Diseases of the Esophagus (2014) ••, ••–•• DOI: 10.1111/dote.12276
Original article
Leptomeningeal carcinomatosis in esophageal cancer: a case series and systematic review of the literature R. V. Lukas,1 N. A. Mata-Machado,2 M. K. Nicholas,1,3,4 R. Salgia,5 T. Antic,6 V. M. Villaflor5 Departments of 1Neurology, 3Surgery-Section of Neurosurgery, 4Radiation and Cellular Oncology, 5 Medicine-Section of Hematology & Oncology and 6Pathology, University of Chicago and 2Department of Pediatric Neurology, Loyola University, Chicago, Illinois, USA
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. KEY WORDS: carcinomatous meningitis, cerebrospinal fluid, esophageal neoplasms, leptomeningeal carcinomatosis, meningeal carcinomatosis.
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
Address correspondence to: Dr Rimas V. Lukas, MD, 5841 South Maryland Avenue, MC 2030, Chicago, IL 60637, USA. Email: [email protected] 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. © 2014 International Society for Diseases of the Esophagus
the largest case series of patients with LC-E. Additionally, we report the results of a systematic review of the literature (Table 2).
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, 1
M
F
M
M
M
M
M
Gender
Moderately differentiated adenocarcinoma
Poorly differentiated adenocarcinoma
Poorly differentiated adenocarcinoma
Poorly differentiated carcinoma
Poorly differentiated adenocarcinoma
Poorly differentiated adenocarcinoma with signetring features Adenocarcinoma
Histology
FISH Wnl. NGS amplification.
IHC 2+
FISH wnl
NA
NA
FISH wnl
FISH wnl
HER2
MRI: Brain: parenchymal and supra- and infratentorial LC Spine: LC in the cervical, thoracic, and lumbar regions. Vertebral body metastases and epidural metastases. MRI: Brain: infratentorial LC Spine: intraparenchymal cervical spinal cord metastases, thoracic dural metastasis, thoracic vertebral body metastases. MRI: Brain: supra- and infratentorial LC. Spine: thoracic vertebral body metastasis. MRI: Brain: infratentorial LC and brain metastases. Pineal lesion representing either metastasis or primary lesion. Spine: unremarkable. MRI: Brain: infratentorial LC. Spine: diffuse LC, diffuse vertebral body metastases. MRI: Brain: infratentorial LC.
MRI: brain and spine unremarkable.
Imaging
NA
NA
NA
NA
NA
WBRT (16 Gy of planned 20 Gy)
NA
WBRT
NA
WBRT (17.5 Gy, out of a planned 35 Gy) extending down to C4 to include the spinal cord metastasis.
WBRT (30 Gy)
NA
IT thiotepa (10 mg) × 2 doses, followed by TMZ (150 mg/m2) for 5 days. NA
Treatment-RT
Treatment-chemotherapy
168
45
37
47
126
50
21
Time to LC-E Dx (weeks)
168
49
43
52
132
55
37
Survival from Dx of Esophageal Cancer (weeks)
2.5
3.5
6
5
6
5
16
Survival from Dx of LC-E (weeks)
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).
