

HR

95% CI

1
8

1
6

100
85.9

0.41

1
0.73

7
2

5
2

89.2
88.5

0.78

4
3

2
3

93.4
83.3

0.14

2
7

1
6

98.3
59.7

<0.00120
67

Retroperitoneal lymphadenectomy
Performed
69
Not performed
18
First-line chemotherapy regimen
Taxane and carboplatin
67
Conventional cisplatin12
based regimen
IGNC grouping
Negative
68
Positive
19

Coxa

OS
(%)

Pb

HR

95% CI

100
87.6

0.58

0.068–17

1
0.34

0.012–9.4

1
0.37

91.3
87.2

0.48

0.015–3.1

1
0.72

0.018–9.6

1
1.8

95.6
83.3

0.051

0.31–9.6

1
4.1

0.47–59

1
14

100
62.0

<0.001

2.7–124

1
25

2.9–768aMultivariate analysis using the Cox proportional hazards model adjusted for patient age and other factorsbCalculated using the univariate log-rank test

DFS, disease-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval

Cox proportional hazards model revealed no significant
differences in this regard. The overall results of univariate
and multivariate analyses adjusted for patient age and otherfactors indicated that only the IGNC grouping was
significantly related to the prognosis.
The screening values of IGNC identification were
calculated. With respect to predicting lymph node involvement, the sensitivity was 66.7%, specificity was 84.8% andlikelihood ratio was 4.4 (Fig. 3a). However, these results
were not statistically significant. TICSs were available in
28 cases (32.2%). Among these cases, three (10.7%) were
Fig. 2 Prognostic analysis performed using the Kaplan-Meiermethod and log-rank test.
IGNC, irregular giant nuclear
cell

identified to be IGNC-positive on TICSs, and all of themwere identified to be IGNC-positive on PTSs. With respect
to predicting IGNC identification on PTSs, the sensitivityof IGNC identification on TICSs was 50.0%, but the
specificity was 100% (Fig. 3b).

Discussion
In the early stages of EOC, it is essential to accurately
predict each patient’s prognosis and select appropriate

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N. Matsumoto et al.

Fig. 3 a Screening value of
IGNC identification for lymph
node involvement. b Screening
value of touch imprint cytology
for histopathological IGNC
identification. P values were
calculated using Fisher’s exact
test. IGNC, irregular giant
nuclear cell

treatment to avoid unnecessary invasive therapy and ensure
a good outcome. Young et al. [6] suggested that womenwith low-risk cancers, defined as stage IA or IB, grade 1 or
2, or non-clear-cell histology, do not need further adjuvant
therapy, and the currently used clinical therapeutic strategies are based on this approach [7, 8]. Moreover, theclinical implications of EOC grades are widely acceptedwith respect to non-clear-cell histology [9–11]. However,
the grading of OCCC remains controversial. It is moredifficult to grade OCCCs than other histological subtypesof EOCs because a single specimen contains various
structures, and nuclear abnormalities tend to be moderateor severe. In the present study, we revealed the prognostic
value of the presence of IGNCs in pT1 OCCC by
employing a method that is easy to use in clinical practice.
The paclitaxel and carboplatin regimen is generally
administered concomitantly to EOC patients as a first-line
adjuvant chemotherapy [12]. The regimen is also prescribedto patients with OCCC [13, 14]. However, the efficacy ofthis therapy has not always been satisfactory in cases of
OCCC [15]. In the present study, the 5-year recurrence rate
was 1.7% in the IGNC-negative group, suggesting a very
good prognosis for this group. Therefore, it seems doubtfulthat every tumor with a clear-cell histology belongs to ahigh-risk group and needs to be uniformly treated by
adjuvant chemotherapy even in stage I cases. Omission of
adjuvant chemotherapy should be considered for IGNCnegative tumors at stage I because they pose a low risk. In
contrast, this therapeutic strategy was inappropriate for the
IGNC-positive group, which was ascertained to be a very
high-risk group.
Total hysterectomy, bilateral salpingo-oophorectomy andomentectomy are considered to be standard initial procedures. In addition, retroperitoneal lymphadenectomy isgenerally performed and is considered to have diagnostic
value. However, its therapeutic value is controversial andthere is no consensus on whether lymphadenectomy
improves outcomes. Maggioni et al. [16] conducted arandomized study on the value of lymphadenectomy fortreating patients with stage I and II EOC (n = 268).
Although the systemic lymphadenectomy group in theirstudy tended to have a better prognosis than the lymph
node biopsy group, the difference was not significant. On
the basis of the results of a large-scale non-randomized
epidemiological survey (n=6,686), Chan et al. [17] suggested that lymphadenectomy for stage I disease improved
survival in non-clear-cell EOC patients but not in OCCC
patients. In a retrospective study (n=205), Suzuki et al. [18]concluded that patients with early-stage OCCC who
underwent lymphadenectomy did not show a significant
improvement in survival. Therefore, the therapeutic valueof retroperitoneal lymphadenectomy in patients with earlystage OCCC remains unclear. Lymph node involvement isobserved in approximately 5–8% of patients with pT1
OCCC [19, 20], which is lower than the rate of 13.7%
observed for pT1 EOCs in general [21]. In the present
study, lymph node involvement was detected in three of 87(3.4%) pT1 cases and three of the 69 (4.3%) lymphadenectomy cases, but just one of the 57 (1.8%) IGNC-negative
cases in which a lymphadenectomy was performed.
Therefore, we questioned whether lymphadenectomy needs
to be performed uniformly in patients with pT1 OCCC. The
results of the present study suggest that lymph node
involvement may be predicted by IGNC identification inpatients with pT1 OCCC.
Our results for IGNC identification on TICSs suggestthat if IGNCs are identified on TICSs, they will also be
identified on PTSs. For example, in cases where atumor is diagnosed as OCCC on the basis of intraoperative frozen-section pathological analysis [22, 23] ortumor cytology [24], we consider that IGNC identification
by intraoperative touch imprint cytology can provide us
with valuable clinical information that would aid thedecision on whether excessively invasive operations can
be avoided.
In renal cell carcinoma, Fuhrman et al. [25] found thatthe existence of large or irregular nuclei was associatedwith a poor prognosis. Subsequently, the prognostic valueof the Fuhrman nuclear grading system has well beenrecognized. However, the interobserver reproducibility is
not considered to be satisfactory because of the complexityof the four-tiered grading system [26–28]. In the present

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Irregular Giant Nuclear Cells Predict Poor Prognosis

study, we have proposed an easy and simplified stratification using identification of IGNCs for OCCC. We hope tocarry out a prospective and larger-scale study to assess theinterobserver reproducibility as well as consolidate theprognostic value of IGNCs in the future.
Acknowledgments The authors thank Prof. Zenya Naito (Department of Integrative Oncological Pathology, Nippon Medical School,
Tokyo, Japan) and Prof. Shin-ichi Tsuchiya (Division of Diagnostic
Pathology, Nippon Medical School Hospital, Tokyo, Japan) for theirpathological diagnostic review.

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