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

DOI	
  10.5195/d3000.2017.70	
  	
  

	
  

	
  

	
  

http://dentistry3000.pitt.edu	
  

	
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  articles	
  in	
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  journal	
  are	
  licensed	
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  Creative	
  Commons	
  Attribution	
  4.0	
  United	
  States	
  License.	
  

	
  
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  journal	
  is	
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  Library	
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  University	
  of	
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  as	
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by	
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  University	
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  Press.	
  

	
  

Etiology	
  and	
  familial	
  inheritance	
  of	
  pleomorphic	
  adenomas	
  
Krysten	
  Clark1	
  
	
  
	
  1University	
  of	
  Pi.sburgh,	
  School	
  of	
  Dental	
  Medicine

Abstract	
  

Background:	
  A	
  pleomorphic	
  adenoma	
  is	
  the	
  most	
  common	
  salivary	
  gland	
  neoplasm	
  in	
  both	
  children	
  and	
  adults.	
  Ple-­‐
omorphic	
  adenomas	
  are	
  derived	
  from	
  ductal	
  and	
  myoepithelial	
  cells	
  and	
  are	
  most	
  commonly	
  found	
  in	
  the	
  superficial	
  
lobe	
  of	
  the	
  paro,d	
  gland.	
  The	
  purpose	
  of	
  this	
  ar,cle	
  is	
  to	
  discuss	
  the	
  genes	
  involved	
  in	
  pleomorphic	
  adenomas	
  and	
  
the	
  possible	
  autosomal	
  dominant	
  mode	
  of	
  inheritance.	
  Case	
  Descrip+on:	
  The	
  first	
  pa+ent	
  was	
  a	
  white	
  male	
  who	
  was	
  
diagnosed	
  with	
  carcinoma	
  ex	
  pleomorphic	
  adenoma,	
  a	
  highly	
  aggressive	
  tumor,	
  at	
  the	
  age	
  of	
  57.	
  He	
  had	
  an	
  undiag-­‐
nosed	
  pleomorphic	
  adenoma	
  for	
  approximately	
  15	
  years	
  prior.	
  The	
  tumor	
  was	
  excised	
  and	
  the	
  pa9ent	
  underwent	
  ra-­‐
dia$on	
   in	
   the	
   loca$on	
  of	
  his	
  paro!d	
  gland	
   for	
  4	
  years	
  un!l	
  he	
  deceased.	
  The	
  second	
  pa!ent	
   is	
  a	
  white	
   female,	
  his	
  
daughter,	
  who	
  was	
  diagnosed	
  with	
  a	
  benign	
  pleomorphic	
  adenoma	
  at	
  the	
  age	
  of	
  46.	
  Her	
  salivary	
  gland	
  tumor	
  was	
  ex-­‐
cised	
  and	
  normal	
   follow	
  up	
  appointments	
  occurred.	
  Prac%cal	
   Implica&ons:	
  Pleomorphic	
  adenomas	
  most	
  commonly	
  
affect	
  the	
  paro+d	
  gland,	
  the	
  largest	
  of	
  the	
  three	
  major	
  salivary	
  gland	
  tumors.	
  Occurrence	
  and	
  excision	
  of	
  this	
  salivary	
  
gland	
  tumor	
  will	
  cause	
  a	
  decrease	
  in	
  the	
  secre2on	
  of	
  saliva,	
  leading	
  to	
  a	
  dry	
  mouth	
  and	
  an	
  increased	
  risk	
  of	
  caries.	
  

	
  

Cita%on:	
   Clark,	
   K.	
   (2017)	
   E"ology	
   and	
   familial	
  
inheritance	
  of	
  pleomorphic	
  adenomas.	
  Den$stry	
  
3000.	
  1:a001	
  doi:10.5195/d3000.2017.70	
  
Received:	
  	
  May	
  9,	
  2017	
  
Accepted:	
  	
  May	
  10,	
  2017	
  
Published:	
  	
  June	
  16,	
  2017	
  
Copyright:	
   ©2017	
   Clark,	
   K.	
   This	
   is	
   an	
   open	
   ac-­‐
cess	
  ar!cle	
   licensed	
  under	
  a	
  Crea!ve	
  Commons	
  
A"ribu%on	
  Work	
  4.0	
  United	
  States	
  License.	
  
Email:	
  kdc40@pi).edu

	
  

Introduction	
  

Pleomorphic	
  adenomas	
  rep-­‐
resent	
  about	
  65%	
  of	
  all	
  salivary	
  gland	
  
neoplasms.	
  They	
  are	
  the	
  most	
  com-­‐
mon	
  salivary	
  gland	
  neoplasm	
  in	
  both	
  
children	
  and	
  adults.	
  	
