Microsoft Word - 66 2017.docx


	
  

Vol	
  5,	
  No	
  1	
  (2017)	
  
ISSN	
  2167-­‐8677	
  (online)	
  

DOI	
  10.5195/d3000.2017.66	
  	
  

	
  

	
  

	
  

http://dentistry3000.pitt.edu	
  

	
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  articles	
  in	
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  Creative	
  Commons	
  Attribution	
  4.0	
  United	
  States	
  License.	
  

	
  
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  journal	
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  University	
  Library	
  System,	
  University	
  of	
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by	
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  Press.	
  

	
  

Could	
  recurrent	
  aphthous	
  stomatitis	
  be	
  linked	
  to	
  cancer	
  	
  
development?	
  
Emily	
  Norton1	
  
	
  
	
  1University	
  of	
  Pi.sburgh,	
  School	
  of	
  Dental	
  Medicine

Abstract	
  

Background:	
  Recurrent	
  aphthous	
  stoma//s	
  is	
  a	
  common	
  mul/factorial	
  oral	
  mucosal	
  disorder.	
  Gene$c	
  and	
  local	
  fac-­‐
tors	
  causing	
  RAS	
  may	
  contribute	
  to	
  the	
  development	
  of	
  cancer.	
  This	
  study	
  aims	
  to	
  explore	
  this	
  connec<on	
  by	
  examin-­‐
ing	
  a	
  family	
  with	
  a	
  history	
  of	
  RAS	
  and	
  ovarian	
  cancer.	
   	
  Case	
  Descrip+on:	
  The	
  family	
  described	
  in	
  the	
  case	
  exhibits	
  a	
  
history	
  of	
  minor	
   recurrent	
   aphthous	
   stoma11s.	
   The	
   severity	
   of	
   this	
   condi1on	
   increases	
  with	
   each	
   genera1on.	
  One	
  
member	
  of	
  the	
  family	
  has	
  no	
  history	
  of	
  RAS	
  but	
  was	
  diagnosed	
  with	
  ovarian	
  cancer.	
  Gene;c	
  tes;ng	
  for	
  BRCA	
  muta-­‐
!ons	
  was	
  nega!ve	
  indica!ng	
  a	
  different	
  gene)c	
  cause	
  of	
  the	
  cancer.	
  All	
  affected	
  members	
  of	
  the	
  family	
  indicate	
  high	
  
levels	
  of	
   stress	
  or	
  difficulty	
   responding	
   to	
  stressful	
   situa4ons.	
  No	
   treatment	
   for	
  RAS	
  was	
  performed	
  due	
   to	
   its	
   self-­‐
limi$ng	
  nature.	
  	
  Prac%cal	
  Implica%ons:	
  Further	
  research	
  is	
  needed	
  before	
  den.sts	
  begin	
  to	
  tell	
  their	
  pa.ents	
  with	
  RAS	
  
they	
  may	
  be	
  at	
  higher	
  risk	
  of	
  developing	
  cancer.	
  Diligent	
  oral	
  cancer	
  screening	
  and	
  stress	
  management	
  counseling	
  can	
  
decrease	
  the	
  risk	
  to	
  the	
  pa.ent.	
  

	
  

Cita%on:	
  Norton,	
  E.	
  (2017)	
  Could	
  recurrent	
  aph-­‐
thous	
  stoma))s	
  be	
  linked	
  to	
  cancer	
  develop-­‐
ment?	
  Den$stry	
  3000.	
  1:a001	
  
doi:10.5195/d3000.2017.66	
  
Received:	
  	
  May	
  1,	
  2017	
  
Accepted:	
  	
  May	
  2,	
  2017	
  
Published:	
  	
  June	
  8,	
  2017	
  
Copyright:	
  ©2017	
  Norton.	
  This	
  is	
  an	
  open	
  access	
  
ar!cle	
   licensed	
   under	
   a	
   Crea!ve	
   Commons	
  
A!ribu%on	
  Work	
  4.0	
  United	
  States	
  License.	
  
Email:	
  emn27@pi).edu

	
  

Introduction	
  

Recurrent	
  aphthous	
  stoma-­‐
titis	
  (RAS)	
  is	
  the	
  most	
  common	
  
oral	
  mucosal	
  lesion,	
  affecting	
  as	
  
much	
  as	
  25%	
  of	
  the	
  world	
  popula-­‐
tion	
  [1-­‐3].	
  This	
  condition	
  is	
  charac-­‐
terized	
  by	
  painful	
  erosions	
  or	
  ul-­‐
cers	
  surrounded	
  by	
  an	
  erythema-­‐
tous	
  halo	
  on	
  the	
  non-­‐keratinized	
  
oral	
  mucosa	
  [2,	
  4].	
  	
  The	
  lesions	
  
may	
  affect	
  the	
  day	
  to	
  day	
  activities	
  
of	
  the	
  patients,	
  especially	
  eating,	
  
drinking	
  and	
  speaking	
  [3].	
  Aphthae	
  
are	
  identified	
  as	
  one	
  of	
  three	
  
types.	
  The	
  three	
  types	
  differ	
  in	
  
size	
  of	
  ulcers,	
  healing	
  time	
  and	
  
scarring	
  upon	
  healing.	
  The	
  first	
  
and	
  most	
  common	
  type,	
  which	
  
comprises	
  80-­‐90%	
  of	
  all	
  cases,	
  is	
  
minor	
  recurrent	
  aphthous	
  stoma-­‐
titis	
  [3].	
  In	
  these	
  cases,	
  the	
  lesions	
  
