Vol  5,  No  1  (2017)  

ISSN  2167-­‐8677  (online)  
DOI  10.5195/d3000.2017.70    
 

Etiology  and  familial  inheritance  of  pleomorphic  adenomas  

1
Krysten  Clark  
 
 1
University  of  Pi.sburgh,  School  of  Dental  Medicine
Cita%on:   Clark,   K.   (2017)   E"ology   and   familial  
Abstract   inheritance  of  pleomorphic  adenomas.   Den$stry  
3000.  1:a001  doi:10.5195/d3000.2017.70  
Background:  A  pleomorphic  adenoma  is  the  most  common  salivary  gland  neoplasm  in  both  children  and  adults.  Ple-­‐ Received:    May  9,  2017  
omorphic   adenomas   are   derived   from   ductal   and   myoepithelial   cells   and   are   most   commonly   found   in   the   superficial   Accepted:    May  10,  2017  
lobe  of  the  paro,d  gland.  The  purpose  of  this  ar,cle  is  to  discuss  the  genes  involved  in  pleomorphic  adenomas  and   Published:    June  16,  2017  
the   possible   autosomal   dominant   mode   of   inheritance.  Case   Descrip+on:   The   first   pa+ent   was   a   white   male   who   was   Copyright:   ©2017   Clark,   K.   This   is   an   open   ac-­‐
diagnosed  with  carcinoma  ex  pleomorphic  adenoma,  a  highly  aggressive  tumor,  at  the  age  of  57.  He  had  an  undiag-­‐ cess   ar!cle   licensed   under   a   Crea!ve   Commons  
nosed   pleomorphic   adenoma   for   approximately   15   years   prior.   The   tumor   was   excised   and   the   pa9ent   underwent   ra-­‐ A"ribu%on  Work  4.0  United  States  License.  
dia$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  
Email:  kdc40@pi).edu
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.  

 
 

Introduction   few  years.  This  chance  increases  up   extremely  important  for  the  patient  
to  9.5%  after  15  years  [1].  The  rate  of   to  visit  a  dentist.  The  five-­‐year  surviv-­‐
Pleomorphic  adenomas  rep-­‐ recurrence  is  under  5%  as  long  as   al  rate  of  carcinoma  ex  pleomorphic  
resent  about  65%  of  all  salivary  gland   complete  excision  occurs.  However,  if   adenoma  is  only  about  30%.  The  pur-­‐
neoplasms.  They  are  the  most  com-­‐ the  tumor  is  poorly  encapsulated,  the   pose  of  this  report  is  to  to  provide  
mon  salivary  gland  neoplasm  in  both   rate  of  recurrence  can  be  quite  high.   evidence  for  an  autosomal  dominant  
children  and  adults.    The  majority  oc-­‐ The  treatment  for  a  pleomorphic  ad-­‐ mode  of  inheritance  of  pleomorphic  
cur  in  the  parotid  gland,  although  it  is   enoma  consists  of  removal  of  the  tu-­‐ adenomas.  
possible  for  them  to  arise  in  minor   mor  and  surrounding  salivary  gland  
salivary  glands  or  the  submandibular   tissue,  leading  to  a  decreased  salivary   Subjects  
and  sublingual  glands.  It  is  a  painless,   flow.    
slow  growing  mass  that  can  be  pal-­‐ A  46-­‐year-­‐old  female  patient  
pated  just  behind  the  ear  once  large   Carcinoma  ex  pleomorphic   was  diagnosed  with  a  pleomorphic  
enough.  They  are  defined  as  mixed   adenoma  is  a  rare  and  aggressive  ma-­‐ adenoma  of  the  parotid  gland  by  an  
tumors  because  they  contain  both   lignant  tumor  that  can  arise  from  a   ENT  after  her  dentist  palpated  a  lump  
epithelial,  mesenchymal,  and  myoepi-­‐ pleomorphic  adenoma.  It  represents   in  the  area  during  a  routine  head  and  
thelial  cells.  Histologically,  pleo-­‐ only  about  12%  of  malignant  salivary   neck  exam.  The  tumor  was  excised,  
morphic  adenomas  are  arranged  in   gland  tumors  [1].  Normally,  the  risk  of   defined  as  benign,  and  after  follow  up  
various  patterns  between  these  three   malignancy  is  very  low  unless  the  ini-­‐ appointments  for  5  years,  no  further  
types  of  cells  [1].   tial  neoplasm  is  untreated  for  a  pro-­‐ treatment  was  necessary.  The  likeli-­‐
longed  period  of  time  or  recurrence   hood  of  recurrence  in  her  case  is  un-­‐
Pleomorphic  adenomas  most   of  the  primary  tumor  occurs.  The   der  5%  [2]..  This  patient’s  father  was  
commonly  arise  in  4th  decade  of  life   mass  is  usually  painless  but  can  cause   diagnosed  with  carcinoma  ex  pleo-­‐
and  have  a  slight  predilection  towards   facial  nerve  paralysis.  Treatment  in-­‐ morphic  adenoma  at  the  age  of  57,  
females.  The  prognosis  of  a  pleo-­‐ cludes  complete  excision  of  the  tu-­‐ and  deceased  4  years  later  after  met-­‐
morphic  adenoma  is  typically  very   mor,  most  likely  followed  by  radia-­‐ astatic  spread  to  his  lungs.  This  pa-­‐
good,  and  the  chance  of  malignancy  is   tion.  During  the  time  of  radiation,  it  is   tient  also  had  the  tumor  excised  and  
less  than  5%  if  it  is  diagnosed  within  a   received  radiation.  Upon  diagnosis  of  

