Meningeal Carcinomatosis in a Patient with Crohn`s Disease

CASE REPORTS
Meningeal Carcinomatosis in a Patient with Crohn’s Disease
DANIELA TRAŞCĂ1, ADELINA SIMONA ŞERBAN1, V. ŞTEFĂNESCU1, ELENA ROŞIANU1, ZELA COFOIAN AMET1,
OANA MORARI1, SABINA ZURAC2,3, CRISTIANA POP2,3, A.. HAIDAR4, RODICA GOGULESCU5, H. BUMBEA6,
DOINA ANTONICĂ7, V. IONESCU2,8, INIMIOARA MIHAELA COJOCARU1,2
1
Department of Neurology, “Colentina” Clinical Hospital, Bucharest, Romania
”Carol Davila” University of Medicine and Pharmacy, 3Department of Pathology,
“Colentina” Clinical Hospital, Bucharest, Romania,
4
Department of Gastroenterology, “Colentina” Clinical Hospital, Bucharest, Romania,
5
Department of Hematology, GRAL Laboratory, “Colentina” Clinical Hospital, Bucharest, Romania,
6
Department of Clinical Hematology, University Emergency Clinical Hospital, Bucharest, Romania,
7
Department of Infectious Diseases, “Prof. Dr. Matei Balş” Institute, Bucharest, Romania,
2,8
Department of Imagistic, PROVITA Center, Bucharest, Romania
2
Leptomeningeal carcinomatosis, also known as carcinomatous meningitis, is defined by
spreading of neoplastic cells to the meninges and ventricles, and is a form of cancer dissemination. In
this case, a patient with inflammatory bowel disease had developed a neoplastic process that spread to
the meninges. A 49-year-old woman developed an abdominal pain, and was diagnosed the same
month with Crohn’s disease, complicated with intestinal perforation, for which she was hospitalized.
Pathological examination revealed acute phase-terminal ileitis. She undergone many hospitalizations
during which she was suspected to have celiac disease, inflammatory bowel disease, and tuberculous
meningitis, as well as femoral head necrosis after she had been unsuccessfully treated with
Prednisone for Crohn’s disease. After she developed peripheral bilateral facial paresis, bilateral
hypoacusia, hypotonia, tetraparesis and diminished osteotendinous reflexes at the legs, the patient was
admitted in our department. Several lumbar punctures were performed but no specific disease could
be detected. The MRI performed showed pachymeningeal and leptomeningeal inflammation.
Tuberculous meningitis was taken into consideration and the patient was transferred into an Infectious
Disease Department where this diagnostic was infirmed. The patient was retransferred into the
Department of Neurology where after an episode of hematemesis she had a cardiac arrest and
deceased. Inflammatory bowel disease may involve different segments of the intestine, and may be
accompanied by a variety of conditions, such as neurologic findings, osteoarticular manifestations and
also may be the starting point of a neoplastic process. The patient had an inflammatory bowel
condition, which by the time it was appropriately diagnosed as being Crohn's disease, a neoplastic
process spread to the meninges, causing multiple cranial nerve palsy, tetraparesis, along other
neurological manifestations.
Key words: meningeal carcinomatosis, Crohn’s disease, inflammatory bowel disease.
Leptomeningeal carcinomatosis, also known
as carcinomatous meningitis, is defined by spreading
of neoplastic cells to the meninges and ventricles,
and is a form of cancer dissemination [1].
The leptomeninges consists of the arachnoid
and pia mater. Interposed between them is a space
filled with cerebrospinal fluid (CSF). Tumor cells
entering the CSF by way of direct extension from a
primary brain tumor, or through hematogenous
dissemination, as is the case of leukemias, are
carried through the spinal fluid and determine
multifocal or diffuse infiltration of the meninges.
When the primary tumor is a solid process the term
used to describe the condition is leptomeningeal
carcinomatosis. Otherwise, when the tumor is not
of a solid type, the condition is referred to as
lymphomatous or leukemic meningitis [2].
