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Risk  of  Thyroid  Cancer  Based  on      Thyroid  Ultrasound  Imaging  Characteristics  

 Diabetes  Update  and  Advances  in  Endocrinology  &  Metabolism        

     

Vickie  A  Feldstein  MD  Rebecca  Smith-­‐Bindman  MD  

 Department  of  Radiology  &  Biomedical  Imaging  RSB:  Director,  Radiology  Outcomes  Research  Lab  

Epidemiology  and  Biostatistics  

University  of  California,  San  Francisco  

Conflict  of  Interest    

 None  

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Utilization  of  Diagnostic  Imaging      

•  Imaging  has  increased  dramatically  over  the  last  20  years    

•   This  is  due  to  increased  imaging  by  radiologists  and  diverse  medical  specialists      

 

Patterns  of  Imaging  Smith-­‐Bindman  R  et  al.  JAMA  2012  

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Ultrasound  Imaging  

•  Utilization  has  doubled  over  last  15  years    •   US  volume  is  >  CT,  MRI  and  Nuclear  Medicine  combined    

Factors  that  Contribute  to  Increase  in  Imaging  

•  Improvement  in  technology  

•  Increased  capacity  due  to  proliferation  of  equipment    

•  Patient  demand  

•  Physician  demand  

•  Malpractice  concerns  

•  Relatively  few  guidelines  for  imaging  

•  High  profitability    

 

 

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Thyroid  Ultrasound    

•  Use  has  increased  dramatically  

•  Coincided  with  increased  ownership  of  US  machines  by  endocrinologists  and  surgeons  

•  This  is  a  well-­‐described  area  of  overuse      

“Choosing  Wisely”  

•  American  Board  of  Internal  Medicine  Foundation  supported  project  to  reduce  imaging,  testing,  treatment  

•  Five  Things  Physicians  and  Patients  Should  Question  

•  Large  number  (49)  societies  contribute  to  the  campaign    

•  Each  recommends  decreasing  testing  in  5  specific  clinical  scenarios  where  there  is  over-­‐use    

•  33  societies  include  reducing  1  or  more  areas  of  imaging    

www.choosingwisely.org  

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Endocrine  Society:  American  Association  of  Clinical  Endocrinologists  

List  of  What  Patients  and  Physicians  Should  Question        

•  Multiple  daily  self-­‐glucose  monitoring  in  adults  with  stable  type  2  diabetes    

•  Routine  measurement    1,25-­‐dihydroxy  vitamin  D    

•  Total/free  T3  when  assessing  T4  dose  in  hypothyroid  patient  

•  Testosterone  without  biochemical  evidence  of  deficiency  

•  Thyroid  ultrasound  after  abnormal  thyroid  function  tests      

     

Why  is  Thyroid  US  on    “Choosing  Wisely”  List  of  Overused  Tests    

•  “Thyroid  ultrasound  is  used  to  identify  and  characterize  thyroid  nodules  

•  US  is  not  part  of  the  evaluation  of  thyroid  function  tests  

•  Incidentally  discovered  thyroid  nodules  are  common  

•   Overzealous  use  of  ultrasound  will  frequently  identify  nodules,  which  are  unrelated  to  the  abnormal  thyroid  function,  and  may  divert  the  clinical  evaluation  to  assess  the  nodules,  rather  than  the  thyroid  dysfunction.”  

 

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Potential  Harm  of  Too  Much  Thyroid  Ultrasound

•  Patient  eventually  diagnosed  with  cancer    -­‐  missed  on  initial  exam.  “false  negative”  

•  Patients  never  diagnosed  with  cancer      -­‐  work-­‐up  prompted  by  US.  “false  positive”  

Patients  with  Thyroid  Cancer  

•  Steep  rise  in  the  diagnosis  of  thyroid  cancer    

•  No  associated  decline  in  mortality    

•  Thought  to  largely  reflect  increased  detection    

•  Thought  to  largely  reflect  over-­‐diagnosis  

•  This  results  in  increased  morbidity,  costs,  labeling,  without  improvement  in  patient-­‐centered  outcomes      

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From:  Current  Thyroid  Cancer  Trends  in  the  United  States,  JAMA  2014  

Thyroid  cancer  vs.  Thyroid  cancer  “detection”  epidemic?  

