Key issues in salivary gland pathology...2016/04/11 · 1. Careful radiation treatment planning...
Transcript of Key issues in salivary gland pathology...2016/04/11 · 1. Careful radiation treatment planning...
Arjan Vissink
Key issues in salivary
gland pathology
Saliva has many functions and although
not essential for the maintenance of life it
contributes to the efficient working and
protection of the human body
Neil Jenkins, 1978
complaints
reduced
quality of life oral pathology
diagnostics lymphoma personalized
medicine
A
B F
E
D
C
FcRL4
Topics
• Hyposalivation versus xerostomia
• Why is water not effective?
• Main causes of xerostomia:
– Drugs, radiotherapy, Sjögren’s syndrome
syndrome
• Recent progress:
– saliva diagnostics
– ultrasonography
– which biopsy?
– MALT lymphoma
Hyposalivation versus xerostomia
• People may complain of dry mouth and
have an abnormal low (<0.1 ml/min)
unstimulated whole saliva flow rate
• People can complain of oral dryness yet
have a normal whole saliva flow rate
• People may have an abnormal low flow
rate of whole saliva and not complain of
oral dryness
Hyposalivation versus xerostomia
• Discrepancy is present in 20-30% of the
subjects
• Hyposalivation = reduced flow
• Xerostomia = sensation of oral dryness
• Xerostomia ≠ hyposalivation
Vissink et al., J Dent Res 1986;65:1121-4
Why is water not effective?
better
worse
Vissink et al., J Dent Res 1986;65:1121-4
water
whole saliva
mucin solutions
Drug-related xerostomia
Don’t forget self care medications
Are side effects a problem?
Sreebny and Vissink. Dry Mouth: the malevolent symptom. Wiley-Blackwell, 2010
Sreebny and Vissink. Dry Mouth: the malevolent symptom. Wiley-Blackwell, 2010
• Not only the amount of saliva, but also the
composition of saliva and how the dryness
signal is interpreted underlie the sensation of
oral dryness
Drugs
Atkinson et al, Gerodontology 1989;8:23-26
0
0,05
0,1
0,15
0,2
0,25
0,3
ml/min
0 1 2 3 4
hour
Unstimulated parotid + SMSL flow
furosemide
placebo
• The lowest secretion rates are seen in
patients using most drugs
• But even in these patients salivary
secretion can usually be stimulated to a
sufficient level
Närhi, J Dent Res 1994;73:20-25
Drugs
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1,6
1,8
0 0 1-3 4-6 >7
ml/min
number of drugs
Secretion of whole saliva
unstimulated
stimulated
• Over 1000 drugs are linked to a sensation of oral dryness
• But often there is no proof that drugs indeed reduce salivary flow
Drugs
Aliko et al., Oral Surg Oral Med Oral Pathol Oral Radiol 2015;120:185-206
Villa et al., Clin Oral Investig 2015;19:1563-80
Villa et al., Oral Dis 2015 Nov 25. doi: 10.1111/odi.12402 [Epub ahead of print]
Head and neck radiotherapy
Salivary glands are radiosensitive
1. Can radiation injury of salivary gland tissue
be prevented?
2. Can radiation damage of salivary gland
tissue be restored?
Key questions
Vissink et al, Int J Radiat Oncol Biol Phys 2010;78:983-91
Vissink et al, Oral Dis 2015;21:e1-11
Grégoire et al., J Clin Oncol 2015;33:3277-84
Jensen et al, J Natl Cancer Inst (in press)
1. Careful radiation treatment planning (mean dose )
2. Salivary gland transfer
3. Amifostine (radical scavenger)
4. Pilocarpine (enhancement of proliferation)
Valdez et al, Int J Radiat Oncol Biol Phys 1993;25:41-7
Burlage et al, Radiother Oncol 2001;61:271-74
Vissink et al, Oral Dis 2015;21:e1-10
time (weeks)
sa
livary
flo
w (
% fro
m b
ase
line)
parotid gland
submandibular gland
Prevention of salivary gland damage
Prevention of salivary gland damage
Kam et al, J Clin Oncol 2007;25:4873-9
Semenenko et al, Phys Med Biol 2008;;53:737-55
Vissink et al, Int J Radiat Oncol Biol Phys 2010;78:983-91
Gupta et al, Radiother Oncol 2012;104:343-8
Vissink et al, Oral Dis 2015;21:e1-10
Grégoire et al, J Clin Oncol 2015;33:3277-84
Minimize exposure of the salivary glands to radiation:
- shielding and conformational field planning
- intensity modulated radiation therapy (IMRT)
A: 3D-Conformatie Radiotherapie B: Standaard IMRTC: Bestralingsbundel met
verschillende intensiteit3D conformal radiotherapy Standard IMRT
Prevention of salivary gland damage
Kam et al, J Clin Oncol 2007;25:4873-9
Semenenko et al, Phys Med Biol 2008;;53:737-55
Vissink et al, Int J Radiat Oncol Biol Phys 2010;78:983-91
Gupta et al, Radiother Oncol 2012;104:343-8
Vissink et al, Oral Dis 2015;21:e1-10
Grégoire et al, J Clin Oncol 2015;33:3277-84
Vissink et al, Int J Radiat Oncol Biol Phys 2010;78:983-91
Vissink et al, Oral Dis 2015;21:e1-10
Prevention of salivary gland damage
IMRT spares salivary glands
May new radiation techniques result in
less xerostomia?
