Case report

Signet-ring cell gastric carcinoma with unusual

metastasis: case report and literature review.
Tiberiu Moldovan1, *, Călin Căinap1,2, *, Emil Pușcaș1,2, Andrei Roman1,3, Rareș Buiga1,4, Diana
Olteanu1, Mădălina Bota5, Simona Căinap5, Ovidiu Bochiș1
1 Oncology Institute “Prof. Dr. Ion Chiricuță”, Cluj-Napoca, Romania
2 Oncology Department, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
3 Medical Radiology Department, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca,

Romania
4 Pathology Department, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania

5 Mother and Child Department, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca,

Romania
* Correspondence: tibi_moldovan2002@yahoo.com, calincainap2015@gmail.com; Tel.: +40730520765 (T. M.).

Abstract: Gastric cancer is the 5th most common malignancy worldwide. Signet-ring cell histology
represents an aggressive subtype of gastric cancer, presenting at a younger age. Both breast and
leptomeningeal metastases are rare locations of tumor dissemination, requiring correct and
immediate diagnosis and treatment. We present a case of a 45-year old female with signet-ring cell
gastric carcinoma who developed both left breast and leptomeningeal metastasis, requiring
multiple chemotherapy lines. As far as we know, this is the first published case in the English
literature of following multiple lines of treatment for both breast and leptomeningeal metastases
from signet-ring cell gastric carcinoma.

Keywords: gastric cancer, breast metastasis, leptomeningeal carcinomatosis.

1. Introduction
In 2018, gastric cancer was the 5th most common malignancy worldwide [1], and the 8th most
common in Europe [2]. In recent years, despite a decrease in the incidence of gastric cancer,
signet-ring cell subtype is steadily increasing, accounting for 35 – 45% of all gastric cancers [3].
Breast metastases from extramammary neoplasms are very uncommon, representing 0.5 – 2%
of all mammary malignancies [4]. Malignant melanoma, lymphoma and lung cancer are the most
frequent origins of breast metastases [5]. In total, we found 39 published cases in the English
literature of breast metastases from gastric cancer. Biopsies and immunohistochemical staining are
essential for the correct diagnosis [4]. There is currently no standard treatment sequencing for gastric
cancer metastasized to the breast.
Leptomeningeal carcinomatosis is an extremely rare and ultimately fatal metastatic location in
gastric cancer, accounting for 0.16 – 0.69% of patients [6]. In total, we found 87 published cases in
English literature of leptomeningeal carcinomatosis from gastric cancer. Positive diagnosis can only
be established by detecting malignant cells in the cerebrospinal fluid [7]. In this situation, there are
currently no established guidelines.
This pattern of metastasis (breast and leptomeningeal carcinomatosis) is extremely rarely
reported. So far, a single case of breast metastasis and leptomeningeal carcinomatosis from gastric
adenocarcinoma has been reported.
2. Case presentation
A 45-year old female, without any prior medical history, was admitted in our clinic in February
2018 after a modified Pap test during a routine health screening.
At the same time, the patient underwent a yearly breast cancer screening with mammography
and breast ultrasonography. Although a high density of the left breast was detected during the
mammography, a mass or calcification was not observed. Ultrasonography showed diffuse
inflammatory changes, skin thickening, with a recommendation to repeat the procedure after the
remission of the inflammatory process.
On examination, the patient was afebrile, had normal blood pressure with no symptoms.
Physical examination revealed diffuse left breast induration with uneven surface, without any
palpable mass.
A 120/147/115 mm right ovarian mass and a smaller (40/42 mm) left ovarian mass were detected
during a CT scan. Also, inflammatory changes in the left breast were observed (Fig. 1.). An ovarian
cancer suspicion was raised and total hysterectomy with bilateral oophorectomy was planned (May
2018). During the surgical intervention, an unresectable gastro-pancreatic mass was detected, as well
as peritoneal carcinomatosis.

Fig. 1. Inflammatory left breast changes detected on CT scan (indicated by the white arrow).

The histopathological examination showed diffuse ovarian infiltration of a poorly differentiated

signet-ring cell carcinoma (Krukenberg tumor), most probably of gastric origin.
Immunohistochemical analysis showed positive staining for CK7, EMA, CEA and negative for
estrogen and progesterone receptors and WT1 (Fig. 2.A. and B.)
Because pathologic examinations of the resected pelvic tumor revealed signet-ring cells which
suggested that the tumor had metastasized from another site and the gastro-pancreatic mass
detected during surgery, upper gastrointestinal endoscopy was performed to identify the primary
site. A circumferential cardia tumor was detected and biopsies were taken, revealing the same
histology as before.
A repeat pretherapeutic CT scan was performed (April 2018), which detected the cardia tumor
and in addition peritoneal carcinomatosis and multiple bone metastases.
Based on these findings, we established a diagnostic of a gastric signet-ring cell carcinoma with
peritoneal carcinomatosis, metastasized to the ovaries and bones and first metastatic line of
chemotherapy with EOX (epirubicin 50 mg/m2, oxaliplatin 130 mg/m2 and capecitabine 1250 mg/m2
q21d) in association with zoledronic acid (Zometa) was started (May 2018).
After 6 cycles of chemotherapy (September 2018), a CT scan was performed, showing stable
disease with persistent inflammatory breast changes. Epirubicin was stopped, and patient continued
receiving CapeOx protocol.
In November 2018, the left breast inflammation progressed (worsening edema and rash, skin
thickening, without any ulcers or pathologic discharge). A biopsy was taken, and the
histopathological examination (December 2018) showed signet-ring cell infiltration (Fig. 2.C., D., E.).
Based on these findings we diagnosed the breast lesions as metastases from the gastric carcinoma.