  The	
  majority	
  oc-­‐
cur	
  in	
  the	
  parotid	
  gland,	
  although	
  it	
  is	
  
possible	
  for	
  them	
  to	
  arise	
  in	
  minor	
  
salivary	
  glands	
  or	
  the	
  submandibular	
  
and	
  sublingual	
  glands.	
  It	
  is	
  a	
  painless,	
  
slow	
  growing	
  mass	
  that	
  can	
  be	
  pal-­‐
pated	
  just	
  behind	
  the	
  ear	
  once	
  large	
  
enough.	
  They	
  are	
  defined	
  as	
  mixed	
  
tumors	
  because	
  they	
  contain	
  both	
  
epithelial,	
  mesenchymal,	
  and	
  myoepi-­‐
thelial	
  cells.	
  Histologically,	
  pleo-­‐
morphic	
  adenomas	
  are	
  arranged	
  in	
  
various	
  patterns	
  between	
  these	
  three	
  
types	
  of	
  cells	
  [1].	
  

Pleomorphic	
  adenomas	
  most	
  
commonly	
  arise	
  in	
  4th	
  decade	
  of	
  life	
  
and	
  have	
  a	
  slight	
  predilection	
  towards	
  
females.	
  The	
  prognosis	
  of	
  a	
  pleo-­‐
morphic	
  adenoma	
  is	
  typically	
  very	
  
good,	
  and	
  the	
  chance	
  of	
  malignancy	
  is	
  
less	
  than	
  5%	
  if	
  it	
  is	
  diagnosed	
  within	
  a	
  

few	
  years.	
  This	
  chance	
  increases	
  up	
  
to	
  9.5%	
  after	
  15	
  years	
  [1].	
  The	
  rate	
  of	
  
recurrence	
  is	
  under	
  5%	
  as	
  long	
  as	
  
complete	
  excision	
  occurs.	
  However,	
  if	
  
the	
  tumor	
  is	
  poorly	
  encapsulated,	
  the	
  
rate	
  of	
  recurrence	
  can	
  be	
  quite	
  high.	
  
The	
  treatment	
  for	
  a	
  pleomorphic	
  ad-­‐
enoma	
  consists	
  of	
  removal	
  of	
  the	
  tu-­‐
mor	
  and	
  surrounding	
  salivary	
  gland	
  
tissue,	
  leading	
  to	
  a	
  decreased	
  salivary	
  
flow.	
  	
  

Carcinoma	
  ex	
  pleomorphic	
  
adenoma	
  is	
  a	
  rare	
  and	
  aggressive	
  ma-­‐
lignant	
  tumor	
  that	
  can	
  arise	
  from	
  a	
  
pleomorphic	
  adenoma.	
  It	
  represents	
  
only	
  about	
  12%	
  of	
  malignant	
  salivary	
  
gland	
  tumors	
  [1].	
  Normally,	
  the	
  risk	
  of	
  
malignancy	
  is	
  very	
  low	
  unless	
  the	
  ini-­‐
tial	
  neoplasm	
  is	
  untreated	
  for	
  a	
  pro-­‐
longed	
  period	
  of	
  time	
  or	
  recurrence	
  
of	
  the	
  primary	
  tumor	
  occurs.	
  The	
  
mass	
  is	
  usually	
  painless	
  but	
  can	
  cause	
  
facial	
  nerve	
  paralysis.	
  Treatment	
  in-­‐
cludes	
  complete	
  excision	
  of	
  the	
  tu-­‐
mor,	
  most	
  likely	
  followed	
  by	
  radia-­‐
tion.	
  During	
  the	
  time	
  of	
  radiation,	
  it	
  is	
  

extremely	
  important	
  for	
  the	
  patient	
  
to	
  visit	
  a	
  dentist.	
  The	
  five-­‐year	
  surviv-­‐
al	
  rate	
  of	
  carcinoma	
  ex	
  pleomorphic	
  
adenoma	
  is	
  only	
  about	
  30%.	
  The	
  pur-­‐
pose	
  of	
  this	
  report	
  is	
  to	
  to	
  provide	
  
evidence	
  for	
  an	
  autosomal	
  dominant	
  
mode	
  of	
  inheritance	
  of	
  pleomorphic	
  
adenomas.	
  

