Hepatocellular carcinoma Diagnostic study of choice: Difference between revisions
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'''Liver biopsy''' | '''Liver biopsy''' | ||
* The [[diagnosis]] of hepatocellular carcinoma is confirmed by [[percutaneous]] [[biopsy]] and [[histopathologic]] analysis. | |||
* [[Percutaneous]] [[biopsy]] should only be performed when [[Diagnosis|diagnostic]] imaging results are uncertain. | |||
* [[Percutaneous]] core [[liver]] [[biopsy]] is the [[Gold standard (test)|gold standard test]] for the [[diagnosis]] of hepatocellular carcinoma. | * [[Percutaneous]] core [[liver]] [[biopsy]] is the [[Gold standard (test)|gold standard test]] for the [[diagnosis]] of hepatocellular carcinoma. | ||
* In addition to the percutaneous approach, there are various other approaches to obtain a sample of the hepatic tissue, such as:<ref name="pmid16636018">{{cite journal |vauthors=Cholongitas E, Quaglia A, Samonakis D, Senzolo M, Triantos C, Patch D, Leandro G, Dhillon AP, Burroughs AK |title=Transjugular liver biopsy: how good is it for accurate histological interpretation? |journal=Gut |volume=55 |issue=12 |pages=1789–94 |year=2006 |pmid=16636018 |pmc=1856467 |doi=10.1136/gut.2005.090415 |url=}}</ref><ref name="pmid14562197">{{cite journal |vauthors=Hollerbach S, Reiser M, Topalidis T, König M, Schmiegel W |title=Diagnosis of hepatocellular carcinoma (HCC) in a high-risk patient by using transgastric EUS-guided fine-needle biopsy (EUS-FNA) |journal=Z Gastroenterol |volume=41 |issue=10 |pages=995–8 |year=2003 |pmid=14562197 |doi=10.1055/s-2003-42920 |url=}}</ref><ref name="pmid21291633">{{cite journal |vauthors=Wang L, Geng J, Li J, Li T, Matsumori A, Chang Y, Lu F, Zhuang H |title=The biomarker N-terminal pro-brain natriuretic peptide and liver diseases |journal=Clin Invest Med |volume=34 |issue=1 |pages=E30–7 |year=2011 |pmid=21291633 |doi= |url=}}</ref> | * In addition to the percutaneous approach, there are various other approaches to obtain a sample of the hepatic tissue, such as:<ref name="pmid16636018">{{cite journal |vauthors=Cholongitas E, Quaglia A, Samonakis D, Senzolo M, Triantos C, Patch D, Leandro G, Dhillon AP, Burroughs AK |title=Transjugular liver biopsy: how good is it for accurate histological interpretation? |journal=Gut |volume=55 |issue=12 |pages=1789–94 |year=2006 |pmid=16636018 |pmc=1856467 |doi=10.1136/gut.2005.090415 |url=}}</ref><ref name="pmid14562197">{{cite journal |vauthors=Hollerbach S, Reiser M, Topalidis T, König M, Schmiegel W |title=Diagnosis of hepatocellular carcinoma (HCC) in a high-risk patient by using transgastric EUS-guided fine-needle biopsy (EUS-FNA) |journal=Z Gastroenterol |volume=41 |issue=10 |pages=995–8 |year=2003 |pmid=14562197 |doi=10.1055/s-2003-42920 |url=}}</ref><ref name="pmid21291633">{{cite journal |vauthors=Wang L, Geng J, Li J, Li T, Matsumori A, Chang Y, Lu F, Zhuang H |title=The biomarker N-terminal pro-brain natriuretic peptide and liver diseases |journal=Clin Invest Med |volume=34 |issue=1 |pages=E30–7 |year=2011 |pmid=21291633 |doi= |url=}}</ref> | ||
** | **[[Transjugular intrahepatic portosystemic shunt|Transjugular]] approach | ||
**[[Laparoscopic surgery|Laparoscopic]] radiographically | **[[Laparoscopic surgery|Laparoscopic]] radiographically guided fine-needle approach | ||
**[[Endoscopic ultrasound]] ([[Endoscopic ultrasound|EUS]])-guided [[Fine-needle aspiration|fine-needle biopsy]] ([[Endoscopic ultrasound|EUS]]-[[Needle aspiration biopsy|FNA]]) | **[[Endoscopic ultrasound]] ([[Endoscopic ultrasound|EUS]])-guided [[Fine-needle aspiration|fine-needle biopsy]] ([[Endoscopic ultrasound|EUS]]-[[Needle aspiration biopsy|FNA]]) | ||
* [[Percutaneous]] [[biopsy]] of focal lesions may be performed in combination with either [[ultrasound]] or [[CT|CT imaging]].