ROM. J. INTERN. MED., 2014, 52, 2, 111–120
CASE REPORT
We present the case of a 49-year-old woman
who developed in November 2013 abdominal pain,
and was diagnosed the same month with Crohn’s
disease, complicated with intestinal perforation for
which she was hospitalized in the Târgovişte
County Hospital. Surgical resection was performed,
the colectomized segment measuring about 50 cm.
Pathological examination revealed acute phaseterminal ileitis, lymph with reactive follicular
hyperplasia, examination which was repeated in
our hospital, and the histopathological appearance
was also interpreted in the context of an intestinal
inflammatory disease, probably Crohn’s disease.
We mention that on the examined fragments, no
malignant lymphoid proliferation was detected.
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Daniela Traşcă et al.
A treatment with Salofalk at a dosage of
1000 mg × 3/day and Debridat (Trimebutine maleate)
100 mg/day was started.
After 3 months, our patient was hospitalized
in the Gastroenterological Department of Fundeni
Clinical Institute for further investigation. Biological
examination revealed only minimal leukocytosis,
elevated CRP, thrombocytosis, mild anemia. The
endoscopy revealed a normal esophagus, oblongated
stomach, duodenal bulb with nodular aspect and
the second portion of the duodenum had scalloping
atrophy. On discharge, the diagnosis was celiac
disease, the patient being recommended gluten-free
diet, Prednisone 40 mg/day, Nolpaza (Pantoprazolum) 40 mg/day, and also to complete investigation
with imunohistochemical tests from the resection
fragment, and entero CT, as well as total IgA and
IgA anti-tissue transglutaminase antibodies (which
were absent).
A month later the patient was rehospitalized
for diffuse abdominal pain, weight loss, loss of
appetite, asthenia, moderate fever and severe right
leg pain. On admission at the Gastroenterological
Department, Târgovişte County Hospital, she was
pale, had lost weight, blood pressure-120/70 mmHg,
heart rate-72/minute, without any palpable abdominal
masses or signs of peritoneal irritation. Biological
tests revealed moderate anemia, thrombocytosis,
inflammatory syndrome, digestive tumor markers
between normal limits. An abdominal radiograph
was performed which did not identify either pneumoperitoneum, or hydroaeric levels. The cortisone
dose was reduced at 20 mg/day (based on the
supposition that the patient developed necrosis of
the femoral head secondary to corticotherapy) and
she was given painkillers and nonsteroidal anti
inflammatories. The patient had no improvement of
the algic symptoms, so the patient was transferred
into the Gastroenterological Department, “Colentina”
Clinical Hospital, Bucharest, for further investigation.
Differential diagnosis was established between
Crohn’s disease with resection of terminal ileum,
aseptic necrosis of the femoral head, and coxofemoral arthritis secondary to Crohn’s disease. The
abdominal and pelvic CT (with administration of iv
contrast) revealed inflammatory changes of the
small intestine in the left flank, with minimal
encysted fluid collection, left ovarian cyst, without
visible bone lesions and femoral heads with normal
sphericity.
At the same time, she presented bilateral
facial asymmetry, boilateral hypoacusia, hypophonia,
tetraparesis predominant in the legs. Nerve
2
conduction studies were suggestive for right S1
radiculopathy-stable chronic degeneration.
From this moment the patient was transferred
into our Department. Neurological examination
revealed peripheral bilateral facial paresis, bilateral
hypoacusia, hypophonia, tetraparesis (2/5MRC) and
diminished osteotendinous reflexes at the legs.
Further biological testing revealed thrombocytosis, marked inflammatory syndrome, elevated
serum alkaline phosphatase and GGT, hepatic
cytolysis. Serology for Borrelia, VDRL, HIV and
CMV tested negative. The CSF examination revealed
clear spinal fluid, elements-120/mm3, cytology:
neutrophils-7%, eosinophils-5%, lymphocytes38%, 50% cells that appear to be from the
lymphoid line, some with racket aspect, with
cytoplasmatic extensions, other, bigger; Pandy
reaction was positive, proteinorachia-261 mg/dl,
glycorachia-30 mg/dl. Ziehl Nielsen coloration was
performed, with negative results. Immunophenotype examination did not detect any atypical
lymphocytic cells, but instead described the
expansion of Natural Killer cells, which suggests a
nonspecific stimulation of cellular immunity in
these locations.
