Leptomeningeal carcinomatosis in esophageal cancer: a case series and systematic review of the literature

Summary

The aim of this study was to more clearly define the clinical course of leptomeningeal carcinomatosis due to esophageal cancer. A single institution retrospective case series was conducted. Additionally, a systematic review of the literature was performed. We present a large case series (n = 7) of leptomeningeal carcinomatosis due to esophageal cancer. Our case series and systematic review of the literature report similar findings. In our series, we report a predominance of male patients (86%) with adenocarcinoma histology (77%). Variable onset of leptomeningeal involvement of esophageal cancer in relation to the original diagnosis of the primary disease (5 months to 3 years and 11 weeks) was noted. Disease progresses quickly and overall survival is poor, measured in weeks (2.5–16 weeks) from the diagnosis of leptomeningeal involvement. Four of our patients initiated whole-brain radiation therapy with only two completing the course prior to clinical deterioration. Our patient with the longest survival (16 weeks) received intrathecal topotecan and oral temozolomide. Leptomeningeal carcinomatosis secondary to esophageal cancer has a poor prognosis. A clearly beneficial treatment modality is lacking.

Introduction

Leptomeningeal carcinomatosis (LC) describes the cerebrospinal fluid (CSF) involvement of cancer. LC due to esophageal cancer (LC-E) is thought to represent a rare pattern of metastatic spread of this tumor.¹ In turn, little is known about the natural history of LC-E. It is possible that as incidence of esophageal adenocarcinoma subtype continues to increase and as systemic therapies improve extra-central nervous system (CNS) control, once rare patterns of spread may be more commonly encountered. We present a case series of patients from a single institution with cytologically proven LC-E (Table 1). This is one of the largest case series of patients with LC-E. Additionally, we report the results of a systematic review of the literature (Table 2).

Table 1

Case series of leptomeningeal carcinomatosis due to esophageal cancer

Case	Age	Gender	Histology	HER2	Imaging	Treatment-chemotherapy	Treatment-RT	Time to LC-E Dx (weeks)	Survival from Dx of Esophageal Cancer (weeks)	Survival from Dx of LC-E (weeks)
1	41	M	Poorly differentiated adenocarcinoma with signet-ring features	FISH wnl	MRI: brain and spine unremarkable.	IT thiotepa (10 mg) × 2 doses, followed by TMZ (150 mg/m2) for 5 days.	NA	21	37	16
2	52	M	Adenocarcinoma	FISH wnl	MRI: Brain: parenchymal and supra- and infratentorial LC	NA	WBRT (30 Gy)	50	55	5
					Spine: LC in the cervical, thoracic, and lumbar regions. Vertebral body metastases and epidural metastases.
3	72	M	Poorly differentiated adenocarcinoma	NA	MRI: Brain: infratentorial LC	NA	WBRT (17.5 Gy, out of a planned 35 Gy) extending down to C4 to include the spinal cord metastasis.	126	132	6
					Spine: intraparenchymal cervical spinal cord metastases, thoracic dural metastasis, thoracic vertebral body metastases.
4	57	M	Poorly differentiated carcinoma	NA	MRI: Brain: supra- and infratentorial LC.	NA	NA	47	52	5
					Spine: thoracic vertebral body metastasis.
5	70	M	Poorly differentiated adenocarcinoma	FISH wnl	MRI: Brain: infratentorial LC and brain metastases. Pineal lesion representing either metastasis or primary lesion.	NA	WBRT	37	43	6
					Spine: unremarkable.
6	69	F	Poorly differentiated adenocarcinoma	IHC 2+	MRI: Brain: infratentorial LC.	NA	NA	45	49	3.5
					Spine: diffuse LC, diffuse vertebral body metastases.
7	62	M	Moderately differentiated adenocarcinoma	FISH Wnl. NGS amplification.	MRI: Brain: infratentorial LC.	NA	WBRT (16 Gy of planned 20 Gy)	168	168	2.5



F, female; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; IT, intrathecal; IV, intravenous; LC, leptomeningeal carcinomatosis; LC-E Dx, diagnosis of leptomeningeal carcinomatosis due to esophageal cancer; M, male; MRI, magnetic resonance imaging; NA, not applicable/available; NGS, next generation sequencing (FoundationOne, Foundation Medicine, Inc., Cambridge, MA, USA); OS, overall survival; RT, radiation therapy; TMZ, temozolomide; TTP-CNS, time to progression in the central nervous system; WBRT, whole-brain radiation therapy; wnl, within normal limits (no evidence of amplification).

