Pancreatic cancer with leptomeningeal carcinomatosis: case report and literature review

Abstract

Leptomeningeal carcinomatosis (LMC) associated with pancreatic cancer is an extremely rare complication. Symptoms vary depending on the site of invasion and include intracranial pressure, and cranial and spinal dysfunction making early diagnosis difficult. We describe a rare case of leptomeningeal metastasis from pancreatic cancer. A 59-year-old man was diagnosed with unresectable pancreatic cancer and subsequently received systemic chemotherapy. Initial chemotherapy was effective. After 12 months the patient’s serum carbohydrate antigen (CA)19-9 level had become elevated, and he presented with neck and back pain, and shoulder stiffness. Tumor enlargement was not detected by computed tomography (CT) and positron emission tomography–CT. Contrast CT of the brain revealed evidence of leptomeningeal enhancement. Cerebrospinal fluid cytology showed atypical, but not malignant cells; the CA19-9 level was further elevated. The patient was finally diagnosed with LMC and, being in poor general condition, received palliative care. During the treatment of pancreatic cancer, the potential existence of LMC should be contemplated when a serum tumor marker becomes rapidly elevated despite the control of primary or metastatic sites.

Introduction

In pancreatic cancer with locally advanced and metastatic disease, the overall 5-years survival rate is less than 5% [1], with the most common sites for metastases being the liver, lung, and peritoneum. Leptomeningeal carcinomatosis (LMC) occurs in 5–8% of solid tumors [2]. For patients with pancreatic cancers, leptomeningeal carcinomatosis is extremely rare, having being reported, to our knowledge, in only 12 cases [3–14]. Furthermore, an early diagnosis is difficult because of varied and non-specific symptoms.

We report a case of unresectable pancreatic cancer that progressed to LMC despite showing a good initial response to chemotherapy.

Case report

A 59-year-old man who was a hepatitis B carrier underwent yearly contrast computed tomography (CT) of the abdomen. CT scanning revealed a 4.0 cm tumor in the tail of the pancreas (Fig. 1a), and a 0.5 cm tumor in segment VII (Fig. 1b) and a 0.4 cm tumor in segment III (Fig. 1c) of the liver. Endoscopic ultrasound fine-needle aspiration of the pancreatic tumor revealed an adenocarcinoma (Fig. 2). The patient was subsequently diagnosed with pancreatic cancer and liver metastasis. The serum carbohydrate antigen (CA) 19-9 level was elevated at 693 U/mL (normal range 0–37 U/mL).

Fig. 1.

Abdominal contrast CT. CT demonstrated a 4.0 cm tumor (arrow) in the tail of the pancreas (a). A 0.5 cm tumor (arrow) in segment VII of the liver (b) and a 0.4 cm tumor (arrow) in segment III (c) were also noted

Fig. 2.

Endoscopic ultrasound-fine needle aspiration. Endoscopic ultrasound showed a hypoechoic tumor in the tail of the pancreas (a). Fine needle aspiration of a pancreatic tumor revealed an adenocarcinoma by light microscopy (b)

The patient underwent chemotherapy with gemcitabine plus nanoparticle albumin bound–paclitaxel as outlined in Fig. 3. After four months (five cycles), the CA19-9 level was found to be elevated at 890 U/mL, with CT showing an enlarged liver metastasis. Chemotherapy was changed to modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) and the CA19-9 level subsequently declined to normal levels (36.2 U/mL) after 4 months (eight cycles). However, 3 months later (total 14 cycles), the CA19-9 level was 160 U/mL, increasing to 960 U/mL a month later, when the patient presented with neck and back pain, as well as shoulder stiffness. Contrast CT revealed that the sizes of the primary tumor and liver metastases remained unchanged. A positron emission tomography (PET)–CT revealed abnormal fluorodeoxyglucose (FDG) accumulation in the lesion of the pancreatic tail (maximum standardized uptake value [SUVmax] of 3.5) and liver (SUVmax 3.5) only. New lesions were not detected.

Fig. 3.