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This  journal  is  published  by  the  University  Library  System,  University  of  Pittsburgh  as  part  of  its  D-­‐Scribe  Digital  Publishing  Program  and  is  cosponored  
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 E!ology  and  familial  inheritance  of  pleomorphic  adenomas  

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

role  in  the  develop-­‐ morphic  adenoma  gene1  (PLAG1),  

ment  of  Warthin’s  tu-­‐ which  is  found  on  chromosome  8  and  
mor,  a  different  type  of   present  in  about  39%  of  diagnosed  
benign  salivary  gland   patients  [5].  The  second  gene  is  the  
tumor  that  also  com-­‐ high  mobility  group  AT-­‐hook  2  gene  
monly  affects  the  pa-­‐ (HMGA2),  located  on  chromosome  12  
rotid  gland  [3].  The  on-­‐ and  found  in  8%  of  patients.  The  
set  and  progression  of   above  two  mutations  are  both  trans-­‐
pleomorphic  adenomas   locations.  Lastly,  the  mucin  1  gene  
has  also  potentially   (MUC1)  has  been  correlated  to  the  
thought  to  be  linked  to   recurrence  and  malignant  transfor-­‐
the  use  of  mobile   mation  of  pleomorphic  adenomas.  
phones,  although  more  
research  needs  to  be     PLAG1  and  HMGA2  mutations  
done.  One  last  envi-­‐ are  both  proto-­‐oncogenes,  also  
ronmental  risk  factor  to   known  as  gain  of  function  mutations.  
Figure  1:  Family  pedigree.  Patient  1  is  in  generation  1  and  had  carci-­‐ the  formation  of  ple-­‐ Proto-­‐oncogenes  are  normal  genes  in  
noma  ex  pleomorphic  adenoma  after  approx.  15  y ears  without  removal   omorphic  adenomas   the  body  that  are  converted  to  onco-­‐
of  primary  tumor.  Patient  2  is  in  generation  2  and  had  a  pleomorphic  
has  viral  origin.  Alt-­‐ genes  by  three  different  mechanisms.  
adenoma.  Offspring  in  generation  3  are  still  in  their  20’s  and  younger  
than  the  average  age  range  for  diagnosis.   hough  EBV  and  cyto-­‐ The  first  mechanism  is  a  point  muta-­‐
megalovirus  do  not   tion  that  results  in  a  continuously  ac-­‐
his  malignant  tumor,  he  admitted  to   tivated  protein.  The  second  mecha-­‐
seem  to  be  correlated,  infection  with  
feeling  a  lump  in  the  same  location   nism  is  localized  duplication  of  a  DNA  
the  Simian  virus,  a  highly  oncogenic  
for  at  least  15  years.  Figure  1  suggests   segment,  leading  to  gene  amplifica-­‐
tumor  virus,  seems  to  play  a  role  in  
a  family  segregation  compatible  with     tion  and  overexpression  of  that  pro-­‐
the  development  of  pleomorphic  ad-­‐
autosomal  dominant  mode  of  inher-­‐ tein.  The  third  mechanism  is  chromo-­‐
enomas  [4].    
itance.   somal  translocation  that  causes  a  dif-­‐