Table 2

Systematic review of leptomeningeal carcinomatosis cases due to esophageal cancer

Reference	Cases	Age	Gender	Histology	Imaging	CSF	Autopsy	Treatment	Time to LC-E Dx	TTP-CNS	OS
Akhavan and Navabii2	1	73	M	Squamous cell carcinoma	+MRI	NA	NA	WBRT (30 Gy)	NA	4 week	NA
Aulakh et al.3	2	61	M	Adenocarcinoma	+MRI	‘Malignant cells’	NA	NA	∼4 months	∼4 weeks	4 weeks
		53	M	Poorly differentiated adenocarcinoma	+MRI	‘malignant cells from poorly differentiated adenocarcinoma’	NA	RT (20 Gy brain, 30 Gy bulky spinal disease) followed by FOLFIRI + BEV, followed by cisplatibn/rinotecan + IT liposomal cytrabine	∼1 year	∼4 months	7 months
Henninger et al.4	1	54	M	Poorly differentiated adenocarcinoma	+MRI	‘Clusters and individual malignant cells with large mucin-containing vacuoles’	NA	NA	NA	NA	NA
Astner et al.5	1	70	M	Esophageal cancer	+MRI	‘Normal’ on 2 LPS. 3rd LP 32 cell/mm3, protein 1310 mg/l, glucose 29 mg/dl, lactate 2.4 mmol/l, ‘atypical cells’. 4th LP (after WBRT) revealed no malignant cells.	NA	IT MTX followed by RT to bulky disease at skull base (30 Gy)	0	∼2 months	∼6 months
Goddeeris et al.6	2	60	M	Moderately differentiated adenocarcinoma	+MRI	Protein 300 mg/dL, glucose 39 mg/dL, WBC 94 cells/uL, ‘malignant cells … very large … pleimorf9ic0, granular nuclear chromatin with some prominent nucleoli-some multinuclear and frequently small vacuoles’	NA	NA	0	NA	42 days
		46	M	Adenocarcinoma	+MRI	Protein 1075 mg/dL, glucose 23 mg/dL, WBC 15.2 cells/uL, ‘malignant cells’.	NA	Corticosteroids	4 months	NA	17 days
Wagemakers et al.7	1	52	M	Signet-ring cell adenocarcinoma	+MRI	‘Numerous undifferentiated cells’, protein 1.63 g/l, glucose 3.5 mmol/l	NA	RT skull base	3 years	NA	16 weeks
Okumura et al.8	1	68	M	Esophageal basaloid carcinoma	+MRI	‘Few cytokeratin positive cells’, CEA mRNA in CSF	NA	Cisplatin/fluoruracil	∼2 weeks	∼5.5 months	∼5.5 months
Abdo et al.9	1	50	M	Moderately differentiated adenocarcinoma	+CT	WBC 35 (8% poly, 84% lymphs, 8% monos), RBC 2, glucose 2.4 mmol/l, protein 1.35 g/l. ‘degenerate atypical cells with features of metastatic carcinoma’	NA	NA	NA	NA	NA
Girola et al.10	1	51	F	Adenocarcinoma	+CT	Glucose 4 mg%, protein 255 mg%, 43 cells/mm3, ‘malignant cells with multiple nuclei and prominent nucleoli … without vacuole(s)’	Carcinomatosis without parenchymal metastatic involvement	NA	26 months	NA	<1 week
Watanabe et al.11	1	49	M	Squamous cell esophageal cancer	+MRI	17 Cells/mm3, protein 138 mg/mL, + cytology	NA	Spinal RT (3 Gy)	NA	NA	1 month
Civantos et al.12	1	68	M	Poorly differentiated squamous cell carcinoma	+CT	WBC (50 poly, 17 monothelial cells) RBC 2, protein 107, glucose 17, ‘poorly differentiated malignant cells’	Grossly normal. Microscopically evident meningeal carcinomatosis with degeneration of multiple cranial nerves.	IT MTX, systemic cisplatin, followed by RT to skull base	0	NA	<4 weeks
Teare et al.13	1	49	M	Adenocarcinoma	-CT	WBC 3, RBC 0, protein 0.09 g/l, glucose 4.0 mmol/l. Cytology not evaluated.	Patchy meningeal deposits from metastatic adenocarcinoma.	NA	0	NA	NA
Coman et al.14	1	NA	NA	Signet-ring cell adenocarcinoma	+MRI	Cytology positive after multiple attempts.	NA	NA	NA	NA	NA
Tanaka et al.15	1	52	M	Moderately differentiated squamous cell carcinoma	+MRI	+	NA	NA	3 months	NA	NA
Giglio et al.16	7	71	M	Adenocarcinoma	+MRI	NA	NA	NA	Mean 418 days (SD ± 402)	NA	0 week
		66	M	Adenocarcinoma	+MRI			WBRT (22 Gy)			8 weeks
		65	M	Adenocarcinoma	+MRI			WBRT (9.26 Gy) + focal spine (15 Gy)			1 weeks
		66	M	Adenocarcinoma	+MRI			RT focal spine (30 Gy)			15 weeks
		61	M	Adenocarcinoma	+MRI			IT topotecan			6 weeks
		39	M	Adenocarcinoma	+MRI			IT MTX, then topotecan, then ara-C			20 weeks
		51	M	Adenocarcinoma	+MRI			Capecitabine			28 weeks



