Special Contribution

Yonago Acta medica 2006;49:63–69

Scirrhous Gastric Cancer: Therapeutic Strategy
Masahide Ikeguchi, Masashi Inoue, Youji Fukumoto, Tomohiro Osaki, SachikoMatsumoto, Kenji Fukuda, Hiroaki Saito, Shigeru Tatebe and Shun-ichi Tsujitani
Department of Surgery, Division of Surgical Oncology, School of Medicine, Tottori University
Faculty of Medicine, Yonago 683-8504 Japan

The prognosis of patients with scirrhous gastric cancer is extremely poor. The management protocol for this type of cancer has not well been documented. In this paper, recent therapeutic outcomes of this type of gastric cancer are reviewed, and we introduce a
new treatment protocol for scirrhous gastric cancer.
Key words: intraperitoneal chemotherapy; laparoscopy; real-time reverse transcriptionpolymerase chain reaction; scirrhous gastric cancer

growth and early metastasis (Aranha et al., 1989;
Kanter et al., 1986). Thus, prognosis is poor inpatients with this disease, and the 5-year survival
rate is low.

Clinicopathological characteristics ofscirrhous gastric cancer
Scirrhous gastric cancer, designated as linitis plastica or Borrmann type 4 gastric cancer, is uniqueamong gastric carcinomas. It is characterized bypoorly differentiated carcinoma cells or signetring cells which diffusely infiltrate the gastricwall with provoking reactive ﬁbrosis. Scirrhous
gastric cancerous cells are located predominantlyin the submucosa, making it difﬁcult to identify
scirrhous gastric cancer using endoscopy. Although accuracy in the diagnosis of other gastriccarcinomas has undoubtedly improved with theadvent of endoscopy (Qizilbash et al., 1980), thesensitivity of detection of scirrhous gastric cancer
by endoscopy was reported to be only 33 to 73%(Evans et al., 1985; Levine et al., 1990). Moreover, Park et al. (2004) indicated that detection of
scirrhous gastric cancer using upper gastrointestinal series or endoscopic examinations at an earlystage was quite difficult. Contrary to normalcases of gastric cancers, scirrhous gastric cancer
tends to spread over the peritoneum with a rapid

Prognosis of patients with scirrhous gastric cancer
Despite curative gastrectomy, the 5-year survival
rate following gastric resection for patients withscirrhous cancer (13%) is signiﬁcantly lower thanthat of patients with other types of carcinoma(67%) (Otsuji et al., 2004). High incidences of serosal invasion and peritoneal metastasis have beenreported in scirrhous gastric cancer, and many
reports indicated that palliative resection of thestomach resulted in poor outcomes for affectedpatients (Takahashi et al., 2000; Yoshikawa et al.,2001). Even when curative gastrectomy is performed, survival of patients remains low. Thus,
Aranha et al. (1989) suggested that scirrhous gastric cancer was not a surgical disease.
In our previous study, between 1991 and2001, scirrhous gastric cancer was detected in 58

Abbreviations: CEA, carcinoembryonic antigen; CY, cytology of peritoneal washing; P, peritoneal metastasis; RT, reverse transcription63

M. Ikeguchi et al.

peritoneal metastasis, 6 months, P = 0.725). Ourdata strongly suggested that in scirrhous gastriccancer, gastrectomy should be performed for patients with P(–)/CY(–). Similar results have beenreported by Kikuchi et al. (2000).

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(7.5%) of 774 patients with gastric cancers treatedat the Tottori University Hospital. Gastrectomy
was performed in 39 (67.2%) patients; and in theother 19 patients, gastrectomy was not performed(nine of them already had pleural effusion or
ascites at diagnosis of scirrhous gastric cancer,
and the other 10 were operated on, but gastrectomy was halted because metastasis was widely
detected in the peritoneal cavity). Peritoneal intraoperative cytology of washings (CY) from the
Douglas cavity was performed for the 39 patients
immediately after laparotomy, according to apreviously demonstrated method (Ikeguchi et al.,1994). Of the 39 scirrhous gastric cancer patients
who underwent gastrectomy, the 5-year survival
rate of 19 patients with no peritoneal metastasis (P)and no peritoneal washing cytology [P(–)/CY(–)]
was 11.6%, and 13 patients with P(+)/CY(+) or 7
patients with P(–)/CY(+) died within 3 years ofoperation. The survival curve of patients with
P(–)/CY(–) was better than that of patients with
P(–)/CY(+) (P = 0.007), and survival curve of 7
patients with P(–)/CY(+) was not different fromthat of 13 patients with P(+)/CY(+) (Fig. 1, P =0.262). Moreover, the 50% survival periods of
20 patients with P(–)/CY(+) or P(+)/CY(+) who
underwent gastrectomy (5 months) was almost
the same as that of 10 patients who were operated with only laparotomy (because of extended