present	
  are	
  less	
  than	
  1	
  cm	
  in	
  di-­‐
ameter,	
  heal	
  within	
  seven	
  to	
  four-­‐

teen	
  days	
  and	
  do	
  not	
  scar	
  [3].	
  The	
  
second	
  type	
  is	
  known	
  as	
  major	
  re-­‐
current	
  aphthous	
  stomatitis	
  and	
  is	
  
characterized	
  by	
  lesion	
  greater	
  
than	
  1	
  cm	
  in	
  diameter	
  that	
  heal	
  
within	
  20-­‐30	
  days	
  with	
  scarring	
  
[3].	
  The	
  final	
  type	
  is	
  known	
  as	
  her-­‐
petiform	
  ulcers,	
  which	
  presents	
  
are	
  multiple,	
  clustered	
  lesions	
  1-­‐3	
  
mm	
  in	
  diameter	
  [3].	
  These	
  lesions	
  
may	
  coalesce	
  to	
  form	
  larger	
  le-­‐
sions	
  and	
  usually	
  heal	
  within	
  fif-­‐
teen	
  days	
  [3].	
  	
  

Despite	
  being	
  an	
  incredibly	
  
common	
  condition,	
  the	
  etiology	
  of	
  
recurrent	
  aphthous	
  stomatitis	
  re-­‐
mains	
  unclear.	
  However,	
  there	
  is	
  a	
  
general	
  consensus	
  that	
  RAS	
  is	
  a	
  
multifactorial	
  condition,	
  with	
  sev-­‐
eral	
  factors	
  implicated	
  in	
  its	
  occur-­‐
rence	
  [1,	
  3,	
  5].	
  Many	
  common	
  lo-­‐
cal	
  factors	
  are	
  thought	
  to	
  be	
  in-­‐
volved	
  such	
  as	
  viral	
  and	
  bacterial	
  

infections,	
  allergic	
  agents	
  (such	
  as	
  
food	
  hypersensitivity),	
  nutritional	
  
deficiencies	
  and	
  stress	
  and	
  anxiety	
  
[3-­‐5].	
  In	
  addition,	
  there	
  are	
  also	
  
genetic	
  factors	
  that	
  can	
  predis-­‐
pose	
  an	
  individual	
  to	
  RAS.	
  Certain	
  
HLA	
  alleles	
  have	
  been	
  found	
  to	
  be	
  
associated	
  with	
  patients	
  with	
  RAS	
  
as	
  well	
  as	
  specific	
  racial	
  and	
  ethnic	
  
segregations	
  [2,	
  5].	
  RAS	
  is	
  associ-­‐
ated	
  with	
  certain	
  genetic	
  syn-­‐
dromes	
  such	
  as	
  Behcet’s	
  syn-­‐
drome	
  [5].	
  RAS	
  is	
  also	
  known	
  to	
  
accumulate	
  in	
  families,	
  giving	
  fur-­‐
ther	
  strength	
  to	
  the	
  theory	
  of	
  a	
  
genetic	
  cause	
  [5].	
  Early	
  studies	
  
proposed	
  an	
  autosomal	
  recessive	
  
or	
  multigene	
  mode	
  of	
  inheritance	
  
with	
  environmental	
  influences	
  [4].	
  	
  

This	
  paper	
  aims	
  to	
  explore	
  
the	
  possible	
  connection	
  between	
  
RAS	
  and	
  cancer	
  development	
  by	
  
examining	
  a	
  family	
  with	
  a	
  history	
  



	
  Could	
  recurrent	
  aphthous	
  stoma11s	
  be	
  linked	
  to	
  cancer	
  development?	
  

Vol	
  5,	
  No	
  1	
  (2017)	
  	
  	
  	
  DOI	
  10.5195/d3000.2017.66	
  

	
  http://dentistry3000.pitt.edu	
  

of	
  RAS	
  as	
  well	
  as	
  cancer.	
  The	
  prac-­‐
tical	
  implications	
  of	
  these	
  findings	
  
in	
  the	
  dental	
  clinic	
  and	
  possible	
  
ethical	
  considerations	
  will	
  also	
  be	
  
discussed.	
  	
  

Case	
  Presentation	
  

	
   The	
  family	
  studied	
  exhibits	
  
three	
  generations	
  of	
  reported	
  re-­‐
current	
  aphthous	
  stomatitis	
  with	
  
varying	
  degrees	
  of	
  severity.	
  One	
  of	
  
the	
  family	
  members	
  in	
  the	
  third	
  
generation	
  is	
  not	
  affected	
  by	
  RAS,	
  
but	
  she	
  was	
  diagnosed	
  with	
  ovari-­‐
an	
  cancer.	
  Figure	
  1	
  is	
  the	
  family’s	
  
pedigree,	
  showing	
  which	
  individu-­‐
als	
  have	
  been	
  affected	
  by	
  RAS.	
  
Three	
  consecutive	
  generations	
  
have	
  been	
  affected,	
  as	
  seen	
  in	
  the	
  
pedigree.	
  The	
  family	
  members	
  in	
  
the	
  fourth	
  generation	
  have	
  not	
  yet	
  
shown	
  as	
  signs	
  of	
  RAS,	
  so	
  their	
  
status	
  is	
  currently	
  unknown.	
  Each	
  
member’s	
  presentation	
  of	
  RAS	
  and	
  
account	
  of	
  other	
  risk	
  factors	
  will	
  
be	
  discussed	
  individually.	
  

