Gastric leptomeningeal carcinomatosis: Multi-center
retrospective analysis of 54 cases
Sung Yong Oh, Su-Jin Lee, Jeeyun Lee, Suee Lee, Sung-Hyun Kim, Hyuk-Chan Kwon, Gyeong-Won Lee,
Jung Hun Kang, In Gyu Hwang, Joung-Soon Jang, Ho Yeong Lim, Young Suk Park, Won Ki Kang, Hyo-Jin Kim
Sung Yong Oh, Suee Lee, Sung-Hyun Kim, Hyuk-Chan
Kwon, Hyo-Jin Kim, Department of Internal Medicine and
Medical Research Center for Cancer Molecular Therapy,
Dong-A University College of Medicine, Busan 602-715,
Su-Jin Lee, Jeeyun Lee, Ho Yeong Lim, Young Suk Park,
Won Ki Kang, Division of Hematology/Oncology, Department
of Medicine, Samsung Medical Center, Seoul 135-710,
Gyeong-Won Lee, Jung Hun Kang, Department of Internal
Medicine, Gyeongsang National University School of Medicine,
Jinju 660-702, South Korea
In Gyu Hwang, Joung-Soon Jang, Department of Internal
Medicine, College of Medicine, Chung-Ang University, Seoul
140-757, South Korea
Author contributions: Oh SY and Lee SJ carried out data
analysis and wrote the manuscript; Kim SH, Kwon HC, Lee S,
Lee GW, Hwang IG and Lim HY participated in data collection
and drafted the manuscript; Lee J, Kang JH, Jang JS and Park
YS carried out data collection and interpretation; Kang WK
and Kim HJ designed the study protocol and participated in
reviewing the manuscript.
Supported by The Dong-A University Research Fund and the
Korea Science and Engineering Foundation (KOSEF) grant funded
by the Korea government (MEST; R13-2002-044-05001-0)
Correspondence to: Hyo-Jin Kim, MD, PhD, Department of
Internal Medicine, Dong-A University College of Medicine, 3-1
Dongdaeshin-dong, Seo-gu, Busan 602-715,
South Korea. email@example.com
Telephone: +82-51-2402951 Fax: +82-51-2465044
Received: July 13, 2009 Revised: September 18, 2009
Accepted: September 25, 2009
Published online: October 28, 2009
AIM: To identify the clinical features and outcomes of
infrequently reported leptomeningeal carcinomatosis
(LMC) of gastric cancer.
METHODS: We analyzed 54 cases of cytologically con-
firmed gastric LMC at four institutions from 1994 to 2007.
RESULTS: The male-to-female ratio was 32:22, and
the patients ranged in age from 28 to 78 years (median,
48.5 years). The majority of patients had advanced
disease at initial diagnosis of gastric cancer. The clini-
cal or pathologic tumor, node and metastasis stage of
the primary gastric cancer was Ⅳ in 38 patients (70%).
The median interval from diagnosis of the primary
malignancy to the diagnosis of LMC was 6.3 mo, rang-
ing between 0 and 73.1 mo. Of the initial endoscopic
findings for the 45 available patients, 23 (51%) of the
patients were Bormann type Ⅲ and 15 (33%) patients
were Bormann type Ⅳ. Pathologically, 94% of cases
proved to be poorly differentiated adenocarcinomas.
Signet ring cell component was also observed in 40%
of patients. Headache (85%) and nausea/vomiting
(58%) were the most common presenting symptoms
of LMC. A gadolinium-enhanced magnetic resonance
imaging was conducted in 51 patients. Leptomeningeal
enhancement was noted in 45 cases (82%). Intrathecal
(IT) chemotherapy was administered to 36 patients-
primarily methotrexate alone (61%), but also in combi-
nation with hydrocortisone/± Ara-C (39%). The median
number of IT treatments was 7 (range, 1-18). Con-
comitant radiotherapy was administered to 18 patients,
and concomitant chemotherapy to seven patients. Sev-
enteen patients (46%) achieved cytological negative
conversion. Median overall survival duration from the
diagnosis of LMC was 6.7 wk (95% CI: 4.3-9.1 wk). In
the univariate analysis of survival duration, hemoglobin,
IT chemotherapy, and cytological negative conver-
sion showed superior survival duration (P = 0.038, P
= 0.010, and P = 0.002, respectively). However, in our
multivariate analysis, only cytological negative conver-
sion was predictive of relatively longer survival duration
(3.6, 6.7 and 14.6 wk, P = 0.030, RR: 0.415, 95% CI:
CONCLUSION: Although these patients had a fatal
clinical course, cytologic negative conversion by IT
chemotherapy may improve survival.