Therapeutic procedures and outcomesof scirrhous gastric cancer
To prolong the survival periods of patients withscirrhous gastric cancer, some surgeons have performed more radical operations such as en bloc
total gastrectomy including the pancreatic bodyand tail, the spleen, the gallbladder, the transverse
colon and the left adrenal gland (Furukawa etal., 1997). However, such radical surgeries may
result in increased risks of operative mortality.
Although other treatments have been attempted
such as chemotherapy (Kobayashi et al., 2002),
radiotherapy (Willett, 2002), hormonal therapy(Furukawa et al., 1994) or immunotherapy (Kimet al., 2001), their antitumor effects have been
insufﬁcient to improve prognosis of patients withscirrhous gastric carcinoma.
Common features of scirrhous gastric cancer
include remarkable fibrosis, rapid invasive progression and high frequency of metastasis to theperitoneum. Using a nude mouse model, Hippo����������

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Fig. 1. Our therapeutic results for patients with scirrhous gastric cancer who underwent gastrectomy between 1991 and 2001. Survival curves of 39 patients.
Line a: 19 patients with no peritoneal metastasis (P) and no peritoneal washing cytology [P(–)/CY(–)].
Line b: 7 patients with P(–)/CY(+).
Line c: 13 patients with P(+)/CY(+).

64

Treatment for scirrhous gastric cancer

Day 0
Cisplatin: 50 mg/m2
with 1000 mL saline

Day 2
Cisplatin: 50 mg/m2
with 1000 mL saline

Day 4
Cisplatin: 50 mg/m2
with 1000 mL saline

Day 5Real-time RT-PCR using CEA mRNA probe
for peritoneal washings after chemotherapy

Laparoscopic observation undergeneral anesthesia

1 Washing cytology
2 Real-time RT-PCR using CEA mRNA probe
for peritoneal washings before chemotherapy

Fig. 2. Our new treatment design for scirrhous gastric cancer using laparoscopic cisplatin-based
intraperitoneal chemotherapy.

cin. Thus, we used cisplatin in our new treatment
protocol (using intraperitoneal chemotherapy) for
scirrhous gastric cancer patients.

et al. (2001) globally analyzed differential gene
expression in scirrhous gastric cancer cells, andthey indicated that scirrhous gastric cancer cells
showed a particularly high potential for metastasis to the peritoneal cavity. Thus, development of
new therapeutic approaches to prevent peritoneal
metastasis is an important issue.

Our new treatment design
for scirrhous gastric cancer
Shiraishi et al. (1999) reported that laparoscopy
was useful for evaluating peritoneal metastatic
statuses. Therefore, to avoid unnecessary laparotomy, we used laparoscopy for the diagnosis ofmacroscopic peritoneal metastases or to perform
peritoneal washing cytology for patients withscirrhous gastric cancer. Moreover, we used intraperitoneal chemotherapy with cisplatin during
laparoscopy for these patients regardless of peritoneal status. We started this new treatment forpatients with scirrhous gastric cancer from 2002
(Fig. 2). Patients with scirrhous gastric cancer
without pleural effusion, ascites, liver metastasis
or extended lymph nodes metastasis by computed
tomography, were treated using laparoscopic diagnosis of peritoneal metastasis and peritoneal
washing cytology under general anesthesia. During this procedure, intraperitoneal chemotherapy
with cisplatin (50 mg/m2) in 1000-mL saline was
performed through a drain tube located in the left
sub-diaphragm; and following 1 h after clamping

Intraperitoneal chemotherapy
for scirrhous gastric cancer
Various investigators have attempted to develop
therapies against peritoneal metastasis in scirrhous gastric carcinoma. Hagiwara et al. (1992)
reported prognostic effectiveness of intraperitoneal administration of mitomycin-C at the time ofoperation in patients with advanced gastric cancer. In addition, we have previously reported that
intraperitoneal chemotherapy showed a survival
beneﬁt for patients with advanced gastric cancer
who had free cancerous cells in their peritoneal
cavities (Hamazoe et al., 1994). Thus, we suggested that intraperitoneal chemotherapy might
have prognostic benefits for patients with scirrhous gastric cancer, by preventing peritoneal metastasis. Moreover, Tsujitani et al. (1993) reported
that foci of peritoneal seeding were more sensitive
to cisplatin than to mitomycin C or to adriamy-65