BEV, Bevacizumab; CEA, carcinoembryonic antigen; CSF, cerebrospinal fluid; CT, computed tomography; Dx, diagnosis; F, female; FOLFIRI, folinic acid, fluorouracil, irinotecan; IT, intrathecal; LC-E, leptomeningeal carcinomatosis due to esophageal cancer; LP, lumbar puncture; M, male; MRI, magnetic resonance imaging; MTX, methotrexate; NA, not available; OS, overall survival since the diagnosis of LC-E; RBC, red blood cells; RT, radiation therapy; TTP-CNS, time to progression in the central nervous system since the diagnosis of LC-E; WBC, white blood cells; WBRT, whole-brain radiation therapy; SD, standard deviation.

Patients and Methods

We reviewed the databases in the Esophageal Oncology and Neuro-Oncology programs at the University of Chicago for patients with diagnoses of esophageal cancer and LC. Charts and imaging were reviewed. The date of esophageal cancer diagnosis was defined as the date where pathology was obtained. The date of LC-E was defined as the date where CSF was obtained confirming the presence of malignant cells. This protocol was approved by the University of Chicago's Biological Science Division's Institutional Review Board.

Next, we performed a systematic review of the literature using PubMed. We used the following combinations of search terms to ascertain previously described cases of LC-E in the literature: LC, carcinomatous meningitis, esophageal cancer, and esophageal carcinoma. This search resulted in a list of 13 articles.^2–13,17 We then narrowed the search to the English-language articles (n = 12).^2–13 We also collected relevant information from the English-language abstract of a French language manuscript.¹⁴ All of the English-language articles were reviewed in full by an author (RVL) for descriptions of unique LC-E cases. Additionally, all of the references listed in the above noted articles were reviewed for specific mention of LC-E and two were found.^15,16 One of these was an English-language abstract of a relevant Japanese-language article.¹⁵ Twenty-three distinct cases of LC-E were described. Data regarding the patient age, gender, tumor histology, presence of imaging findings, CSF findings, autopsy findings, interval between initial diagnosis of esophageal cancer and LC-E, time to progression (TTP) in the CNS from diagnosis of LC-E, time to death from diagnosis of LC-E, and treatment of LC-E were tabulated. A similar table was created with the respective data for our case series. Our search method would have omitted any LC-E cases that would have been classified in clinical trials or non-esophageal cancer-specific case series. In either of these settings, LC-E would have likely comprised only a very small percentage of the cases. Details regarding the LC-E cases in those types of studies would be expected to be limited, and in turn it was felt they would not contribute significantly to an overview of LC-E.

Results

Case reports

Case 1

A 41-year-old man was diagnosed with metastatic esophageal adenocarcinoma following 2 months of dysphagia, chest pain, and weight loss. The patient had an extensive family history of gastrointestinal cancers but did not fit into a classical cancer inheritance syndrome pattern nor test positively for Li–Fraumeni or Lynch syndrome. Upper endoscopy demonstrated a distal esophageal ulcerative lesion. Biopsy revealed a poorly differentiated adenocarcinoma with signet-ring features. Biopsies of the stomach showed no evidence of malignancy. At the time of diagnosis, magnetic resonance imaging (MRI) showed diffuse bony metastases with extensive involvement of vertebral bodies. Computed tomography (CT) showed an enlarged gastrohepatic lymph node measuring 1.5 cm, prominent mesenteric lymph nodes, and multiple lytic and sclerotic bone lesions. The patient was immediately treated with six cycles of epirubicin, cisplatin, and fluorouracil. Treatment was complicated by nausea and vomiting for which he was placed on a chemotherapy holiday.