Patients  without  Thyroid  Cancer  

•  US  will  identify  large  number  of  thyroid  nodules  

•  Around  50%  of  the  population  has  a  nodule  

•  The  number  of  benign:malignant  nodules  50:1      

•  It  is  important  to  use  rational,  evidence-­‐based  criteria  to  decide  which  nodules  to  biopsy  –  otherwise  there  is  a  lot  of  attention  focused  on  chasing  benign  common  findings  because  of  fear  of  missing  a  single  cancer  

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“Rational  and  Reasonable”  Criteria    

•  There  is  a  very  large  reservoir  of  thyroid  cancer    

•  If  the  goal  is  to  diagnose  every  single  cancer  of  the  thyroid,  the  only  way  to  do  this  is  to  biopsy  everyone  

•  Suggestion:  Create  guidelines  for  imaging  so  that  patients  in  whom  biopsy  is  deferred  will  have  a  low  risk  (not  zero  risk)  of  thyroid  cancer  

Levels  of  Evidence  for  the  Value  of    Tests  

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What  is  the  Best  Evidence  on  Which  to  Base    Clinical  Interpretations/Decisions  ?    

•  An  experienced  MD’s  opinion  (the  expert)  

•  A  case  series  (i.e.  a  number  of  examples)  

•  A  consensus  opinion  –  e.g.  society  guidelines  •  A  large  well-­‐done  observational  study  without  bias  

•  Several  well-­‐done  observational  studies  and  a  statistical  summary  of  those  results  

•  A  randomized  controlled  trial  

Biases  Important  In  Imaging  

 

•  Selection  Bias:  patients  reported  are  not  typical  

•  Ascertainment  Bias:  outcomes  –  the  truth  –  are  often  obtained  only  in  patients  with  suspected  abnormalities,  and  therefore  you  don’t  learn  about  misses  

•  Over-­‐diagnosis  Bias:  if  you  look  for  disease,  you  will  find  a  large  reservoir  of  cases  that  would  never  have  been  symptomatic  and  that  otherwise  would  never  have  been  known.  it  is  easy  to  “cure”  such  cases  

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Selection  Bias  

•  Patients  you  read  about  are  not  typical  of  those  in  whom  you  are  applying  the  test  

•  It  is  easier  to  diagnose  advanced  disease  -­‐    cancer,  birth  defects,  infection,  vascular  dz    

•   You  cannot  conclude  because  you  were  able  to  diagnose  advanced  dz  that  you  can  detect  early  dz  

Ascertainment  Bias  

•  What  happened  to  the  patients  studied?  

•  Need  to  follow-­‐up  on  patients  with  a  finding  and  those  without  a  finding  

•  If  you  only  follow-­‐up  on  those  in  whom  you  suspect  a  problem,  you  will  overestimate  the  accuracy  -­‐  a  lot!!!  

•  Basically,  if  you  don’t  make  an  effort  to  find  your  misses,  you  assume  they  don’t  occur  

•  This  is  incredibly  important  in  the  area  of  thyroid  US  

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Guidelines  on  Thyroid  US  

•  All  of  the  existing  studies  have  ascertainment  bias  •  The  recommendations  of  all  societies  

§  Society  of  Radiologists  in  Ultrasound  §  American  Thyroid  Association  §  American  Association  of  Clinical  Endocrinologists    §  European  Thyroid  Association  §  Associazione  Medici  Endocrinologi  §  Korean  Society  of  Neuro  &  Head  &  Neck  Radiology  are  based  on  expert  opinion  combined  with  flawed  studies,  as  there  were  no  well  done  observational  studies  

Over-­‐Diagnosis  Bias  

•  There  is  a  spectrum  of  disease  for  every  kind  of  pathology  

•  If  you  do  a  lot  of  testing  for  disease  (as  opposed  to  waiting  until  patients  are  symptomatic)  you  will  find  a  lot  more  disease  than  you  think  exists    