Family	
  Member	
  I:2	
  

The	
  initial	
  presentation	
  of	
  
RAS	
  is	
  seen	
  in	
  the	
  first	
  generation,	
  
in	
  patient	
  I:2.	
  The	
  family	
  account	
  
of	
  her	
  condition	
  is	
  limited	
  at	
  this	
  
time.	
  Her	
  son,	
  family	
  member	
  II:1,	
  
states	
  he	
  remembers	
  his	
  mother	
  
getting	
  “canker	
  sores	
  a	
  few	
  times”	
  
when	
  he	
  was	
  growing	
  up.	
  He	
  could	
  
not	
  remember	
  any	
  information	
  
about	
  the	
  size	
  of	
  the	
  sores	
  or	
  the	
  
frequency	
  of	
  the	
  episodes.	
  No	
  
other	
  signs	
  that	
  would	
  indicate	
  a	
  
systemic	
  disease,	
  such	
  as	
  Behcet’s,	
  
were	
  reported.	
  Family	
  member	
  
II:1	
  indicated	
  that	
  his	
  mother	
  was	
  
not	
  under	
  a	
  high	
  level	
  of	
  stress	
  but	
  
did	
  seem	
  to	
  be	
  easily	
  upset	
  in	
  
some	
  situations.	
  

Family	
  Member	
  II:1	
  

Family	
  member	
  II:1	
  indi-­‐
cated	
  that	
  he	
  shared	
  the	
  same	
  
proclivity	
  as	
  his	
  mother	
  for	
  “can-­‐
ker	
  sores”.	
  He	
  stated	
  that	
  he	
  
would	
  get	
  “attacks”	
  about	
  three	
  or	
  
four	
  times	
  a	
  year,	
  lasting	
  for	
  about	
  
a	
  week	
  at	
  a	
  time.	
  He	
  said	
  that	
  the	
  
lesions	
  were	
  “mostly	
  small”	
  and	
  
based	
  on	
  this	
  information	
  and	
  
known	
  prevalence	
  of	
  the	
  different	
  
types	
  of	
  aphthae,	
  it	
  is	
  safe	
  to	
  as-­‐
sume	
  he	
  was	
  afflicted	
  with	
  minor	
  
RAS.	
  Again,	
  no	
  indications	
  of	
  sys-­‐
temic	
  disease	
  were	
  noted.	
  When	
  
asked	
  about	
  his	
  stress	
  level,	
  he	
  
indicated	
  that	
  his	
  job	
  was	
  moder-­‐
ately	
  stressful.	
  He	
  also	
  mentioned	
  
that	
  a	
  few	
  of	
  his	
  “attacks”	
  coincid-­‐
ed	
  with	
  times	
  were	
  his	
  job	
  stress	
  
was	
  slightly	
  higher.	
  	
  

Family	
  Member	
  III:2	
  

Family	
  member	
  III:1	
  is	
  the	
  
third	
  member	
  of	
  this	
  family	
  to	
  be	
  
affected	
  by	
  RAS.	
  She	
  stated	
  she	
  
would	
  have	
  “frequent	
  outbreaks	
  
of	
  canker	
  sores	
  four	
  to	
  five	
  times	
  a	
  
year”.	
  She	
  remembered	
  her	
  father	
  
being	
  affected	
  by	
  canker	
  sores	
  “of	
  
similar	
  size	
  and	
  duration”	
  as	
  those	
  
that	
  she	
  experienced.	
  This	
  indi-­‐
cates	
  she	
  also	
  suffered	
  from	
  the	
  
minor	
  type	
  of	
  RAS.	
  She	
  also	
  men-­‐
tioned	
  that	
  the	
  “sores”	
  affected	
  
her	
  ability	
  to	
  eat,	
  drink	
  and	
  carry	
  
on	
  with	
  some	
  day	
  to	
  day	
  activities.	
  
Still	
  no	
  indications	
  of	
  systemic	
  dis-­‐
ease	
  were	
  noted	
  in	
  this	
  family	
  
member.	
  Regarding	
  daily	
  stress,	
  
she	
  stated	
  that	
  she	
  did	
  not	
  have	
  a	
  
stressful	
  job,	
  but	
  admitted	
  to	
  “not	
  
always	
  handling	
  stressful	
  situa-­‐
tions	
  well”.	
  She	
  could	
  not	
  remem-­‐
ber	
  specifically	
  if	
  her	
  outbreaks	
  
coincided	
  with	
  times	
  of	
  stress.	
  

Family	
  Member	
  III:3	
  

Family	
  member	
  III:3	
  stated	
  
that	
  she	
  “has	
  never	
  had	
  an	
  out-­‐
break	
  of	
  canker	
  sores”	
  like	
  her	
  sis-­‐
ter	
  or	
  father.	
  However,	
  she	
  was	
  
diagnosed	
  with	
  Stage	
  I	
  ovarian	
  
cancer	
  within	
  the	
  past	
  two	
  years.	
  