<ref name="pmid15278290">{{cite journal |vauthors=Schirmacher P, Fleig WE, Tannapfel A, Langner C, Dries V, Terracciano L, Denk H, Dienes HP |title=[Bioptic diagnosis of chronic hepatitis. Results of an evidence-based consensus conference of the German Society of Pathology, of the German Society for Digestive and Metabolic Diseases and of Compensated Hepatitis (HepNet)] |language=German |journal=Pathologe |volume=25 |issue=5 |pages=337–48 |year=2004 |pmid=15278290 |doi=10.1007/s00292-004-0692-7 |url=}}</ref> | * [[Percutaneous]] [[biopsy]] of focal lesions may be performed in combination with either [[ultrasound]] or [[CT|CT imaging]].<ref name="pmid15278290">{{cite journal |vauthors=Schirmacher P, Fleig WE, Tannapfel A, Langner C, Dries V, Terracciano L, Denk H, Dienes HP |title=[Bioptic diagnosis of chronic hepatitis. Results of an evidence-based consensus conference of the German Society of Pathology, of the German Society for Digestive and Metabolic Diseases and of Compensated Hepatitis (HepNet)] |language=German |journal=Pathologe |volume=25 |issue=5 |pages=337–48 |year=2004 |pmid=15278290 |doi=10.1007/s00292-004-0692-7 |url=}}</ref> | ||
* [[Percutaneous]] [[liver biopsy]] remains the cornerstone of [[diagnosis]]. It is quick and simple to perform [[liver biopsy]] in a patient with normal [[Platelet|platelet count]] and [[Prothrombin time|INR]].<ref name="pmid22833761">{{cite journal |vauthors=Tannapfel A, Dienes HP, Lohse AW |title=The indications for liver biopsy |journal=Dtsch Arztebl Int |volume=109 |issue=27-28 |pages=477–83 |year=2012 |pmid=22833761 |pmc=3402072 |doi=10.3238/arztebl.2012.0477 |url=}}</ref> | * [[Percutaneous]] [[liver biopsy]] remains the cornerstone of [[diagnosis]]. It is a quick and simple to perform [[liver biopsy]] in a patient with normal [[Platelet|platelet count]] and [[Prothrombin time|INR]].<ref name="pmid22833761">{{cite journal |vauthors=Tannapfel A, Dienes HP, Lohse AW |title=The indications for liver biopsy |journal=Dtsch Arztebl Int |volume=109 |issue=27-28 |pages=477–83 |year=2012 |pmid=22833761 |pmc=3402072 |doi=10.3238/arztebl.2012.0477 |url=}}</ref> | ||
*Surgical resection | *Surgical resection | ||
* Two out of the following three positive stains upon liver biopsy confirm HCC:<ref name="pmid19177576">{{cite journal |vauthors= |title=Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia |journal=Hepatology |volume=49 |issue=2 |pages=658–64 |year=2009 |pmid=19177576 |doi=10.1002/hep.22709 |url=}}</ref><ref name="pmid20400233">{{cite journal |vauthors=Karabork A, Kaygusuz G, Ekinci C |title=The best immunohistochemical panel for differentiating hepatocellular carcinoma from metastatic adenocarcinoma |journal=Pathol. Res. Pract. |volume=206 |issue=8 |pages=572–7 |year=2010 |pmid=20400233 |doi=10.1016/j.prp.2010.03.004 |url=}}</ref> | * Two out of the following three positive stains upon liver biopsy confirm HCC:<ref name="pmid19177576">{{cite journal |vauthors= |title=Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia |journal=Hepatology |volume=49 |issue=2 |pages=658–64 |year=2009 |pmid=19177576 |doi=10.1002/hep.22709 |url=}}</ref><ref name="pmid20400233">{{cite journal |vauthors=Karabork A, Kaygusuz G, Ekinci C |title=The best immunohistochemical panel for differentiating hepatocellular carcinoma from metastatic adenocarcinoma |journal=Pathol. Res. Pract. |volume=206 |issue=8 |pages=572–7 |year=2010 |pmid=20400233 |doi=10.1016/j.prp.2010.03.004 |url=}}</ref> | ||
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'''Hep Par 1 Antibody Stain''' | '''Hep Par 1 Antibody Stain''' | ||