• IMRT has resulted in some reduction of xerostomia
and its related complaints
• Will further demarcating the radiation portals result
in less damage to salivary gland tissue?
Konings et al, Int J Radiat Oncol Biol Phys 2005;62:1090-5
Konings et al, Int J Radiat Oncol Biol Phys 2005;63:1584-91
Konings et al, Int J Radiat Oncol Biol Phys 2006;64:98-105
• Is parotid gland stem cell sparing radiotherapy a
reasonable thought?
Pringle et al, Stem Cells 2013;31:613-9
May new radiation techniques result in
less xerostomia?
• parotid gland stem cell sparing radiotherapy for head
and neck cancer
May new radiation techniques result in
less xerostomia?
van Luijk et al., Sci Transl Med 2015;7:305ra147
• parotid gland stem cell sparing radiotherapy for head
and neck cancer
van Luijk et al., Sci Transl Med 2015;7:305ra147
May new radiation techniques result in
less xerostomia?
• IMRT has resulted in some reduction of xerostomia
and its related complaints
• Will further demarcating of the radiation portals
result in less damage to salivary gland tissue?
• Might proton radiotherapy be a solution?
May new radiation techniques result in
less xerostomia?
Konings et al, Int J Radiat Oncol Biol Phys 2005;62:1090-5
Konings et al, Int J Radiat Oncol Biol Phys 2005;63:1584-91
Konings et al, Int J Radiat Oncol Biol Phys 2006;64:98-105
Diepte in centimeters
Dosis
DO
SIS
Fotonen
Protonen Bragg-peak
"Spread Out" Bragg peak
Target
Photons
Bragg peak
Spread-out Bragg peak
Advantage protons
Advantage protons
Depth in centimetres
Do
se
Van de Water et al. Work in progress
Courtesy Hans Langendijk
May new radiation techniques result in
less xerostomia?
IMPT
66.5 Gy
51.3 Gy
40.0 Gy
20.0 Gy
10.0 Gy
Isodose
lines:
Van de Water et al, Int J Radiat Oncol Biol Phys 2011;79:1216-24
IMRT
May new radiation techniques result in
less xerostomia?
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 10 20 30 40 50 60 70
Gemiddelde dosis oorspeekselklieren (Gy)
Kan
s o
p d
rog
e m
on
d
Model
3D-CRT
IMRT
IMPT
Mean dose parotid glands (Gy)
Pa
tients
with
xe
rosto
mia
(%
)
Van de Water et al, Int J Radiat Oncol Biol Phys 2011;79:1216-24
May new radiation techniques result in
less xerostomia?
• Can radiation injury of salivary gland tissue
be prevented?
• Can radiation damage of salivary gland
tissue be restored?
Key questions
Vissink et al, Int J Radiat Oncol Biol Phys 2010;78:983-91
Vissink et al, Oral Dis 2015;21:e1-11
Grégoire et al., J Clin Oncol 2015;33:3277-84
Jensen et al, J Natl Cancer Inst (in press)
• Few acinar cells survive radiation
• Thus, little to no primary fluid secretion will occur
• Ductal compartment, although water impermeable,
is better preserved than acinar compartment
• Introduction of a water channel (aquaporine) in
ductal cells
• Transfection with hAQP1 gene
AdhAQP1(encodes water channel protein)
Baum and O’Connell 1995
Delporte et al , Proc Natl Acad Sci USA 1997;94:3268-73
Shan et al, Mol Ther 2005;11:444-51
Is gene therapy the answer?
Baum et al, Proc Natl Acad Sci U S A 2012;109:19403-7
Baum, Oral Dis 2014;20:115-8
Baum, Oral Dis 2016;22:81-4
Is gene therapy the answer?