62
7
57
4
69
72
3
6
52
2
70
41
1
5
Age
Case series of leptomeningeal carcinomatosis due to esophageal cancer
Case
Table 1
2 Diseases of the Esophagus
© 2014 International Society for Diseases of the Esophagus
73
61 53
1
2
1
1
2
1
1
1
Akhavan and Navabii2 Aulakh et al.3
Henninger et al.4
Astner et al.5
Goddeeris et al.6
© 2014 International Society for Diseases of the Esophagus
Wagemakers et al.7
Okumura et al.8
Abdo et al.9
50
68
M
M
M
M
46
52
M
M
M
M M
M
Gender
60
70
54
Age
Cases
Esophageal basaloid carcinoma Moderately differentiated adenocarcinoma
Signet-ring cell adenocarcinoma
Adenocarcinoma
Moderately differentiated adenocarcinoma
Poorly differentiated adenocarcinoma Esophageal cancer
Squamous cell carcinoma Adenocarcinoma Poorly differentiated adenocarcinoma
Histology
+CT
+MRI
+MRI
+MRI
+MRI
+MRI
+MRI
+MRI +MRI
+MRI
Imaging
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’
‘Clusters and individual malignant cells with large mucin-containing vacuoles’ ‘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. 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’ Protein 1075 mg/dL, glucose 23 mg/dL, WBC 15.2 cells/uL, ‘malignant cells’. ‘Numerous undifferentiated cells’, protein 1.63 g/l, glucose 3.5 mmol/l ‘Few cytokeratin positive cells’, CEA mRNA in CSF
‘Malignant cells’ ‘malignant cells from poorly differentiated adenocarcinoma’
NA
CSF
Systematic review of leptomeningeal carcinomatosis cases due to esophageal cancer
Reference
Table 2
NA
NA
NA
Cisplatin/fluoruracil
RT skull base
Corticosteroids
NA NA
NA
IT MTX followed by RT to bulky disease at skull base (30 Gy)
NA RT (20 Gy brain, 30 Gy bulky spinal disease) followed by FOLFIRI + BEV, followed by cisplatibn/rinotecan + IT liposomal cytrabine NA
WBRT (30 Gy)
Treatment
NA
NA
NA
NA NA
NA
Autopsy
NA
∼5.5 months
∼2 weeks NA
NA
NA
NA
NA
∼5.5 months
16 weeks
17 days
42 days
∼6 months
∼2 months
3 years
4 months
0
0
NA
4 weeks 7 months
NA
OS
NA
∼4 weeks ∼4 months
∼4 months ∼1 year
NA
4 week
TTP-CNS
NA
Time to LC-E Dx
Leptomeningeal carcinomatosis esophageal CA 3
1
1
1
1
7
Civantos et al.12
Teare et al.13
Coman et al.14
Tanaka et al.15
Giglio et al.16
M
M M
M M M
M
66 65
66 61 39
51
M
NA
M
M
M
F
Gender
71
52
NA
49
68
49
51
Age
Adenocarcinoma
Adenocarcinoma Adenocarcinoma Adenocarcinoma
Adenocarcinoma Adenocarcinoma
Signet-ring cell adenocarcinoma Moderately differentiated squamous cell carcinoma Adenocarcinoma
Adenocarcinoma
Squamous cell esophageal cancer Poorly differentiated squamous cell carcinoma
Adenocarcinoma
Histology
+MRI
+MRI +MRI +MRI
+MRI +MRI
+MRI
+MRI
+MRI
-CT
+CT
+MRI
+CT
Imaging
NA
WBC 3, RBC 0, protein 0.09 g/l, glucose 4.0 mmol/l. Cytology not evaluated. Cytology positive after multiple attempts. +
WBC (50 poly, 17 monothelial cells) RBC 2, protein 107, glucose 17, ‘poorly differentiated malignant cells’
Glucose 4 mg%, protein 255 mg%, 43 cells/mm3, ‘malignant cells with multiple nuclei and prominent nucleoli . . . without vacuole(s)’ 17 Cells/mm3, protein 138 mg/mL, + cytology
CSF
Spinal RT (3 Gy)
NA
Treatment
NA
NA
WBRT (22 Gy) WBRT (9.26 Gy) + focal spine (15 Gy) RT focal spine (30 Gy) IT topotecan IT MTX, then topotecan, then ara-C Capecitabine
NA
NA
Grossly normal. IT MTX, systemic cisplatin, followed by RT to skull Microscopically base evident meningeal carcinomatosis with degeneration of multiple cranial nerves. Patchy meningeal NA deposits from metastatic adenocarcinoma. NA NA
NA
Carcinomatosis without parenchymal metastatic involvement
Autopsy
NA
NA
NA
NA
NA
NA
TTP-CNS
Mean 418 daysNA (SD ± 402)
3 months
NA
0
0
NA
26 months
Time to LC-E Dx
28 weeks
15 weeks 6 weeks 20 weeks
8 weeks 1 weeks
0 week
NA
NA
NA
Original article
Leptomeningeal carcinomatosis in esophageal cancer: a case series and systematic review of the literature R. V. Lukas,1 N. A. Mata-Machado,2 M. K. Nicholas,1,3,4 R. Salgia,5 T. Antic,6 V. M. Villaflor5 Departments of 1Neurology, 3Surgery-Section of Neurosurgery, 4Radiation and Cellular Oncology, 5 Medicine-Section of Hematology & Oncology and 6Pathology, University of Chicago and 2Department of Pediatric Neurology, Loyola University, Chicago, Illinois, USA
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. KEY WORDS: carcinomatous meningitis, cerebrospinal fluid, esophageal neoplasms, leptomeningeal carcinomatosis, meningeal carcinomatosis.