The  simian  virus  (SV40)  was   ferent  promoter  to  promote  inappro-­‐
Discussion  
originally  in  monkeys,  but  accidental-­‐ priate  expression  of  a  protein  that  is  
The  exact  cause  of  pleo-­‐ ly  transferred  to  many  humans  who   normally  under  gene  control  [6].  
morphic  adenomas  is  unknown,  alt-­‐ received  an  anti-­‐polio  vaccine.  How-­‐ HMGA2  and  most  commonly  PLAG1  
hough  70%  of  cases  show  some  form   ever,  based  on  research,  it  seems  that   are  both  transformed  into  oncogenes  
of  chromosomal  abnormality.  There   even  individuals  who  did  not  receive   by  translocation.  However,  trisomy  8  
are  both  genetic  and  environmental   the  polio  vaccine  have  been  infected   is  a  possible  mechanism  for  the  over-­‐
risk  factors.  One  well  known  envi-­‐ with  SV40[4].  The  virus  has  recently   expression  of  PLAG1.  
ronmental  risk  factor  is  exposure  to   been  found  to  be  involved  with  dif-­‐
ferent  types  of  human  tumors,  includ-­‐   PLAG1,  found  on  chromo-­‐
therapeutic  radiation.  According  to  
ing  brain  and  bone  tumors,  mesothe-­‐ some  8,  has  been  consistently  rear-­‐
research,  patients  treated  with  radia-­‐
liomas,  thyroid  carcinomas,  and  pitui-­‐ ranged  and  over-­‐expressed  in  indi-­‐
tion  for  childhood  malignancies  had  
tary  adenomas.  Through  the  use  of   viduals  with  pleomorphic  adenomas.  
an  increased  risk  of  developing  a  sali-­‐
PCR,  it  was  discovered  that  the  SV40   The  most  common  PLAG1  transloca-­‐
vary  gland  neoplasm.  Survivors  of  the  
Tag  sequence  was  often  found  in  ple-­‐ tion  is  found  at  8q12,  leading  PLAG1  
atomic  bomb  drop  have  also  shown  
omorphic  adenomas  but  not  in  nor-­‐ to  be  ubiquitously  expressed.  The  two  
an  increased  risk.  However,  many  of  
mal  salivary  gland  tissue  [4].  These   most  common  translocation  genes  
these  developing  tumors  were  malig-­‐
results  indicate  that  the  Simian  virus   are  CTNNB1  found  on  chromosome  3  
nant  mucoepidermoid  carcinomas  
likely  plays  a  role  in  the  onset  or  pro-­‐ and  LIFR  found  on  chromosome  5  [5].  
instead  of  pleomorphic  adenomas  [2].  
gression  of  pleomorphic  adenomas.     Also,  mosaic  trisomy  8  is  the  most  
Also,  according  to  research  studies,  
common  chromosomal  deviation  as-­‐
smoking  surprisingly  does  not  seem  
  Three  genes  have  been  corre-­‐ sociated  with  salivary  gland  tumors  
to  have  a  strong  association  with  the  
lated  with  the  development  of  pleo-­‐ [7].  Based  on  recent  research  it  has  
development  of  pleomorphic  adeno-­‐
morphic  adenomas.  The  first  is  pleo-­‐ been  noted  that  PLAG1  acts  as  a  pro-­‐
mas,  although  it  plays  a  significant  