Tissue [[microarray technology]] is uses to test Hep Par 1 [[antibody]] [[stain]] which is showing promising results in differential diagnosis of HCC.<ref name="Fanvan de Rijn2003">{{cite journal|last1=Fan|first1=Zhen|last2=van de Rijn|first2=Matt|last3=Montgomery|first3=Kelli|last4=Rouse|first4=Robert V.|title=Hep Par 1 Antibody Stain for the Differential Diagnosis of Hepatocellular Carcinoma: 676 Tumors Tested Using Tissue Microarrays and Conventional Tissue Sections|journal=Modern Pathology|volume=16|issue=2|year=2003|pages=137–144|issn=0893-3952|doi=10.1097/01.MP.0000052103.13730.20}}</ref> | * Tissue [[microarray technology]] is uses to test Hep Par 1 [[antibody]] [[stain]] which is showing promising results in differential diagnosis of HCC.<ref name="Fanvan de Rijn2003">{{cite journal|last1=Fan|first1=Zhen|last2=van de Rijn|first2=Matt|last3=Montgomery|first3=Kelli|last4=Rouse|first4=Robert V.|title=Hep Par 1 Antibody Stain for the Differential Diagnosis of Hepatocellular Carcinoma: 676 Tumors Tested Using Tissue Microarrays and Conventional Tissue Sections|journal=Modern Pathology|volume=16|issue=2|year=2003|pages=137–144|issn=0893-3952|doi=10.1097/01.MP.0000052103.13730.20}}</ref> | ||
* A [[biopsy]] is not necessary if the [[clinical]], [[Medical laboratory|laboratory]], and [[Radiologic sign|radiologic]] data suggest hepatocellular carcinoma. | * A [[biopsy]] is not necessary if the [[clinical]], [[Medical laboratory|laboratory]], and [[Radiologic sign|radiologic]] data suggest hepatocellular carcinoma. | ||
* [[Liver biopsy]] may be suggestive of [[etiology]]: | * [[Liver biopsy]] may be suggestive of [[etiology]] as the following: | ||
** [[Alcoholic liver disease]] : [[Liver biopsy]] may show [[hepatocyte]] [[necrosis]], presence of [[Mallory body|mallory bodies]], [[Neutrophil|neutrophilic]] infiltration and perivenular [[inflammation]]. | ** [[Alcoholic liver disease]] : [[Liver biopsy]] may show [[hepatocyte]] [[necrosis]], presence of [[Mallory body|mallory bodies]], [[Neutrophil|neutrophilic]] infiltration and perivenular [[inflammation]]. | ||
** [[Primary biliary cirrhosis|Primary biliary cirrhosis]] : [[Gold standard (test)|Gold standard diagnostic modality]] is the detection of [[antimitochondrial antibodies]] along with [[liver biopsy]] as confirmation of florid [[bile duct]] lesions. | ** [[Primary biliary cirrhosis|Primary biliary cirrhosis]] : [[Gold standard (test)|Gold standard diagnostic modality]] is the detection of [[antimitochondrial antibodies]] along with [[liver biopsy]] as confirmation of florid [[bile duct]] lesions. | ||
* There is a small but significant risk associated with [[liver biopsy]], and the underlying [[cirrhosis]] in the patients with HCC itself predisposes to complications due to [[liver biopsy]].<ref>{{cite journal |last=Grant |first=A|year=1999 | title=Guidelines on the use of liver biopsy in clinical practice |journal=Gut |volume=45 |issue=Suppl 4 |pages=1-11 |id=PMID 10485854 |url=http://gut.bmj.com/cgi/content/full/45/suppl_4/IV1|quote=The main cause of mortality after percutaneous liver biopsy is intraperitoneal haemorrhage as shown in a retrospective Italian study of 68,000 percutaneous liver biopsies in which all six patients who died did so from intraperitoneal haemorrhage. Three of these patients had had a laparotomy, and all had either cirrhosis or malignant disease, both of which are risk factors for bleeding. }}</ref> | * There is a small but significant risk associated with [[liver biopsy]], and the underlying [[cirrhosis]] in the patients with HCC itself predisposes to complications due to [[liver biopsy]].<ref>{{cite journal |last=Grant |first=A|year=1999 | title=Guidelines on the use of liver biopsy in clinical practice |journal=Gut |volume=45 |issue=Suppl 4 |pages=1-11 |id=PMID 10485854 |url=http://gut.bmj.com/cgi/content/full/45/suppl_4/IV1|quote=The main cause of mortality after percutaneous liver biopsy is intraperitoneal haemorrhage as shown in a retrospective Italian study of 68,000 percutaneous liver biopsies in which all six patients who died did so from intraperitoneal haemorrhage. Three of these patients had had a laparotomy, and all had either cirrhosis or malignant disease, both of which are risk factors for bleeding. }}</ref> | ||