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
Address correspondence to: Dr Rimas V. Lukas, MD, 5841 South Maryland Avenue, MC 2030, Chicago, IL 60637, USA. Email: [email protected] 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. © 2014 International Society for Diseases of the Esophagus
the largest case series of patients with LC-E. Additionally, we report the results of a systematic review of the literature (Table 2).
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, 1
M
F
M
M
M
M
M
Gender
Moderately differentiated adenocarcinoma
Poorly differentiated adenocarcinoma
Poorly differentiated adenocarcinoma
Poorly differentiated carcinoma
Poorly differentiated adenocarcinoma
Poorly differentiated adenocarcinoma with signetring features Adenocarcinoma
Histology
FISH Wnl. NGS amplification.
IHC 2+
FISH wnl
NA
NA
FISH wnl
FISH wnl
HER2
MRI: Brain: parenchymal and supra- and infratentorial LC Spine: LC in the cervical, thoracic, and lumbar regions. Vertebral body metastases and epidural metastases. MRI: Brain: infratentorial LC Spine: intraparenchymal cervical spinal cord metastases, thoracic dural metastasis, thoracic vertebral body metastases. MRI: Brain: supra- and infratentorial LC. Spine: thoracic vertebral body metastasis. MRI: Brain: infratentorial LC and brain metastases. Pineal lesion representing either metastasis or primary lesion. Spine: unremarkable. MRI: Brain: infratentorial LC. Spine: diffuse LC, diffuse vertebral body metastases. MRI: Brain: infratentorial LC.
MRI: brain and spine unremarkable.
Imaging
NA
NA
NA
NA
NA
WBRT (16 Gy of planned 20 Gy)
NA
WBRT
NA
WBRT (17.5 Gy, out of a planned 35 Gy) extending down to C4 to include the spinal cord metastasis.
WBRT (30 Gy)
NA
IT thiotepa (10 mg) × 2 doses, followed by TMZ (150 mg/m2) for 5 days. NA
Treatment-RT
Treatment-chemotherapy
168
45
37
47
126
50
21
Time to LC-E Dx (weeks)
168
49
43
52
132
55
37
Survival from Dx of Esophageal Cancer (weeks)
2.5
3.5
6
5
6
5
16
Survival from Dx of LC-E (weeks)
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).