 http://dentistry3000.pitt.edu  
 E!ology  and  familial  inheritance  of  pleomorphic  adenomas  

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

to-­‐oncogene,  and  the  overexpression   in  normal  salivary  glands.  However,  in   decrease  in  the  production  of  saliva.  
of  this  gene  is  crucial  to  the  develop-­‐ a  study  by  Hamada  et  al,  the   Saliva  plays  an  essential  role  in  the  
ment  of  pleomorphic  adenomas.  It   MUC1/DF3  mutation  was  found  in  4   prevention  of  caries,  and  a  decreased  
has  also  been  noted  that  the  role  of   of  9  patients  with  recurrent  pleo-­‐ salivary  flow  in  the  oral  cavity  makes  
PLAG1  is  confined  to  pleomorphic   morphic  adenomas,  but  only  in  3  of   an  individual  more  prone  to  the  de-­‐
adenomas  and  carcinoma  ex  pleo-­‐ 40  patients  with  non-­‐recurrent  pleo-­‐ velopment  of  caries.  If  a  pleomorphic  
morphic  adenoma  and  does  not  play   morphic  adenomas  [9].  According  to   adenoma  does  develop  into  carcino-­‐
a  role  in  other  types  of  salivary  gland   literature,  the  expression  of   ma  ex  pleomorphic  adenoma  and  
neoplasms.  PLAG1  encodes  a  zinc  fin-­‐ MUC1/DF3  could  be  used  as  a  marker   radiation  therapy  is  required  after  
ger  protein  and  activates  DNA  tran-­‐ to  detect  the  possible  recurrence  and   surgical  removal,  the  likelihood  of  
scription  by  binding  to  DNA  in  a  se-­‐ malignant  transformation  of  pleo-­‐ caries  increases  exponentially.  Radia-­‐
quence-­‐specific  manner.  One  poten-­‐ morphic  adenomas.     tion  therapy  causes  an  individual  to  
tial  binding  site  of  PLAG1  was  found   lose  almost  all  salivary  flow,  and  fre-­‐
on  the  promoter  region  of  human   The  evidence  shows  that  ple-­‐ quent  dental  visits  are  required  dur-­‐
insulin-­‐like  growth  factor  II  (IGF-­‐II),   omorphic  adenomas  do  tend  to  have   ing  this  time.    
leading  to  its  overexpression  [7].  The   a  familial  component  and  the  two  
activation  of  IGFII  causes  growth   modes  of  inheritance  for  pleomorphic     Genetic  testing  for  pleo-­‐
promoting  activity,  which  could  lead   adenomas  are  autosomal  dominant   morphic  adenomas  could  cause  po-­‐
to  the  formation  of  a  tumor.     inheritance  and  a  somatic  mutation   tentially  lead  to  ethical  implications  
[7].  If  pleomorphic  adenomas  are   related  to  insurance  companies.  Also,  
  Mutations  in  HMGA2  seem  to   passed  in  an  autosomal  fashion,  a   there  may  be  a  fine  line  between  
be  more  common  in  carcinoma  ex   patient’s  offspring  would  have  a  50%   normal  and  abnormal  palpation  dur-­‐
pleomorphic  adenoma,  and  are  only   chance  of  passing  the  disease  down   ing  a  head  and  neck  exam.  It  is  very  
found  in  around  8%  of  benign  pleo-­‐ to  offspring.  Based  on  the  presented   important  that  a  dentist  refers  a  pa-­‐
morphic  adenomas.  HMGA2,  a  small   case,  the  first  male  patient  likely  had   tient  to  a  specialist  if  they  feel  any-­‐
non-­‐histone  associated  protein  locat-­‐ a  mutation  and  passed  the  mutated   thing  abnormal,  and  missing  a  mass  in  
ed  on  chromosome  12,  can  modify   gene  to  his  daughter  in  an  autosomal   a  major  or  minor  salivary  gland  could  
transcription  by  altering  the  chroma-­‐ dominant  type  fashion.  However,  fur-­‐ be  an  ethical  implication.  Overall,  
tin  structure.  This  gene  also  mutates   ther  research  needs  to  be  done  to   pleomorphic  adenomas  are  very  
through  translocation,  leading  to  the   potentially  link  familial  inheritance  to   treatable  when  caught  early  and  do  
expression  of  HMGA2,  loss  of  regula-­‐ the  PLAG1  mutation,  the  mutated   not  recur.  There  does  seem  to  be  a  
tion,  and  promotion  of  cell  growth   gene  most  commonly  found  in  pleo-­‐ genetic  link  between  pleomorphic  
[8].  The  amplification  of  this  gene  has   morphic  adenomas.   adenomas  and  a  few  genes,  like  the  
been  suggested  to  play  a  role  in  the   PLAG1  gene.  More  research  needs  to  
malignant  transformation  of  pleo-­‐   Pleomorphic  adenomas  can   be  completed  on  families  with  history  
morphic  adenomas.  Since  both  PLAG1   cause  an  increase  in  dental  caries.   of  pleomorphic  adenoma  to  discover  
and  HMGA2  mutations  are  consistent   The  parotid  gland  is  entirely  serous   a  possible  autosomal  mode  of  inher-­‐
with  pleomorphic  adenoma,  the  de-­‐ and  drains  into  the  oral  cavity   itance.  
tection  of  these  mutations  can  aid  in   through  Stenson’s  duct.  It  produces  
the  diagnosis.     approximately  20%  of  the  salivary   References  
content  in  the  oral  cavity.  The  sub-­‐
  Although  the  recurrence  rate   mandibular  gland,  produces  around   1.  PLAG1  gene  alterations  in  sali-­‐
of  pleomorphic  adenomas  is  low  in   65%  of  saliva  and  enters  the  oral  cavi-­‐ vary  gland  pleomorphic  adenoma  
many  cases  where  surgical  excision  is   ty  through  Wharton’s  duct.  Although  
properly  performed,  if  recurrence   pleomorphic  adenomas  most  typically   and  carcinoma  ex-­‐pleomorphic  
does  occur,  the  chance  of  re-­‐ arise  in  the  parotid  gland,  it  can  arise   adenoma:  a  combined  study  using  
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