Shortly after his last chemotherapy and less than 2 months after his initial diagnosis, the patient presented with 3 days of worsening headache, photophobia, and intractable nausea and vomiting. Craniospinal MRI demonstrated a new focus of enhancement at the T3 vertebral body with slight anterior vertebral body compression suspicious for new metastasis. No radiographic evidence of LC was observed. CSF analysis was positive for tumor cells. Symptomatic elevated intracranial pressure that persisted despite dexamethasone and therapeutic lumbar punctures was relieved with a combination Ommaya reservoir and ventricular peritoneal shunt. The patient received two 10-mg doses of intrathecal (IT) thiotepa, given 4 days apart, along with oral temozolomide (150 mg/m² for 5 days). He tolerated the chemotherapy well and was discharged to home for palliative care. The patient died 37 weeks after initial diagnosis of esophageal cancer and 16 weeks after diagnosis of LC-E.

Case 2

A 52-year-old man was diagnosed with stage IV (T3N1M1) esophageal adenocarcinoma after 5 months of slowly progressing dysphagia and weight loss. Staging revealed extensive lymphadenopathy and liver metastases. Initial treatment course consisted of 12 cycles of leucovorin, fluorouracil, oxaliplatin (FOLFOX) with radiotherapy (RT) to the primary tumor (30-Gy, 3-Gy fractions). Restaging studies demonstrated partial response of metastatic disease.

Ten months after diagnosis, the patient presented with a syncopal episode preceded by severe nausea, headache, and gait instability. MRI revealed multiple enhancing parenchymal lesions supra- and infratentorialy as well as leptomeningeal lesions in the bilateral cerebellar hemispheres. The patient was treated with whole-brain radiotherapy (WBRT) to 30 Gy in 3-Gy fractions with concomitant dexamethasone. During treatment, he developed progressive confusion, lower back pain, bilateral lower extremity weakness, and urinary retention. MRI of the spine revealed multiple vertebral body metastases and enhancement throughout the entire cervical, thoracic, and lumbar CSF space. Adrenal metastases were also noted. No frank cord compression was observed. The patient's performance status rapidly declined and the patient was enrolled in hospice. The patient died 55 weeks after initial diagnosis of esophageal cancer and 5 weeks after diagnosis of LC-E.

Case 3

A 72-year-old man diagnosed with T3N1 poorly differentiated adenocarcinoma of the distal esophagus who presented with several months of slowly progressive dysphagia. He received induction chemoradiation (50.5-Gy photons with concurrent fluorouracil and cisplatin), followed by transhiatal esophagectomy. The patient has stage IVA ypT3N1. Risk factors included invasion into paraesophageal soft tissue with no lymphovascular or perineural space invasion, and 2/10 lymph nodes were involved without extranodal extension. Resection margins were free from tumor. Thirteen months following surgery, he developed recurrence at the proximal suture line and a right cerebellar lesion. The esophageal mass was treated with palliative radiation to 36 Gy and the cerebellar lesion was treated with gamma knife stereotactic radiosurgery to an unspecified dose. He was then given intravenous irinotecan single agent as palliative systemic therapy.

Approximately 2.5 years after diagnosis, the patient presented with slowly progressive fatigue, left-sided ptosis, and rightward leaning gait. MRI brain demonstrated areas of nodular enhancement between the folia of the cerebellum, nodular lesions anterior to the brain stem, and a lesion in the anterior upper cervical spinal cord. The radiographic findings were concerning for LC and confirmed with CSF positive for metastatic carcinoma. The patient was treated with WBRT extending the field to C4. During the course of radiation, the patient developed right facial weakness as well as worsening fatigue, unsteady gait, and left-sided ptosis. MRI of the spine revealed intraparenchymal lesions in the C-spine with the most prominent one at C2, as well as destructive lesions within the vertebral bodies of the thoracic spine, and a dural-based lesion posterior to the spinal cord at T2/3. Due to rapidly worsening neurological function, therapy was ceased and patient was enrolled in hospice. The patient received 17.5 Gy out of a planned 35 Gy. The exact date of death was unable to be obtained but was able to be approximated to a 2-week interval. The patient died approximately 132 weeks after his initial diagnosis and 6 weeks after diagnosis of LC-E.