A. Signet-ring cells in ovaries B. Positive CK7 staining on IHC

C. Signet-ring cells in breast biopsy D. Negative estrogen receptors on IHC

E. Positive CK staining on IHC F. Signet-ring cells in cerebrospinal fluid

Fig. 2. Histological examinations of ovaries (A., B.), breast (C., D., E.) and cerebrospinal fluid
(F.).

In December 2018, a repeat CT scan was performed, showing stable gastric, bone lesions and
stable breast inflammation. Left pleurisy with left pulmonary atelectasis was detected, and the
cytological analysis also showed signet-ring cell infiltration.
 A diagnostic of progressive disease was made and second metastatic line of chemotherapy with
paclitaxel 80 mg/m2 q7d in association with ramucirumab 8 mg/kg q14d was started (December
2018).
During the second cycle of paclitaxel (January 2019), the patient presented facial rash,
restlessness, respiratory difficulties, symptoms which worsened and anaphylactic shock set in
(perioral edema and cyanosis, maxillary incrustation). Following standard treatment, symptoms
resolved, but the paclitaxel administration was permanently discontinued.
During the same hospitalization, the patient presented grade 3 anemia, which required blood
transfusions. A gastroscopy was performed, showing an increased friability of the gastric tumor and
cauterization was conducted. Ramucirumab treatment was continued for another cycle, but the
increased vascular friability persisted and inferior digestive bleeding occurred, so it was decided to
stop the administration of ramucirumab.
Third metastatic line with irinotecan 180 mg/m2, q14d was started in February 2019.
In April 2019, the patient presented with persistent headaches and diplopia. A cerebral CT scan
was performed, without any sign of focal lesions. A neurological exam and cerebral MRI with
gadolinium enhancement were conducted, again without any pathologic lesions. An
ophthalmological exam determined stasis and papillary edema in both eyes. Irinotecan
monotherapy was continued for another month, with worsening of the neurological symptoms.
Additionally, several newly appeared skin lesions in the xiphoid processus were detected in
May 2019, which were interpreted as “in transit” cutaneous metastases from the signet-ring cell
gastric carcinoma.
Due to the worsening of the neurological symptoms, a spinal tap was performed. The
cerebrospinal fluid (CSF) had normal pressure and appearance. Protein, glucose and chloride levels
were also normal, while the LDH level was elevated (21 IU/L), raising the suspicion of a
cerebrospinal dissemination. CSF cytology revealed 4 nucleated cells/mm 3 with signet-ring aspect,
confirming the diagnosis of leptomeningeal carcinomatosis (Fig. 2.F.).
Intrathecal methotrexate (total dose of 12 mg, q2d) and fourth line of metastatic chemotherapy
with docetaxel (60 mg/m2, q21d) were started (May 2019), with a visible improvement of
neurological symptoms (amelioration of headaches and normalization of sight) occurring after 6
administration of methotrexate every 2 days. The CSF cytology remained positive for signet-ring
cells, their number varying between 1 and 5 after repeated spinal taps.
We decided to continue the administration of methotrexate thereafter on a weekly basis.
One week after the first administration of docetaxel, the patient presented with grade 4 oral
mucositis, with an approximately 3 kg weight loss due to the impossibility of feeding. Blood tests
revealed grade 4 neutropenia. Granulocyte colony stimulating factor (G-CSF) treatment was started,
with a partial remission of the mucositis and a total remission of the neutropenia.
The administration of weekly intrathecal methotrexate and intravenous docetaxel was
continued, with prophylactic G-CSF administrations, without any recurrence of a severe
neutropenia or oral mucositis.
In July 2019, the patient presented with “orange peel” aspect of the left breast, without pain.
Patient underwent left breast radiotherapy for a total dose of 30 Gray in 10 fractions divided in 14
days.
We conducted a control CT scan in which we observed stable gastric tumor, bone lesions and
peritoneal nodules. Brain imaging was normal, and we continued biweekly intrathecal metothrexate
administration at a dose of 12 mg associated with docetaxel 60 mg/m2 q3w.
Currently, the patient has a survival of 17 months from the diagnosis of stage IV signet-ring cell
gastric carcinoma, 10 months from the diagnosis of left breast metastasis from signet-ring cell gastric
carcinoma and 5 months from the diagnosis of leptomeningeal carcinomatosis from signet-ring cell
gastric carcinoma, with a good performance status despite the polymetastatic context and the use of
multiple lines of metastatic chemotherapy. Repeated cerebrospinal fluid cytology was performed
and for the last 3 cycles of intrathecal methotrexate it was negative for malignant cells. She is
currently at her DE VERIFICATth cycle of weekly intrathecal methotrexate (15 administrations in
total) and 5th cycle of intravenous docetaxel.

