HEPATOLOGY, Vol. 61, No. 1, 2015
PAULETTE BIOULAC-SAGE, M.D.5,6 PHILIPPE COMPAGNON, M.D.7 JESSICA ZUCMAN-ROSSI, M.D., PH.D.8 DANIEL AZOULAY, M.D., PH.D.7 KAREN LEROY, M.D., PH.D.1-3 ELIE SERGE ZAFRANI, M.D.1,2 JULIEN CALDERARO, M.D.1,2 1 Assistance Publique-H^ opitaux de Paris Department of Pathology Cre teil, France 2 Universite Paris-Est Cre teil Faculte de M e decine Cre teil, France 3 Inserm U955 Institut Mondor de Recherche Biome dicale Cre teil, France 4 Assistance Publique-H^ opitaux de Paris Department of Hepatology Cre teil, France 5 CHU de Bordeaux Pellegrin Hospital Department of Pathology Bordeaux, France 6 Inserm UMR-1053 Universite de Bordeaux Bordeaux, France 7 Assistance Publique-H^ opitaux de Paris Department of Digestive and Hepatobiliary Surgery Cre teil, France
CORRESPONDENCE
405
8 Inserm UMR-1162 Genomique fonctionnelle des tumeurs solides, IUH Paris, France
References 1. Bhathal PS, Hughes NR, Goodman ZD. The so-called bile duct adenoma is a peribiliary gland hamartoma. Am J Surg Pathol 1996;20:858864. 2. Allaire GS, Rabin L, Ishak KG, Sesterhenn IA. Bile duct adenoma. A study of 152 cases. Am J Surg Pathol 1988;12:708-715. 3. Hasebe T, Sakamoto M, Mukai K, Kawano N, Konishi M, Ryu M, et al. Cholangiocarcinoma arising in bile duct adenoma with focal area of bile duct hamartoma. Virchows Arch 1995;426:209-213. 4. Pinho AC, Melo RB, Oliveira M, Almeida M, Lopes J, Graca L, et al. Adenoma-carcinoma sequence in intrahepatic cholangiocarcinoma. Int J Surg Case Rep 2012;3:131-133. 5. Sia D, Tovar V, Moeini A, Llovet JM. Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies. Oncogene 2013;32: 4861-4870. 6. Rosenberg DW, Yang S, Pleau DC, Greenspan EJ, Stevens RG, Rajan TV, et al. Mutations in BRAF and KRAS differentially distinguish serrated versus non-serrated hyperplastic aberrant crypt foci in humans. Cancer Res 2007;67:3551-3554. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27133 Potential conflict of interest: Nothing to report.
Quick Diagnosis of Hepatic Encephalopathy: Fact or Fiction? To the Editor: Limited attention has been devoted to the differential diagnosis of neurological/psychiatric disturbances in cirrhosis. Therefore, there is a risk that in these patients virtually any neurological/psychiatric abnormality will be considered, by default, to be due to hepatic encephalopathy (HE).1 We run a daily HE clinic, to which patients are referred for evaluation of diagnosed/suspected HE, or for pretransplant screening. Our evaluation includes laboratory tests (full blood count, liver/kidney function, electrolytes, venous ammonia, thyroid stimulating hormone [TSH], C-reactive protein [CRP], and vitamin B12), examination by a physician and a neuropsychologist, a comprehensive set of neuropsychological tests, critical flicker frequency (CFF), and electroencephalography (EEG). If needed, cerebral imaging and/or repeat evaluations after the institution of appropriate treatment are performed. A final diagnosis is reached after joint review of patient history and all tests, taking into account the known features of the HE profile (i.e., impairment of psychomotor speed, attention, executive function and inhibition, with relatively preserved memory, slowed EEG, low CFF, and high ammonia levels). Between June 2009 and May 2013, we evaluated 276 patients (94% outpatients; 200 males, age 58 6 11 years, Child-Pugh A 37%, B 41%, C 22%, Model for Endstage Liver Disease [MELD] 13 6 6), 61 of whom were seen more than once. Of the 276, 99 (36%) were neuropsychiatrically unimpaired; 90 (33%) had clinically obvious neurological/psychiatric abnormalities and 87 (32%) had subclinical abnormalities (neuropsychological and/or EEG and/or CFF). Of 90 patients with overt abnormalities, 35 were