• Single, escalating doses of AdhAQP1 (safety)
• Assessments:
• Effectiveness of AdhAQP1 to increase parotid gland salivary
output
• Improvement of symptoms associated with irradiation-induced
parotid hypofunction
First trial in human Effect of AdhAQP1 on salivary flow in patients treated with
radiation for head and neck cancer (NCT00372320)
Is gene therapy the answer?
Baum et al, Proc Natl Acad Sci U S A 2012;109:19403-7
Baum, Oral Dis 2014;20:115-8
Baum, Oral Dis 2016;22:81-4
First results are promising
Baum et al, Proc Natl Acad Sci U S A 2012;109:19403-7
Baum, Oral Dis 2014;20:115-8
Baum, Oral Dis 2016;22:81-4
• Salivary glands can undergo renewal if enough
stem cells survive
• If too few stem cells survive, transplantation of
undamaged (donor)stem cells could enable the
gland to regenerate
• Ductal cells remain relatively intact and could
serve as a natural engraftment place for
transplanted cells
Lombaert et al, Clin Cancer Res 2006;12:1804-12
Lombaert et al, Stem Cells 2008;26:2595-601
Lombaert et al, Plos ONE 2008 Apr 30;3(4):e2063
Lombaert et al, Oral Dis 2011;17:445-9
Is stem cell therapy a reasonable
approach?
Feng et al, Radiother Oncol 2009;92:466-71
Coppes and Stokman, Oral Dis 2011;17:143-53
Pringle et al, J Vis Exp 2011;(48). pii: 2484
Nanduri et al, Radiother Oncol 2011;99:367-72
Nanduri et al, Radiother Oncol 2013;108:458-63
Vissink et al, Oral Dis 2015;21:e1-10
Is stem cell therapy a reasonable
approach?
How to obtain stem cells
Is stem cell therapy a reasonable
approach?
Single cell derived spheres form salivary gland like organoids
Feng et al, Radiother Oncol 2009;92:466-71
Coppes and Stokman, Oral Dis 2011;17:143-53
Pringle et al, J Vis Exp 2011;(48). pii: 2484
Nanduri et al, Radiother Oncol 2011;99:367-72
Nanduri et al, Radiother Oncol 2013;108:458-63
Vissink et al, Oral Dis 2015;21:e1-10
Pringle et al., Stem Cells 2016 Feb 16. doi: 10.1002/stem.2278. [Epub ahead of print]
Is stem cell therapy a reasonable
approach?
Stem cell therapy results in partial return of secretion
Awaiting proof in human!!
Is stem cell therapy a reasonable
approach?
Key Research Questions
Where are we?
1. Can radiation injury of salivary gland
tissue be prevented?
Yes, to a certain extent
2. Can radiation damage of salivary gland
tissue be restored?
Probably, animal and first results
in human are promising
Sjögren’s syndrome • Chronic, progressive, inflammatory and
lymphoproliferative disease
• Mononuclear cell infiltration of exocrine
glands
• Dry eyes, dry mouth, fatigue
• Female/male ratio of 9:1
• Prevalence 0.1-1.0%
Sjögren’s syndrome • Local & systemic B-cell hyperactivity
(hyper IgG, rheumatoid factor, anti-
SSA/SSB)
• Presence of CD4+ and CD8+
activated T-cells
• ≈ 7.5% of patients develop B-cell
lymphoma (frequently MALT-
lymphoma in major salivary glands)
Non Hodgkin lymphoma
Pollard et al., J Rheumatol 2011;38:2198-2208
Many other systems can be involved too
Pijpe et al., Ann Rheum Dis 2007;66:107-12
Atkinson et al., J Rheumatol 1990;17:318-22
Salivary gland function in Sjögrens’syndrome
Progression (duration of symptoms)
0
0,05
0,1
0,15
0,2
0,25
0,3
0,35
0,4
0,45
0,5
mL
/min
UWS U-SM/SL S-SM/SL S-Parotid
Healthy
<1 year
1-4 years
>4 years
AECG (<0.1 ml/min)
• early stage: reduction of the secretion of
the (sero)mucous glands
• advanced stage: reduction of parotid
glands (Par)
• early stage: nocturnal oral dryness (SM)
• advanced stage: dryness throughout the
day (SM + Par)
Sjögren’s syndrome
Pijpe et al., Ann Rheum Dis 2007;66:107-12
Topics
• Hyposalivation versus xerostomia
• Why is water not effective?