3. Discussion
In 2018, gastric cancer was the 5th most common type of cancer worldwide, with 1,033,701 new
cases. In the same year, gastric cancer had the 3rd highest mortality with 782,685 deaths [1]. In 2018
in Europe, gastric cancer’s incidence was lower– 8th most common type of cancer, and with the 6th
highest mortality [2].
In recent decades, despite a decrease in the overall incidence of gastric cancer, signet-ring cell
gastric carcinoma (SRCC) has a constantly increasing incidence, in both Europe and Asia, accounting
for 35% to 45% in recent studies [3]. This increase in the proportion of signet-ring cell histology can
be explained by changes in histopathological classifications.
According to the WHO classification [8], SRCC is defined as “a poorly cohesive carcinoma
composed predominantly of tumor cells with prominent cytoplasmic mucin and a crescent-shaped
nucleus eccentrically placed”.
SRCC has been shown to have a better or at least equal prognostic compared to gastric
adenocarcinomas in early gastric cancer [9, 10]. By comparison, in advanced gastric cancer, the
prognostic is commonly thought to be poor. A retrospective study of more than 3500 advanced
SRCC patients demonstrated a significant worse 5-year survival rate compared to non-SRCC [11].
Other smaller studies failed to indicate a worse survival for SRCC [12, 13]. The only drawback is that
most of the studies on this subject are based on Asian patients.
SRCC usually occurs in younger patients, with a mean age of onset between 55 and 61 years,
approximately 7 years before the onset of non-SRCC. In our case, the patient’s age of diagnosis was
45. SRCC is located more frequent in the middle stomach and associated with more advanced cancer
(stage IV, T3/T4 tumors with N2) [14]. In our case, the primary tumor was located near the cardia,
with a clinical stage IV, with peritoneal carcinomatosis, Krukenberg tumors and bone metastases.
In advanced SRCC, the most frequent metastatic site is the peritoneum [15], as was the case of
our patient. Riihimäki et al. [16] evaluated the metastatic spread of 7559 gastric cancer patients from
the Swedish national registries. Cardia cancer, like our patient had, has a completely different
metastatic pattern than non-cardia cancer, metastasizing more frequently to the lungs, bone and
nervous system. Signet-ring cell carcinoma metastasize almost twice as often within the peritoneum,
and also to the bone. Our patient presented with both peritoneal and bone metastases.
The breast is an uncommon site of metastasis from an extramammary neoplasm, representing
0.5 – 2% of all mammary malignancies [4]. The most frequent origins of breast metastasis are
malignant melanoma, lymphoma, lung cancer, followed by ovarian carcinoma, soft tissue sarcoma,
gastrointestinal and genitourinary tumors [5, 17].
We conducted a search on PubMed in order to identify published cases of breast metastases
from gastric cancer written in English. In total, we found 39 cases. [18-52] (Table 1).
Median age of diagnosis among these cases was 43.47 years, which is slightly lower than
previous reported values (46 years, Iesato A. et al [48]). Our patient was diagnosed at 45 years, which
confirms the younger age of occurrence for breast metastasis from gastric carcinoma. Approximately
54% of the patients had left breast metastasis, as was our case. Lee et al. [4] reported that either a
lymphatic pathway or invasion of the breast via the left supraclavicular lymph node might cause
this laterality.
It has been speculated [38] that the increased incidence of breast metastases from gastric cancer
in premenopausal women might be caused by an increased breast blood supply and other hormonal
factors linked to adhesion and growth of carcinoma cells. Vergier et al. [53] hypothesized that
estrogen may play a role in promoting extra-mammary tumorigenesis. Thirteen of the 39 patients
had Krukenberg tumors and 21 of the 39 patients had lymph node metastases, further highlighting
the concepts of lymphatic pathway breast invasion and favorable hormonal factors.
Matsuyama et al. [55] demonstrated that estrogen receptor β (which can mediate the effects of
estrogen, specifically in signet-ring cell adenocarcinoma) is found in stomach adenocarcinoma.
Author Year published Age Histology Localization Clinical presentation Other metastases Time to breast metastasis Prognosis
18
Dawson E.K. 1936 25 Sig Bilateral None Krukenberg tumor, pancreas, lymph nodes Concurrent Not specified
19
Abrams H.L. et al 1950 Ns Ns Not specified Not specified Not specified Not specified Not specified
20
Sandison A. T. 1959 56 Sig Left Nodule None 3 months before 3 months, died
21
Nance F. C. et al 1966 59 Lin Bilateral Mastitis Lymph nodes 4 months 6 months, died
22
Hajdu S. I. et al 1972 Ns ADK Left Not specified Not specified Not specified Not specified
23
Schmutzer K. J. et al 1973 22 PDA Left Nodule Krukenberg tumor, lymph nodes, peritoneum, pleura 22 months 2 months, died
24
Silverman E. M. et al 1974 Ns Muc Not specified Not specified Not specified Concurrent Not specified
25
Nielsen M. et al 1981 59 Muc Left Mastitis Lymph nodes, urinary bladder, brain Concurrent 0.1 months, died
26
Tsuchiya S. et al 1988 48 Sig Bilateral Nodule Lung 24 months 8 months, died
27
Alexander H. R. et al 1989 28 Muc Bilateral Nodule None 5 months 18 months
28
Hamby L. S. et al 1991 31 Sig Right Nodule Krukenberg tumor Concurrent 2 months, died
29
Cavazzini G. et al 1993 50 Sig Left Mastitis Ascites, pleura, lymph nodes 10 months 0.75 months, died
30
Doi C. et al 1996 57 Sig Left Mastitis Lung, lymph nodes Concurrent 3 months, died
31
Domanski H. A. 1996 48 Sig Left Nodule Lymph nodes Concurrent Not specified
32
de la Cruz M. et al 1998 61 Sig Left Nodule Pleura Not specified Not specified
33
Briest S. et al 1999 46 Sig Bilateral Nodule Lymph nodes 2 months Not specified
34
Kwak J.Y. et al 2000 41 Sig Left Mastitis Krukenberg tumor, lymph nodes Concurrent Not specified
23 Sig Right Mastitis Lymph nodes Concurrent Not specified
35
Madan A. K. et al 2002 39 Sig Right Nodule Krukenberg tumor, peritoneum 3 months Not specified
36
Di Cosimo S. et al 2003 39 Sig Bilateral Nodule Krukenberg tumor, skin Concurrent Not specified
37
Qureshi S. S. et al 2005 34 Sig Left Nodule None Concurrent 6 months, died
38
Boutis A. L. et al 2006 37 Sig Left Mastitis Krukenberg tumor Concurrent 6 months, died
39
Gugić D. et al 2007 43 Sig Right Nodule Lymph nodes 60 months 22 months, died
40
Sato T. et al 2008 67 Sig Left Mastitis Lymph nodes 5 months 4 months, died
41
Timuçin Ç. et al 2009 63 Sig Left Mastitis Lymph nodes, lung 12 months 4 months, died
65 Sig Left Nodule Krukenberg tumor, hepatic, lung 24 months 6 months, died
42
Doval D. C. et al 2009 34 Sig Bilateral Nodule Krukenberg tumor, lymph nodes, bone Concurrent Not specified
43
Parrell Soler C. et al 2011 37 Sig Left Nodule Krukenberg tumor, peritoneum 2 months 7 months, died
44
Luk Y. S. et al 2012 54 Sig Right Nodule Krukenberg tumor, bone, peritoneum Concurrent 11 months, died
45
Kim S. J. 2013 41 Sig Left Mastitis Lymph nodes Concurrent Not specified, died
46
Hebbar A. K. et al 2014 45 PDA Left Nodule None Concurrent Not specified
47
He C. L. et al 2015 48 Sig Right Nodule Lymph node 1 month 4 months
48
Iesato A. et al 2015 41 Sig Bilateral Mastitis Krukenberg tumor Concurrent 10 months, died
34 Sig Left Nodule Cervical polyp Concurrent 7 months
49
Tian Q. et al 2016 37 Sig Left Nodule Colon, lymph nodes 53 months 18 months, died
31 Sig Right Nodule Lymph nodes Concurrent 9 months, died
50
Wei L. Y. et al 2017 49 Sig Right Nodule Lymph nodes 24 months 10 months, died
Dulskas A. et al51 2017 34 Sig Left Nodule Lymph nodes Concurrent 12 months
52
Yan H. et al 2017 39 Sig Left Nodule Krukenberg tumor, lymph nodes 18 months 3 months, died