Subjects	
  

A	
  46-­‐year-­‐old	
  female	
  patient	
  
was	
  diagnosed	
  with	
  a	
  pleomorphic	
  
adenoma	
  of	
  the	
  parotid	
  gland	
  by	
  an	
  
ENT	
  after	
  her	
  dentist	
  palpated	
  a	
  lump	
  
in	
  the	
  area	
  during	
  a	
  routine	
  head	
  and	
  
neck	
  exam.	
  The	
  tumor	
  was	
  excised,	
  
defined	
  as	
  benign,	
  and	
  after	
  follow	
  up	
  
appointments	
  for	
  5	
  years,	
  no	
  further	
  
treatment	
  was	
  necessary.	
  The	
  likeli-­‐
hood	
  of	
  recurrence	
  in	
  her	
  case	
  is	
  un-­‐
der	
  5%	
  [2]..	
  This	
  patient’s	
  father	
  was	
  
diagnosed	
  with	
  carcinoma	
  ex	
  pleo-­‐
morphic	
  adenoma	
  at	
  the	
  age	
  of	
  57,	
  
and	
  deceased	
  4	
  years	
  later	
  after	
  met-­‐
astatic	
  spread	
  to	
  his	
  lungs.	
  This	
  pa-­‐
tient	
  also	
  had	
  the	
  tumor	
  excised	
  and	
  
received	
  radiation.	
  Upon	
  diagnosis	
  of	
  



E!ology	
  and	
  familial	
  inheritance	
  of	
  pleomorphic	
  adenomas	
  

Vol	
  5,	
  No	
  1	
  (2017)	
  	
  	
  	
  DOI	
  10.5195/d3000.2017.70	
  

	
  http://dentistry3000.pitt.edu	
  

his	
  malignant	
  tumor,	
  he	
  admitted	
  to	
  
feeling	
  a	
  lump	
  in	
  the	
  same	
  location	
  
for	
  at	
  least	
  15	
  years.	
  Figure	
  1	
  suggests	
  
a	
  family	
  segregation	
  compatible	
  with	
  	
  
autosomal	
  dominant	
  mode	
  of	
  inher-­‐
itance.	
  

Discussion	
  

The	
  exact	
  cause	
  of	
  pleo-­‐
morphic	
  adenomas	
  is	
  unknown,	
  alt-­‐
hough	
  70%	
  of	
  cases	
  show	
  some	
  form	
  
of	
  chromosomal	
  abnormality.	
  There	
  
are	
  both	
  genetic	
  and	
  environmental	
  
risk	
  factors.	
  One	
  well	
  known	
  envi-­‐
ronmental	
  risk	
  factor	
  is	
  exposure	
  to	
  
therapeutic	
  radiation.	
  According	
  to	
  
research,	
  patients	
  treated	
  with	
  radia-­‐
tion	
  for	
  childhood	
  malignancies	
  had	
  
an	
  increased	
  risk	
  of	
  developing	
  a	
  sali-­‐
vary	
  gland	
  neoplasm.	
  Survivors	
  of	
  the	
  
atomic	
  bomb	
  drop	
  have	
  also	
  shown	
  
an	
  increased	
  risk.	
  However,	
  many	
  of	
  
these	
  developing	
  tumors	
  were	
  malig-­‐
nant	
  mucoepidermoid	
  carcinomas	
  
instead	
  of	
  pleomorphic	
  adenomas	
  [2].	
  
Also,	
  according	
  to	
  research	
  studies,	
  
smoking	
  surprisingly	
  does	
  not	
  seem	
  
to	
  have	
  a	
  strong	
  association	
  with	
  the	
  
development	
  of	
  pleomorphic	
  adeno-­‐
mas,	
  although	
  it	
  plays	
  a	
  significant	
  

role	
  in	
  the	
  develop-­‐
ment	
  of	
  Warthin’s	
  tu-­‐
mor,	
  a	
  different	
  type	
  of	
  
benign	
  salivary	
  gland	
  
tumor	
  that	
  also	
  com-­‐
monly	
  affects	
  the	
  pa-­‐
rotid	
  gland	
  [3].	
  The	
  on-­‐
set	
  and	
  progression	
  of	
  
pleomorphic	
  adenomas	
  
has	
  also	
  potentially	
  
thought	
  to	
  be	
  linked	
  to	
  
the	
  use	
  of	
  mobile	
  
phones,	
  although	
  more	
  
research	
  needs	
  to	
  be	
  
done.	
  One	
  last	
  envi-­‐
ronmental	
  risk	
  factor	
  to	
  
the	
  formation	
  of	
  ple-­‐
omorphic	
  adenomas	
  
has	
  viral	
  origin.	
  Alt-­‐
hough	
  EBV	
  and	
  cyto-­‐
megalovirus	
  do	
  not	
  

seem	
  to	
  be	
  correlated,	
  infection	
  with	
  
the	
  Simian	
  virus,	
  a	
  highly	
  oncogenic	
  
tumor	
  virus,	
  seems	
  to	
  play	
  a	
  role	
  in	
  
the	
  development	
  of	
  pleomorphic	
  ad-­‐
enomas	
  [4].	
  	
