Leptomeningeal Disease in Pancreas Ductal Adenocarcinoma: A Manifestation of Longevity

Abstract

Background/Objectives:

Pancreatic adenocarcinoma (PDAC) metastatic to the leptomeninges is a rare and lethal event. Leptomeningeal disease (LMD) research is limited in PDAC, and insights into clinical descriptors, possible disease predictors, and treatment strategies is necessitated.

Methods:

Memorial Sloan Kettering databases were queried with Institutional Review Board approval to identify patients with LMD and PDAC treated between January 2000 and June 2020. Medical record review was used to abstract clinical, genomic, pathologic, and radiographic data. Overall survival was calculated from date of PDAC diagnosis to date of death. Previously published literature on LMD from PDAC was reviewed.

Results:

Four patients with LMD from PDAC were identified, two males and two females. Age at diagnosis ranged from 57 to 68 years. All four patients had predominant lung metastasis and a relatively low burden of intra-abdominal disease. Somatic testing indicated alterations typical of PDAC and no PDAC defining pathogenic germline mutations were identified. An extended clinical course prior to LMD diagnosis was observed in all patients, ranging from 16 to 148 months. Upon diagnosis of LMD, three patients elected for supportive care and one patient received a limited course of craniospinal radiation. The median survival following diagnosis of LMD was 1.6 months (range 0.5–2.8 months).

Conclusions:

LMD from PDAC is a rare occurrence that may be more frequent in patients with lung metastasis and/or a more indolent clinical course. Following diagnosis of LMD, prognosis is poor, and survival is short. New treatment strategies for this manifestation of PDAC are needed.

Background

Pancreatic ductal adenocarcinoma (PDAC) is a challenging malignancy to treat, with an overall five-year survival rate of less than 10%^{1, 2}. At least 50% of patients present with metastatic disease. Sites of metastasis commonly include the liver, lymph nodes, peritoneum, and lungs. In comparison, metastasis to the leptomeninges is very rare³. Leptomeningeal disease (LMD) is metastasis to the arachnoid and pia mater, and often is diagnosed concurrently with dural and/or parenchymal brain involvement ². LMD is detected in 5–8% of patients with solid tumors, and typically occurs in patients with breast, lung, and melanoma malignancies⁴. In PDAC, metastasis to the brain or central nervous system (CNS) is estimated to occur in approximately 0.6% of patients⁵. However, autopsy reports indicate that the actual incidence of LMD is higher than clinically reported ⁶. Data suggests that LMD will become increasingly common as cancer patients continue to live longer^{7, 8}.

Multi-agent systemic chemotherapies, such as FOLFIRINOX (5-fluorouracil, oxaliplatin, leucovorin, irinotecan), gemcitabine/nab-paclitaxel, and liposomal irinotecan/5-fluorouracil, have improved progression-free survival (PFS) and overall survival for PDAC patients^9–11. In addition, targeted genetic therapies have shown to extend PFS in genomically defined subsets of patients¹². As disease control continues to improve for PDAC patients, we hypothesize LMD may be more frequently observed.

Upon diagnosis of LMD, the median survival time of PDAC patients is a few short weeks to several months^{3, 8}. LMD is commonly diagnosed with cerebrospinal fluid (CSF) cytology and/or contrast enhanced MR imaging ¹³. Indicators of possible LMD observed in CSF include increased opening pressure, elevated protein levels, and decreased glucose levels and positive cytology^{13, 14}. LMD typically manifests in the form of headaches, mental status changes, confusion, seizures, diplopia, poor balance and weakness^{8, 15}. The remarkably poor prognosis can be partially attributed to the common occurrence of LMD in the setting of systemic disease¹⁴. Additionally, the blood brain barrier reduces the efficacy of chemotherapeutic agents in permeating the metastasis^{6, 16}. Although treatment guidelines are limited, common approaches include whole-brain and focal spinal radiation, continuation of systemic chemotherapy, and/or intrathecal chemotherapy (IT)^{2, 6}. The aim of treatment is to maximize quality of life and preserve neurologic functioning^{2, 17}.