© 2009 The WJG Press and Baishideng. All rights reserved.
Key words: Carcinomatosis; Gastric cancer; Intrathecal
Peer reviewers: Gerardo Rosati, MD, Medical Oncology
Unit, “S. Carlo” Hospita, Via Potito Petrone, 1, Potenza 85100,
Italy; Cuneyt Kayaalp, MD, Professor, Department of General
Surgery, Turgut Ozal Medical Center, Inonu University,
Malatya 44315, Turkey
Oh SY, Lee SJ, Lee J, Lee S, Kim SH, Kwon HC, Lee GW,
Kang JH, Hwang IG, Jang JS, Lim HY, Park YS, Kang WK,
Kim HJ. Gastric leptomeningeal carcinomatosis: Multi-center
retrospective analysis of 54 cases. World J Gastroenterol 2009;
Online Submissions: wjg.wjgnet.com
firstname.lastname@example.org World Journal of Gastroenterology ISSN 1007-9327
doi:10.3748/wjg.15.5086 © 2009 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol 2009 October 28; 15(40): 5086-5090
Oh SY et al. Leptomeningeal carcinomatosis of gastric cancer 5087
15(40): 5086-5090 Available from: URL: http://www.wjgnet.
com/1007-9327/15/5086.asp DOI: http://dx.doi.org/10.3748/
Leptomeningeal carcinomatosis (LMC) is defined
as malignant infiltration of the pia mater and the
arachnoid membrane. LMC is one of the most serious
complications that can occur in cancer patients.
According to the results of a large autopsy study, the
incidence of LMC was 5%-8% in cancer patients.
As a significant proportion of these patients have
asymptomatic microscopic disease, the clinical diagnosis
of LMC has been established in 2%-4% of patients
during the course of their malignancy. LMC is
frequently detected in patients with leukemia, breast
cancer, lymphoma, and lung cancer. Among solid
tumors, LMC is observed more frequently in cases
of disseminated and progressive disease. Although a
subset of patients, particularly those with lymphoma or
breast cancer, may survive for more than 12 mo with a
reasonable quality of life, leptomeningeal metastasis from
solid tumors is associated with a poor overall prognosis.
The treatment of LMC is palliative and unsatisfactory.
No evidence demonstrating the superiority of intrathecal
(IT) treatment compared to best palliative care is
currently available from clinical trials.
Furthermore, the development of LMC from a gas-
tric cancer is a very rare occurrence. Some articles have
reported that the incidence of LMC in patients with
gastric cancer was responsible for 0.16% of all cases of
gastric cancer. Due to its rarity, the clinical features and
prognostic factors of LMC as a metastasis from gastric
carcinoma have yet to be clearly characterized. The ben-
efits of IT chemotherapy are also currently a matter of
Gastric cancer is the most common malignancy in
Korea. Because of the high prevalence of gastric cancer
in Korea, we took the opportunity to study gastric cancer
patients with LMC. The principal objective of this study
was to review our experience with LMC associated with
gastric cancer, and to evaluate its clinical features and the
efficacy of a variety of treatment modalities in terms of
neurological status and overall survival (OS).
MATERIALS AND METHODS
From 1995 to 2007, 22 154 patients were diagnosed
with gastric cancer at four independent institutions.
Among them, 54 patients who were diagnosed with
leptomeningeal seeding metastasis of gastric cancer were
analyzed. Although it is not representative of the cohort
of patients, the prevalence of LMC was 0.24%.