  

The	
  simian	
  virus	
  (SV40)	
  was	
  
originally	
  in	
  monkeys,	
  but	
  accidental-­‐
ly	
  transferred	
  to	
  many	
  humans	
  who	
  
received	
  an	
  anti-­‐polio	
  vaccine.	
  How-­‐
ever,	
  based	
  on	
  research,	
  it	
  seems	
  that	
  
even	
  individuals	
  who	
  did	
  not	
  receive	
  
the	
  polio	
  vaccine	
  have	
  been	
  infected	
  
with	
  SV40[4].	
  The	
  virus	
  has	
  recently	
  
been	
  found	
  to	
  be	
  involved	
  with	
  dif-­‐
ferent	
  types	
  of	
  human	
  tumors,	
  includ-­‐
ing	
  brain	
  and	
  bone	
  tumors,	
  mesothe-­‐
liomas,	
  thyroid	
  carcinomas,	
  and	
  pitui-­‐
tary	
  adenomas.	
  Through	
  the	
  use	
  of	
  
PCR,	
  it	
  was	
  discovered	
  that	
  the	
  SV40	
  
Tag	
  sequence	
  was	
  often	
  found	
  in	
  ple-­‐
omorphic	
  adenomas	
  but	
  not	
  in	
  nor-­‐
mal	
  salivary	
  gland	
  tissue	
  [4].	
  These	
  
results	
  indicate	
  that	
  the	
  Simian	
  virus	
  
likely	
  plays	
  a	
  role	
  in	
  the	
  onset	
  or	
  pro-­‐
gression	
  of	
  pleomorphic	
  adenomas.	
  	
  

	
   Three	
  genes	
  have	
  been	
  corre-­‐
lated	
  with	
  the	
  development	
  of	
  pleo-­‐
morphic	
  adenomas.	
  The	
  first	
  is	
  pleo-­‐

morphic	
  adenoma	
  gene1	
  (PLAG1),	
  
which	
  is	
  found	
  on	
  chromosome	
  8	
  and	
  
present	
  in	
  about	
  39%	
  of	
  diagnosed	
  
patients	
  [5].	
  The	
  second	
  gene	
  is	
  the	
  
high	
  mobility	
  group	
  AT-­‐hook	
  2	
  gene	
  
(HMGA2),	
  located	
  on	
  chromosome	
  12	
  
and	
  found	
  in	
  8%	
  of	
  patients.	
  The	
  
above	
  two	
  mutations	
  are	
  both	
  trans-­‐
locations.	
  Lastly,	
  the	
  mucin	
  1	
  gene	
  
(MUC1)	
  has	
  been	
  correlated	
  to	
  the	
  
recurrence	
  and	
  malignant	
  transfor-­‐
mation	
  of	
  pleomorphic	
  adenomas.	
  

	
   PLAG1	
  and	
  HMGA2	
  mutations	
  
are	
  both	
  proto-­‐oncogenes,	
  also	
  
known	
  as	
  gain	
  of	
  function	
  mutations.	
  
Proto-­‐oncogenes	
  are	
  normal	
  genes	
  in	
  
the	
  body	
  that	
  are	
  converted	
  to	
  onco-­‐
genes	
  by	
  three	
  different	
  mechanisms.	
  
The	
  first	
  mechanism	
  is	
  a	
  point	
  muta-­‐
tion	
  that	
  results	
  in	
  a	
  continuously	
  ac-­‐
tivated	
  protein.	
  The	
  second	
  mecha-­‐
nism	
  is	
  localized	
  duplication	
  of	
  a	
  DNA	
  
segment,	
  leading	
  to	
  gene	
  amplifica-­‐
tion	
  and	
  overexpression	
  of	
  that	
  pro-­‐
tein.	
  The	
  third	
  mechanism	
  is	
  chromo-­‐
somal	
  translocation	
  that	
  causes	
  a	
  dif-­‐
ferent	
  promoter	
  to	
  promote	
  inappro-­‐
priate	
  expression	
  of	
  a	
  protein	
  that	
  is	
  
normally	
  under	
  gene	
  control	
  [6].	
  
HMGA2	
  and	
  most	
  commonly	
  PLAG1	
  
are	
  both	
  transformed	
  into	
  oncogenes	
  
by	
  translocation.	
  However,	
  trisomy	
  8	
  
is	
  a	
  possible	
  mechanism	
  for	
  the	
  over-­‐
expression	
  of	
  PLAG1.	
  