The analysis herein aims to evaluate and characterize LMD in PDAC and identify possible predictive clinical descriptors for LMD. Specifically, this analysis focuses on LMD and not brain metastasis from PDAC¹⁸.

Methods

Upon Institutional Review and Privacy Board approval and oversight with waiver of consent, Memorial Sloan Kettering databases were queried to identify patients with PDAC metastatic to the leptomeninges treated between January 2000 and June 2020. The search was specified to identify patients with pathology reports and PDAC and radiology reports containing the terms “leptomeningeal” or “brain metastasis,” billing codes for neoplasms of the meninges or CNS (ICD: C70.1, C79.32, C79.40, C79.490), or pathology reports indicating malignant cells in the CSF. Medical records were retrospectively reviewed to abstract the clinical and pathologic characteristics of patients who met the inclusion criteria. Data abstracted included age and stage at presentation, sites of metastasis, treatment regimens and genomic profiles, including germline and somatic mutations. The features of leptomeningeal metastasis were further detailed with observed neurologic symptoms, methods of diagnosis (MRI, CT, and/or CSF cytology), treatment strategies and outcome data.

A literature review was also conducted to identify the current state of knowledge of PDAC metastatic to the leptomeninges.

Results

Our initial search identified 104 patients. Ninety-five patients were excluded for not having LMD and five patients were excluded for not having PDAC (Figure 1). Four patients ultimately met inclusion criteria (Table 1). Two patients were male and two were female. The median age at diagnosis of PDAC was 63 years (range 57–68 years). Two patients presented with PDAC with stage II disease and two presented with stage IV disease. The median age at diagnosis of LMD was 70 (range 58–76 years). All patients had predominant lung metastasis and no liver metastasis. All patients underwent MR imaging that confirmed the diagnosis of LMD. Three patients did not receive further active therapy and one patient received a limited course of craniospinal radiation. The median OS was 65 months (range 18–149 months) and the median survival post diagnosis of LMD was 1.6 months (range 0.5–2.8 months).

Figure 1:

Consort Diagram

Table 1.

Summary of PDAC Patients with Leptomeningeal Disease

	61, Female	68, Male	57, Female	65, Male
Year of PDAC Dx	2006	2009	2018	2018
Stage at Diagnosis	II, II (Two primaries)	II	IV	IV
Surgery	Distal pancreatectomy Whipple/completion pancreatectomy	Distal pancreatectomy	No	No
Lines of Treatment Before LMD Dx	3	8	4	2
Year of LMD Dx	2018	2018	2020	2020
LMD in Spine	No	No	Yes	No
Other sites of Met.	Lung, lymph nodes, soft tissue, bone, brain	Lung, lymph nodes, adrenal, bone, brain	Lung	Lung, lymph nodes, peritoneum
Neurologic Symptoms at LMD Dx	Nausea, headache, confusion, vision loss, facial twitching	Nausea, headache, confusion, change in mental status	Nausea, headache, dizziness	Nausea, headache, neck stiffness, diplopia, dizziness
MRI/CT	MRI: Positive CT: Negative	MRI: Positive CT: Negative	MRI: Positive	MRI: Positive
MRI Impression	Leptomeningeal disease predominantly in the posterior fossa including about the cerebral aqueduct and in the right frontal operculum	Slightly increased size of lesions suspicious for metastases, again representing either parenchymal metastases or leptomeningeal deposits with parenchymal invasion	Superficial enhancing foci in the posterior aspect of the cervical cord, representing leptomeningeal disease	Leptomeningeal enhancement consistent with leptomeningeal carcinomatosis
Lumbar Puncture Analysis	None	Cytology: Suspicious for carcinoma Glucose: 92 mg/dL Protein: 56 mg/dL	Cytology: Non-malignant Glucose: 60 mg/dL Protein: 42 mg/dL	Cytology: Malignant cells Glucose: 106 mg/dL, 102 mg/dL Protein: 34 mg/dL, 21 mg/dL
Germline Mutations	MUTYH	-	-	-
Somatic Mutations	PDAC Primary: KRAS G12D, ATM	Lung: KRAS G12D, TP53, DNMT3A, NTRK1, PTPRT, POLE Adrenal: KRAS G12D, TP53, CARD11, DNMT3A, NTRK1, PTPRT, STAT3	CSF: KRAS G12R, TP53, MYC, CDKN2B, CDKN2Ap, SMAD4	Insufficient tissue
Tumor Mutation Burden (TMB) and Microsatellite Instable (MSI) Sensor Score	PDAC Primary: TMB 2 mt/Mb, MSI Sensor Score 0.11	Lung: TMB 4.9 mt/Mb, MSI Sensor Score 0 Adrenal: TMB 6.1 mt/Mb, MSI Sensor Score 0	CSF: TMB: 2.6 mt/Mb, MSI Sensor Score 0.39	Insufficient tissue
Overall Survival	12.4 years	9.2 years	1.5 years	1.6 years
Survival following LMD Diagnosis	0.5 months	2.8 months	2.1 months	1.1 months