Case 4

A 57-year old man was diagnosed with esophageal adenocarcinoma in February 2006. Liver and adrenal metastases were present at diagnosis. The patient started on chemotherapy with cisplatin and irinotecan. His course was complicated by anaphylaxis to cisplatin and he was switched to a regimen of carboplatin and irinotecan. The patient tolerated this therapy well and repeat imaging showed partial response.

About 10 months after diagnosis, the patient presented with lethargy and morning headaches associated with nausea and vomiting. Brain MRI revealed subtle small foci of enhancement in the right frontal lobe and right cerebellar hemisphere and the meninges overlying the cerebellar vermis. CSF analysis was positive for poorly differentiated carcinoma. Intracranial pressure was normal (13-cm H₂O) and the patient underwent placement of an Ommaya reservoir in preparation for IT liposomal cytarabine. The patient did not receive IT chemotherapy due to rapid clinical decline. He died approximately 52 weeks after initial diagnosis of esophageal cancer and 5 weeks after diagnosis of LC-E.

Case 5

A 70-year-old man initially presented with 5 month history of progressive dysphagia and chest pain. He was initially diagnosed with T3N1 gastroesophageal junction/distal esophageal poorly differentiated adenocarcinoma, Her-2-neu not amplified by fluorescence in situ hybridization (FISH). He was treated with curative intent using induction chemotherapy of FOLFOX followed by concurrent chemoradiation with carboplatin, paclitaxel, and focal radiation therapy to 50.4 Gy. He underwent an esophagectomy with final pathologic staging ypT3N1.

Approximately 8 months after his initial diagnosis and 2 months following completion of his definitive treatment, he presented with a 2-week history of progressive diplopia, dizziness, nausea, and severe weight loss. Systemic restaging demonstrated a new pleural effusion. Brain MRI revealed both parenchymal brain metastases as well as enhancement within the CSF space consistent with LC. CSF analysis demonstrated normal opening pressure (15-cm H₂O), mildly decreased glucose (49 mg/dL), mildly elevated protein (61 mg/dL), elevated cell count (12 cells/UL), and presence of malignant cells (Fig. 1). Due to worsening performance status, the patient enrolled in hospice. The patient passed away in hospice 43 weeks after initial diagnosis of esophageal cancer and 6 weeks following the diagnosis of LC-E.

Fig. 1

(a) Diff-quick stain. (b) Papanicolaou stain. Cerebrospinal fluid shows cells with hyperchromatic nuclei with irregular nuclear membranes pushed to the periphery by a mucinous vacuole. The cells have a typical morphology of ‘signet-ring cell’ in poorly differentiated adenocarcinoma.

Case 6

A 69-year-old woman presented with a few month history of progressive dysphagia, odynophagia, and pain radiating to back. She was diagnosed with TXN2M1 metastatic poorly differentiated esophageal adenocarcinoma, Her-2-neu not amplified on FISH. Genomic alterations identified include EGFR F795V, PIK3R1 N564D, TP53 Y205S, and PBRM1 splice. The patient was treated with FOLFOX with a good response to chemotherapy. Approximately 5 months after her diagnosis, she was noting worsening back pain and weakness. On evaluation, she was found to have an intradural lesion involving the cauda equina. She underwent a complete resection of this revealing a myxopapillary ependymoma (WHO grade I). Following surgery she resumed chemotherapy with continued response.

Ten months following her initial diagnosis, she developed headaches, falls, and altered mental status. On evaluation, her systemic disease was noted to have remained stable. Brain MRI revealed significant enhancement within the CSF space (Fig. 2). CSF analysis revealed presence of metastatic adenocarcinoma with signet-ring features. No evidence of disseminated ependymoma was noted. CSF protein (121 mg/dL) and cell count (14 cells/UL with 87% representing malignant cells) were both elevated. The patient received palliative steroids. Due to the patients age and poor prognosis, the patient and her family decided on enrollment in hospice. She passed away 49 weeks following initial diagnosis and 3.5 weeks following diagnosis of LC-E.

Fig. 2

Sagital T1 postcontrast magnetic resonance imaging images. (a) Enhancement is evident between the cerebellar folia on the image of the brain. (b) Enhancement is apparent on the anterior and posterior surfaces of the spinal cord as well as between the cerebellar folia on the cervical spine imaging. (c) Enhancement is again noted on the anterior and posterior surfaces of the spinal cord on the thoracic spine imaging.