	
   PLAG1,	
  found	
  on	
  chromo-­‐
some	
  8,	
  has	
  been	
  consistently	
  rear-­‐
ranged	
  and	
  over-­‐expressed	
  in	
  indi-­‐
viduals	
  with	
  pleomorphic	
  adenomas.	
  
The	
  most	
  common	
  PLAG1	
  transloca-­‐
tion	
  is	
  found	
  at	
  8q12,	
  leading	
  PLAG1	
  
to	
  be	
  ubiquitously	
  expressed.	
  The	
  two	
  
most	
  common	
  translocation	
  genes	
  
are	
  CTNNB1	
  found	
  on	
  chromosome	
  3	
  
and	
  LIFR	
  found	
  on	
  chromosome	
  5	
  [5].	
  
Also,	
  mosaic	
  trisomy	
  8	
  is	
  the	
  most	
  
common	
  chromosomal	
  deviation	
  as-­‐
sociated	
  with	
  salivary	
  gland	
  tumors	
  
[7].	
  Based	
  on	
  recent	
  research	
  it	
  has	
  
been	
  noted	
  that	
  PLAG1	
  acts	
  as	
  a	
  pro-­‐

Figure	
  1:	
  Family	
  pedigree.	
  Patient	
  1	
  is	
  in	
  generation	
  1	
  and	
  had	
  carci-­‐
noma	
  ex	
  pleomorphic	
  adenoma	
  after	
  approx.	
  15	
  years	
  without	
  removal	
  
of	
  primary	
  tumor.	
  Patient	
  2	
  is	
  in	
  generation	
  2	
  and	
  had	
  a	
  pleomorphic	
  
adenoma.	
  Offspring	
  in	
  generation	
  3	
  are	
  still	
  in	
  their	
  20’s	
  and	
  younger	
  
than	
  the	
  average	
  age	
  range	
  for	
  diagnosis.	
  



E!ology	
  and	
  familial	
  inheritance	
  of	
  pleomorphic	
  adenomas	
  

Vol	
  5,	
  No	
  1	
  (2017)	
  	
  	
  	
  DOI	
  10.5195/d3000.2017.70	
  

	
  http://dentistry3000.pitt.edu	
  

to-­‐oncogene,	
  and	
  the	
  overexpression	
  
of	
  this	
  gene	
  is	
  crucial	
  to	
  the	
  develop-­‐
ment	
  of	
  pleomorphic	
  adenomas.	
  It	
  
has	
  also	
  been	
  noted	
  that	
  the	
  role	
  of	
  
PLAG1	
  is	
  confined	
  to	
  pleomorphic	
  
adenomas	
  and	
  carcinoma	
  ex	
  pleo-­‐
morphic	
  adenoma	
  and	
  does	
  not	
  play	
  
a	
  role	
  in	
  other	
  types	
  of	
  salivary	
  gland	
  
neoplasms.	
  PLAG1	
  encodes	
  a	
  zinc	
  fin-­‐
ger	
  protein	
  and	
  activates	
  DNA	
  tran-­‐
scription	
  by	
  binding	
  to	
  DNA	
  in	
  a	
  se-­‐
quence-­‐specific	
  manner.	
  One	
  poten-­‐
tial	
  binding	
  site	
  of	
  PLAG1	
  was	
  found	
  
on	
  the	
  promoter	
  region	
  of	
  human	
  
insulin-­‐like	
  growth	
  factor	
  II	
  (IGF-­‐II),	
  
leading	
  to	
  its	
  overexpression	
  [7].	
  The	
  
activation	
  of	
  IGFII	
  causes	
  growth	
  
promoting	
  activity,	
  which	
  could	
  lead	
  
to	
  the	
  formation	
  of	
  a	
  tumor.	
  	
  

	
   Mutations	
  in	
  HMGA2	
  seem	
  to	
  
be	
  more	
  common	
  in	
  carcinoma	
  ex	
  
pleomorphic	
  adenoma,	
  and	
  are	
  only	
  
found	
  in	
  around	
  8%	
  of	
  benign	
  pleo-­‐
morphic	
  adenomas.	
  HMGA2,	
  a	
  small	
  
non-­‐histone	
  associated	
  protein	
  locat-­‐
ed	
  on	
  chromosome	
  12,	
  can	
  modify	
  
transcription	
  by	
  altering	
  the	
  chroma-­‐
tin	
  structure.	
  This	
  gene	
  also	
  mutates	
  
through	
  translocation,	
  leading	
  to	
  the	
  
expression	
  of	
  HMGA2,	
  loss	
  of	
  regula-­‐
tion,	
  and	
  promotion	
  of	
  cell	
  growth	
  