M. Ikeguchi et al.

of the drain tube, saline with cisplatin was discharged from the drain tube located at the pouchof Douglas (Fig. 3). This type of intraperitoneal
chemotherapy was performed thrice on every other day (initial chemotherapy was performed during laparoscopic diagnosis under general anesthesia, but following intraperitoneal chemotherapies
were performed without anesthesia). Following
the end of intraperitoneal chemotherapy, patientswere treated with systemic chemotherapy using
5-ﬂuorouracil (500 mg/m2) and cisplatin (10 mg/m2), intravenously for 4 days/week. Systemic chemotherapy was maintained for 4 weeks. Patients
who were diagnosed as P(–) at initial laparoscopy
underwent gastrectomy with lymphadenectomy
after systemic chemotherapy. Patients who werediagnosed as P(+) received intraperitoneal chemotherapy using laparoscopy under general anesthesia for more than twice (Ikeguchi et al., 2005).

��Fig. 3. Locations of tubes during intraperitoneal
chemotherapy. A: drain tube located in the left subdiaphragm. B: drain tube located at the pouch of Douglas.

RNA extraction. Cytological examination was
not performed at this time, because it was usually
difﬁcult to gather sufﬁcient volume of samples forcytological examination.
Fifty milliliters of peritoneal wash samples
were centrifuged for 10 min at 400 × g, and total
RNA was extracted from the resulting pellets
using an RNeasy Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer’s protocol.
cDNA was synthesized from 1 µg total RNA using Ready-to-Go You-Prime First-Strand Beads(Amersham Pharmacia Biotech, Piscataway, NJ).
Specific primers and a TaqMan probe for CEA
were synthesized (Ikeguchi et al., 2003). PCR
was carried out with incubation at 50°C for 2 min,denaturing at 95˚C for 10 min, 45 cycles at 95˚C
for 15 s and 61˚C for 1 min (Bustin et al., 1991).
Different concentrations of KATO-III cells(10–106) were added to 1.5-mL peripheral blood
samples from 1 healthy volunteer (6 × 106 peripheral blood granulocytes). CEA mRNA expression
levels from different concentrations of KATOIII cells were analyzed by real-time RT-PCR.
All PCR experiments were done in triplicates.
Numbers of cancerous cells were derived fromthe CEA calibration curve (Yajima et al., 1998)
derived from plots representing the log of KATOIII cells in 6 × 106 granulocytes on the x-axis andcycle numbers on the y-axis. Therefore, formulafor CEA expression was y = 40 – 3x (r 2 = 0.994)

Detection of cancerous cells
in peritoneal washing samples
using real-time RT-PCR
In order to investigate therapeutic effects of intraperitoneal chemotherapy for patients with gastriccancer, we analyzed numbers of cancerous cells inperitoneal washing samples obtained just prior toand after intraperitoneal chemotherapy using carcinoembryonic antigen (CEA) mRNA based realtime reverse transcription (RT)-PCR. One hundred and ﬁfty milliliters of saline were introduced
into the Douglas cavity of each individual at the
beginning of laparoscopic operations, and aspirated after gentle stirring. Fifty-milliliter samplesof each peritoneal washing were prepared for cytological diagnosis of free cancerous cells, and other
50-mL samples were used for RNA extraction. At
post-operative day 5 (after the end of intraperitoneal chemotherapy), peritoneal cavities of scirrhous
patients were washed with 150-mL saline from thetube located on the left sub-diaphragm. Fifty milliliters of peritoneal washing were then collectedfrom the tube located at the pouch of Douglas for66Treatment for scirrhous gastric cancer(Fig. 4). For each peritoneal washing sample,
relative numbers of cancerous cells (amounts of
CEA mRNA) were determined from the standard
curve (Nakanishi et al., 2000).

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Therapeutic beneﬁts of laparoscopic
intraperitoneal chemotherapy forpatients with scirrhous gastric cancer

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Fig. 4. The standard curve based on the different concentration of KATO-III cells in 6 × 10 6 granulocytes.
The log of KATO-III cells in 6 × 106 granulocytes wasset on the x-axis. The threshold line was set at an Rnof 0.1. The cycle numbers at which each amplification curve of the different concentration of KATO-III
crossed the threshold (0.1) was set on the y-axis. For
each sample, the number of cancer cells was estimatedfrom this standard curve and it was described as thenumber of cancer cells/6 × 106 granulocytes.