• Main causes of xerostomia:
– Drugs, radiotherapy, Sjögren’s syndrome
syndrome
• Recent progress (Sjögren’s):
– saliva diagnostics
– ultrasonography
– which biopsy?
– MALT lymphoma
Courtesy David Wong
Proteonomics primary Sjögren’s syndrome
• ‘Down-regulated’ proteins:
dermcidin, cystatin C, carbonic anhydrase VI (three isoforms),
calgranulin A, prolactin inducible protein and Von Ebner’s gland
protein
• ‘Up-regulated’ proteins:
alpha-enolase, fructose bisphosphate aldolase A, caspase 14, S100
calcium binding protein A, fatty acid-binding protein, imunoglobulins,
and beta-2-microglobulin
Hu et al., Arthritis Rheum 2007;56:3588-600
Hu et al., Arthritis Care Res (Hoboken) 2010;62:1633-8
Sjögren’s syndrome patients can be
distinguished from controls and SLE patients
Delaleu et al., Arthritis Rheumatol 2015;67:1084-95
Salivary Biomarkers for Sjögren’s Syndrome Detection –
A Multi-Center Study
(420 patients)
NIDCR Award 2 U01 DE017593
David Wong, Kathy Sivils, Arjan Vissink
Parotid gland ultrasonography
Sjögren’s syndrome healthy
sialogram
ultrasound
Parotid gland ultrasonography
• Indirectly validated (labial salivary glands)
• In need of (further) validation against
other salivary gland diseases (currently
mainly disease controls)
• In need of validation against parotid gland
function and parotid gland histopathology
Bootsma et al., Arthritis Rheum 2013;65:21-3
Delli et al., Oral Dis 2015;21:792-800
Jousse-Joulin et al., Rheumatology (Oxford) 2015 Dec 14 [Epub ahead of print]
Mossel, Delli, van Nimwegen (in progress)
Histopathology
Mostly taken from minor salivary glands (labial)
Alternatives: - parotid gland
- lacrimal gland
- submandibular gland Invasive procedure of 10 min.
Important for:
- diagnostic reasons
- prognostic reasons
- evaluation of new treatment options
- pathogenesis of the disease
Salivary glands
Lacrimal gland
Fox et al., Ann Rheum Dis 2011;70:1351-3
Theander et al., Ann Rheum Dis 2011;7-:1363-8
Bootsma et al., Arthritis Rheum 2013;65:21-3
Delli et al., Oral Maxillofac Surg Clin North Am 2014;26:23-33
Labial biopsy
Delli et al., Oral Maxillofac Surg Clin North Am 2014;26:23-33
Shiboski et al., Arthritis Care Res 2012;64:475-87 (ACR)
Pijpe et al., Rheumatology 2007;46:335-41 (labial versus parotid)
Vitali et al., Ann Rheum Dis 2002;61:554-8 (AECG)
Parotid biopsy
Delli et al., Oral Maxillofac Surg Clin North Am 2014;26:23-33
Pijpe et al., Rheumatology 2007;46:335-41
Vitali et al., Ann Rheum Dis 2002;61:554-8
Parotid versus labial biopsy
Parotid gland Labial gland
Courtesy Erlin Haacke
Delli et al., Ann Rheum Dis 2016 Jan 12 [Epub ahead of print]
Baseline number of CD20+B-cells/mm2 is
prognostic biomarker for efficacy of rituximab
Lymphoma
• ≈ 7.5% of patients develop B-cell lymphoma
• Mostly a mucosa associated lymphoid
tissue (MALT) lymphoma in major salivary
glands
Courtesy Erlin Haacke
pSS focus MALT lymphoma
MALT lymphoma
• MALT lymphomas express Fc receptor-
like 4 (FcRL4/IRTA1/CD307d)
• Normally FcRL4 is expressed on a very
small subset of mucosa-associated B-
cells
• FcRL4+B-cells might be closely related to
MALT lymphoma cells
Falini et al., Histopathology 2012;61:930-41
MALT lymphoma
• Are FcRL4+B-cells present in inflamed
parotid gland tissue?
A
B F
E
D
C
MALT lymphoma Parotid gland Labial gland
FcRL4
H&E
Haacke et al., Scand J Immunol 2015;81: 380-381
MALT lymphoma
• FcRL4+B-cells are enriched in parotid
glands compared to the labial glands
• FcRL4+B-cells are likely the cells from
which MALT lymphomas arise
Haacke et al., Scand J Immunol 2015;81:380-381
complaints
reduced
quality of life oral pathology
diagnostics lymphoma personalized
medicine
A
B F
E
D
C
FcRL4
NIH sponsored trial