Table 1. Literature review of breast metastases from gastric cancer. Ns = Not specified; Sig = Signet-ring cell carcinoma; Lin = linitis plastica; ADK =
adenocarcinoma; PDA = poorly differentiated adenocarcinoma; Muc = mucinous differentiation..
 Infrequently breast metastases present as a increased firmness of the breast parenchyma,
associated with skin edema and erythema, mimicking inflammatory breast carcinoma [56].
About 28% of patients had inflammatory breast changes resembling mastitis like our patient.
Breast metastasis symptoms are unspecific in terms of breast nodules, swelling, tenderness and pain
compared with the symptoms of primary breast cancer [34], although Chang et al. [56] reported a
quadruple incidence of inflammatory changes in breast metastases from gastric cancer that in
primary breast cancer (which is about 1% - 5%).
In cases of breast inflammation or lumps, biopsy should be performed, even in the presence of
an extramammary neoplasm [38].
Mammary involvement may either be the first step in the metastatic process, or there may be a
polymetastatic context [57].
On mammography or ultrasonography, the absence of mass lesions or microcalcifications were
considered typical of metastatic disease in signet-ring cell gastric carcinoma by Kwak et al. [34].
Metastatic lesions may be well circumscribed masses, difficult to differentiate from benign solid
breast lesions. Due to the fact that there is barely any desmoplastic reaction present in metastatic
lesions, spicules are absent. In conclusion, the presence of spicules and microcalcifications on the
mammogram is linked to primary breast carcinoma, practically ruling out breast metastases from
other primary locations [34].
To establish a definitive diagnosis of breast metastasis, histologic similarities between the
primary and breast lesions need to exist. A periductal and/or perilobular distribution of malignant
cells and absence of an in situ lesions is highly indicative of a metastatic process from another site
[48].
In 80% of these cases signet-ring cell features were present, a type that accounts for
approximately 10% of all gastric cancers [58]. Our patient also had signet-ring cell gastric carcinoma,
confirming the increased incidence of breast metastases from this gastric cancer subtype.
Immunohistochemical (IHC) staining is essential for accurate diagnosis and specimens
obtained by core biopsy are more effective for differentiation [4]. There are only a few tumor
markers that are very specific for breast metastases from gastric cancer, although they have limited
sensitivity. Immunohistochemical staining in this cases is usually negative for ErbB-2, estrogen
receptors, progesterone receptors, GCDFP-15 and positive for CEA, CK7, CK20 [38, 40, 59]. In our
case, IHC staining was positive for CEA and CK7 and negative for estrogen and progesterone
receptors, helping guide our diagnostic.
Thirteen patients received any form of breast surgery (excisional biopsy, wide local resection,
mastectomy) but none had a favorable outcome, with primary disease progression and a median
survival of 9.72 months. It has been noted [35] that the usual treatment methods for primary breast
cancer (wide local resection, radiation, axillary node dissection) are inappropriate for the treatment
of metastatic gastrointestinal cancer to the breast.
A breast lumpectomy is currently the recommended treatment in case of nodular breast
metastases. Furthermore, previous evidence [49] has indicated that radiotherapy may not be
effective in the treatment of breast metastases. In order to improve the survival benefits of these
patients, an adequate tumoral resection of the primary lesion and the local tumoral extension is
warranted, especially if an optimal cytoreductive surgery is performed, together with adequate
systemic chemotherapy [60, 61]. In our case, breast metastasis mimicking mastitis delayed our
diagnosis until the primary disease disseminated, warranting only systemic chemotherapy, with no
local treatment. Radiotherapy was offered to the patient as a palliative treatment, for local control of
disseminated disease and in order to improve the quality of life.
Median survival of the published cases was just 7.2 months, which is consistent with other
reported values. Breast metastasis from gastric carcinoma has a poor overall prognosis, more than
80% of patients dying within one year [22]. Our patient currently has a 10-month survival.
Leptomeningeal carcinomatosis (LMC) is defined as diffuse spreading of malignant cells
throughout the arachnoid membrane and the pia mater by propagation in the cerebrospinal fluid
(CSF). The majority of patients diagnosed with LMC have a prior cancer diagnosis [62]. LMC occurs
in approximately 5–8% of all patients with cancer and is the third most common metastatic
complication of the central nervous system [63]. LMC represents a very rare complication of gastric
cancer, occurring in 0.16 – 0.69% of patients [6], while other malignances have a higher rate of LMC
(breast cancer = 12 – 14%; lung cancer = 10 – 26%; melanoma = 17 – 25%) [65].
Adenocarcinoma is the predominant histological type in LMC of solid tumors [64]. The
majority of gastric cancer patients with LMC have poorly differentiated or signet-ring cell cancer
[65]. In most cases, there is an active disease outside the nervous system, including lung, liver and
bone dissemination [66].
There are 6 ways in which the tumor cells gain access to the CSF [67, 68]:
1) hematogenously: penetration of the arachnoid vessels;
2) direct invasion: through the coroid plexus;
3) direct extension: from subdural, epidural or intraparenchymal metastases;
4) by tracking along peripheral nerves;
5) rarely, tumors arise directly within the meninges (primary CSF lymphoma, primary
meningeal melanoma, primary meningeal sarcomas);