Clinical course from diagnosis. This graph demonstrates changes in the serum CA19-9 level and the timeline from initial diagnosis. GEM + nab-PTX (GnP) gemcitabine, naoparticle albumin bound–paclitaxel modified, FOLFIRINOX (mFFX) fluorouracil, leucovorin, irinotecan, and oxaliplatin, LMC leptomeningeal carcinomatosis, CA19-9 cancer antigen 19–9

Within 3 weeks, symptoms had not improved and the patient was consequently admitted to hospital with weakness in the lower extremities, dysarthria, and neck stiffness, and an elevated CA19-9 level (5167 U/mL). Contrast CT of the brain showed evidence of leptomeningeal enhancement of the right and left cerebellar hemispheres (Fig. 4). Laboratory analysis of cerebrospinal fluid (CSF) revealed an elevated protein level of 239 mg/dL (normal range 15–45 mg/dL) and a decreased glucose level of 30 mg/dL (normal range 50–75 mg/dL). The opening intracranial pressure was 120 mmH₂O (normal range 8–15 mmH₂O) and an elevated CA19-9 level of 52,845 U/mL was detected. Cytological examination of CSF revealed atypical cells.

Fig. 4.

Head contrast CT. CT revealed leptomeningeal enhancement that involved the right and left cerebellar hemispheres (arrows)

The patient was diagnosed as having LMC with pancreatic cancer based on contrast CT findings and the elevated CA19-9 level in the CSF. A lumber puncture was performed only once due to continual movement by the patient. Repeat lumber puncture was not done due to the progressive disease. Because of a Karnofsky performance status (KPS) score of less than 60, the patient received best supportive care and died 15 days after admission.

Discussion

LMC occurs in 5–8% of cases with solid tumors such as lung, breast, and melanoma [2]. LMC is extremely rare in patients with pancreatic cancer. To our knowledge, only 12 cases [3–14] of pancreatic cancer with LMC have been previously reported (Table 1).

Table 1.

Reported cases of leptomeningeal metastasis with pancreatic cancer

References	Age/gender	Initial symptoms	Imaging findings	CSF cytology	Treatment for LMC	Outcome
Ferreira [3]	49/M	Headache, vomiting	CT: negative	Malignant cells (initial)	Intrathecal chemotherapy (methotrexate, cytarabine)	Died after 1.5 m
Yagi [4]	64/M	Headache, vomiting	MRI: positive	No malignancy (initial)	Whole-brain radiation	Alive after 20 m
Grira [5]	55/M	Headache, vomiting	CT: negative	Malignant cells (two times)	Palliative care	Died after 2 m
Hirota [6]	64/M	Headache, vomiting	MRI: positive	NA	Whole-brain radiation	Died after 38 days
Minchom [7]	59/M	Leg flank pain, seizure	MRI: positive	Malignant cells (initial)	Intrathecal chemotherapy (methotrexate, cytarabine)	Died after 1.5 m
Blows [8]	72/M	Hypoacusis	negative	No malignancy (initial)	Intravenous dexamethasone	Died after < 1 m
Anne [9]	45/F	Headache, slurred speech agitation	CT, MRI: positive	Malignant cells (initial)	Palliative care	Died (date NA)
Rao [10]	57/M	Seizure	MRI: positive	Atypical cells (initial)	Whole-brain radiation	NA
Hong [11]	72/F	Headache, ataxia slurred speech	MRI: positive	Atypical cells (initial)	Palliative care	Died after 8.5 m
Yoo [12]	80/M	Headache, seizure	MRI: positive	Atypical cells (three times)	Whole-brain radiation	NA
Naqvi [13]	58/F	Confusion, agitation	CT: positive	Malignant cells (initial)	Intravenous dexamethasone	Died after < 1 m
Johnson [14]	53/M	Headache, dysarthria	MRI: positive	NA	Whole-brain radiation	Died after 12 m
Our case	59/M	Neck and back pain shoulder stiffness	CT: positive	Atypical cells (initial)	Palliative care	Died after 15 days

NA not available

Clinical symptoms of LMC are varied and non-specific, with common findings that include increased intracranial pressure, cranial nerve palsy, and spinal nerve root palsy, depending on the invasion site. Increased intracranial pressure presents as a headache, nausea/vomiting, and stiffness in the neck. Cranial nerve palsy includes III, IV, VI, VII, and VIII, and leads to diplopia, facial weakness, and hearing loss [15] while spinal nerve root palsy presents as limb weakness, sensory loss, and radicular pain (e.g. neck, back). An early diagnosis of LMC in pancreatic cancer is difficult due to varied or non-specific symptoms, and because the coexistence of LMC with this cancer is relatively unknown.