*There is a 3% risk of tumor spread in the percutaneous needle path, risks of [[liver biopsy]] include:<ref name="pmid22047762">{{cite journal |vauthors=Clavien PA, Lesurtel M, Bossuyt PM, Gores GJ, Langer B, Perrier A |title=Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report |journal=Lancet Oncol. |volume=13 |issue=1 |pages=e11–22 |year=2012 |pmid=22047762 |pmc=3417764 |doi=10.1016/S1470-2045(11)70175-9 |url=}}</ref> | *There is a 3% risk of tumor spread in the [[percutaneous]] needle path, risks of [[liver biopsy]] include:<ref name="pmid22047762">{{cite journal |vauthors=Clavien PA, Lesurtel M, Bossuyt PM, Gores GJ, Langer B, Perrier A |title=Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report |journal=Lancet Oncol. |volume=13 |issue=1 |pages=e11–22 |year=2012 |pmid=22047762 |pmc=3417764 |doi=10.1016/S1470-2045(11)70175-9 |url=}}</ref> | ||
*[[Bleeding|Hemorrhage]] | *[[Bleeding|Hemorrhage]] | ||
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**[[Laparoscopic surgery|Laparoscopic]] [[liver biopsy]] performed on a sedated patient with moderate [[coagulopathy]] | **[[Laparoscopic surgery|Laparoscopic]] [[liver biopsy]] performed on a sedated patient with moderate [[coagulopathy]] | ||
***Advantage: | ***Advantage: | ||
****Allows direct | ****Allows direct visualization of the [[liver]] | ||
'''Transjugular [[liver biopsy]]:''' | '''Transjugular [[liver biopsy]]:''' | ||
* Used in patients with severe clotting disorders | * Used in patients with severe [[clotting]] disorders | ||
**Advantage: | **Advantage: | ||
***Risk of [[Peritoneum|intraperitoneal]] [[Bleeding|bleed]] is less | ***Risk of [[Peritoneum|intraperitoneal]] [[Bleeding|bleed]] is less | ||
| Line 71: | Line 72: | ||
The core needle biopsy should be performed when:<ref name="pmid23091805">{{cite journal |vauthors=Song DS, Bae SH |title=Changes of guidelines diagnosing hepatocellular carcinoma during the last ten-year period |journal=Clin Mol Hepatol |volume=18 |issue=3 |pages=258–67 |year=2012 |pmid=23091805 |pmc=3467428 |doi=10.3350/cmh.2012.18.3.258 |url=}}</ref> | The core needle biopsy should be performed when:<ref name="pmid23091805">{{cite journal |vauthors=Song DS, Bae SH |title=Changes of guidelines diagnosing hepatocellular carcinoma during the last ten-year period |journal=Clin Mol Hepatol |volume=18 |issue=3 |pages=258–67 |year=2012 |pmid=23091805 |pmc=3467428 |doi=10.3350/cmh.2012.18.3.258 |url=}}</ref> | ||
* A positive hepatic leision is detected in the patient on imaging studies. | * A positive hepatic leision is detected in the patient on imaging studies. | ||
* The patient has underlying risk factors i.e HBV infection,HCV infection or liver cirrhosis. | * The patient has underlying risk factors i.e [[HBV infection]], [[HCV infection]] or [[liver cirrhosis]]. | ||
=== Diagnostic Criteria === | === Diagnostic Criteria === | ||
* Hepatocellular carcinoma may be diagnosed at any time if the following criteria is met: | * Hepatocellular carcinoma may be diagnosed at any time if the following criteria is met: | ||
Revision as of 20:28, 10 January 2019
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2]
Overview
Hepatocellular carcinoma is best diagnosed on a core biopsy of the liver. Core biopsy is done in a single visit at the hospital.