The chest radiography did not identify any
lesions, and the cerebral MRI with contrast agent
administration (0.5 T) identified only an arachnoid
cyst on the right side, without any other
pathological changes.
Some neoplastic markers (CA15.5, CA19.9,
CA12.5, CEA, AFP were absent.
We continued with Dexamethasone 24 mg/day
and symptomatic treatment, with subsequent
transfer into the Infectious Diseases Department,
“Prof. Dr Matei Balş” Institute, for confirmation/
infirmation of tuberculous meningitis. After admission,
the patient was hemodynamically stable, cachectic,
complaining about abdominal pain, and biological
data revealed leukocytosis, thrombocytosis, significant hepatic cytolysis, cholestasis, but with
negative hepatitic markers, hyponatremia and
hypokaliemia.
Another CSF examination was performed,
with a clear CSF, 200 elements/mm³, cytology with
prevalence of lymphocytes (10% neutrophils, 25%
large lymphocytes, 30% medium lymphocytes, 35%
small lymphocytes), strongly positive Pandy reaction,
proteinorachia 563 mg/dl, glycorachia 52 mg/dl,
negative China ink reaction, lactic acid 63 mg/dl,
no Baar corpuscles were found and PCR examination was negative for Mycobacterium
tuberculosis.
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Meningeal carcinomatosis in a patient with Crohn’s disease
The next CSF examination did not reveal
significant changes from the last review, a decreased proteinorachia (315 mg/dl), chlorurorachia
680 mg/dl, and latex agglutination tests for bacteria –
negative.
The last CSF was clear, number of elements
450/mm3, cytology with the prevalence of
lymphocytes (2% neutrophils, large lymphocytes
69%, medium lymphocytes 10%, small lymphocytes 15%), the large lymphocytes showed
cytoplasmic extensions, embattled nuclei, low
chromatin, abundant cytoplasm with eosinophilic
granulations, intense positive Pandy reaction,
proteinorachia 399 mg/dl, glycorachia 57.2 mg/dl,
lactic acid 57 mg/dl, PCR for Mycobacterium
tuberculosis negative.
The last cerebral MRI made with iv contrast
(3T) was evocative for a pachymeningeal and
leptomeningeal inflammation, regarding especially
the tank portions of some cranial nerves: facial and
acoustic nerves bilateral, and the right trigeminal
nerve (Figs. 1-4).
Figure 1. Cerebral MRI-T2 lesion of the pachymeninges.
Figure 2. Cerebral ADC map showing carcinomatous
infiltration of the meninges.
Figure 3. Cerebral DWI sequence again showing infiltration
of the meninges.
Figure 4. Cerebral MRI T2 darkfluid sequence.
Note the bilateral thickening of the parietal meninges.
No meningitic reaction was identified, so the
patient was transferred back into Neurological
113
Department, where she presented acute urinary
retention.
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Daniela Traşcă et al.
The electroneurographic examination showed
global reducing of the amplitude of motor unit
potentials both for motor and sensory velocity,
prolonged distal latencies of median and tibial
nerves bilaterally, prolonged F waves. Conclusion:
Sensory-motor demyelinating polyneuropathy, with
conservation of sural and cubital nerves.
Consecutively, the patient presented hematemesis. Endoscopical examination revealed a normal
aspect of the esophagus, important biliary stasis at
the level of the fornix, hyperemic antral gastritis,
and on the bulbar mucous many nipple-like formations from which biopsy samples were obtained.
The histopathological examination, revealed
partially flattened villi with erosive areas, moderate
polymorphic inflammatory infiltrate in the corium
with intraepithelial lymphocytic extension, cystic
dilated glands, minimal periglandular fibrosis,
4
interstitial edema and hyperemia, fibrino-leukocyte
detritus, no H. pylori was identified (Figs. 5-10).