Based on a literature review, five cases of pancreatic cancer with synchronous LMC and seven cases with metachronous LMC have been reported. All cases were examined for cranial nerve palsy, increased intracranial pressure, and disturbance of consciousness. No specific findings for both synchronous and metachronous cases were found. Of the seven metachronous cases, only one was diagnosed with a rise in the CA19-9 level.

The gold standard for a diagnosis of LMC is cytological evidence of malignant cells in the CSF [16]. Initial CSF cytology is positive in only 50% of patients, which can improve to 90% after three lumbar punctures [16–18]. CSF analysis revealed a high opening intracranial pressure, as well as elevated protein and tumor marker levels, and a low glucose level [19]. A diagnosis is sometimes difficult to make with negative CSF cytology. T1-weighted gadolinium-enhanced magnetic resonace imaging (MRI) [18], and contrast CT [19] imaging of the brain can support a diagnosis. In typical radiological findings, LMC shows a diffuse leptomeningeal contrast enhancement, and multiple nodular deposits in the subarachnoid space, cerebellar folia, or cortical surface [20]. The sensitivity of MRI is approximately 70–87% [20–23], higher than for initial CSF cytology, whereas that of contrast CT is 30% [24].

The treatment of LMC has been stratified according to each patient's risk group. For example, patients in a good risk group (KPS score > 60, no major neurologic deficits, minimal systemic diseases) may undergo radiotherapy, as well as intrathecal or systemic chemotherapy, to improve or stabilize their neurological function and quality of life, and to prolong survival [10, 12]. Whole-brain radiotherapy [25] may be effective for symptoms caused by cranial nerve palsy and, in particular, spinal nerve root palsy. Systemic chemotherapy is limited to that which penetrates the blood–brain barrier; chemotherapeutic agents used have included high-dose methotrexate, and high-dose cytrabine [26]. Commonly used intrathecal agents include methotrexate and cytarabine in combination with hydrocortisone [16]. Patients in a poor risk group (KPS score < 60, multiple serious major neurologic deficits, bulky central nervous system disease, encephalopathy) usually receive palliative care. If the prognosis is extremely poor, the median overall survival is between 4 and 8 weeks without any treatment [18].

In our case, the patient presented with only neck pain, shoulder stiffness, and back pain thought to be a radicular syndrome so that a diagnosis of LMC was difficult. The KPS score at the onset of the initial symptoms was > 60; if LMC had been diagnosed earlier, the patient would have received appropriate treatment. Since cranial nerve or increased intracranial pressure symptoms were not apparent, LMC was not immediately identified. An imaging examination of the brain or a lumber puncture were not performed immediately, which led to the delayed diagnosis.

Initial CSF cytology revealed only atypical cells, but the patient had a high CA19-9 level and so additional CSF examinations were warranted. However, the patient was unable to rest because of continual movement. Repeat lumber puncture was not performed due to the progressive disease. If LMC had been considered earlier, it may have been possible to make a diagnosis of LMC with cytology. Moreover, contrast CT revealed enhancement of the right and left cerebellar hemispheres, leading to a diagnosis of leptomeningeal metastasis. The patient had encephalopathy and a KPS score < 60 when diagnosed, so received best supportive care. LMC or brain metastasis should be differentiated when the CA19-9 level becomes abnormally elevated in a short period of time and no new lesions are revealed on the chest and abdominal CT or PET–CT. Since LMC may progress rapidly after the appearance of symptoms, as in our case, LMC should be considered when a rapid increase in a tumor marker or new symptoms are found.

Conclusion

LMC associated with pancreatic cancer is exceedingly rare. A delayed diagnosis leads to fewer treatment options, a devastated quality of life, and a poor prognosis. The possible presence of LMC in pancreatic cancer should be heeded when a serum tumor marker rapidly becomes elevated despite control of primary or metastatic sites.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.