Case 7

A 62-year-old man was diagnosed with T3N1 moderately differentiated esophageal adenocarcinoma. While Her2 amplification was not detected via FISH, it was noted via next generation sequencing. Additional genomic alterations identified include AKT3 amplification, CDK6 amplification, CDKN2A L32fs*9, DNMT3A R882H, TP53 R249S. The patient underwent surgery followed by FOLFOX (minus oxaliplatin) plus GDC-0449 or placebo. With progression of disease, he was switched to ASG-5ME (a monoclonal antibody to SLC44A4 conjugated to Monomethyl auristatin E). He developed additional systemic progression. Synchronous with this, he developed mild head discomfort and nausea upon awakening in the mornings. MRI brain revealed subtle enhancement in the posterior fossa concerning for LC-E. CSF analysis revealed a slightly elevated opening pressure but was otherwise unremarkable. There was no evidence of malignant cells. The patient was initiated on taxotere/trastuzumab for the treatment of his systemic disease with plans for WBRT between the first and second cycle. The patient developed progressive fatigue and hyponatremia due to syndrome of inappropriate diuretic hormone secretion as well as vocal cord paralysis leading to shortness of breath requiring tracheostomy. His clinical course was further complicated by aspiration pneumonia.

Approximately 8 weeks after his first CSF analysis, he developed intermittent diplopia leading to a second evaluation. Opening pressure was again slightly elevated with CSF, this time revealing malignant cells. Palliative WBRT and steroids were initiated. The patient received four fractions (16 Gy) before WBRT was held after a cardiac arrest. Patient subsequently enrolled in hospice and died 198 weeks after initial diagnosis of esophageal cancer and 2.5 weeks after diagnosis of LC-E.

Review of the literature

Our search revealed 12 English-language articles and published abstracts addressing LC-E detailing 23 cases. The majority of the described patients were male (21/22, 95%) with a mean age of 58 (range 39–73 years). Adenocarcinoma was the histology most frequently encountered (17/22, 77%), although other histologies were reported as well. The diagnosis of LC-E ranged from synchronous with the diagnosis of extra-CNS esophageal cancer up to 3 years after the initial esophageal cancer diagnosis. Almost all of the cases reported findings on either MRI or CT raising concern for a pathologic process within the CSF space. These radiographic findings ranged from the typical enhancement seen with LC deep within the sulci or between the cerebellar folia to slightly more atypical radiographic findings mimicking primary CNS tumors. The majority of patients also demonstrated evidence of malignancy on evaluation for CSF. However, CSF analysis was not performed or reported in all of the cases. No other CSF parameters were definitively associated with a diagnosis of LC-E. Only three patients underwent autopsy, all of whom demonstrated findings typical of LC.

Prognosis of LC-E was universally grim. There were no long-term survivors reported. Survival from the time of diagnosis of LC-E ranged from less than a month up to 7 months. Due to inconsistent reporting of survival from the time of diagnosis of LC-E, a reliable median or mean survival can not be calculated. It is not completely clear from the reports what percentage of patients died of progressive disease in the CNS or systemically. A number of the reports are suggestive that CNS progression was the primary driver of morbidity and mortality. No consistent imaging protocol was employed to follow these patients. No consistent treatment protocol was followed. Management included palliative care, steroids, radiation therapy, systemic chemotherapy, and IT chemotherapy. Due to the limited number of cases inferences of potential benefit from specific treatment, regimens can not be made.