Case Summaries

Patient 1

In 2006, a 61-year-old female underwent a pancreaticoduodenectomy for AJCC stage IIA PDAC (T3N0M0). The patient received adjuvant gemcitabine, capecitabine, and docetaxel and was disease free for five years. In 2012, the patient underwent a distal pancreatectomy and splenectomy, and pathology revealed a second primary PDAC. Lung metastasis was soon identified, and the patient received gemcitabine/nab-paclitaxel for 3.5 years. Somatic testing of her primary tumor demonstrated a KRAS and ATM mutation, with a tumor mutation burden (TMB) of 2 mutations per megabase (mt/Mb) and a microsatellite instable (MSI) sensor score of 0.11 (microsatellite stable). Germline testing identified an MUTYH mutation. Six years after the second PDAC primary was diagnosed, the patient reported confusion, vision loss, and headaches. An MRI confirmed brain metastasis and LMD. Over the next three weeks, the patient experienced seizures, agitation and confusion. She elected for palliative care and transferred to hospice, passing away three weeks after her diagnosis of LMD. Table 1 summarizes the data for all four patients.

Patient 2

In 2009, a 68-year-old male underwent a distal pancreatectomy and splenectomy and received adjuvant gemcitabine for a body PDAC, AJCC stage IIA (T3N0M0). One year later, the patient was treated with chemoradiation for locally recurrent disease. Following three years of disease-free survival, a solitary lung nodule was resected. Somatic testing of the metastasis revealed KRAS, TP53, DNMT3A, NTRK1, PTPRT, and POLE mutations, with a TMB of 4.9 mt/Mb and an MSI sensor score of 0 (microsatellite stable). He initiated FOLFIRINOX two years later in the setting of disease progression in the lungs, lymph nodes, and adrenal glands. Somatic testing of an adrenal metastasis revealed KRAS, TP53, CARD11, DNMT3A, NTRK1, PTPRT, and STAT3 mutations, with a TMB of 6.1 mt/Mb and an MSI sensor score of 0. After a favorable therapy response, the patient received combination CTLA-4 and CCR4 inhibitors on a clinical trial with transient benefit. Nine years into his disease course, the patient experienced clinical decline, fever, nausea, and headache. A CT scan demonstrated lesions in the brain and an MRI confirmed LMD. Cerebrospinal fluid (CSF) cytology demonstrated cells suspicious for carcinoma. Laboratory analysis indicated elevated protein levels of 56 mg/dL (reference range 21–38 mg/dL) and elevated glucose levels of 92 mg/dL (reference range 38–82 mg/dL). Given further clinical decline, supportive care was pursued, and the patient died three months after his LMD diagnosis.

Patient 3

In 2018, a 57-year-old female was diagnosed with stage IV PDAC metastatic to the lungs and initiated FOLFIRINOX. Germline testing was negative for pathogenic mutations. With regression of lung metastasis and a stable pancreas tumor, she underwent definitive chemoradiation to the primary tumor. The patient subsequently received FOLFIRI and gemcitabine/nab-paclitaxel. Sixteen months after her diagnosis of PDAC, the patient developed headache, nausea, and dizziness. An MRI brain demonstrated LMD, also evident on spine MRI (Figure 2b). Cytology from lumbar puncture was negative for malignant cells, although somatic KRAS, TP53, and SMAD4 mutations were observed, felt to be consistent with the presence of malignant cells. The TMB of the sample was 2.6 mt/Mb and the MSI sensor score was 0.39. CSF analysis identified elevated protein levels of 42 mg/dL and normal glucose levels. The patient transitioned to hospice, where she died two months following her diagnosis of LMD.

