Gastric linitis adenocarcinoma and carcinomatous meningitis: An infrequent but aggressive association – report of four cases

Annals of Oncology 12: 869-871. 2001. © 2001 Kluwer Academic Publishers Primed in the Netherlands.

Clinical case Gastric linitis adenocarcinoma and carcinomatous meningitis: An infrequent but aggressive association - report of four cases T. Delaunoit,' V. Boige,1 J. Belloc,1 D. Elias,2 P. Lasser,2 P. Duvillard3 & M. Ducreux1 'Service d'Oncologie digestive Medicate, 2Service d'Oncologie digestive Chirurgicale, } Service d'Anatomopathologie. Institut Custave Roussy. Villejuif, France

Summary Carcinomatous meningitis (CM) is a very rare complication of gastrointestinal malignancies and especially gastric adenocarcinoma. Linitis plastica (LP), which is a specific form of gastric neoplasia, locally penetrates through the gastric wall to reach the peritoneum. Lymph node involvement is frequent and metastatic sites are almost exclusively observed in the abdominal cavity. The meningeal localization is extremely rare with only a few cases described in the literature. We report here, over a five-year period, four cases of CM on a total of eighty linitis cases diagnosed and treated in our institution, which represent 5% of a non selected linitis population. The clinical manifestations were clearly poor, and characterized by aspecific neuro-

logical signs. The diagnosis was made by the discovery of signet cells in the cerebrospinal fluid. Invasive treatment, consisting of intrathecal infusion of chemotherapy, was undertaken with mixed clinical response and no cytological normalization of the cerebrospinal fluid (CSF). In conclusion, our observation which is based on a large series of successive gastric linitis, demonstrates a 5% frequency of developing CM with a predominance among metastatic patients. Furthermore, the diagnosis of CM must be done as soon as possible because of the clear effectiveness of a therapeutic approach on the improvement of symptoms and quality of life. Key words: carcinomatous meningitis, cerebrospinal fluid, gastric adenocarcinoma, metothrexate, signet ring cells

Introduction

Case report

Digestive linitis plastica (LP) is a special form of poorly differentiated adenocarcinoma that can affect all the segments of the digestive tube and especially the stomach, which is the most frequent localization [1-3]. Histopathological findings are characterized by the presence of signet cells in varying quantities associated with a marked fibroblastic stroma reaction. Typically, LP massively infiltrates the gastric wall with a common involvement of peritoneum, lymph nodes and frequently produces metastases. Carcinomatous meningitis (CM) arises in approximately 8% of patients with systemic cancer and is mostly found in cases with haematological disease or solid tumours such as breast cancer, smallcell lung carcinoma (SCLC) and melanoma [4]. In our knowledge, CM is a very rare localization in LP. Actually, only a few isolated case reports are described in the literature [5-7]. All these cases appeared in young patients suffering from gastric linitis who died rapidly after the diagnosis. We describe here four new cases which have been diagnosed in our institution over a five-year period, in order to specify the diagnostic modalities and therapeutical strategy of this rare situation.

Between January 1995 and December 1999, 4 cases of CM were isolated from a total of 80 metastatic gastric linitis cases diagnosed and treated in our institution. Of these three men and one woman, all were diagnosed with gastric linitis and suffered from a disseminated disease at the time of diagnosis except one patient (patient 1) who was considered disease-free just after curative gastrectomy. Disseminated disease included peritoneal carcinomatosis in three and liver metastases in two. All of them received systemic chemotherapy combining 5-fluorouracil (5-FU), cisplatin (CDDP) and epiadriamycin at the time of the diagnosis, which was first suspected by the appearance of non-specific neurological signs including: cranial nerve paralysis (patient 2), diplopia (patient 1), severe headache (patients 1, 3,4), sciatalgia (patient 2) walk and speech trouble (patients 3 and 4), nausea and vomiting (patient 4). A computer tomography was performed to exclude cerebral mass in all of them and remained negative. Afterwards, lumbar puncture was carried out and allowed the diagnosis in three of four patients by detecting signet ring cells in the cerebro spinal fluid (CSF) associated with a high level of protein in the CSF. The fourth patient had no tumoral cells but significant hyperproteinorachia. Nevertheless, the association of neurological signs and biological

870 Table I. Patient characteristics.

Age

Patient 1

Patient 2

Patient 3

Patient 4

50

48

53

60

Sex

Male

Female

Male

Male

Primary site

Gastric

Gastric

Gastric

Gastric

Histopathological findings

LP

LP

LP

LP

Treatment of the primary disease

Surgery

Surgery + chemotherapy

Surgery + chemotherapy

Surgery + chemotherapy

Metastatic disease

No

Yes

Yes

Yes

CM symptoms

Diplopia, headache

Cranial nerve paralysis, sciatalgia

Headache, walk and speech trouble

N+.V+, headache, walk trouble

CM diagnosis

Signet cells + hyperproteinorachia in the CSF

Hyperproteinorachia

Signet cells + hyperproteinorachia in the CSF

Signet cells + hyperproteinorachia in the CSF

CM treatment

IT MTX + HC

IT MTX + HC

IT MTX + HC

IT MTX + HC

Survival (months)