Eligibility for this study included: (1) patients
with histologically confirmed adenocarcinoma of
the stomach; (2) cytologically confirmed malignancy
on cerebrospinal fluid (CSF) analysis, patients with
suspected LMC by magnetic resonance imaging (MRI)
and negative cytology were excluded; (3) no history of
any other malignancies.
We retrospectively analyzed the patients’ medical
records including the patients’ characteristics, clinical
symptoms, laboratory and radiologic findings, treatment
modality and outcomes, final follow-up, and survival
Comparisons of categorical variables among groups
were conducted using the chi-square test and Fisher’s
exact test. OS was calculated from the cytological con-
firmation of LMC and plotted via the Kaplan-Meier
method. Comparison of survival according to prognos-
tic factors was evaluated via a log-rank test, and forward
stepwise Cox proportional hazard models were em-
ployed to evaluate the joint effect of predictive variables.
P < 0.05 was considered significant. Analysis of the data
was conducted using SPSS for Windows V. 15.0 (SPSS
Inc., Chicago, IL, USA) statistical software.
We analyzed 54 cases of cytologically confirmed gastric
LMC at four institutions from 1994 to 2007. The clini-
cal characteristics of these patients are summarized in
Table 1. The male-to-female ratio was 32:22, and patients
ranged in age from 28 to 78 years (median, 48.5 years). The
majority of patients had advanced disease at initial diag-
nosis of gastric cancer. The clinical or pathologic tumor,
node and metastasis stage of the primary gastric cancer
was Ⅳ in 47 patients (87%). Stage Ⅰ-Ⅲ patients received
curative operation. Among the stage Ⅳ patients, 13 pa-
tients had T4N1-2 or N3 (No. of nodes > 15) by patho-
logic features through curative operation. M1 node posi-
tive patients were counted as palliative surgery. Of the
initial endoscopic findings in the available 45 patients,
Bormann type Ⅲ and Ⅳ were reported for 23 (51%)
and 15 (33%) patients, respectively. Pathologically, 94%
of cases proved to be poorly differentiated adenocarci-
nomas. Signet ring cell component was also observed in
40% of patients.
The median interval from diagnosis of the primary
gastric cancer to the diagnosis of LMC was 6.3 mo,
ranging from 0 to 73.1 mo. Five patients presented with
initial LMC. The majority of patients (59.3%) initially
presented with metastatic gastric cancer without LMC,
and then progressed to LMC. One-third of the patients
presented with curable disease at the initial diagnosis of
gastric cancer (Table 2).
The most frequently observed presenting symptoms
of LMC were nonspecific symptoms such as headache
(85%) and nausea/vomiting (58%). In addition, various
neurological clinical signs and symptoms were noted
including altered mental status, seizure, motor weakness,
sensory change, diplopia, hearing loss, and facial palsy
CSF analysis and image findings
Lumbar puncture and analysis of CSF is a crucial
laboratory test in the diagnosis of LMC. All the patients
presented with malignant cells on cytological analysis via
the inclusion criteria. An elevated opening pressure on
lumbar puncture was noted in 58% of the subjects. The
mean CSF pressure in the patients was 222.1 mm CSF.
78.8% and 53.8% of patients had elevated white blood
cells and protein in CSF, respectively (Table 4).
Brain computed tomography was assessed in eight
patients and leptomeningeal enhancement was observed
only in one patient. A gadolinium-enhanced MRI was
conducted in 51 patients. Leptomeningeal enhancement
was noted in 45 cases (82%).
Treatment modalities and outcomes
IT chemotherapy was administered to 36 patients,
principally with methotrexate (MTx) alone (61%) or in
combination with hydrocortisone/± Ara-C (41%). The
median number of IT treatments was 7 (range, 1-18).
Seventeen patients (46%) achieved cytological negative
conversion (Table 5).
Thirteen patients were treated with whole brain ir-
radiation coupled with IT chemotherapy. Six patients
received radiation treatment alone.