Immunohistochemical tests revealed: CD 3
positive in most lymphocytes from the corium (T
lymphocytes), CD20 positive in approximately
20% form the corium lymphocytes. Immunophenotype polymorphism of inflammatory infiltrate
supports the reactive nature. This aspect can be
interpreted in the context of a duodenal lesion
which can be found in Crohn’s disease.
IgA and IgG anti-gliadin antibodies were absent.
ACE testing was negative.
Final diagnosis was established: Meningeal
carcinomatosis of undetermined cause. Crohn’s
disease. Chronic sensory-motor demyelinating polyneuropathy.
Neurological outcome was stationary, the
patient presented further haematemesis, and finally
she died after suffering a cardiac arrest.
Figure 5A
Figure 5 B
Figures 5A and 5B. Surgical specimen: 1-2. granulation tissue bordering the fistula; the inflammatory
infiltrate is polymorphic: lymphocytes, plasma cells, eosinophils, histiocytes and occasional giant cells. HE x 200.
5
Meningeal carcinomatosis in a patient with Crohn’s disease
Figure 6. Surgical specimen: fibrinous and leukocytic exudate covering
the serous surface (HE x 100).
Figure 7. Duodenal biopsy: duodenal mucosa with partial flattened villi and erosions.
Moderate inflammatory infiltrate (HE x 100).
Figure 8. Duodenal biopsy: moderate inflammatory infiltrate consisting in lymphocytes,
histiocytes, plasma cells and eosinophils; occasional erosions of the superficial epithelium (HE x 200).
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Daniela Traşcă et al.
6
Figure 9. Duodenal biopsy: most of the lymphocytes within the lamina propria are T cell (CD3+);
all the intraepithelial lymphocytes are CD3+ (T cells) (CD 3 x 200).
Figure 10. Duodenal biopsy: Several lymphocytes are B cells, mostly arranged in small nodules
in lamina propria (CD 20 x 200).
DISCUSSION
EPIDEMIOLOGY
Meningeal carcinomatosis (MC) is encountered
in approximately 1-8% of patients with cancer. Of
them, 20% have already a primary tumor and
neurologic findings at the moment of diagnosis [3-4].
The most frequent cancers which spread to
the meninges are adenocarcinomas of the breast,
lung, melanoma, leukemia, lymphoma and tumors
of the gastro-intestinal tract [1]
Small cell lung cancer disseminates to the
meninges in up to 25% of the cases, melanomas in
23% and breast cancers in 5%, but due to the
different frequencies of each type in the general
population, breast cancers have the greatest overall
association with leptomeningeal carcinomatosis [3].
The frequency of leptomeningeal carcinomatosis also rises with the time of exposure to the
carcinomatous process [39].
PATHOPHYSIOLOGY
Metastatic seeding of the leptomeninges may
be explained by the following 6 postulated
mechanisms: 1) hematogenous spread to choroid
plexus and then to leptomeninges, 2) primary
hematogenous metastasis through the leptomeningeal
vessels, 3) metastasis via the Batson venous plexus,
4) retrograde dissemination along perineural lymphatics and sheats, 5) centripetal extension along
perivascular and perineural lymphatics from axial
lymphatics nodes and vessels through the intervertebral and possibly from the cranial foramina to
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Meningeal carcinomatosis in a patient with Crohn’s disease
the leptomeninges, and 6) direct extension from
contiguous tumor deposits [2].
PATHOLOGIC FINDINGS
Typical macroscopic appearance is the
diffuse opacification and thickening of the leptomeninges. Sometimes it is described as slight
opacities or small white nodules, especially gathered
around the base of the brain and along spinal nerve
roots. Most often the spread is restricted to the
leptomeninges, although cases with superficial
invasion of the brain, mainly Virchow-Robin
spaces, have been known to exist.
At microscopic level it is noted a diffuse
infiltration of the subarachnoid space by the neoplastic cells. Due to the frequent involvement of the
cerebral ventricles, spreading through the choroid
plexus has been hypothesized [5, 6].