6) after surgical resection of cerebellar metastases.
An experimental model [69] suggests that in the development of LMC in gastric cancer, the
predominant route for the tumor cells to reach the subarachnoid space is Batson’s venous plexus or
perivenous spread from bone marrow metastasis.
We conducted a search on PubMed of the English literature in order to identify all the
published cases of LMC due to the gastric cancer. In total, we found 87 published cases [7, 62, 66, 70 –
105 (Table 2).
Median age of diagnosis was 53.94 years. Our patient was diagnosed with LMC at 46 years of
age. 41.4% of the patient had a histopathological diagnosis of signet-ring cell carcinoma, like our
patient had, followed by 24.13% poorly differentiated adenocarcinoma, confirming the increased
incidence of LMC in signet-ring cell or poorly differentiated histology.
Only a few of the patients (13 out of 87) didn’t have any other site of metastasis. The majority,
41.37%, had lymph node metastases, followed by 22.72% who had bone metastases. Our patient had
multiple bone metastases, which may be the pathway through which tumor cells entered the
cerebrospinal fluid.
In the literature, the time from gastric cancer to LMC diagnosis is approximately 12 months
[106]. Among the 87 cases of LMC from gastric cancer, the mean time to LMC diagnosis was 11.55
months, consistent with data from literature. Our patient was diagnosed with LMC 12 months after
the signet-ring cell carcinoma diagnosis.
Due to the fact that tumor cells gain access to every level of the neuraxis, patients with LMC
may present with a variety of signs and symptoms. These symptoms may be separated into cranial
nerves, spinal cord and spinal nerves deficits or involvement of the cerebral hemispheres or
symptoms related to the obstruction of the flow of CSF [107, 108]. As a consequence, patient may
complain of gastrointestinal symptoms (nausea, vomiting), headache, changes in mental status,
diplopia, hearing loss, loss of visual acuity, headache, pain in the neck or back, paresthesias, or even
diabetes insipidus [88]. Our patient accused uncontrollable headaches, diplopia and loss of visual
acuity.
The diagnosis of LMC is usually established by clinical presentation, imaging techniques (CT or
MRI) and CSF cytology. In the literature [106], the sensitivity of cranial MRI in the diagnosis of LMC
had been reported as between 65% and 75%. In many cases, imaging modalities to not aid in
diagnosis of LMC, so the definitive diagnosis is delayed until neurological symptoms set in [65]. In
our case, cranial MRI was normal, despite the presence of neurological symptoms, such as
headaches and diplopia.
Author Year published Sex Age Histology Other metastases Time to diagnosis Prognosis EANO-ESMO Classification
70
Meissner G. F. 1953 M 73 UDA Lymph nodes, lungs, bone marrow Concurrent, post-mortem 0.17 months, died PM
M 51 PDA Lymph nodes, peritoneum, hepatic Concurrent, post-mortem Not specified, died PM
M 50 Muc None Concurrent, post-mortem Not specified, died PM
M 63 PDA Lymph nodes Concurrent, post-mortem 0.15 months, died PM
71
Agnelli G. et al 1980 M 49 Sig Bone Concurrent 2 months, died ID
72
McCrary J. A. et al 1986 F 60 Muc Bone Concurrent Not specified ID
73
Grove A. 1991 M 52 Sig Not specified Concurrent, post-mortem 5 months, died IA
74
Mouallem M. et al 1998 F 67 Sig Lymph nodes, Krukenberg tumor, omentum 6 months 0.5 months, died ID
75
Mertes N. et al 1999 M 52 Sig Not specified Concurrent, post-mortem Not specified PM
76
Nakatsuji Y. et al 2001 Ns Ns Ns Not specified Concurrent, post-mortem Not specified PM
77
Höllinger P. et al 2002 M 59 Sig Lymph nodes Concurrent, post-mortem 0.3 months, died ID
66
Lee J. L. et al 2004 F 43 PDA Lymph nodes, peritoneum 4.7 months 0.3 months Not mentioned
F 38 Sig Lymph nodes, peritoneum, adrenal gland 0.7 months 0.3 months Not mentioned
F 62 Ns Liver 9.4 months 0.4 months Not mentioned
F 47 PDA Lymph nodes, hepatic, peritoneum 17.8 months Not specified Not mentioned
M 52 Sig Bone, bone marrow 1.4 months 9.2 months Not mentioned
M 52 Sig Lymph nodes, hepatic, bone, brain 1.8 months 2.7 months Not mentioned
M 31 Sig Bone, adrenal 5 months 4.3 months Not mentioned
M 64 MDA None 8.9 months 0.1 months Not mentioned
M 46 Sig None 10.5 months 2.5 months Not mentioned
F 46 PDA Peritoneum 33.4 months 9 months Not mentioned
M 55 PDA Lymph nodes, peritoneum 10.8 months 0.3 months Not mentioned
M 59 Sig Lymph nodes, bone 7.4 months 0.7 months Not mentioned
M 39 Sig Lymph nodes, bone 6.7 months 1.2 months Not mentioned
F 40 Sig Lymph nodes, bone, bone marrow, Krukenberg tumor 28.2 months 1.6 months Not mentioned
M 16 PDA Bone Concurrent 0.4 months Not mentioned
M 40 PDA Lymph nodes, peritoneum 3.2 months 1.1 months Not mentioned
M 57 WDA Lymph nodes 6.6 months 2.2 months Not mentioned
F 51 Ns Lymph nodes, bone, peritoneum Concurrent 4.2 months Not mentioned
M 70 PDA Not specified 0.9 months 0.3 months Not mentioned
78
Fuchizaki U. et al 2005 M 42 Sig Lymph nodes Concurrent 1.5 months, died IA
79
Braeuninger S. et al 2005 M 68 PDA Lymph nodes, brain Concurrent 2 months, died IA
7
Baba S. et al 2006 M 59 WDA None 16 months 1 month, died IB
80
Lee H. G. et al 2007 F 49 Sig Lymph nodes 0.2 months Not specified ID
81
Yamada T. et al 2008 M 53 PDA None Concurrent 4 months, died IA
82
Raj K. P. et al 2009 F 62 Sig Lymph nodes 2 months 15 months, died IA
83
Gdovinova Z. et al 2009 F 40 WDA Lymph nodes, Krukenberg tumor, peritoneum Concurrent, post-mortem 0.33 months, died ID
F 49 Sig Not specified Concurrent 0.1 months, died IA
84
Ohno T. et al 2010 M 62 PDA Lymph nodes, brain Concurrent 3 months, died IIC
Hayashi Y. et al85 2010 F 77 Sig None Concurrent 0.5 months, died IA
86
Cavanna L. et al 2011 F 77 WDA Bone marrow, brain 6 months 3 months, died IA