62
7
57
4
69
72
3
6
52
2
70
41
1
5
Age
Case series of leptomeningeal carcinomatosis due to esophageal cancer
Case
Table 1
2 Diseases of the Esophagus
© 2014 International Society for Diseases of the Esophagus
73
61 53
1
2
1
1
2
1
1
1
Akhavan and Navabii2 Aulakh et al.3
Henninger et al.4
Astner et al.5
Goddeeris et al.6
© 2014 International Society for Diseases of the Esophagus
Wagemakers et al.7
Okumura et al.8
Abdo et al.9
50
68
M
M
M
M
46
52
M
M
M
M M
M
Gender
60
70
54
Age
Cases
Esophageal basaloid carcinoma Moderately differentiated adenocarcinoma
Signet-ring cell adenocarcinoma
Adenocarcinoma
Moderately differentiated adenocarcinoma
Poorly differentiated adenocarcinoma Esophageal cancer
Squamous cell carcinoma Adenocarcinoma Poorly differentiated adenocarcinoma
Histology
+CT
+MRI
+MRI
+MRI
+MRI
+MRI
+MRI
+MRI +MRI
+MRI
Imaging
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’
‘Clusters and individual malignant cells with large mucin-containing vacuoles’ ‘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. 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’ Protein 1075 mg/dL, glucose 23 mg/dL, WBC 15.2 cells/uL, ‘malignant cells’. ‘Numerous undifferentiated cells’, protein 1.63 g/l, glucose 3.5 mmol/l ‘Few cytokeratin positive cells’, CEA mRNA in CSF
‘Malignant cells’ ‘malignant cells from poorly differentiated adenocarcinoma’
NA
CSF
Systematic review of leptomeningeal carcinomatosis cases due to esophageal cancer
Reference
Table 2
NA
NA
NA
Cisplatin/fluoruracil
RT skull base
Corticosteroids
NA NA
NA
IT MTX followed by RT to bulky disease at skull base (30 Gy)
NA RT (20 Gy brain, 30 Gy bulky spinal disease) followed by FOLFIRI + BEV, followed by cisplatibn/rinotecan + IT liposomal cytrabine NA
WBRT (30 Gy)
Treatment
NA
NA
NA
NA NA
NA
Autopsy
NA
∼5.5 months
∼2 weeks NA
NA
NA
NA
NA
∼5.5 months
16 weeks
17 days
42 days
∼6 months
∼2 months
3 years
4 months
0
0
NA
4 weeks 7 months
NA
OS
NA
∼4 weeks ∼4 months
∼4 months ∼1 year
NA
4 week
TTP-CNS
NA
Time to LC-E Dx
Leptomeningeal carcinomatosis esophageal CA 3
1
1
1
1
7
Civantos et al.12
Teare et al.13
Coman et al.14
Tanaka et al.15
Giglio et al.16
M
M M
M M M
M
66 65
66 61 39
51
M
NA
M
M
M
F
Gender
71
52
NA
49
68
49
51
Age
Adenocarcinoma
Adenocarcinoma Adenocarcinoma Adenocarcinoma
Adenocarcinoma Adenocarcinoma
Signet-ring cell adenocarcinoma Moderately differentiated squamous cell carcinoma Adenocarcinoma
Adenocarcinoma
Squamous cell esophageal cancer Poorly differentiated squamous cell carcinoma
Adenocarcinoma
Histology
+MRI
+MRI +MRI +MRI
+MRI +MRI
+MRI
+MRI
+MRI
-CT
+CT
+MRI
+CT
Imaging
NA
WBC 3, RBC 0, protein 0.09 g/l, glucose 4.0 mmol/l. Cytology not evaluated. Cytology positive after multiple attempts. +
WBC (50 poly, 17 monothelial cells) RBC 2, protein 107, glucose 17, ‘poorly differentiated malignant cells’
Glucose 4 mg%, protein 255 mg%, 43 cells/mm3, ‘malignant cells with multiple nuclei and prominent nucleoli . . . without vacuole(s)’ 17 Cells/mm3, protein 138 mg/mL, + cytology
CSF
Spinal RT (3 Gy)
NA
Treatment
NA
NA
WBRT (22 Gy) WBRT (9.26 Gy) + focal spine (15 Gy) RT focal spine (30 Gy) IT topotecan IT MTX, then topotecan, then ara-C Capecitabine
NA
NA
Grossly normal. IT MTX, systemic cisplatin, followed by RT to skull Microscopically base evident meningeal carcinomatosis with degeneration of multiple cranial nerves. Patchy meningeal NA deposits from metastatic adenocarcinoma. NA NA
NA
Carcinomatosis without parenchymal metastatic involvement
Autopsy
NA
NA
NA
NA
NA
NA
TTP-CNS
Mean 418 daysNA (SD ± 402)
3 months
NA
0
0
NA
26 months
Time to LC-E Dx
28 weeks
15 weeks 6 weeks 20 weeks
8 weeks 1 weeks
0 week
NA
NA
NA