Figure 2:

Leptomeningeal disease on MRI. Panel A demonstrates sulcal enhancement in the frontal lobe on sagittal T1-weighted post contrast imaging; Panel B demonstrates small cervical leptomeningeal nodule on sagittal T1-weighted post contrast imaging.

Patient 4

A 65-year-old male was diagnosed with PDAC metastatic to lungs and lymph nodes. He received gemcitabine/nab-paclitaxel and a PD-1 inhibitor with a partial response maintained for five months. The patient developed drug-related pneumonitis and therapy was subsequently switched to modified FOLFIRINOX. One year later, he developed nausea, headaches, weakness, diplopia and unsteadiness. An MRI identified LMD in the brain without spinal involvement (Figure 2a). The patient underwent two lumbar punctures, both of which were positive for malignant cells, the second performed to improve headaches (Figure 3). Further CSF examination identified normal protein levels of 34 mg/dL and elevated glucose levels of 102 mg/dL. The patient was enrolled on a clinical trial of proton craniospinal radiation for LMD, but experienced worsening gait, confusion, nausea, and headaches. In view of progressive clinical decline, radiation therapy was terminated, and the patient died one month after his LMD diagnosis.

Figure 3:

Cytospin slide from cerebrospinal fluid specimen shows clusters of malignant epithelial cells with flocculent, vacuolated cytoplasm and a rare mitotic figure. (Papanicolaou stain, 600x)

Discussion

Leptomeningeal disease (LMD) in the setting of pancreatic adenocarcinoma (PDAC) is a rare occurrence that further complicates an already aggressive malignancy. Herein, we analyzed a series of patients to further detail clinical, genomic, and radiographic characteristics of PDAC patients with LMD.

Our literature search revealed that the majority of LMD research in PDAC consists of single case reports and these data are summarized in Table 2. These case reports include ten male and three female patients between the ages of 45 to 80 years at diagnosis of PDAC. Following a diagnosis of LMD, seven patients pursued whole brain radiation and/or chemotherapy. OS ranged from 1.5 months to 41 months and survival post LMD diagnosis ranged from 15 days to 12 months.

Table 2.