She	
  was	
  initially	
  treated	
  with	
  six	
  
rounds	
  of	
  chemotherapy	
  with	
  min-­‐
imal	
  complications.	
  During	
  treat-­‐
ment,	
  she	
  was	
  also	
  tested	
  for	
  mu-­‐
tations	
  of	
  the	
  BRCA	
  genes,	
  none	
  of	
  
which	
  were	
  found.	
  Within	
  the	
  last	
  
year,	
  a	
  CA125	
  test	
  revealed	
  ele-­‐
vated	
  values	
  and	
  the	
  family	
  was	
  
concerned	
  about	
  a	
  possible	
  recur-­‐
rence,	
  although	
  all	
  scans	
  were	
  
clear.	
  Subsequent	
  testing	
  revealed	
  
no	
  change	
  in	
  the	
  values	
  and	
  the	
  
initial	
  elevation	
  was	
  attributed	
  to	
  
the	
  presence	
  of	
  multiple	
  hernias	
  
at	
  the	
  initial	
  incision	
  site,	
  rather	
  
than	
  recurrence.	
  However,	
  during	
  
the	
  time	
  between	
  tests,	
  the	
  pa-­‐
tient	
  became	
  so	
  stressed	
  that	
  she	
  
was	
  prescribed	
  Xanax	
  to	
  help	
  her	
  
relax.	
  Based	
  on	
  this	
  and	
  observa-­‐
tions	
  from	
  other	
  family	
  members,	
  
it	
  has	
  been	
  concluded	
  that	
  family	
  
member	
  III:3	
  should	
  be	
  character-­‐
ized	
  as	
  a	
  high	
  stress	
  individual.	
  	
  

Discussion	
  

	
   The	
  goal	
  of	
  this	
  study	
  is	
  to	
  
examine	
  the	
  possible	
  relationship	
  
between	
  recurrent	
  aphthous	
  sto-­‐
matitis	
  and	
  cancer.	
  In	
  the	
  family	
  
described,	
  the	
  link	
  between	
  RAS	
  
and	
  ovarian	
  cancer	
  specifically	
  will	
  
be	
  discussed.	
  The	
  discussion	
  will	
  
focus	
  on	
  the	
  possible	
  genetic	
  fac-­‐
tors	
  making	
  members	
  of	
  this	
  fami-­‐
ly	
  susceptible	
  to	
  these	
  diseases	
  as	
  
well	
  as	
  the	
  local	
  factor	
  of	
  stress.	
  
Also,	
  the	
  ethical	
  concerns	
  and	
  
possible	
  implications	
  of	
  a	
  familial	
  



	
  Could	
  recurrent	
  aphthous	
  stoma11s	
  be	
  linked	
  to	
  cancer	
  development?	
  

Vol	
  5,	
  No	
  1	
  (2017)	
  	
  	
  	
  DOI	
  10.5195/d3000.2017.66	
  

	
  http://dentistry3000.pitt.edu	
  

presentation	
  such	
  as	
  the	
  one	
  de-­‐
scribe	
  in	
  a	
  dental	
  practice	
  will	
  also	
  
be	
  discussed.	
  

Inheritance	
  Pattern	
  

Examining	
  Figure	
  1,	
  it	
  is	
  
clear	
  that	
  this	
  family	
  has	
  three	
  
consecutive	
  generations	
  affected	
  
by	
  RAS	
  and	
  a	
  fourth	
  generation	
  
that	
  could	
  show	
  signs	
  of	
  RAS	
  but	
  
have	
  not	
  to	
  date.	
  Also	
  both	
  male	
  
and	
  female	
  family	
  members	
  have	
  
been	
  affected.	
  Using	
  this	
  infor-­‐

mation	
  alone,	
  it	
  may	
  be	
  postulat-­‐
ed	
  that	
  RAS	
  is	
  being	
  inherited	
  in	
  
an	
  autosomal	
  dominant	
  fashion.	
  
This	
  would	
  be	
  in	
  direct	
  contradic-­‐
tion	
  to	
  the	
  initial	
  proposal	
  of	
  auto-­‐
somal	
  recessive	
  inheritance	
  in	
  
1965	
  [4].	
  However,	
  this	
  family	
  is	
  
relatively	
  small,	
  making	
  the	
  sam-­‐
ple	
  size	
  too	
  small	
  to	
  reliably	
  de-­‐
termine	
  mode	
  of	
  inheritance	
  from	
  
the	
  pedigree	
  alone.	
  Also	
  multiple	
  
members	
  of	
  the	
  family	
  are	
  known	
  
to	
  have	
  high	
  stress	
  levels	
  or	
  diffi-­‐
culty	
  properly	
  dealing	
  with	
  stress-­‐
ful	
  situations.	
  This	
  information	
  

supports	
  the	
  widely	
  accepted	
  the-­‐
ory	
  of	
  a	
  multifactorial	
  inheritance	
  
pattern.	
  	
  

Genetic	
  Factors	
  

Aphthous	
  ulcers	
  arise	
  due	
  
to	
  an	
  abnormal	
  immune	
  interac-­‐
tion	
  on	
  the	
  oral	
  mucosal	
  cells,	
  cat-­‐
egorizing	
  it	
  as	
  an	
  autoinflammato-­‐
ry	
  disease	
  [5].	
  It	
  is	
  thought	
  that	
  
disruption	
  in	
  both	
  the	
  humoral	
  
and	
  cellular	
  immune	
  systems	
  con-­‐
tribute	
  to	
  the	
  occurrence	
  of	
  RAS	
  

[4,	
  5].	
  Specifically,	
  im-­‐
paired	
  activation	
  of	
  proin-­‐
flammatory	
  components	
  
such	
  as	
  tumor	
  necrosis	
  
factors	
  and	
  interleukin-­‐1	
  
(IL-­‐1)	
  have	
  been	
  implicat-­‐
ed	
  [4,	
  5].	
  The	
  IL-­‐1	
  family	
  
are	
  primary	
  activators	
  of	
  
the	
  expression	
  of	
  endothe-­‐
lial	
  cell	
  adhesion	
  mole-­‐
cules	
  which	
  facilitates	
  the	
  
migration	
  of	
  leukocytes	
  
into	
  tissues	
  [4].	
  A	
  member	
  
of	
  the	
  IL-­‐1	
  family,	
  IL-­‐1β,	
  is	
  
primarily	
  released	
  by	
  
monocytes	
  and	
  macro-­‐
phages,	
  as	
  well	
  as	
  some	
  
nonimmune	
  cells,	
  such	
  as	
  

fibroblasts	
  and	
  endothelial	
  cells	
  at	
  
sites	
  of	
  injury	
  to	
  stimulate	
  in-­‐
creased	
  migration	
  of	
  leukocytes	
  