Discussion

Our case series (n = 7), one of the largest reported, with the addition of those already noted in the literature describe a total of 30 cases of LC-E. While still a rare pattern of spread, there is the potential that it may be more commonly encountered as the incidence of esophageal adenocarcinoma increases.¹⁸ Among our seven cases, all had adenocarcinoma with no increase in HER2 expression via FISH in those evaluated and one patient with HER2 amplification via next generation sequencing (Table 1). In the previously described cases, the majority had adenocarcinoma (70%, n = 16), with a smaller number with squamous cell carcinoma (17%, n = 4), basaloid cancer (4%, n = 1), or undefined esophageal cancer (9%, n = 2). Only a limited number of our patients (detailed in cases 6 and 7) underwent additional genetic analyses of their primary tumor tissue. The majority of our patients were male (86%, n = 6) similar to what has previously been described (95%, n = 21), reflecting at least in part a higher incidence of esophageal cancer in men. Among our cases, the time interval from initial diagnosis of esophageal cancer to diagnosis of LC-E ranged from 5 months to 3 years and 11 weeks with a median of 45 weeks (mean = 70 weeks). For the previously described cases this interval ranged from synchronous to 3 years. There appears to be some heterogeneity in the interval between diagnosis of esophageal cancer and its clinical involvement of the CSF. Data regarding TTP in the CNS in both our study population and the prior literature is limited. This is secondary to the lack of stability of CNS disease in the majority of patients and their rapid progression of clinical neurologic symptomatology. Median overall survival (OS) from the diagnosis of LC-E in our cases was 5 weeks (range 2.5–16 weeks, mean = 6.3 weeks). These findings echo similar findings in the previously described cases with a median OS of 6 weeks (range < 1 week to 7 months, mean ≈ 11 weeks). There were no long-term survivors in either our case series or among previously described patients.

No consistent imaging modality was employed to evaluate our patients or those who have been previously described. Additionally, there was no consistent schedule for restaging of the CNS. Most (86%, n = 6), but not all, of our patients had imaging findings consistent with LC. This is similar to what has been previously described (95%, n = 21 with radiographic findings suggestive of LC). These radiographic findings most often consisted of enhancement infratentorially between the cerebellar folia, as exemplified by Figure 1. All of our patients underwent CSF evaluation and were found to have malignant cells. In the majority malignant cells were detected with a single LP. In one patient, malignant cells were detected 8 weeks after the initial nondiagnostic LP. It is possible that patients with LC-E, but no evidence of malignancy on CSF analyses would not have been included in our study. The limited number of CSF samples limits the power of our analyses. We present CSF data (Table 3) to provide a preliminary understanding of CSF results of LC-E. Opening pressure in the majority of the cases where it was checked was within normal limits (mean 18.7-cm H₂O). Seventy-five percent (6/8) of CSF samples had abnormal glucose with both decreased (n = 3) and increased (n = 3) levels compared with institutional norms. Protein was also abnormal in 75% (6/8) with it elevated in most (n = 5) of these cases. Cell count was also elevated in the majority of samples (n = 6, 75%). None of these findings are specific to LC-E. Details of CSF analyses from the literature were not consistently reported. (Table 2) While none of our cases underwent autopsy, the three cases described in our literature review noted findings that are typical of LC with no findings specific to LC-E.

Table 3

Cerebrospinal fluid results from case series

Case	OP (cm H2O)	Glucose (mg/dL)	Protein (mg/dL)	Cell count (cells/UL)	Cytology/pathology
1	NA	68	41	30	Malignant adenocarcinoma
2	15.5	22	92	38	Metastatic carcinoma
3	14.5	77	177	8	Metastatic carcinoma
4	NA	24	48	10	Poorly differentiated carcinoma
5	15	49	61	12	Metastatic adenocarcinoma
6	NA	84	121	14	Metastatic adenocarcinoma
7	22.5	57	26	1	Negative
First sample
7	26	95	12	5	Metastatic malignant cells
Second sample



OP, opening pressure; NA, not available.

Management of LC-E in our patients as well as those previously described varied between hospice, RT, chemotherapy, or a combination thereof. Among our cases, almost half elected for hospice immediately. Over half (n = 4, 57%) received WBRT with only two completing the course prior to clinical deterioration. One patient received a ventriculoperitoneal shunt, IT chemotherapy with thiotepa followed by oral temozolomide. Historically, approximately 40% of the LC-E patients received some for of RT including WBRT, RT to the skull base, and focal RT to bulky disease in the spine. In the literature, 18% (n = 4) received systemically administered chemotherapy while 23% (n = 5) received IT chemotherapy. The number of cases is too small and the treatments too varied to attempt any conclusions regarding the potential efficacy of treatments for LC-E. As LC-E becomes more common, further studies are needed to stratify which patients are likely to develop this disease and perhaps evaluate the treatments that may improve quality as well as quantity of life in these unfortunate patients.

Author notes

Author contributions: Drs Lukas, Mata-Machado, Nicholas, Salgia, Antic, and Villaflor made substantial contributions to the conception of the study, acquisition of data, and interpretation of data. They also participated in the drafting and critical revision of the manuscript and gave final approval of the version being submitted.