CLINICAL FINDINGS AND POSITIVE DIAGNOSIS
Patients present with headache accompanied
by nausea and vomiting, gait disturbance, memory
problems, sensory abnormalities, seizures and pain
being the most frequent symptoms. Clinical
examination reveals involvement of the cerebrum
(headache, lethargy, papilledema, gait disturbances);
cranial nerves (most often palsies of nerves III, V
and VI, multiple nerve involvement being the
general rule), or spinal root lesions (meningeal
irritation with nuchal rigidity, neck and back pain,
or invasion of spinal roots with leg weakness,
radiculopathy, positive Babinski reflex, and sphincter
incontinence). Consistently, symptoms of cranial
nerve damage due to leptomeningeal carcinomatosis are the more often clinical finding [1, 7-20].
Diagnosis is made after lumbar puncture,
although 10% of patients do not have positive CSF
cytology. The low positivity of CSF cytology
makes it difficult not only to diagnose MC but also
to assess the response to treatment. Biochemical
markers, immunohistochemistry, and molecular
biology techniques applied to CSF have been used
in an attempt to find a reliable biologic marker of
disease [21-26].
Imagistic evaluation reveals subarachnoid
masses, diffuse contrast enhancement of the meninges,
or hydrocephalus without a mass lesion. Magnetic
resonance imaging with gadolinium enhancement
(MR-Gd) is the technique of choice to evaluate
patients with suspected MC. T1-weighted sequences,
with and without contrast, combined with fat
117
suspension T2-weighted sequences, constitute the
standard examination. MR-Gd still has a 30%
incidence of false-negative results, so that a normal
study does not exclude the diagnosis of MC. In
cases with a typical clinical presentation, abnormal
MR-Gd alone is adequate to establish the diagnosis
of MC [27-32].
Radionucleide studies using 111Indium-diethylenetriamine pentaacetic acid or 99Tc macroaggregated albumine constitute the technique of
choice to evaluate CSF flow dynamics. Abnormal
CSF circulation has been demonstrated in 30% to
70% of patients with MC, with blocks commonly
occuring at the skull base, the spinal cord, and over
the cerebral convexities.
111
Indium-DTPA CSF flow studies predict
patient survival and are useful in determining
which patients would be candidates for intra-CSF
chemotherapy administration [33].
EVOLUTION AND TREATMENT
Without treatment, MC is fatal in 4-6 weeks.
Early diagnosis and treatment raises survival rate to
3-6 months.
The standard therapies are radiation therapy
to symptomatic sites and regions where imaging
has demonstrated bulk disease, intrathecal chemotherapy and surgery [34-40].
Aggressive treatment may result in a necrotising leukoencephalopathy, which becomes clinically
expressed after a few months [6].
Several pitfalls have to be taken into account
during the diagnostic process, as the neurologic
symptoms may stem either from the chronic
inflammatory status present in celiac sprue and/or
Chrohn’s disease, paraneoplastic neuropathy, or
even the association between them.
Celiac sprue has been known to be accompanied
by a variety of neurological symptoms, including
ataxia, neuropathy or even malignancy, such as
primary CNS lymphoma [41].
The mechanism underlying neurological
symptoms and neuronal damage is poorly understood, and is considered to be the result of
hyperproduction of anti-gliadin antibodies [42].
Some cohort sudies, performed by Chin et al.,
showed that 5% of patients having been diagnosed
with celiac sprue, have signs of polyneuropathy, as
demonstrated by nerve biopsy samples and nerve
conduction studies, although the findings can be
minimal. It is also known that celiac disease may
be accompanied by malignancy, such as primary
CNS lymphoma [43].
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Daniela Traşcă et al.
Because the patient had an important history
of inflammatory bowel disease, the neurologic
symptoms were considered a neuropathy probably
secondary to Crohn’s disease. There is a primary
immune-mediated neuropathy as an extraintestinal
disorder associated with IBD; even men with IBD
may be more susceptible to the development of
polyneuropathy than women, women may be prone
to demyelinating neuropathies [44-46].
Paraneoplastic neuropathies have to be taken
also into consideration, and although the patient did
not have any direct sign of cancer, i.e positive
histological findings, the elevated proteinorrachia –
above 260 mg/dl, and lack of neoplastic cells in the
CSF immune phenotype tests, which described an
expansion in the Natural Killer cell line, that
indicates a non specific cellular immunity reaction,
may also hint to an expansive process.