[6].	
  The	
  increased	
  migration	
  of	
  
leukocytes	
  caused	
  by	
  increased	
  
release	
  of	
  IL-­‐1β	
  could	
  account	
  for	
  
the	
  damage	
  to	
  mucosal	
  cells	
  that	
  
results	
  in	
  RAS	
  [4].	
  Gene	
  polymor-­‐
phisms	
  associated	
  with	
  IL-­‐1β	
  have	
  
been	
  thought	
  to	
  correlate	
  to	
  a	
  
higher	
  incidence	
  of	
  RAS,	
  however	
  
studies	
  of	
  these	
  polymorphisms	
  
have	
  produced	
  conflicting	
  results	
  
[4].	
  Because	
  research	
  into	
  specific	
  
IL-­‐1	
  mutations	
  has	
  produced	
  in-­‐

conclusive	
  results	
  it	
  is	
  difficult	
  to	
  
say	
  if	
  a	
  mutation	
  in	
  IL-­‐1β	
  could	
  be	
  
responsible	
  for	
  the	
  presentation	
  of	
  
RAS	
  seen	
  in	
  this	
  family.	
  However,	
  
it	
  has	
  been	
  previously	
  concluded	
  
that	
  multiple	
  factors	
  are	
  involved	
  
in	
  the	
  presentation	
  of	
  RAS	
  so	
  a	
  
mutation	
  of	
  IL-­‐1β	
  could	
  be	
  con-­‐
tributing	
  to	
  the	
  development	
  of	
  
aphthous	
  ulcers	
  in	
  this	
  family.	
  Ge-­‐
netic	
  testing	
  of	
  this	
  family	
  may	
  be	
  
helpful	
  in	
  determining	
  if	
  IL-­‐1β	
  is	
  a	
  
major	
  component	
  of	
  their	
  RAS	
  and	
  
could	
  also	
  reveal	
  possible	
  genes	
  to	
  
focus	
  on	
  for	
  future	
  research.	
  Given	
  
the	
  history	
  of	
  cancer	
  within	
  this	
  
family	
  it	
  seems	
  likely	
  that	
  tumor	
  
necrosis	
  factor-­‐α	
  could	
  have	
  a	
  
large	
  influence	
  on	
  the	
  disease	
  
presentation	
  seen.	
  

Tumor	
  necrosis	
  factor-­‐α	
  
(TNF-­‐α)	
  is	
  another	
  inflammatory	
  
cytokine	
  involved	
  with	
  RAS.	
  TNF-­‐α	
  
has	
  been	
  implicated	
  as	
  a	
  major	
  
contributor	
  to	
  the	
  development	
  of	
  
RAS.	
  It	
  is	
  a	
  major	
  proinflammatory	
  
cytokine	
  involved	
  with	
  the	
  chemo-­‐
taxis	
  of	
  immune	
  components,	
  such	
  
as	
  neutrophils	
  and	
  major	
  histo-­‐
compatibility	
  complexes	
  (MHC)	
  
[5].	
  	
  TNF-­‐α	
  is	
  involved	
  in	
  cell	
  sig-­‐
naling	
  pathways,	
  one	
  of	
  which	
  is	
  
involved	
  in	
  apoptosis	
  of	
  cells	
  [6].	
  
Increased	
  production	
  of	
  TNF-­‐α	
  
could	
  explain	
  the	
  destruction	
  of	
  
mucosal	
  cells	
  in	
  RAS	
  through	
  acti-­‐
vation	
  of	
  the	
  apoptotic	
  pathway.	
  It	
  
is	
  also	
  effective	
  in	
  the	
  T	
  cell-­‐
mediated	
  immune	
  response,	
  
which	
  is	
  responsible	
  for	
  a	
  part	
  of	
  
the	
  immune-­‐mediated	
  pathogene-­‐
sis	
  of	
  RAS	
  [5].	
  It	
  has	
  been	
  found	
  
that	
  the	
  number	
  of	
  CD4+	
  T	
  cells	
  is	
  
decreased	
  and	
  the	
  number	
  of	
  
CD8+	
  T	
  cells	
  is	
  increased	
  in	
  pa-­‐

Figure	
  1.	
  Family	
  pedigree.	
  Individuals	
  with	
  RAS	
  are	
  identified	
  
by	
  the	
  shaded	
  figures.	
  Member	
  III:3	
  presented	
  with	
  ovarian	
  
cancer,	
  marked	
  OC.	
  RAS	
  presentation	
  in	
  members	
  IV:1	
  and	
  
IV:2	
  has	
  not	
  yet	
  been	
  diagnosed,	
  indicated	
  by	
  the	
  “?”.	
  



	
  Could	
  recurrent	
  aphthous	
  stoma11s	
  be	
  linked	
  to	
  cancer	
  development?	
  