Table 2. Literature review of leptomeningeal carcinomatosis from gastric cancer. M – male; F – female; UDA – undifferentiated adenocarcinoma; PDA –
poorly differentiated adenocarcinoma; Muc – mucinous carcinoma; Sig – signet-ring cell carcinoma; Ns – not specified; MDA – moderately differentiated
adenocarcinoma; WDA – well differentiated adenocarcinoma, PM – post-mortem.
 87
Emoto S. et al 2011 F 51 Sig Peritoneum 11 months 5 months, died IA
F 86 WDA Not specified 17 months 1 month, died ID
F 52 Sig Peritoneum, Krukenberg tumor, pleural 7 months 2 months, died IA
M 49 Sig Bone, lung 2.5 months 0.3 months, died ID
F 64 PDA Peritoneum, Krukenberg tumor, bone 36 months 0.7 months, died Not mentioned
F 36 Sig Peritoneum 13 months 0.1 months, died IA
F 65 Sig Peritoneum 51 months Not specified ID
88
Bulut G. et al 2011 F 39 PDA Pleura, Krukenber tumor, bone, lymph nodes 6 months Not specified IA
89
Park K. K. et al 2012 F 69 Sig Lymph nodes 29 months 0.6 months, died ID
90
Tomita H. et al 2012 M 73 Ns Not specified Not specified 0.5 months, died Not mentioned
M 63 Ns Not specified Not specified 3 months, died Not mentioned
F 41 Ns Not specified Not specified 2 months, died Not mentioned
M 70 Ns Not specified Not specified 0.45 months, died Not mentioned
F 30 Ns Not specified Not specified 3 months, died Not mentioned
M 63 Ns Not specified Not specified 2 months, died Not mentioned
M 59 Ns Not specified Not specified 1.5 months, died Not mentioned
M 59 Ns Not specified Not specified 17.8 months, died Not mentioned
F 66 Ns Not specified Not specified 4 months, died Not mentioned
M 59 Ns Not specified Not specified 3.5 months, died Not mentioned
91
Kusumoto T. et al 2013 F 57 Sig Lymph nodes 24 months Not specified, died PM
M 42 Ns Lymph nodes, ascites 4 months Not specified IA
F 66 Ns Krukenberg tumor, ascites 28 months Not specified IA
62
Guo J. W. et al 2014 F 40 Sig None Concurrent 4 months, died IC
92
Kawasaki A. et al 2014 F 80 WDA None Concurrent Not specified ID
93
Kim S. J. et al 2014 M 58 Sig Bone 24 months Not specified IB
94
Saad N. et al 2014 M 81 Sig Lymph node 12 months 0.5 months, died ID
95
Kim N. H. et al 2014 M 37 Sig Lung 5 months 4 months, died IA
M 67 MDA Bone, skin 11 months 2 months, died ID
M 47 Und Hepatic 6 months 10 months, died IIA
F 64 MDA None 9 months 3 months, died IA
M 65 MDA None 4 months 1 month, died IA
F 72 Sig Lymph nodes 27 months 4 months, died IA
M 42 PDA Peritoneum 76 months 1 month, died ID
M 53 PDA Peritoneum, lymph nodes Concurrent 2 months, died IA
M 51 PDA Lymph nodes, brain, bone 28 months 9 months, died IA
96
Taghizadeh-Kermani A. et al 2015 M 56 WDA Lymph nodes 1 month 0.15 months, died ID
97
Nishie H. et al 2015 F 30 PDA Lymph nodes Not specified Not specified, died Not mentioned
98
Rakusic Z. et al 2015 F 60 PDA Cerebellar, lymph nodes Concurrent, post-mortem 1.5 months, died IA
99
Yamasaki T. et al 2016 M 35 Sig Peritoneum 0.17 months 12 months, died ID
100
Ali S. et al 2017 F 56 Sig None Concurrent Not specified IA
101
Vergoulidou M. 2017 F 48 Sig Liver, lymph nodes, lungs, bone Concurrent 2 months, died IA
102
Liu Y. 2017 M 50 PDA Lymph nodes 24 months 11 months, died ID
103
Kountourakis P. et al 2018 F 64 Sig None Concurrent 1 month, died IA
M 51 Sig None 76 months 12 months, died IA
104
Jiao X. D. et al 2018 M 39 Sig Bone 2 months Not specified ID
105
Kimura A. et al 2019 M 66 PDA Peritoneum, lymph nodes, hepatic, pancreas 18 months 1.5 months, died ID