Diagnostic Study of Choice
Liver biopsy
- The diagnosis of hepatocellular carcinoma is confirmed by percutaneous biopsy and histopathologic analysis.
- Percutaneous biopsy should only be performed when diagnostic imaging results are uncertain.
- Percutaneous core liver biopsy is the gold standard test for the diagnosis of hepatocellular carcinoma.
- In addition to the percutaneous approach, there are various other approaches to obtain a sample of the hepatic tissue, such as:[1][2][3]
- Transjugular approach
- Laparoscopic radiographically guided fine-needle approach
- Endoscopic ultrasound (EUS)-guided fine-needle biopsy (EUS-FNA)
- Percutaneous biopsy of focal lesions may be performed in combination with either ultrasound or CT imaging.[4]
- Percutaneous liver biopsy remains the cornerstone of diagnosis. It is a quick and simple to perform liver biopsy in a patient with normal platelet count and INR.[5]
- Surgical resection
- Two out of the following three positive stains upon liver biopsy confirm HCC:[6][7]
Hep Par 1 Antibody Stain
- Tissue microarray technology is uses to test Hep Par 1 antibody stain which is showing promising results in differential diagnosis of HCC.[8]
- A biopsy is not necessary if the clinical, laboratory, and radiologic data suggest hepatocellular carcinoma.
- Liver biopsy may be suggestive of etiology as the following:
- Alcoholic liver disease : Liver biopsy may show hepatocyte necrosis, presence of mallory bodies, neutrophilic infiltration and perivenular inflammation.
- Primary biliary cirrhosis : Gold standard diagnostic modality is the detection of antimitochondrial antibodies along with liver biopsy as confirmation of florid bile duct lesions.
- There is a small but significant risk associated with liver biopsy, and the underlying cirrhosis in the patients with HCC itself predisposes to complications due to liver biopsy.[9]
- There is a 3% risk of tumor spread in the percutaneous needle path, risks of liver biopsy include:[10]
- Hemorrhage
- Biliary peritonitis
- Hematoma
- Perforation of other viscera
- Mortality rates of between 0.01% and 0.1%
- Patients with moderate coagulopathy:
- Plugged liver biopsy : Injection of gelatin sponges or metal coils down the tract after biopsy
- Laparoscopic liver biopsy performed on a sedated patient with moderate coagulopathy
- Advantage:
- Allows direct visualization of the liver
- Advantage:
Transjugular liver biopsy:
- Used in patients with severe clotting disorders
- Advantage:
- Risk of intraperitoneal bleed is less
- Disadvantages:
- Advantage:
The comparison table for diagnostic studies of choice for hepatocellular carcinoma:[11]
| Diagnostic Test | Sensitivity | Specificity |
|---|---|---|
| Percutaneous Ultrasound guided liver biopsy | 90% | 91% |
| Percutaneous CT guided liver biopsy | 92% | 98% |
Sequence of Diagnostic Studies
The core needle biopsy should be performed when:[12]
- A positive hepatic leision is detected in the patient on imaging studies.
- The patient has underlying risk factors i.e HBV infection, HCV infection or liver cirrhosis.
Diagnostic Criteria
- Hepatocellular carcinoma may be diagnosed at any time if the following criteria is met:
References
- ↑ Cholongitas E, Quaglia A, Samonakis D, Senzolo M, Triantos C, Patch D, Leandro G, Dhillon AP, Burroughs AK (2006). "Transjugular liver biopsy: how good is it for accurate histological interpretation?". Gut. 55 (12): 1789–94. doi:10.1136/gut.2005.090415. PMC 1856467. PMID 16636018.