•  Prostate  cancer  is  a  well  known  example  of  this,  but  thyroid  cancer  is  just  as  common  

•  There  is  a  huge  amount  of  early  disease  and  you  cannot  consider  finding  this  “disease”  to  be  inherently  beneficial  to  patients  if  the  disease  was  not  going  to  hurt  them  

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Thyroid  Ultrasound  •  Performed  in  large  numbers  of  patients  •  Thyroid  nodules  common    

•  Up  to  50%  of  adult  population  •  Thyroid  cancer,  uncommon  

•  1%  of  all  cancer  •  Symptomatic    1/10,000  patients  per  year  

•  Mostly  indolent  •  5  year  survival  is  98%  even  without  treatment  •  Not  clear  how  aggressive  we  should  be  to  find  

6 mm

Interpreting  Thyroid  US  

•  Large  number  of  studies  published  on  accuracy  of  US    •  All  are  plagued  with  selection  bias  /  ascertainment  bias  

•  All  studies  limited  their  analysis  to  FNA’d  nodules    •  FNA  decision  based  on  size  /  worrisome  features  •  Nodules  without  worrisome  features  not  studied  

•  Selection  bias  including  known  and  symptomatic  cancers  

•  Both  will  inflate  the  accuracy  of  US  

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Purpose  

•  To  determine  the  sonographic  features  statistically  associated  with  thyroid  cancer      

•  Unique  aspect  of  study:  we  included  nodules  subjected  to  FNAB/surgery  AND  those  not  initially  biopsied  -­‐  through  follow-­‐up  with  tumor  registry    

 •  Goal:  to  identify  nodules  with  low  risk  of  cancer  so  

that  FNAB  can  be  deferred/avoided      

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Study  Methods  

•  Retrospective  case  -­‐  cohort  study  •  11,618  patients  w/  thyroid  US  at  UCSF  between  

January  2000  –  March  2005    

•  Cohort  linked  to  California  Cancer  Registry      •  Outcome  is  known  with  high  degree  of  certainty  for  all  

patients  

•  Average  time  from  US  to  surgery:  0.4  yrs  (range  0-­‐4.2)    

•  Mean  follow-­‐up  period:  3.7  yrs  (range  2-­‐6.9)  

Selection  of  Ultrasound  Exams  to  Review  

•  Cancer  Patients:  Thyroid  cancer  ,  no  other  cancer.  Had  a  pre-­‐operative  US  at  UCSF  (N=105.  of  these,  96  cases  retrieved  on  PACS)  

•  Control  Patients:  No  thyroid  cancer  diagnosis  at  least  2  years  after  ultrasound.    No  other  cancer.    

•  Sample  of  controls  were  matched  to  Cancer  Patients  by  age,  gender  and  year  of  US  exam  (N=369)  

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Table  1:  Histologic  Findings  of  the  Study  Cancers  

Thyroid  Ultrasound  Review  

•  Earliest  available  study  chosen,  reviewed  in  PACS  

•  All  sonograms  reviewed  by  2  experienced  board-­‐certified  radiologists  blinded  to  outcome  

•  US  features  of  thyroid  gland  and  individual  nodules  recorded  for  each  patient  

•  Nodules  included  if  mean  diameter  5  mm  or  larger  

•  Findings  for  up  to  4  nodules  recorded  for  each  patient  

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Large  Number  of  Features  Assessed  

§  Size  §  Shape  §  Margins  §  Composition  (proportion  cystic/solid  tissue,  appearance)  §  Echotexture,  echogenicity  §  Micro-­‐calcifications  §  Coarse  calcifications  §  Comet  tail  artifact  §  Rim  calcifications  §  Halo  /  absence  of  halo  §  Central  and  peripheral  Doppler  flow  signal    

Extracapsular  extension  or  lymph  nodes  not  assessed  

Ultrasound-­‐Pathology  Correlation  

•  Some  Cancer  Patients  had  benign  and  malignant  nodules  

•  Rad-­‐Path-­‐Surgical  correlation  completed  for  Cancer  Patients  who  had  surgery  at  UCSF  

•  Nodule  considered  “cancer”  if  US  findings  (location  and  size)  matched  pathology  description  