Fig. 1. Time-course of the neurological/psychiatric profile of a 68-yearold female patient with alcohol-related cirrhosis (abstinent > 5 years), qualified as having both overt HE and cerebrovascular disease at baseline. Dark grey plot: relative theta power, or slow activity, of the electroencephalogram (EEG);2 light grey plot: psychometric hepatic encephalopathy score (PHES).3 Dark grey dashed line: abnormality threshold for the relative theta power (35%); light grey dashed line: abnormality threshold for the PHES (4; Italian normative data). After the institution of ammonia-lowering treatment (lactulose and then lactulose plus rifaximin), both the EEG and psychometric performance initially improved (i.e. reduction in EEG slow activity and increase in PHES score). Over time, psychometric performance worsened in the absence of significant changes in the EEG, ammonia levels or the degree of hepatic failure, suggesting that cerebrovascular disease had started to dominate the picture. Imaging confirmed the development of significant cerebral atrophy and she is now under the joint care of a hepatologist and a geriatrician. (Critical flicker frequency data are not presented as they were obtained only on two occasions.) deemed to have HE and 55 had other comorbidities that could contribute or fully explain their neurological/psychiatric profiles (Fig. 1). Of 87 patients with subclinical abnormalities, 47 were
406
CORRESPONDENCE
deemed to have minimal HE and 40 had comorbidities that could contribute or fully explain their profiles. Thus, 95/177 patients (54%) with overt or subclinical alterations had comorbidities other than HE that could contribute to these alterations. Comorbidities and confounders included recent alcohol misuse (n 5 15), cerebrovascular disease (17), malnutrition (6), severe hyponatremia (2) or hypoglycemia (1), hypothyroidism (2), infection/sepsis (5), psychoactive drugs (4), and various combinations of the above in a single patient. Several of these comorbidities are unlikely to benefit from a new liver. Patients with comorbidities/confounders were significantly older than those without (59.8 6 10.8 versus 56.8 6 11.5 years, P 5 0.04). Short, stand-alone tests for HE diagnosis such as CFF, brief sets of questions, and quick computerized tests have long been advocated for use in the clinic or at the bedside, and may be adequate for screening purposes. However, considerably more comprehensive evaluations seem necessary as a second step, especially for patients on a transplant list. In the same way as we do not expect an ECG, an echocardiogram, or an angiogram to provide us with comprehensive information on cardiac function as standalone tests, we should not expect one test to provide us with comprehensive information on cerebral function in cirrhosis. It is our impression that for the time being the HE quick diagnosis
HEPATOLOGY, January 2015
remains fiction, and the specificity of any neurological/psychiatric test a myth. SARA MONTAGNESE, PH.D. SAMI SCHIFF, PH.D. PIERO AMODIO, M.D. Department of Medicine University of Padova Italy
References 1. Montagnese S, Merkel C, Amodio P. Encephalopathy or hepatic encephalopathy? J Hepatol 2012;57:928-929. 2. Amodio P, Marchetti P, Del Piccolo F, de Tourtchaninoff M, Varghese P, Zuliani C, et al. Spectral versus visual EEG analysis in mild hepatic encephalopathy. Clin Neurophysiol 1999;110:1334-1344. 3. Weissenborn K, Ennen JC, Schomerus H, R€ uckert N, Hecker H. Neuropsychological characterization of hepatic encephalopathy. J Hepatol 2001;34:768-7673. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27127 Potential conflict of interest: Nothing to report.