[8].	
  The	
  amplification	
  of	
  this	
  gene	
  has	
  
been	
  suggested	
  to	
  play	
  a	
  role	
  in	
  the	
  
malignant	
  transformation	
  of	
  pleo-­‐
morphic	
  adenomas.	
  Since	
  both	
  PLAG1	
  
and	
  HMGA2	
  mutations	
  are	
  consistent	
  
with	
  pleomorphic	
  adenoma,	
  the	
  de-­‐
tection	
  of	
  these	
  mutations	
  can	
  aid	
  in	
  
the	
  diagnosis.	
  	
  

	
   Although	
  the	
  recurrence	
  rate	
  
of	
  pleomorphic	
  adenomas	
  is	
  low	
  in	
  
many	
  cases	
  where	
  surgical	
  excision	
  is	
  
properly	
  performed,	
  if	
  recurrence	
  
does	
  occur,	
  the	
  chance	
  of	
  re-­‐
recurrence	
  is	
  high.	
  These	
  tumors	
  are	
  
often	
  multi-­‐nodular	
  and	
  poorly	
  en-­‐
capsulated.	
  Mucin-­‐1	
  gene	
  is	
  one	
  of	
  
the	
  glycoproteins	
  that	
  makes	
  up	
  mu-­‐
cus.	
  There	
  is	
  no	
  expression	
  of	
  MUC1	
  

in	
  normal	
  salivary	
  glands.	
  However,	
  in	
  
a	
  study	
  by	
  Hamada	
  et	
  al,	
  the	
  
MUC1/DF3	
  mutation	
  was	
  found	
  in	
  4	
  
of	
  9	
  patients	
  with	
  recurrent	
  pleo-­‐
morphic	
  adenomas,	
  but	
  only	
  in	
  3	
  of	
  
40	
  patients	
  with	
  non-­‐recurrent	
  pleo-­‐
morphic	
  adenomas	
  [9].	
  According	
  to	
  
literature,	
  the	
  expression	
  of	
  
MUC1/DF3	
  could	
  be	
  used	
  as	
  a	
  marker	
  
to	
  detect	
  the	
  possible	
  recurrence	
  and	
  
malignant	
  transformation	
  of	
  pleo-­‐
morphic	
  adenomas.	
  	
  

The	
  evidence	
  shows	
  that	
  ple-­‐
omorphic	
  adenomas	
  do	
  tend	
  to	
  have	
  
a	
  familial	
  component	
  and	
  the	
  two	
  
modes	
  of	
  inheritance	
  for	
  pleomorphic	
  
adenomas	
  are	
  autosomal	
  dominant	
  
inheritance	
  and	
  a	
  somatic	
  mutation	
  
[7].	
  If	
  pleomorphic	
  adenomas	
  are	
  
passed	
  in	
  an	
  autosomal	
  fashion,	
  a	
  
patient’s	
  offspring	
  would	
  have	
  a	
  50%	
  
chance	
  of	
  passing	
  the	
  disease	
  down	
  
to	
  offspring.	
  Based	
  on	
  the	
  presented	
  
case,	
  the	
  first	
  male	
  patient	
  likely	
  had	
  
a	
  mutation	
  and	
  passed	
  the	
  mutated	
  
gene	
  to	
  his	
  daughter	
  in	
  an	
  autosomal	
  
dominant	
  type	
  fashion.	
  However,	
  fur-­‐
ther	
  research	
  needs	
  to	
  be	
  done	
  to	
  
potentially	
  link	
  familial	
  inheritance	
  to	
  
the	
  PLAG1	
  mutation,	
  the	
  mutated	
  
gene	
  most	
  commonly	
  found	
  in	
  pleo-­‐
morphic	
  adenomas.	
  

	
   Pleomorphic	
  adenomas	
  can	
  
cause	
  an	
  increase	
  in	
  dental	
  caries.	
  
The	
  parotid	
  gland	
  is	
  entirely	
  serous	
  
and	
  drains	
  into	
  the	
  oral	
  cavity	
  
through	
  Stenson’s	
  duct.	
  It	
  produces	
  
approximately	
  20%	
  of	
  the	
  salivary	
  
content	
  in	
  the	
  oral	
  cavity.	
  The	
  sub-­‐
mandibular	
  gland,	
  produces	
  around	
  
65%	
  of	
  saliva	
  and	
  enters	
  the	
  oral	
  cavi-­‐
ty	
  through	
  Wharton’s	
  duct.	
  Although	
  
pleomorphic	
  adenomas	
  most	
  typically	
  
arise	
  in	
  the	
  parotid	
  gland,	
  it	
  can	
  arise	
  
in	
  either	
  of	
  the	
  major	
  salivary	
  glands.	
  