•  This  part  of  the  characterization  was  not  blinded  and  was  completed  after  the  ultrasound  interpretation  

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Accuracy  Statistics:  which  ones  are  important  

•  Sensitivity:  tells  you  about  how  well  the  test  performs  in  patients  with  the  disease  you  are  looking  for    

•  Specificity:  tells  you  about  how  the  test  performs  in  normals  

•  You  need  statistics  that  combines  these  measures  

•  PPV/NPV:  if  test  is  normal  or  abnormal,  risk  of  disease  

•  Likelihood  ratio:  how  well  does  the  test  discriminate  between  those  affected  and  those  not  

Accuracy  Statistics  

•  PPV:  highly  sensitive  to  the  prevalence  of  disease  

•  In  case-­‐control  studies  where  the  number  of  subjects  is  chosen  by  the  researcher,  this  statistic  is  meaningless  

•  In  a  cohort  study,  where  you  know  all  subjects:  useful  

•  Likelihood  ratio  is  stable  across  different  study  designs  

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Likelihood  Ratios      

•  Allows  you  to  look  at  a  finding  and  figure  out  how  much  it  increases  the  risk  of  disease  

•  Stable  across  different  prevalence  of  disease,  so  does  not  matter  how  many  cases  or  controls  are  selected  

•  Don’t  need  to  know  how  common  the  diagnosis  is  

Likelihood  Ratios  

Combines  Sensitivity  (Sens)  and  Specificity  (Spec)      

 Positive  LR:        Positive  test  in  those  with  Dz    =                Sens__      Positive  test  in  those  w/o  Dz                            1-­‐Spec  

 Negative  LR:    Negative  test  in  those  with  Dz    =          1-­‐Sens_  

                 Negative  test  in  those  w/o  Dz                        Spec  

If  the  test  is  positive,  the  risk  increases  by  x  times  If  the  test  is  negative,  the  risk  decreases  by  y  times  

PLR:  NLR:  

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How  to  Interpret  Likelihood  Ratios  •  Positive  LR:    The  bigger  the  better  the  test  at  ruling  in  disease  

 1-­‐5:        Not  very  helpful    5-­‐10:    Moderately  helpful    >  10:      Extremely  helpful  (risk  increases  10  times)  

 

•  Negative  LR:    The  smaller  the  better  the  test  at  ruling  out  disease    1:          Absence  of  finding  does  not  lower  risk  at  all    0.5-­‐1:            Not  terribly  helpful    0.1-­‐0.5  :    Moderately  helpful    <  0.1  :          Extremely  helpful    (risk  decreases  90%)  

 

Likelihood  Ratio  of  1  =  no  association  between  finding  &  outcome  

Results  :  Patient  analysis  Characteristics  of  Patients  Included  in  the  Study  

Cancer  Patients  N=96  (%)  

Control  Patients  N=  369  (%)  

Age  Distribution              <  40  years              41  –  60  years              >  60  years  

   41  (43%)  36  (37%)  19  (20%)  

 164  (44%)  132  (36%)  76    (20%)  

Gender  Female  Male  

 71  (74%)  25  (26%)  

 286  (78%)  83  (22%)  

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Thyroid  Nodules  Distribution  of  #  of  Nodules  Among  

Cases  and  Controls  

Cancer  Patients  N=96  (%)  

Control  Patients  N=369  (%)    

#  of  nodules  0  nodule  1  nodule  2  nodules  3  nodules    4  or  more  nodules  

Total    

 3      (3%)  43  (45%)  21  (22%)  12  (13%)  17  (17%)        189            

 161  (44%)  83  (23%)  63  (17%)  29      (8%)  33      (9%)      428          

Thyroid  nodules  were  COMMON.  Found  in  97%  of  patients  diagnosed  with  cancer  and  in  56%  of  controls.  