Between 2002 and 2005, 13 patients were diagnosed as scirrhous gastric cancer and diagnosed
as no pleural effusion, no ascites, no liver metastasis or no extended lymph node metastasis bycomputed tomography. They were performed
laparoscopic diagnosis for peritoneal metastasis
followed by intraperitoneal chemotherapy. Details of these patients are summarized in Table
1. Four patients were diagnosed as P(+)/CY(+),
3 were as P(–)/CY(+) and 6 were as P(–)/CY(–).
While, cancerous cells were detected in peritoneal
washings of all 13 patients using CEA-based realtime RT-PCR. More than 90% of cancerous cells

were removed from the peritoneal cavity following cisplatin intraperitoneal treatment in 8 patients(Table 1). Moreover, CEA-positive cells could not

Table 1. Characteristics of the 13 scirrhous gastric cancer patients treated with laparoscopic
intraperitoneal chemotherapy
Patient Agenum- (year)
ber

Sex

P/CY

1
2
3
4
5
6
7
8
9
10
11
12
13

F
M
M
F
F
F
F
F
M
M
M
F
F

+/+
+/+
–/–
+/+
+/+
–/+
–/+
–/–
–/–
–/–
–/–
–/–
–/+

55
37
62
68
82
45
30
49
79
69
74
69
58

Number of cancerous cells/ Cancerous cells† Gastrectomy
6 × 106 granulocytes
reduced after
after
chemotherapy chemotherapy
BeforeAfterchemotherapy chemotherapy(%)
263,027
27,35314
707,946
2884
2399
130
3311
49
9
1000
43
25,11923,9881148
22109,648
1288
0
167
0
0
0
800
3
1995

91
96
0
85
55
100
0
100
100
100
20
93
92

No
No
Yes
No
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes

Prognosis§
after intraperitoneal
chemotherapy
9 mo, dead
9 mo, dead22 mo, dead
4 mo, dead14 mo, dead
9 mo, dead
6 mo, dead12 mo, dead28 mo, dead
5 mo, dead
5 mo, dead14 mo, alive
8 mo, alive

CY, cytological free cancerous cells; F, female; M, male; mo, months; P, peritoneal metastasis.
† Percentage of the reduced number of cancerous cells after intraperitoneal chemotherapy was calculated as follows:(a – b)/a × 100%; a, number of cancerous cells before intraperitoneal chemotherapy; b, number of cancerous cells after intraperitoneal chemotherapy.
§ dead, died of disease: alive, alive with disease.

67

M. Ikeguchi et al.

be detected in peritoneal wash samples by realtime RT-PCR from 4 patients after chemotherapy.
We grouped the 8 patients into the “intraperitoneal
chemotherapy effective group”. In the remaining
5 patients, the percentages of reduced numbers ofcancerous cells after chemotherapy were less than
90% (Table 1). We named these patients as the“intraperitoneal chemotherapy ineffective group”.
In these patients, cancer cells may have resistanceto cisplatin chemotherapy. The 50% survival
period of the intraperitoneal chemotherapy effective group was longer (9 months) than that of theintraperitoneal chemotherapy ineffective group (6months), but the difference was not signiﬁcant (P= 0.342, Fig. 5) with a log rank test based on the
Kaplan-Meier method.

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Fig. 5. Survival periods of 13 scirrhous gastric cancer
patients treated with our new treatment protocol.

Our treatment protocol for patients withscirrhous gastric cancer

Pleural effusion/ascites

Care

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Patients withscirrhous gastric cancer

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Our treatment protocol for patients with scirrhous gastric cancer is summarized in Fig. 6. In
the present study, the observation period was too
short to estimate survival benefits of cisplatinbased intraperitoneal chemotherapy for patientswith scirrhous gastric cancer. Therefore, continuous follow-up is required.

–Detection of distant metastasis,
extended lymph node metastasis orextended invasion to other organs
by computed tomography+–

Systemicchemotherapy

Laparoscopy

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Fig. 6. Our treatment protocol for patients with scirrhous gastric cancer from 2002.

68

Treatment for scirrhous gastric cancer

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Received February 13, 2006; accepted April 4, 2006
Corresponding author: Masahide Ikeguchi, MD

69