Table 2 continued.
 The presence of malignant cells in CSF is mandatory for the positive diagnosis of CSF [7].
Wasserstrom et al. [108] had reported that the first CSF sampling has a diagnostic sensitivity of 54%,
and with repeated samplings, this percentage increases up to 91%. CSF findings indicative of LMC
include an increased opening pressure, pleocytosis, elevated protein concentration, decreased
glucose concentration and the presence of tumor markers (carcinoembryonic antigen – CEA or
carbohydrate antigen 19-9 – CA19-9) [89]. There are some methods that help increase the probability
of finding malignant cells in a CSF sample. These methods are obtaining at least 10.5 mL of CSF,
immediately processing the sample (within 1 hour after the spinal tap [109]) and obtaining the
sample from a site adjacent to the affected central nervous system region [110]. In our case, a positive
diagnosis of LMC was made after the first CSF cytology detected signet –ring cells.
The 2017 EANO-ESMO guidelines for leptomeningeal metastasis from solid tumors [111]
established a classification of leptomeningeal carcinomatosis based on CSF cytology and MRI
findings (Table 3). These guidelines are based on data from breast, lung and melanoma LMC studies
and the applicability to gastric cancer LMC has not been studied.

Cyotology/ MRI Confirmed Probablea Possiblea Lack of

biopsy evidence
Type I: IA + Linear Yes n/a n/a n/a
positive CSF IB + Nodular Yes n/a n/a n/a
cytology or IC + Linear + Yes n/a n/a n/a
biopsy nodular
ID + Normal Yes n/a n/a n/a
Type II: IIA - or equivocal Linear n/a With typical Without typical n/a
clinical clinical signs clinical signs
findings and IIB - or equivocal Nodular n/a With typical Without typical n/a
neuroimaging clinical signs clinical signs
only IIC - or equivocal Linear + n/a With typical Without typical n/a
nodular clinical signs clinical signs
IID - or equivocal Normal n/a n/a With typical Without
clinical signs typical
clinical
signs
Table 3. Diagnostic criteria for LMC, according to EANO-ESMO clinical guidelines [111] (a –
requires history of cancer; + - positive; -, negative; n/a – not applicable).

We were able to classify leptomeningeal metastases according to the EANO-ESMO guidelines

in only 49 cases. There was no mention on the investigations prior to LMC diagnosis in 31 cases, and
in 7 cases, due to the extremely rapid decline in patient status, the LMC diagnosis was made
post-mortem. LMC type IA was diagnosed in 51% of patients (Table 4), linear leptomeningeal
enhacement being the most frequent finding on MRI. In 39% of patients there was no obvious
alteration in imaging techniques. Only 2 patients had negative CSF cytology, confirming the high
rate of CSF sensitivity after repeated spinal taps.
Median time to type IA LMC diagnosis from the gastric cancer diagnosis was 9.04 months and
13.15 months for type ID LMC diagnostic (p = 0.16). The longer period of diagnosis could be owed to
the fact that, due to normal MRI aspect, the spinal tap is delayed.
Median overall survival was 3.31 months in type IA LMC and 2.37 months in type ID LMC (p =
0.23), consistent with the reported median survival of LMC [112].
We found no statistical significance between type IA and ID LMC time to diagnosis and overall
survival. This could be caused by the low number of patients included in the analysis. Other
subtypes of LMC couldn’t be included in the analysis due to the extremely low number of patients.
 Our patient was diagnosed with type ID LMC (positive CSF cytology, normal MRI), her time to
LMC diagnosis from the diagnosis of signet-ring cell gastric carcinoma was 13 months and her
current survival from LMC diagnosis is 5 months.
LMC is usually a fatal disease [68]. If untreated, the median survival of patients is 4 – 6 weeks,
and 2 – 4 months with therapy [112]. Patient with LMC from breast cancer or lymphoid
malignancies, which represent a minority of LMC patiens, may achieve disease-free survival of a
year or even more [113, 114]. In our literature review, median survival was approximately 3 months.
Our patient’s current overall survival from the diagnosis of LMC is 4 months.
Survival of patients with LMC is influenced by several clinical risk factors, such as performance
status, primary malignant disease, previous effect of anticancer therapy. A poor prognosis is given
to patients with poor performance status, chemoresistant disease, pronounced neurological
symptoms, heavy pretreatment status. In these patients, conservative treatment should be offered
[116].