Case Reports of Leptomeningeal Disease in Pancreas Cancer

Ref. (year)	Age, M/F	LMD Synchronous or Asynchronous	Other Sites of Met.	Neurologic Signs	Positive or Negative Imaging	CSF: Malignant or Atypical Cells	CSF: Other characteristics	Treatment for LMD	Overall Survival	Survival Post LMD Diagnosis
Ikeda (2020)17	59, M	Asynchronous	Liver	Neck pain, back pain, dysarthria	CT: +	Atypical	Elevated protein, decreased glucose	Palliative	3–4 months	15 days
Ceccon (2020)16	51, M	Asynchronous	Kidney, spleen, lung	Headache, neck stiffness	MRI: +	Negative	Elevated protein, decreased glucose, mild pleocytosis	Gemcitabine/nab-paclitaxel	35 months	3 months
Johnson (2018)19	53, M	Asynchronous	Liver, brain	Headache, dysarthria	MRI: +	Not reported	Not reported	Whole-brain radiation, intrathecal topotecan, capecitabine, irinotecan, bevacizumab	41 months	12 months
Yoo (2015)3	80, M	Synchronous	Liver	Headache, seizure	MRI: +	Negative	Slightly elevated protein, slightly decreased glucose	Whole-brain radiation	Not reported	Not reported
Naqvi (2015)39	58, F	Asynchronous	Lymph nodes	Confusion, agitation	CT: +	Malignant	Not reported	Palliative	2 months	1 month
Hong (2014)8	72, F	Asynchronous	Liver, peritoneum	Ataxia, slurred speech, headache	MRI: +	Atypical	Elevated protein	Palliative	8.5 months	2.5 months
Madhurima (2013 40	45, F	Asynchronous	Peritoneum, lymph nodes	Headache, slurred speech, weakness, agitation	CT: + MRI: +	Malignant	Elevated protein	Palliative	Not reported	Not reported
Rao (2013)24	57, M	Synchronous	Lung, liver	Seizure, weakness, neck stiffness, photophobia	MRI: +	Atypical	Elevated protein	Whole-brain and spine radiation	Not reported	Not reported
Blows (2012) 41	72, M	Post-mortem	Liver, lymph nodes	Deafness, facial nerve palsy, bulbar nerve palsy, ataxia, consciousness	MRI: −	Negative	Elevated protein, decreased glucose	Palliative	Post-mortem report	Post-mortem report
Minchom (2010) 23	59, M	Synchronous	-	Leg flank pain, seizure	MRI: +	Malignant	Elevated protein, elevated white blood cell count	Intrathecal methotrexate and cytarabine, gemcitabine	1.5 months	1.5 months
Hirota (2008)20	64, M	Asynchronous	Vertebrae, peritoneum	Headache, vomiting	MRI: +	Not reported	Not reported	Whole-brain radiation	41 months	1 month
Grira (2007)22	55, M	Synchronous	Not reported	Bilateral vision loss, headaches, vomiting	CT: −	Malignant	Not reported	Palliative	2 months	2 months
Ferreira (2001)21	49, M	Asynchronous	Ribs, lymph nodes	Headache, vomiting, urinary retention, paraplegia	CT: −	Malignant	Elevated protein	Intrathecal methotrexate, cytarabine, thiotepa	6–7 months	1.5 months

A notable characteristic of our case series is that all four patients had an OS of at least 18 months following their initial PDAC diagnosis, with a range of 18 to 149 months. Previous case reports have also noted longer clinical courses of three to four years in patients who developed LMD, supporting the hypothesis that PDAC patients with a longer OS are more likely to develop LMD^{16, 19, 20}. However, it is important to note that LMD has also been reported in PDAC patients with shorter clinical courses and has been diagnosed synchronously^{3, 8, 17, 21–24}.

Further characterizing our cohort, all four patients had predominant lung metastasis and a relatively low burden of intra-abdominal disease. Notably, none of the patients had liver metastasis. Patient 1 and 2 were both noted to have lung metastasis at their first metastatic recurrence following surgical resection, a pattern suggesting relative biologic indolence²⁵. While most previous case studies observed LMD in the setting of metastatic disease, LMD in the setting of lung metastasis was not as common, noted in two out of thirteen previous literature reports^{15, 22}.

All patients in this cohort underwent germline genetic testing and only Patient 1 was identified to have a germline mutation (MUTYH), likely unrelated to her PDAC. Of the three patients with somatic testing, all three had a somatic KRAS (2 G12D, 1 G12R) mutation, and two had a TP53 mutation (Table 1). Although limited by the very small size of the cohort, these data do not support that PDAC patients with LMD are a genomically-defined subset. In contrast, lung cancer patients harboring an EGFR mutation are more likely to develop LMD. In an analysis of 5387 patients with lung cancer, 9.4% of patients with an EGFR mutation developed LMD in comparison to 1.7% of patients with wild-type EGFR²⁶.

In the past, LMD was most frequently diagnosed with CSF cytology. However, the sensitivity of CSF cytology is limited, as only approximately 50% of initial specimens yield malignant cells in patients with LMD. With recent improvements in visualization and quality, MR imaging is a standard to definitively diagnose LMD¹³. Of the three patients with CSF cytology analysis, one patient had positive malignant cytology, one specimen was noted to have cells “suspicious for carcinoma”, and one specimen was negative, although somatic mutations in KRAS, TP53, and SMAD4 were observed in this patient’s CSF, consistent with the presence of malignant cells. Our study and previous findings underscore MR imaging as a critical diagnostic tool for detection of LMD and highlights the sensitivity limitations of CSF cytology.