Complete	
  removal	
  of	
  these	
  tumors	
  
causes	
  a	
  decrease	
  in	
  the	
  production	
  
of	
  one	
  of	
  the	
  major	
  salivary	
  glands.	
  
This	
  will	
  almost	
  certainly	
  lead	
  to	
  a	
  

decrease	
  in	
  the	
  production	
  of	
  saliva.	
  
Saliva	
  plays	
  an	
  essential	
  role	
  in	
  the	
  
prevention	
  of	
  caries,	
  and	
  a	
  decreased	
  
salivary	
  flow	
  in	
  the	
  oral	
  cavity	
  makes	
  
an	
  individual	
  more	
  prone	
  to	
  the	
  de-­‐
velopment	
  of	
  caries.	
  If	
  a	
  pleomorphic	
  
adenoma	
  does	
  develop	
  into	
  carcino-­‐
ma	
  ex	
  pleomorphic	
  adenoma	
  and	
  
radiation	
  therapy	
  is	
  required	
  after	
  
surgical	
  removal,	
  the	
  likelihood	
  of	
  
caries	
  increases	
  exponentially.	
  Radia-­‐
tion	
  therapy	
  causes	
  an	
  individual	
  to	
  
lose	
  almost	
  all	
  salivary	
  flow,	
  and	
  fre-­‐
quent	
  dental	
  visits	
  are	
  required	
  dur-­‐
ing	
  this	
  time.	
  	
  

	
   Genetic	
  testing	
  for	
  pleo-­‐
morphic	
  adenomas	
  could	
  cause	
  po-­‐
tentially	
  lead	
  to	
  ethical	
  implications	
  
related	
  to	
  insurance	
  companies.	
  Also,	
  
there	
  may	
  be	
  a	
  fine	
  line	
  between	
  
normal	
  and	
  abnormal	
  palpation	
  dur-­‐
ing	
  a	
  head	
  and	
  neck	
  exam.	
  It	
  is	
  very	
  
important	
  that	
  a	
  dentist	
  refers	
  a	
  pa-­‐
tient	
  to	
  a	
  specialist	
  if	
  they	
  feel	
  any-­‐
thing	
  abnormal,	
  and	
  missing	
  a	
  mass	
  in	
  
a	
  major	
  or	
  minor	
  salivary	
  gland	
  could	
  
be	
  an	
  ethical	
  implication.	
  Overall,	
  
pleomorphic	
  adenomas	
  are	
  very	
  
treatable	
  when	
  caught	
  early	
  and	
  do	
  
not	
  recur.	
  There	
  does	
  seem	
  to	
  be	
  a	
  
genetic	
  link	
  between	
  pleomorphic	
  
adenomas	
  and	
  a	
  few	
  genes,	
  like	
  the	
  
PLAG1	
  gene.	
  More	
  research	
  needs	
  to	
  
be	
  completed	
  on	
  families	
  with	
  history	
  
of	
  pleomorphic	
  adenoma	
  to	
  discover	
  
a	
  possible	
  autosomal	
  mode	
  of	
  inher-­‐
itance.	
  

References	
  

1.	
  PLAG1	
  gene	
  alterations	
  in	
  sali-­‐
vary	
  gland	
  pleomorphic	
  adenoma	
  
and	
  carcinoma	
  ex-­‐pleomorphic	
  
adenoma:	
  a	
  combined	
  study	
  using	
  
chromosome	
  banding,	
  in	
  situhy-­‐
bridization	
  and	
  immunocytochem-­‐
istry.	
  Martins	
  C,	
  Fonseca	
  I,	
  Roque	
  
L,	
  Pereira	
  T,	
  Ribeira	
  C,	
  Bullerdiek	
  J,	
  



E!ology	
  and	
  familial	
  inheritance	
  of	
  pleomorphic	
  adenomas	
  

Vol	
  5,	
  No	
  1	
  (2017)	
  	
  	
  	
  DOI	
  10.5195/d3000.2017.70	
  

	
  http://dentistry3000.pitt.edu	
  

Soares	
  J.	
  Modern	
  Pathology.	
  2005;	
  
18:1048–1055.	
  6	
  May	
  2006.	
  PMID:	
  
15920557.	
  