Nodule  Level  Analysis  

Cancer  Nodule   Benign  Nodule  

Cancers   102   87  

Controls    

0   428  

Total      

102   515  

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Accuracy  of  Individual  US  Characteristics  (Univariate)  

Sensitivity  102        

N  (%)  

False  Positives  

518    N  (%)  

Likelihood  Ratio  

Odds  Ratio  

Microcalcifications   39  (38%)   28  (5%)   7.0   11.6  

Echotexture        Hypoechoic  to  strap  muscle        Iso-­‐Hyperechoic  to  strap  

 16  (16%)  51  (50%)  

 34  (6%)  

198  (38%)  

 2.4  1.3  

 2.9  1.8  

Shape        Taller  than  wide  

 18  (18%)  

 42  (8%)  

 2.2  

 2.3  

Composition          Solid          Mixed          Cystic  

 68  (67%)  34  (33%)  0  (0%)  

 220  (43%)  248  (48%)  37  (7%)  

 1.6  0.7  

0.034  

 2.2  1  0  

Accuracy  of  Individual  US  Characteristics  (Univariate)  

Sensitivity          

N  (%)  

False  Positives  

 N  (%)  

Likelihood  Ratio  

Odds  Ratio  

Nodule  Size        <  1  cm        1  –  2  cm        >  2  cm  

 30  (29%)  38  (37%)  34  (33%)  

 248  (48%)  169  (33%)    97  (19%)  

 0.6  1.1  1.8  

 1  1.9  3.1  

Central  flow   40  (39%)   136  (26%)   1.5   1.6  

Coarse  Calcifications   13  (13%)   34  (7%)   1.9   2.1  

Margins  Ill-­‐defined  /  lobulated    

 61  (60%)  

 212  (41%)  

 1.5  

 2.0  

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Features  Predictive  of  Malignancy,  Univariate  Analysis  

Existing  Literature   UCSF  Study  

Microcalcifications   √   ++  

Hypoechogenicity   √   ++  

Taller  than  wide  shape   √   ++  

Solid  composition   √   ++  

Nodule  size,  >  2  cm   √   ++  

Central  Flow   √   +  

Coarse  calcifications   √   +  

Ill-­‐defined  margins   √   +  

Peripheral  vascular  flow   √   -­‐  

Halo,  absence   √   -­‐  

Comet-­‐tail  artifact,  absence   √   -­‐  

Rim  calcifications   √   -­‐  

Features  Predictive  of  Malignancy,  Univariate  Analysis  

Microcalcifications  Hypoechogenicity  

Taller  than  wide  shape  

Solid  composition  

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Benign  Thyroid  Nodules  

Multivariate  Results:    Only  Three  Variables  Remained  Significantly  

Associated  with  Thyroid  Cancer  

Odds  Ratio  

Microcalcifications   8.1  

Nodule  size,  >  2  cm   3.6  

Solid  composition   4.0  

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Thyroid  Nodules  

Papillary  Thyroid  Cancer  

2  cm  

Microcalcifications  had  the  strongest  association  with  cancer  -­‐  seen  in  38%  of  cancers  and  5%  of  benign  nodules  

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Combining  Significant  Characteristics  Accuracy  of  Several  Definitions  of  Abnormal  US  Result  

Sensitivity   False  Positive  

Likelihood  Ratio  

Risk  of  cancer    

#  Needed  to  Biopsy  

1/3  Findings   88%   44%   2.0   2%   56  

     Solid   77%   32%   2.4   2%   48  

     Size  >  2  cm   39%   21%   1.9   2%   59  

     Microcalcifications   39%   4%   9.7   8%   12  

2/3  Findings   52%   7%   7.1   6%   16  

3/3  Findings   7%   0%   28   100%   1  

 Microcalcifications  or  Solid  AND  >  2  cm    

 54%    

 8%    

 6.7    

 6%    

 17    

Risk  of  Thyroid  Cancer  Based  on  Appearance  of  Thyroid    and  Characteristic  of  Any  Nodules  Identified  

Number  of  Cancers    per  1000  patients  

Lowest  Risk  

Homogenous  Gland   0.6  

Very  Low  

0/3  features   2  

No  nodule  with  2+  features   5  

Low  

Thyroid  has  nodule  with  1/3   18  

Moderate  

Nodule  with  2+  features   62  

 Microcalcifications   82  

 Microcalc’ns  or  Solid  and  >  2  cm   58  

Very  High  

Nodule  with  3/3  features   960  

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Sample  Comparison  Guidelines  