Vol	
  5,	
  No	
  1	
  (2017)	
  	
  	
  	
  DOI	
  10.5195/d3000.2017.66	
  

	
  http://dentistry3000.pitt.edu	
  

tients	
  with	
  RAS	
  [5].	
  TNF-­‐α	
  has	
  
many	
  beneficial	
  functions,	
  in	
  addi-­‐
tion	
  to	
  its	
  role	
  in	
  the	
  immune	
  re-­‐
sponse,	
  including	
  maintenance	
  of	
  
homeostasis	
  by	
  regulating	
  the	
  
body’s	
  circadian	
  rhythm	
  and	
  pro-­‐
moting	
  the	
  remodeling	
  of	
  injured	
  
tissue	
  [7].	
  However,	
  prolonged	
  
existence	
  of	
  TNF-­‐α	
  in	
  the	
  body	
  can	
  
produce	
  negative	
  effects.	
  After	
  
remaining	
  in	
  the	
  body	
  for	
  a	
  long	
  
time,	
  TNF-­‐α	
  loses	
  its	
  anti-­‐tumor	
  
activity,	
  which	
  could	
  result	
  in	
  the	
  
growth	
  of	
  various	
  tumors	
  
throughout	
  the	
  body	
  [7].	
  Devel-­‐
opment	
  of	
  RAS	
  indicates	
  an	
  in-­‐
crease	
  in	
  TNF-­‐α	
  activity,	
  which	
  
could	
  lead	
  to	
  a	
  decrease	
  in	
  the	
  an-­‐
ti-­‐tumor	
  function	
  of	
  the	
  cytokine.	
  
This	
  would	
  prevent	
  TNF-­‐α	
  from	
  
destroying	
  the	
  developing	
  cancer	
  
cells,	
  allowing	
  a	
  tumor	
  to	
  form.	
  As	
  
tests	
  for	
  other	
  genetic	
  mutations	
  
associated	
  with	
  ovarian	
  cancer	
  
were	
  negative,	
  it	
  is	
  possible	
  that	
  
increased	
  TNF-­‐α	
  activity	
  could	
  be	
  
a	
  contributing	
  factor	
  to	
  the	
  devel-­‐
opment	
  of	
  cancer	
  in	
  family	
  mem-­‐
ber	
  III:3.	
  

Local	
  Factors:	
  Stress	
  

Psychological	
  stress	
  has	
  
been	
  implicated	
  as	
  a	
  factor	
  induc-­‐
ing	
  RAS.	
  All	
  members	
  of	
  the	
  family	
  
studied	
  reported	
  higher	
  than	
  
normal	
  levels	
  of	
  stress	
  or	
  de-­‐
creased	
  ability	
  to	
  handle	
  stress.	
  It	
  
has	
  been	
  found	
  that	
  patients	
  with	
  
RAS	
  had	
  higher	
  overall	
  stress	
  lev-­‐
els	
  than	
  patients	
  without	
  RAS	
  [8].	
  
Also	
  many	
  patients	
  with	
  RAS	
  indi-­‐
cate	
  that	
  their	
  outbreaks	
  correlate	
  
to	
  high	
  stress	
  times	
  in	
  their	
  life	
  [8].	
  
As	
  previously	
  described,	
  the	
  path-­‐
ogenesis	
  of	
  RAS	
  involves	
  increased	
  
immune	
  activity	
  leading	
  to	
  de-­‐

struction	
  of	
  the	
  oral	
  mucosa	
  [4,	
  5,	
  
8].	
  Stress	
  contributes	
  to	
  this	
  activi-­‐
ty	
  by	
  increasing	
  the	
  number	
  of	
  
leukocytes	
  at	
  sites	
  of	
  inflammation	
  
[8].	
  	
  In	
  this	
  family	
  only	
  one	
  mem-­‐
ber,	
  II:1,	
  could	
  recall	
  a	
  correlation	
  
between	
  stress	
  levels	
  and	
  appear-­‐
ance	
  of	
  aphthae.	
  This	
  discrepancy	
  
from	
  the	
  literature	
  is	
  probably	
  due	
  
to	
  the	
  inaccuracy	
  of	
  the	
  patient’s	
  
memory,	
  rather	
  than	
  a	
  lack	
  of	
  as-­‐
sociation	
  between	
  stress	
  and	
  RAS.	
  
Also,	
  stress	
  is	
  a	
  complex	
  factor	
  
which	
  affects	
  each	
  person	
  differ-­‐
ently	
  [8].	
  This	
  could	
  account	
  for	
  
the	
  different	
  levels	
  of	
  severity	
  de-­‐
scribed	
  by	
  family	
  members	
  II:1	
  
and	
  III:2.	
  	
  

Psychological	
  stress	
  has	
  
been	
  found	
  to	
  have	
  an	
  effect	
  on	
  
cancer	
  development	
  as	
  well.	
  It	
  has	
  
been	
  shown	
  the	
  increased	
  stress	
  
levels	
  could	
  affect	
  cellular	
  pro-­‐
cesses,	
  such	
  as	
  those	
  involved	
  in	
  
DNA	
  repair	
  [9].	
  This	
  could	
  lead	
  to	
  
oncogenic	
  mutations.	
  It	
  has	
  also	
  
been	
  found	
  that	
  stress	
  may	
  in-­‐
crease	
  the	
  rate	
  of	
  tumor	
  growth	
  
[9].	
  Family	
  member	
  III:3	
  and	
  her	
  
family	
  indicated	
  that	
  she	
  may	
  not	
  
handle	
  stressful	
  situations	
  well.	
  