Is Segmental Transarterial Yttrium 90 Radiation a Curative Option for Solitary Hepatocellular Carcinoma £5 cm? To the Editor: Recently, Vouche et al.1 reported their experience with segmental transarterial yttrium 90 radiation (STAY90R) as a potential curative option for unresectable solitary hepatocellular carcinomas (HCCs) 5 cm not amenable to radiofrequency ablation (RFA). However, careful analysis of the study’s results calls for some comments. First, almost half of the patients were Child-Pugh-B and onethird underwent liver transplantation (LT) a short time after STAY90R. In this setting, relevant comparison of overall and local tumor progression-free survivals after STAY90R with those reported after RFA should require a specific analysis in Child-Pugh-A patients censored to LT (no more risk of local recurrence after LT). Beyond the difficulty to assess the response to STAY90R with imaging, the question is how to know if such a method has enough reliable and predictable antitumor effects to be used like RFA for curative purposes. Vouche et al. pointed out that 51% of HCC 5 cm showed complete necrosis (CN) at histopathological examinations after STAY90R, a result that they assume is quite similar to after RFA. Mazzaferro et al.2 have nicely shown that time to transplantation (TTT) was strongly associated with a dramatic increase in the probability to find viable tumor in the ablation zone (30%/3 months of waiting time). The TTT was shorter in the Vouche et al. study (6.3 months [3.6-9.7]) compared to the RFA studies of Mazzaferro et al. (9.5 months [2-47]) and Lu et al. (7.5 months [0.5-21.1]).2,3 Therefore, the direct comparison based on CN between STAY90R and RFA made by Vouche et al. appears spurious. Moreover, focusing on HCCs 3 cm, 54.1% of CN are reported by Vouche et al., while it was up to 63% in the Mazzaferro et al. and 83% in Lu et al. studies. The superiority of RFA in achieving CN of small HCCs becomes more obvious when one considers no-touch multipolar RFA, which achieved up to 89.6% of CN of HCC 5 cm with 8.4 months median TTT.4 In addition, as Vouche et al. did not report histologic data concerning the
nontumorous liver, the comparison of the method to segmentectomy appears to be somewhat overstated. Finally, for nonresectable small HCC, a clear definition of tumors not amenable to RFA is critical because such a judgment leads to treatments with a higher risk of incomplete response. Vouche et al. pointed out the potential technical limitations of RFA related to specific locations. However, currently most of these limitations could be overcome and therefore are no longer regarded as definite contraindications in expert centers.5 Only a central location abutting primary main bile ducts remains a common contraindication for thermotherapy like RFA. In conclusion, Vouche et al. showed that STAY90R can induce CN in roughly 50% of HCC 5 cm. Thus, STAY90R could be regarded only as one of the second-line intraarterial treatments in the very rare cases of small HCCs not amenable to resection or RFA.
OLIVIER SEROR, M.D., PH.D. JEAN-CHARLES NAULT, M.D., PH.D. PIERRE NAHON, M.D., PH.D. GISELE N’KONTCHOU, M.D. JEAN-CLAUDE TRINCHET, M.D., PH.D. H^ opital Jean Verdier Groupe des Hopitaux Universitaires Paris Saint Denis Assistance Publique H^ opitaux de Paris, Radiology Bondy, France
References 1. Vouche M, Habib A, Ward TJ, Kim E, Kulik L, Ganger D, et al. Unresectable solitary HCC not amenable to RFA. Multicenter radiologypathology correlation and survival of radiation segmentectomy. HEPATOLOGY 2014;60:192-201.
PAULETTE BIOULAC-SAGE, M.D.5,6 PHILIPPE COMPAGNON, M.D.7 JESSICA ZUCMAN-ROSSI, M.D., PH.D.8 DANIEL AZOULAY, M.D., PH.D.7 KAREN LEROY, M.D., PH.D.1-3 ELIE SERGE ZAFRANI, M.D.1,2 JULIEN CALDERARO, M.D.1,2 1 Assistance Publique-H^ opitaux de Paris Department of Pathology Cre teil, France 2 Universite Paris-Est Cre teil Faculte de M e decine Cre teil, France 3 Inserm U955 Institut Mondor de Recherche Biome dicale Cre teil, France 4 Assistance Publique-H^ opitaux de Paris Department of Hepatology Cre teil, France 5 CHU de Bordeaux Pellegrin Hospital Department of Pathology Bordeaux, France 6 Inserm UMR-1053 Universite de Bordeaux Bordeaux, France 7 Assistance Publique-H^ opitaux de Paris Department of Digestive and Hepatobiliary Surgery Cre teil, France
CORRESPONDENCE
405
8 Inserm UMR-1162 Genomique fonctionnelle des tumeurs solides, IUH Paris, France
References 1. Bhathal PS, Hughes NR, Goodman ZD. The so-called bile duct adenoma is a peribiliary gland hamartoma. Am J Surg Pathol 1996;20:858864. 2. Allaire GS, Rabin L, Ishak KG, Sesterhenn IA. Bile duct adenoma. A study of 152 cases. Am J Surg Pathol 1988;12:708-715. 3. Hasebe T, Sakamoto M, Mukai K, Kawano N, Konishi M, Ryu M, et al. Cholangiocarcinoma arising in bile duct adenoma with focal area of bile duct hamartoma. Virchows Arch 1995;426:209-213. 4. Pinho AC, Melo RB, Oliveira M, Almeida M, Lopes J, Graca L, et al. Adenoma-carcinoma sequence in intrahepatic cholangiocarcinoma. Int J Surg Case Rep 2012;3:131-133. 5. Sia D, Tovar V, Moeini A, Llovet JM. Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies. Oncogene 2013;32: 4861-4870. 6. Rosenberg DW, Yang S, Pleau DC, Greenspan EJ, Stevens RG, Rajan TV, et al. Mutations in BRAF and KRAS differentially distinguish serrated versus non-serrated hyperplastic aberrant crypt foci in humans. Cancer Res 2007;67:3551-3554. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27133 Potential conflict of interest: Nothing to report.