EANO-ESMO Percentage Median time to Median overall

classification (number) diagnosis survival
IA (linear) 51 (25) 9.04 months 3.31 months1
IB (nodular) 4 (2) 20 months 1 month2
IC (linear + nodular) 2 (1) Concurrent 4 months*
ID (normal) 39 (19) 13.15 months 2.37 months3
IIA (linear) 2 (1) 6 months 10 months
IIB (nodular) 0 (0) n/a n/a
IIC (linear + nodular) 2 (1) Concurrent 3 months
IID (normal) 0 (0) n/a n/a
Table 4. Literature classification according to EANO-ESMO LMC guidelines (1 – the overall
survival was specified only in 21 out of 25 patients; 2 – the overall survival was specified in only 1 out
of 2 patients; 3 – overall survival was specified in only 14 out of 19 patients).

Several treatment options are used for patients with LMC, including intrathecal (IT)
chemotherapy and radiotherapy (RT). Most chemotherapeutic agents commonly used in gastric
cancer treatment do not penetrate the blood-brain barrier. IT chemotherapy includes methotrexate
(MTX), cytarabine (Ara-C), thiotepa and steroids. The benefit achieved by IT chemotherapy in LMC
is debatable.
Despite limited success and serious adverse effects, the most commonly utilized drug for IT
therapy remains methotrexate [116, 117]. The usual dose of IT MTX is 10 to 15 mg, generally
administered twice weekly for 8 treatments, followed by weekly administration for 4 treatments,
and finally by monthly treatment [112]. In 20% of cases IT MTX successfully clears malignant cells
from the CSF [118, 119]. The optimum duration of therapy in patients who respond is not known.
However, treatment beyond 6 months may be unnecessary [120].
There are reports that combination IT chemotherapy with MTX, Ara-C and hydrocortisone is
more effective than MTX alone in LMC from solid tumors. A recent study by Kim et al [121] of 55
patients with LMC from solid tumors demonstrated that the combination of IT MTX and Ara-C had
a superior median survival (18.6 weeks) compared with MTX alone (10.4 weeks). However, patients
with gastric cancer enrolled in this study consisted of only 10% of the total number of patients and it
is questionable if Ara-C has any effect in gastric cancer.
In contrast, an earlier clinical trial by Hitchins et al. [122] comprising of 44 patients with LMC
from solid tumors demonstrated a statistically significant median overall survival for methotrexate
alone (12 weeks) compared with combination methotrexate and cytarabine (7 weeks).
Novel therapeutic strategies for solid tumors LMC that present moderate response rates
comprise of intrathecal topotecan (22%) [123], intrathecal etoposide (26%) [124] and intrathecal
mafosfamide [118].
 Oh et al. [65] noted that clearance of CSF after IT chemotherapy is independently associated
with a longer survival. Other reports showed that patients receiving IT chemotherapy have a better
survival compared to those receiving best supportive care [125].
In case of symptomatic or bulky LMC, RT is the preferred treatment modality. RT can quickly
relieve pain (in particular radicular pain) and other neurologic symptoms, thus greatly improving
quality of life [68]. In addition, RT may improve CSF flow, improving the efficacy of intrathecal
chemotherapy [126].
Oh et al. [65] conducted a multicenter retrospective analysis of patients with LMC from gastric
cancer and revealed no definitive proof of an additional effect of cranio-spinal RT to IT
chemotherapy. In opposition, a prospective study conducted by Bokstein et al. [127] provided no
benefit of IT chemotherapy added to systemic treatment and RT. There was no difference in the
median survival (4 months) between the two groups: the first one consisted of 54 patients treated
with RT, IT and systemic chemotherapy and the second group consisted of 50 patients treated with
RT and systemic chemotherapy.
A recent paper published in 2011 by Tomita et al. [90] reported a favorable outcome with triple
combination therapy (IT chemotherapy, whole brain irradiation and ventriculoperitoneal shunt)
compared with combination therapy (IT chemotherapy and whole brain irradiaton) and
monotherapy (IT chemotherapy).
There is a hypothesis, confirmed by an experimental model [128], that suggests that due to the
fact that in most cases of LMC the blood-brain barrier is destroyed and LMC is associated with
highly permeable blood vessels, systemic chemotherapy may be effective.
In our case, we opted for IT MTX in a total dose of 12 mg administered every 2 days until
symptoms improved, followed by weekly administration for a total of 15 cycles, followed by
biweekly administration for another 2 cycles, associated with fourth line of metastatic chemotherapy
with Docetaxel. We opted for the increased dose of IT MTX, due to the patient’s good performance
status and her wishes. Currently, the patient’s clinical status has improved (resolution of neurologic
symptoms) and undetectable malignant cells in 3 consecutive CSF cytology.
The presence of both breast metastases and leptomeningeal carcinomatosis in signet-ring cell
gastric carcinoma is extremely rare. A single case [48] has been reported in the English literature of
this specific polimetastatic context. In that case, the patient developed leptomeningeal
carcinomatosis after 10 months from the diagnosis of breast metastasis and died, without being able
to start any treatment.

4. Conclusions
Signet-ring gastric cancer may present uncommon and rare metastases (breast,
leptomeningeal), prompting the immediate recognition of signs and symptoms and requiring urgent
biopsies in order to establish a positive diagnosis.
Breast nodules or lumps require biopsy, especially in a pre-menopause patient, even if there are
no other malignant conditions. Primary tumor treatment is essential in case of breast metastases.
Presently, there are no established guidelines for the diagnosis and treatment of signet-ring cell
gastric carcinoma with leptomeningeal carcinomatosis. IT chemotherapy remains the mainstay of
treatment. In addition, in the presence of severe neurological symptoms or bulky disease require
cranio-spinal RT.
According to the EANO-ESMO guidelines, type IA and ID LMC were the most prevalent cases,
we couldn’t establish any correlation between these LMC subtypes and median time to diagnosis or
median overall survival.
To our knowledge, this is the first published case of a signet-ring cell gastric carcinoma patient
treated for breast metastases and leptomeningeal carcinomatosis.
Conflicts of Interest:Authors declare no conflict of interest.

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