The	
  situation	
  mentioned	
  in	
  this	
  
study	
  (increased	
  CA125	
  levels	
  for	
  a	
  
recovering	
  cancer	
  patient)	
  would	
  
be	
  an	
  extremely	
  stressful	
  time	
  for	
  
anyone	
  and	
  may	
  not	
  be	
  the	
  best	
  
indicator	
  of	
  this	
  patient’s	
  response	
  
to	
  stress.	
  However,	
  the	
  family	
  ob-­‐
served	
  other	
  situations	
  in	
  which	
  
the	
  patient’s	
  response	
  to	
  stress	
  
was	
  extreme,	
  showing	
  a	
  pattern	
  
for	
  this	
  patient.	
  	
  

Practical	
  Implications	
  and	
  Ethical	
  Con-­‐
cerns	
  

Due	
  to	
  the	
  common	
  nature	
  
of	
  RAS,	
  it	
  is	
  highly	
  likely	
  that	
  a	
  
dentist	
  will	
  see	
  and	
  diagnose	
  many	
  
patients	
  with	
  this	
  condition	
  
throughout	
  their	
  career.	
  The	
  theo-­‐
ry	
  posed	
  in	
  this	
  study	
  raises	
  the	
  
question:	
  What	
  should	
  a	
  dentist	
  
do	
  considering	
  their	
  patient	
  with	
  
RAS	
  may	
  be	
  at	
  higher	
  risk	
  of	
  can-­‐
cer?	
  Another	
  ethical	
  question	
  may	
  
be	
  whether	
  to	
  tell	
  the	
  patient	
  
about	
  this	
  possible	
  increased	
  risk.	
  
At	
  this	
  point,	
  there	
  is	
  not	
  enough	
  
research	
  to	
  support	
  this	
  theory	
  to	
  
warrant	
  alarming	
  a	
  patient	
  with	
  
simple	
  RAS.	
  However,	
  the	
  dentist	
  
may	
  keep	
  this	
  theory	
  in	
  mind	
  
when	
  examining	
  a	
  patient	
  with	
  a	
  
history	
  of	
  RAS.	
  It	
  may	
  be	
  prudent	
  
for	
  the	
  dentist	
  to	
  screen	
  these	
  pa-­‐
tients	
  for	
  oral	
  cancer	
  more	
  fre-­‐
quently	
  in	
  an	
  attempt	
  to	
  discover	
  
any	
  cancerous	
  changes	
  early.	
  The	
  
dentist	
  may	
  also	
  consider	
  counsel-­‐
ing	
  their	
  RAS	
  patients	
  regarding	
  
their	
  stress	
  level.	
  This	
  would	
  both	
  
reduce	
  their	
  risk	
  of	
  RAS	
  outbreaks	
  
and	
  possibly	
  the	
  development	
  of	
  
cancer.	
  Regarding	
  the	
  family	
  stud-­‐
ied,	
  the	
  children	
  in	
  the	
  fourth	
  gen-­‐
eration	
  have	
  not	
  yet	
  shown	
  any	
  
signs	
  of	
  RAS.	
  However,	
  given	
  the	
  
family	
  history,	
  it	
  would	
  be	
  logical	
  
to	
  monitor	
  them	
  closely	
  for	
  any	
  
signs	
  of	
  RAS	
  or	
  even	
  cancer	
  
growth.	
  

Conclusion	
  

	
   This	
  study	
  has	
  examined	
  
the	
  possible	
  connection	
  between	
  
recurrent	
  aphthous	
  stomatitis	
  and	
  
the	
  development	
  of	
  cancer	
  by	
  
looking	
  at	
  a	
  family	
  with	
  a	
  history	
  
of	
  both	
  conditions.	
  Both	
  genetic	
  
and	
  local	
  factors	
  contribute	
  to	
  the	
  
development	
  of	
  RAS	
  as	
  well	
  as	
  



	
  Could	
  recurrent	
  aphthous	
  stoma11s	
  be	
  linked	
  to	
  cancer	
  development?	
  

Vol	
  5,	
  No	
  1	
  (2017)	
  	
  	
  	
  DOI	
  10.5195/d3000.2017.66	
  

	
  http://dentistry3000.pitt.edu	
  

cancer.	
  In	
  this	
  family,	
  it	
  was	
  sug-­‐
gested	
  that	
  increased	
  TNF-­‐α	
  activ-­‐
ity	
  combined	
  with	
  high	
  psycholog-­‐
ical	
  stress	
  contributed	
  to	
  the	
  de-­‐
velopment	
  of	
  RAS	
  in	
  family	
  mem-­‐
bers	
  I:2,	
  II:1	
  and	
  III:2.	
  These	
  same	
  
factors,	
  coupled	
  with	
  the	
  lack	
  of	
  
other	
  genetic	
  mutations,	
  could	
  
have	
  contributed	
  to	
  the	
  develop-­‐
ment	
  of	
  ovarian	
  cancer	
  in	
  family	
  
member	
  III:3.	
  As	
  far	
  as	
  the	
  practic-­‐
ing	
  dentist	
  is	
  concerned,	
  patients	
  
with	
  RAS	
  should	
  be	
  closely	
  moni-­‐
tored,	
  but	
  at	
  this	
  point	
  more	
  harm	
  
than	
  good	
  would	
  be	
  done	
  by	
  tell-­‐
ing	
  these	
  patients	
  they	
  could	
  pos-­‐
sibly	
  develop	
  cancer.	
  More	
  re-­‐
search	
  needs	
  to	
  be	
  done	
  to	
  solidify	
  
a	
  connection	
  between	
  RAS	
  and	
  
the	
  development	
  of	
  cancer.	
  This	
  
research	
  could	
  also	
  elucidate	
  new	
  
genes	
  to	
  study	
  regarding	
  the	
  
pathogenesis	
  of	
  RAS.	
  