Prior research suggests that rare cell capture technology used to detect circulating tumor cells (CTC) improves CSF cytology sensitivity in detecting LMD. In a study by Pentsova et al, the sensitivity of CSF cytology, MRI, and circulating tumor cell (CTC) cytology was evaluated in 95 patients with various solid tumors suspicious for LMD. Receiver operating characteristic analysis revealed that CTC-CSF had the highest sensitivity of 93% (95% CI, 84–100%), with a specificity of 95% (95% CI, 90–100%), positive predictive value 90% (95% CI, 79–100%), and negative predictive value of 97% (95% CI, 93–100%)²⁷. In our study, Patient 4 was observed to have elevated CTC in his CSF. Increased use of CTC-CSF may aid in the early detection of LMD.

LMD is a prognostic indicator of a very poor outcome. In our cohort, all four patients had an OS of less than three months following LMD diagnosis, and three did not receive further therapy. In the past, IT has been preferred to X-ray-based photon craniospinal irradiation (CSI) due to toxicities. However, recent data suggests that patients without extra-CNS disease and high neurological functioning may experience greater benefit from x-ray-based photon CSI^{28, 29}. Additionally, the control CSI toxicity has improved with Helical TomoTherapy (HT), which allows for homogenous dose distribution, in contrast to the field junctions required by traditional linear accelerators^30–33. More recently, a phase I trial of CSI for solid tumor LMD using proton beam radiation demonstrated lower toxicity than reported with X-ray-based photon CSI and promising survival outcomes (median CNS PFS=7 months, OS=8 months)³⁴. Although further investigation is needed, improved patient selection and advancements in radiation makes CSI a possible treatment option for LMD patients^{28, 29}.

While many patients elect for palliative care, there are instances in which LMD from PDAC has been treated and briefly controlled. In the case study by Ceccon et al, the patient received gemcitabine/nab-paclitaxel following a diagnosis of LMD. The patient experienced clinical improvement for three months and CSF cytology demonstrated the elimination of tumor cells¹⁶. Previous research has shown that gemcitabine crosses the blood brain barrier, and therefore, could be effective in palliating LMD^{35, 36}. In the case study by Johnson et al, a patient fared exceptionally well following a diagnosis of LMD, living for an additional nine months. The patient received whole-brain radiation therapy followed by multiple lines of therapy including, intrathecal topotecan, capecitabine and irinotecan (CAPIRI) and bevacizumab¹⁹.

The optimal therapeutic strategy for LMD in the setting of PDAC is unknown given its rarity. In lung and breast cancer, there is a greater depth of knowledge. LMD is more frequent and most patients are treated for LMD. In a retrospective review of 233 patients with breast cancer and LMD, Abouharb et al observed that only 10% of patients went directly to hospice³⁷. Likewise, in an analysis of 171 patients with non-small-cell lung cancer, Nevel et al observed that 11% of patients transitioned straight to hospice post LMD diagnosis³⁸.

Median OS of lung and breast cancer patients following diagnosis of LMD remains comparable to those with PDAC. In the cohort from Nevel et al, median OS from LMD diagnosis was 4.2 months (95% CI 3.6–4.9)³⁸. In the cohort from Abouharb et al median OS from LMD diagnosis was 4.4 months for HER2+BC (95 % CI 2.8, 6.9), 3.7 months (95 % CI 2.4, 6.0) for HR+/HER2−BC, and 2.2 months (95 % CI 1.5, 3.0) for TNBC (p = 0.0002)³⁷. The remarkably poor prognosis and need for better treatment options is shared by patients with LMD in the setting of various solid tumors, including breast and lung cancers.

The key limitations of this study are the retrospective nature, single institution design and very small sample size accrued over an extended time period, although notably all four patients were diagnosed in recent years. Nonetheless, this analysis represents the largest series of PDAC patients with LMD.

Conclusion

LMD from PDAC is a rare diagnosis and is associated with relative longevity and may be more frequent in the setting of lung metastasis. Somatic driver oncogenic changes for patients with LMD appear typical of PDAC. Prognosis is poor and life expectancy is short following diagnosis of LMD. Further insight into therapeutic strategies for LMD from any solid organ malignancy is critically needed.