•  Most  existing  society  guidelines  are  complex  and  requite  discretion  on  part  of  performing  MD  

•  Example:      Society  of  Radiologist  in  Ultrasound  guidelines:  

§  Nodules  >  10  mm  if  microcalcifications  §  Nodules  >  15  mm  if  solid  or  predominantly  solid  or  if  coarse  calcifications  

§  Nodules  >  20  mm  if  mixed  solid/cystic  or  cystic  with  mural  nodule  

Frates  et  al.  Management  of  thyroid  nodules  detected  at  US:    Society  of  Radiologists  in  Ultrasound  Consensus  Conference  statement  

Radiology  2005,  237:794  

NO  mention  of  nodules  <  1  cm  

Frates  et  al.  Management  of  thyroid  nodules  detected  at  US:    Society  of  Radiologists  in  Ultrasound  Consensus  Conference  statement  

Radiology  2005,  237:794  

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Size  of  Nodule  (mm)  

 5-­‐10  

 10-­‐15      

15-­‐20        

>  20    

ATA*    (FNA  if  ...)  

 Clinical  risk  factors  &  suspicious  US  features  

 Nodule  w/    

microcalcifications  or  solid    

Nodule  w/  microcalcifications,  solid,  or  both  solid/cystic    w/  suspicious  features  

 All  nodules  except  purely  

cystic  ones    

SRU  (Strongly  consider  FNA  if  ...)  

 No  recommendations  

   

Nodule  w/  microcalcifications      

Nodule  w/  microcalcifications  or  solid  w/  coarse  calcifications  

   

Nodule  w/  microcalcifications,  solid,  coarse  calcifications,  

solid/cystic  or    cystic  +  mural  nodule  

 *Cooper  et  al.  Revised  ATA  Management  Guidelines  for  Patients  with  Thyroid  Nodules  

Thyroid  2009,  19:11        ATA  suggests  testing  TSH  and  biopsy  of  those  w/  normal  or  elevated  levels  

RSB:  Conclusions  

•  If  1  feature  is  used  as  indication  for  biopsy:  most  cases  of  cancer  detected  (sens  88%)  with  high  false  +  rate  (44%)  and  low  +  LR  (2.0).  56  biopsies/ca  

•  If  2  features  used  as  indication  for  biopsy:  fewer  cases  detected  (sens  52%)  with  lower  false  +  rate  (7%)  and  higher  +  LR  (7.1).  Only  16  biopsies/ca  

•  Compared  with  biopsy  of  all  nodules  >  5mm,  this  approach:      (>  2  features  to  prompt  biopsy)  would  reduce  unnecessary  biopsies  by  90%  while  maintaining  low  risk  of  cancer  (5/1000  patients  for  whom  biopsy  is  deferred)  

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RSB:  Recommendations  and  Practice  

•  Biopsy  nodules  with  microcalcifications  •  Biopsy  nodules  if  larger  than  2  cm  and  entirely  solid            OR  just  Biopsy  when  two  features  are  present  

•  Nodules  without  these  findings  need  not  be  biopsied  or  followed.  There  is  no  evidence  that  surveillance  has  any  value.  

•  Patients  in  whom  biopsy  is  deferred  have  a  risk  of  cancer  <  0.5%  

Summary  •  Thyroid  nodules  are  extremely  common,  >  50%  of  controls  

•  Fewer  than  2%  are  cancer,  98%  benign  

•  Unnecessary  tissue  sampling  is  invasive,  costly,  leads  to  repeated  sampling  and  open  surgical  procedures  due  to  inadequate  sampling  and  non-­‐diagnostic  pathology  

 

•  Only  3  features:    

   Microcalcifications  

   Size  >  2  cm    

   Solid    

are  statistically  associated  with  cancer  and  these  US  features  can  be  used  to  decide  which  nodules  to  biopsy  

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Vickie.Feldstein@ucsf.edu  Rebecca.Smith-­‐Bindman@ucsf.edu  

Thank  you