Alive (9)

Dead (8)

Dead (11)

Alive (24)

Abbreviations: CM - carcinomatous meningitis; CSF: cerebrospinal fluid; HC - hydrocortisone; IT - intrathecal; LP - linitis plastica; MTX methotrexate; N+ - nausea: V+ - vomiting.

abnormalities in the CSF ensured an almost certain diagnosis. A magnetic resonance imaging (MRI) was performed in three of four and remained negative. Intrathecal chemotherapy combining metothrexate (MTX) 8 mg/m 2 and hydrocortisone 100 mg was started immediately in all four patients. The number of chemotherapy courses varied for each patient (patients 1, 3, 4 = six courses, patient 2 = one course). The response to treatment was heterogeneous: patients 1, 3 and 4 showed good response with clear improvement but no disappearance of all neurological signs. After six courses of intrathecal chemotherapy, two of three patients had persistent signet cells in the CSF, which justified stopping treatment in spite of clinical improvement. Patient 2 received one course of chemotherapy with a worsening of neurological signs: death occurred rapidly after one month. Two of the four patients are still alive with a respective survival of nine and twenty-four months since the diagnosis of gastric tumour and two and three months since the beginning of neurological signs. The other two died rapidly after 8 and 11 months after diagnosis of a primary tumour, respectively.

Discussion Thirteen percent of gastric cancer is accompanied by extra abdominal illness including lung injury and, in very rare cases, neurological involvement [6-8]. Almost all cases of CM described in the literature were associated with breast cancer, small-cell lung carcinoma (SCLC), melanoma and bladder cancer and very rarely with a particular gastric adenocarcinoma called LP, which is the most common and severe form of signet cells cancer. LP is an infiltrating tumour associated with a poor prognosis because of rapid evolution and large involve-

ment of intraperitoneal organs including ovaries, peritoneum, lymph nodes, small bowel, colon and rectum [1-3]. Fifty percent to eighty percent can be treated by surgery with a median survival rate after resection of about eighteen months [9]. All of our four patients had gastric linitis and three showed disseminated disease at the time of diagnosis. Chemotherapeutic treatment was given with good response in terms of abdominal illness. Nevertheless, because chemotherapeutic agents used in gastric linitis (5-FU, CDDP and epiadriamycin) had a poor penetration in the CSF, neurological involvement was hardly controlled in three of the four patients who developed their CM under adequate treatment for their primary tumour. Furthermore, symptoms and signs observed in our cases of CM were heterogeneous and non specific as described in the literature [10-12]. For this reason, physicians must be very careful when a patient with gastric cancer shows neurological signs and particularly when it is linitis. It is of interest to mention that radiological examination including computerized tomography and magnetic resonance imaging (MRI) were not helpful for diagnosis. Nevertheless, it must be carried out to exclude intracranial mass before performing lumbar puncture, which remains the best investigation to diagnose CM by detection of malignant cells in the CSF [13, 14]. Nevertheless, up to one third of patients will have cytologically negative CSF [15] when lumbar puncture is performed. In our experience of CM associated with gastric linitis, CSF analysis was cytologically positive in three of the four (75%) patients and hyperproteinorachia was found in all of them. No data are available in the literature about systematic lumbar puncture in patients with systemic neoplasia. The prognosis for patients with CM is clearly poor in the literature with a median survival of two to three months with therapy and four to six weeks without treatment [16-18]. In a large series of

871 SCLC, Rosen et al. demonstrated that about 50% of patients diagnosed with CM and receiving intrathecal chemotherapy cleared their CSF of malignant cells; however, complete disappearance of neurological symptoms is less frequent [16]. Our observation does not confirm the efficiency of the treatment in terms of CSF clearance because none of our patients normalized their CSF. However, all of our patients improved their neurological symptoms without any signs of MTX neurotoxicity, which remains important to diagnose [19]. Despite a poor prognosis, 2 patients are still alive 9 and 24 months, respectively, after diagnosis. Several approaches could be used in the management of CM, including intrathecal or systemic chemotherapy and irradiation [20]. Intrathecal injections of chemotherapeutic agents such as metothrexate, thiotepa, cytarabine or cytosine arabinoside must be carried out as soon as possible because of their effectiveness in improving neurological signs. There is no evidence to support the superiority of combined therapy over single agent therapy [21]. New chemotherapeutic agents such as liposomally encapsulated ara-C [22], intrathecal depot of cytarabine [23] or slow-release intrathecal cytarabine have been developed and may be more effective and easier to use than intrathecal MTX [24]. In conclusion, CM is a rare complication of gastric linitis but not the least in terms of gravity. Intrathecal chemotherapy with MTX seems to be effective in terms of symptom improvement and could be used to improve quality of life among patients with a short life expectancy.

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Received 22 December 2000; accepted 12 January 2001.

Correspondence toM. Ducreux, MD Service d'Oncologie Digestive 39, rue Camille Desmoulins 94805 Villejuif France E-mail: [email protected]