Additional systemic chemotherapy was given to 10
patients. Three patients were treated with the orally
available 5-fluorouracil (5-FU) drugs - capecitabine, S-1,
and tegafur-uracil. Irinotecan/leucovorin/5-FU, 5-FU/
cisplatin, and paclitaxel/cisplatin were administered to
four, two and one patients, respectively. Seven patients
were treated with chemotherapy plus IT chemotherapy.
Three patients received chemotherapy alone. The me-
dian number of cycles administered was 2 (range, 1-6).
Among the treated patients, only one exhibited a detect-
able response to treatment.
Survival and prognostic factors
Median OS duration from diagnosis of LMC was 6.7 wk
(95% CI: 4.3-9.1 wk) (Figure 1). In the univariate analy-
sis of survival duration, hemoglobin, IT chemotherapy,
and cytologic negative conversion showed superior
Table 1 Patients’ characteristics (n = 54)
No. of patients
≥ 60/< 60
Initial endoscopic finding (n = 47)
Diffuse whole stomach
Borrmann type (n = 45)
Early gastric cancer
Ⅳ (diffuse infiltrative)
Differentiation (n = 47)
Poor with signet ring cell
32 (59.3)/22 (40.7)
15 (27.8)/39 (72.2)
Table 2 Patterns of leptomeningeal carcinomatosis (n = 54)
Time to LMC (mo)
LMC: Leptomeningeal carcinomatosis.
Table 3 Symptoms of leptomeningeal carcinomatosis (n = 54)
Nausea & vomiting
Table 4 CSF finding of leptomeningeal carcinomatosis
Pressure (mm CSF)
No. of > WNL1
mean ± SD
222.1 ± 158.4
36.7 ± 59.0
129.5 ± 250.8
1CSF pressure > 160 mm; CSF protein > 50 mg/dL; Cell count > 5/mm3.
CSF: Cerebrospinal fluid; WNL: Within normal limit; WBC: White blood cell.
5088 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol October 28, 2009 Volume 15 Number 40
survival duration (P = 0.038, P = 0.010, and P = 0.002,
respectively). However, in the multivariate analysis, only
cytologic negative conversion was predictive of relatively
longer survival duration (3.6, 6.7 and 14.6 wk, P = 0.030,
RR: 0.415, 95% CI: 0.188-0.918) (Table 6, Figure 2).
Adenocarcinoma is the predominant histological type in
LMC of solid tumors. Among patients diagnosed with
LMC, the most frequently encountered solid tumors
are breast (12%-34%), lung (14%-29%), and melanoma
(17%-25%). Unlike Western reports, gastric cancer is
the principal etiology of LMC in solid tumors in Korea.
CNS metastasis is a very rare complication of
gastric cancer, and occurs in 0.16%-0.69% of gastric
cancer patients in general, including Korean reports[4,8,9].
Although all the included patients demonstrated CSF
cytologically confirmed malignancy, the prevalence
of LMC in this study was 0.24% in all gastric cancer
Consistent with other studies, the majority of patients
had Bormann type Ⅲ or Ⅳ advanced gastric cancer of
poorly differentiated or signet-ring cell histopathology,
which increased the tendency for distant metastasis and
poor prognosis[4,10,11]. Similar to the results of a previous
study, LMC patients presented with an advanced stage
and Bormann type Ⅲ or Ⅳ advanced gastric cancer of
poorly differentiated or signet-ring cell histopathology.
LMC is an ultimately fatal disease[12-15]. A minority of
patients, usually those with breast cancer or lymphoid
malignancies, may achieve disease-free survival of a year
or more, however, the median OS for patients with LMC
is only 4-6 wk if untreated and 2-4 mo with therapy[6,12,15].
In our study, the median survival duration was just
Table 5 Treatment with intrathecal chemotherapy (n = 36)
MTx + steroid
MTx + Ara-C + steroid
No. of cycles
MTx: Methotrexate; Ara-C: Cytarabine.