References	
  

1. Nasry	
  SA,	
  El	
  Shenawy	
  HM,	
  
Mostafa	
  D,	
  Ammar	
  NM.	
  
Different	
  modalities	
  for	
  
treatment	
  of	
  recurrent	
  
aphthous	
  stomatitis.	
  A	
  
Randomized	
  clinical	
  trial.	
  J	
  
Clin	
  Exp	
  Dent.	
  2016	
  Dec	
  
1;8(5):e517-­‐e522.	
  eCollec-­‐
tion	
  2016	
  Dec.	
  PubMed	
  
PMID:	
  27957263;	
  PMCID:	
  
PMC5149084.	
  

2. Najafi	
  S,	
  Mohammadzadeh	
  
M,	
  Zare	
  Bidoki	
  A,	
  Meighani	
  
G,	
  Aslani	
  S,	
  Mahmoudi	
  M,	
  
Rezaei	
  N.	
  HLA-­‐DRB	
  and	
  
HLA-­‐DQB	
  Allele	
  and	
  Haplo-­‐
type	
  Frequencies	
  in	
  Iranian	
  
Patients	
  with	
  Recurrent	
  
Aphthous	
  Stomatitis.	
  Iran	
  J	
  
Allergy	
  Asthma	
  Immunol.	
  

2016	
  Aug;15(4):289-­‐295.	
  
PMID:	
  27921409.	
  

3. Han	
  M,	
  Fang	
  H,	
  Li	
  QL,	
  Cao	
  
Y,	
  Xia	
  R,	
  Zhang	
  ZH.	
  Effec-­‐
tiveness	
  of	
  Laser	
  Therapy	
  
in	
  the	
  Management	
  of	
  Re-­‐
current	
  Aphthous	
  Stomati-­‐
tis:	
  A	
  Systematic	
  Review.	
  
Scientifica	
  (Cairo).	
  
2016;2016:9062430.	
  doi:	
  
10.1155/2016/9062430.	
  
Epub	
  2016	
  Dec	
  18.	
  Review.	
  
PubMed	
  PMID:	
  28078164;	
  
PMCID:	
  PMC5203897.	
  

4. Ślebioda	
  Z,	
  Krawiecka	
  E,	
  
Rozmiarek	
  M,	
  Szponar	
  E,	
  
Kowalska	
  A,	
  Dorocka-­‐
Bobkowska	
  B.	
  Clinical	
  phe-­‐
notype	
  of	
  recurrent	
  aph-­‐
thous	
  stomatitis	
  and	
  inter-­‐
leukin-­‐1β	
  genotype	
  in	
  a	
  
Polish	
  cohort	
  of	
  patients.	
  J	
  
Oral	
  Pathol	
  Med.	
  2016	
  Dec	
  
9.	
  doi:	
  10.1111/jop.12533.	
  
[Epub	
  ahead	
  of	
  print]	
  
PMID:	
  27935125.	
  

5. Yigit	
  S,	
  Tekcan	
  A,	
  Rustemo-­‐
glu	
  A,	
  Tumer	
  MK,	
  Kalkan	
  G,	
  
Yerliyurt	
  K.	
  Investigation	
  of	
  
CD40	
  gene	
  rs4810485	
  and	
  
rs1883832	
  mutations	
  in	
  
patients	
  with	
  recurrent	
  
aphthous	
  stomatitis.	
  Arch	
  
Oral	
  Biol.	
  2017	
  Feb;74:51-­‐
54.	
  doi:	
  
10.1016/j.archoralbio.2016
.11.003.	
  Epub	
  2016	
  Nov	
  5.	
  
PMID:	
  27875792.	
  

6. Zhang	
  JM,	
  An	
  J.	
  Cytokines,	
  
inflammation,	
  and	
  pain.	
  Int	
  
Anesthesiol	
  Clin.	
  2007	
  
Spring;45(2):27-­‐37.	
  Re-­‐
view.	
  PubMed	
  PMID:	
  
17426506;	
  PMCID:	
  
PMC2785020.	
  

7. Esposito	
  E,	
  Cuzzocrea	
  S.	
  
TNF-­‐alpha	
  as	
  a	
  therapeutic	
  
target	
  in	
  inflammatory	
  dis-­‐
eases,	
  ischemia-­‐
reperfusion	
  injury	
  and	
  
trauma.	
  Curr	
  Med	
  Chem.	
  
2009;16(24):3152-­‐67.	
  
PMID:	
  19689289.	
  

8. Gallo	
  Cde	
  B,	
  Mimura	
  MA,	
  
Sugaya	
  NN.	
  Psychological	
  
stress	
  and	
  recurrent	
  aph-­‐
thous	
  stomatitis.	
  Clinics	
  
(Sao	
  Paulo).	
  
2009;64(7):645-­‐8.	
  doi:	
  
10.1590/S1807-­‐
59322009000700007.	
  
PubMed	
  PMID:	
  19606240;	
  
PMCID:	
  PMC2710437.	
  

9. Chida	
  Y,	
  Hamer	
  M,	
  Wardle	
  
J,	
  Steptoe	
  A.	
  Do	
  stress-­‐
related	
  psychosocial	
  fac-­‐
tors	
  contribute	
  to	
  cancer	
  
incidence	
  and	
  survival?	
  Nat	
  
Clin	
  Pract	
  Oncol.	
  2008	
  
Aug;5(8):466-­‐75.	
  doi:	
  
10.1038/ncponc1134.	
  Epub	
  
2008	
  May	
  20.	
  Review.	
  
PMID:	
  18493231.