The main factor that hindered early diagnosis
was the lack of neoplastic cells in tissue samples
that were obtained both from the excised bowel
segment and from the duodenal biopsies. Also, in
both inflammatory bowel disease and intestinal
cancer, the patient may lose weight and present
anemia [47].
However, due to the fact that colorectal
cancer has a higher incidence in patients with IBD
[48] we have to take into consideration that a
8
neoplastic process may have developed and
eventually spread to the meninges.
Other contributing factors were the lack of
imagistic findings – chest X-ray did not show any
thoracic tumors and the lack of some neoplastic
markers; cerebral imagery identified basal pachymeningeal and leptomeningeal inflammation which
involve the cysternal portion of cranial nerves VII,
VIII and V on the right side, suggesting MC.
Studies have shown that in paraneoplastic
neuropathies, there should be elevated serum levels
of anti-Hu, anti-Yo, and anti-Ri antibodies [49] but
laboratory tests to emphasize their presence were
not possible at the time due to financial reasons.
After dissemination to the meningeal
coverings, the prognosis is poor, usually the patient
only survives 4-6 weeks if left untreated.
CONCLUSIONS
MC is a neoplastic dissemination with poor
prognosis.
It is important that MC be included in the
differential diagnosis of mycotic, tuberculosis and
other forms of chronic meningitis.
Association of MC with Crohn’s disease may
be an indicator of neoplastic degeneration of the
IBD.
Carcinomatoza leptomeningeală, cunoscută şi sub denumirea de meningită
carcinomatoasă (MC), este definită prin diseminarea celulelor neoplazice în
meninge şi ventriculi şi este o formă de extindere a cancerului. O pacientă cu
boală inflamatorie intestinală a dezvoltat un proces neoplazic ce a diseminat spre
meninge. Pacienta de 49 ani a prezentat iniţial dureri abdominale, fiind
diagnosticată în aceeaşi lună cu boală Crohn, complicată cu perforaţie intestinală,
pentru care a fost spitalizată. Examenul anatomopatologic a relevat ileită
terminală în fază acută. Ulterior a prezentat internări multiple în cursul cărora a
fost suspicionată de boală celiacă, boală inflamatorie intestinală şi meningită
tuberculoasă, precum şi necroză a capului femural după tratament cu Prednison
pentru boală Crohn. Pacienta a prezentat paralizie facială periferică bilaterală,
hipoacuzie bilaterală, tetrapareză, hipotonie musculară şi abolirea reflexelor
osteotendinoase la membrele inferioare, motive pentru care a fost transferată în
Clinica de Neurologie. S-au efectuat mai multe examinări ale LCR recoltat prin
puncţii lombare, dar nu a fost decelată nicio boală specifică. IRM efectuat a
relevat inflamaţie pachi- şi leptomeningeală. S-a luat în consideraţie meningita
tuberculoasă, pacienta a fost transferată la Institutul de Boli infecţioase unde s-a
infirmat acest diagnostic, ulterior retransferată în Clinica de Neurologie unde,
după un episod de hematemeză, aceasta prezintă stop cardiac şi decedează. Boala
inflamatorie intestinală poate implica diferite segmente ale tubului digestiv şi
poate fi însoţită de o varietate de manifestări ca semne neurologice, osteoarticulare, de asemenea, poate fi punctul de pornire al unui proces neoplazic.
Pacienta a prezentat o boală inflamatorie intestinală ce în timp a fost diagnosticată
9
Meningeal carcinomatosis in a patient with Crohn’s disease
119
adecvat ca fiind boală Crohn, un proces neoplazic diseminat spre meninge,
determinând paralizii multiple de nervi cranieni, tetrapareză şi alte manifestări
neurologice.
Corresponding author: Daniela Traşcă, MD
Department of Neurology, “Colentina” Clinical Hospital
19-21 Şos. Ştefan cel Mare
020125, Bucharest, Romania
E-mail: danna_ox1@yahoo.com
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Received May 24, 2014