- ↑ Hollerbach S, Reiser M, Topalidis T, König M, Schmiegel W (2003). "Diagnosis of hepatocellular carcinoma (HCC) in a high-risk patient by using transgastric EUS-guided fine-needle biopsy (EUS-FNA)". Z Gastroenterol. 41 (10): 995–8. doi:10.1055/s-2003-42920. PMID 14562197.
- ↑ Wang L, Geng J, Li J, Li T, Matsumori A, Chang Y, Lu F, Zhuang H (2011). "The biomarker N-terminal pro-brain natriuretic peptide and liver diseases". Clin Invest Med. 34 (1): E30–7. PMID 21291633.
- ↑ Schirmacher P, Fleig WE, Tannapfel A, Langner C, Dries V, Terracciano L, Denk H, Dienes HP (2004). "[Bioptic diagnosis of chronic hepatitis. Results of an evidence-based consensus conference of the German Society of Pathology, of the German Society for Digestive and Metabolic Diseases and of Compensated Hepatitis (HepNet)]". Pathologe (in German). 25 (5): 337–48. doi:10.1007/s00292-004-0692-7. PMID 15278290.
- ↑ Tannapfel A, Dienes HP, Lohse AW (2012). "The indications for liver biopsy". Dtsch Arztebl Int. 109 (27–28): 477–83. doi:10.3238/arztebl.2012.0477. PMC 3402072. PMID 22833761.
- ↑ 6.0 6.1 "Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia". Hepatology. 49 (2): 658–64. 2009. doi:10.1002/hep.22709. PMID 19177576.
- ↑ Karabork A, Kaygusuz G, Ekinci C (2010). "The best immunohistochemical panel for differentiating hepatocellular carcinoma from metastatic adenocarcinoma". Pathol. Res. Pract. 206 (8): 572–7. doi:10.1016/j.prp.2010.03.004. PMID 20400233.
- ↑ Fan, Zhen; van de Rijn, Matt; Montgomery, Kelli; Rouse, Robert V. (2003). "Hep Par 1 Antibody Stain for the Differential Diagnosis of Hepatocellular Carcinoma: 676 Tumors Tested Using Tissue Microarrays and Conventional Tissue Sections". Modern Pathology. 16 (2): 137–144. doi:10.1097/01.MP.0000052103.13730.20. ISSN 0893-3952.
- ↑ Grant, A (1999). "Guidelines on the use of liver biopsy in clinical practice". Gut. 45 (Suppl 4): 1–11. PMID 10485854.
The main cause of mortality after percutaneous liver biopsy is intraperitoneal haemorrhage as shown in a retrospective Italian study of 68,000 percutaneous liver biopsies in which all six patients who died did so from intraperitoneal haemorrhage. Three of these patients had had a laparotomy, and all had either cirrhosis or malignant disease, both of which are risk factors for bleeding.
- ↑ Clavien PA, Lesurtel M, Bossuyt PM, Gores GJ, Langer B, Perrier A (2012). "Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report". Lancet Oncol. 13 (1): e11–22. doi:10.1016/S1470-2045(11)70175-9. PMC 3417764. PMID 22047762.
- ↑ El-Serag HB, Marrero JA, Rudolph L, Reddy KR (2008). "Diagnosis and treatment of hepatocellular carcinoma". Gastroenterology. 134 (6): 1752–63. doi:10.1053/j.gastro.2008.02.090. PMID 18471552.
- ↑ Song DS, Bae SH (2012). "Changes of guidelines diagnosing hepatocellular carcinoma during the last ten-year period". Clin Mol Hepatol. 18 (3): 258–67. doi:10.3350/cmh.2012.18.3.258. PMC 3467428. PMID 23091805.
- ↑ Di Tommaso L, Roncalli M (2017). "Tissue Biomarkers in Hepatocellular Tumors: Which, When, and How". Front Med (Lausanne). 4: 10. doi:10.3389/fmed.2017.00010. PMC 5322593. PMID 28280721.