Table 6 Survival duration and prognostic factors
Median OS (mo)Univariate Multivariate
(HR: 0.415, 95%
OS: Overall survival; PS (LMC): Performance status scale by Eastern
Cooperative Oncology Group at leptomeningeal carcinomatosis; Hb
(LMC): Hemoglobin at leptomeningeal carcinomatosis; MRI: Magnetic
resonance imaging; CSF: Cerebrospinal fluid; IT: Intrathecal; HR: Hazard
ration; CI: Confidence interval.
0 5 10 15 20 25 30 35 40 45 50
Overall survival (wk)
Figure 1 Median overall survival (OS) duration from diagnosis of
leptomeningeal carcinomatosis. Median OS was 6.7 wk (95% CI: 4.3-9.1 wk).
0 5 10 15 20 25 30 35 40 45 50
Overall survival (wk)
Figure 2 Cytologically negative conversion proved predictive of relatively
longer survival duration (P = 0.030, RR: 0.415, 95% CI: 0.188-0.918).
IT chemo (+)
14.6 wk (95 CI: 10.6-18.6)
IT chemo (+)
6.7 wk (95 CI: 5.1-8.3)
IT chemo (-)
3.6 wk (95 CI: 0-7.2)
Oh SY et al. Leptomeningeal carcinomatosis of gastric cancer 5089
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6.7 wk. Although LMC patients tend to have a poor
performance status, approximately two-thirds of patients
who receive IT chemotherapy and 47.2% patients who
responded to therapy achieved longer survival duration.
The independent prognostic factor for survival was
cytologic negative conversion by IT chemotherapy.
Although the small sample size and inherent selection
bias of the retrospective design of this study makes
any conclusions regarding the outcomes of treatment
somewhat difficult, the findings of our study indicate
that cytologic negative conversion by IT chemotherapy
may improve survival by arresting neurologic progression
in selected patients.
MTx remains the most frequently utilized drug for
IT administration, despite its limited success and serious
complications[16,17]. Combination IT chemotherapy with
MTx, arabinoside and hydrocortisone has been reported
to be more effective than MTx alone in solid tumor
LMC. However, approximately 10% of gastric cancer
patients were enrolled in this study, and the efficacy of
arabinoside against gastric cancer is questionable.
Craniospinal irradiation may be a one-treatment
modality. However, the additional or sequential role
of radiation has been controversial. In our study,
additional effects of radiotherapy were not observed. As
response to radiation is associated with the sensitivity
or resistance of primary tumors and malignant cells
circulating in the CSF space, radiation is occasionally not
feasible for palliative treatment.
Systemic chemotherapy was also administered to a
limited number of patients who had better performance
status[6,15,20]. In our study, patients who were treated with
systemic chemotherapy showed the best median OS
duration (21.6 wk, 95% CI: 3.2-40 wk). However, all the
treatments were administered sequentially after IT che-
motherapy and the patients responded to treatment.
Leptomeningeal carcinomatosis (LMC) occurs in approximately 5% of cancer
patients. The most common cancers involving the leptomeninges are breast
and lung cancer. However, gastric adenocarcinoma has been infrequently
reported in conjunction with LMC. This retrospective analysis was performed
to identify the clinical features and outcomes of infrequently reported LMC of
This is the first large scale study on gastric LMC. LMC is a rare component in the
clinical manifestation of gastric cancer. LMC usually presents at a relatively young
age, at an advanced stage, and is of a poorly differentiated pathologic type.
Innovations and breakthroughs
Although gastric LMC had a fatal clinical course, the findings of our study
suggest that cytologic negative conversion by intrathecal (IT) chemotherapy
may improve survival by arresting neurologic progression in selected patients.
These results could provide basic clinical data on gastric LMC for physicians
and demonstrate the role of IT chemotherapy.
Leptomeninges (literally thin meninges) is a term referring to the pia mater and
arachnoid mater. LMC is a condition in which a tumor diffusely spreads to the
leptomeninges. Intrathecal chemotherapy involves anticancer drugs injected
into the fluid-filled space between the thin layers of tissue that cover the brain
and spinal cord.
The results are interesting and suggest that cytologic negative conversion by
IT chemotherapy may improve survival by arresting neurologic progression in
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