2.	
  Salivary	
  gland	
  tumors	
  in	
  survi-­‐
vors	
  of	
  childhood	
  cancer.	
  Whatley	
  
WS,	
  Thompson	
  JW,	
  Rao	
  B.	
  2006	
  
March;	
  124	
  (3):385-­‐388.	
  PMID:	
  
16500432	
  

3.	
  Smoking	
  and	
  risk	
  of	
  parotid	
  
gland	
  tumors:	
  a	
  nationwide	
  case-­‐
control	
  study.	
  Sadetzki	
  S,	
  Ober-­‐
man	
  B,	
  Mandelzweig	
  L,	
  Chetrit	
  A,	
  
Ben-­‐Tal	
  T,	
  Jarus-­‐Hakak	
  A,	
  
Duvdevani	
  S,	
  Cardis	
  E,	
  Wolf	
  M.	
  
2008	
  May	
  1;	
  112(9):	
  1974-­‐82.	
  
PMID:	
  18361448	
  

4.	
  Simian	
  Virus	
  40	
  Sequences	
  and	
  
Expression	
  of	
  the	
  Viral	
  Large	
  T	
  An-­‐
tigen	
  Oncoprotein	
  in	
  Human	
  Ple-­‐
omorphic	
  Adenomas	
  of	
  Parotid	
  
Glands.	
  Martinelli,	
  M,	
  Martini,	
  F,	
  
Rinaldi,	
  E,	
  Caramanico,	
  L,	
  Magri,	
  E,	
  
Grandi,	
  E,	
  Carinci	
  F,	
  Pastore	
  A,	
  
Tognon,	
  M.	
  2002	
  Oct;	
  161(4):	
  
1127–1133.	
  PMID:	
  PMC1867276	
  

5.	
  Conserved	
  mechanism	
  of	
  PLAG1	
  
activation	
  in	
  salivary	
  gland	
  tumors	
  
with	
  and	
  without	
  chromosome	
  
8q12	
  abnormalities:	
  identification	
  
of	
  SII	
  as	
  a	
  new	
  fusion	
  partner	
  
gene.	
  Astrom	
  AK,	
  Voz	
  ML,	
  Kas	
  K,	
  
Roijer	
  E,	
  Wedell	
  B,	
  Mandahl	
  N,	
  
Van	
  de	
  Ven	
  W,	
  Mark	
  J,	
  Stenman	
  G.	
  
1999	
  Feb	
  15;	
  59(4):	
  918-­‐923.	
  PMID	
  
10029085	
  

6.	
  Lodish	
  H,	
  Berk	
  A,	
  Zipursky	
  SL,	
  
Matsudaira	
  P,	
  Baltimore	
  D,	
  Darnell	
  

J	
  (2000)	
  Molecular	
  Cell	
  Biology.	
  
New	
  York:	
  W.	
  H.	
  Freeman.	
  	
  

7.PLAG1	
  gene	
  alterations	
  in	
  salivar
y	
  gland	
  pleomorphic	
  adenoma	
  and
	
  carcinoma	
  ex-­‐
pleomorphicadenoma:	
  
a	
  combined	
  study	
  using	
  chromoso
me	
  banding,	
  
in	
  situ	
  hybridization	
  and	
  immunoc
ytochemistry.	
  Martins	
  C,	
  Fonseca	
  
I,	
  Roque	
  L,	
  Pereira	
  T,	
  Ribeiro	
  C,	
  
Bullerdiek	
  J,	
  Soares	
  J.	
  2005	
  Aug;	
  
18(8):	
  1048-­‐1055.	
  PMID:	
  
15920557	
  

8.	
  Aberrant	
  PLAG1	
  expression	
  in	
  
pleomorphic	
  adenomas	
  of	
  the	
  sal-­‐
ivary	
  gland:	
  a	
  molecular	
  genetic	
  
and	
  immunohistochemical	
  study.	
  
Matsuyama	
  A,	
  Hisaoka	
  M,	
  Nagao	
  
Y,	
  Hashimoto	
  H.	
  2011	
  May;	
  458(5):	
  
583-­‐92.	
  PMID	
  21394649	
  

9.	
  Mucin	
  expression	
  in	
  pleo-­‐
morphic	
  adenoma	
  of	
  salivary	
  
gland:	
  a	
  potential	
  role	
  for	
  MUC1	
  
as	
  a	
  marker	
  to	
  predict	
  recur-­‐
rence.	
  Hamada	
  T,	
  Matsukita	
  S,	
  Go-­‐
to	
  M,	
  Kitajima	
  S,	
  Batra	
  S	
  K,	
  Irimura	
  
T,	
  Sueyoshi	
  K,	
  Sugihara	
  K,	
  Yoneza-­‐
wa	
  S.	
  2004;	
  57(8),	
  813–821.	
  PMID	
  
PMC1770389