Quick Diagnosis of Hepatic Encephalopathy: Fact or Fiction? To the Editor: Limited attention has been devoted to the differential diagnosis of neurological/psychiatric disturbances in cirrhosis. Therefore, there is a risk that in these patients virtually any neurological/psychiatric abnormality will be considered, by default, to be due to hepatic encephalopathy (HE).1 We run a daily HE clinic, to which patients are referred for evaluation of diagnosed/suspected HE, or for pretransplant screening. Our evaluation includes laboratory tests (full blood count, liver/kidney function, electrolytes, venous ammonia, thyroid stimulating hormone [TSH], C-reactive protein [CRP], and vitamin B12), examination by a physician and a neuropsychologist, a comprehensive set of neuropsychological tests, critical flicker frequency (CFF), and electroencephalography (EEG). If needed, cerebral imaging and/or repeat evaluations after the institution of appropriate treatment are performed. A final diagnosis is reached after joint review of patient history and all tests, taking into account the known features of the HE profile (i.e., impairment of psychomotor speed, attention, executive function and inhibition, with relatively preserved memory, slowed EEG, low CFF, and high ammonia levels). Between June 2009 and May 2013, we evaluated 276 patients (94% outpatients; 200 males, age 58 6 11 years, Child-Pugh A 37%, B 41%, C 22%, Model for Endstage Liver Disease [MELD] 13 6 6), 61 of whom were seen more than once. Of the 276, 99 (36%) were neuropsychiatrically unimpaired; 90 (33%) had clinically obvious neurological/psychiatric abnormalities and 87 (32%) had subclinical abnormalities (neuropsychological and/or EEG and/or CFF). Of 90 patients with overt abnormalities, 35 were
Fig. 1. Time-course of the neurological/psychiatric profile of a 68-yearold female patient with alcohol-related cirrhosis (abstinent > 5 years), qualified as having both overt HE and cerebrovascular disease at baseline. Dark grey plot: relative theta power, or slow activity, of the electroencephalogram (EEG);2 light grey plot: psychometric hepatic encephalopathy score (PHES).3 Dark grey dashed line: abnormality threshold for the relative theta power (35%); light grey dashed line: abnormality threshold for the PHES (4; Italian normative data). After the institution of ammonia-lowering treatment (lactulose and then lactulose plus rifaximin), both the EEG and psychometric performance initially improved (i.e. reduction in EEG slow activity and increase in PHES score). Over time, psychometric performance worsened in the absence of significant changes in the EEG, ammonia levels or the degree of hepatic failure, suggesting that cerebrovascular disease had started to dominate the picture. Imaging confirmed the development of significant cerebral atrophy and she is now under the joint care of a hepatologist and a geriatrician. (Critical flicker frequency data are not presented as they were obtained only on two occasions.) deemed to have HE and 55 had other comorbidities that could contribute or fully explain their neurological/psychiatric profiles (Fig. 1). Of 87 patients with subclinical abnormalities, 47 were
406
CORRESPONDENCE
deemed to have minimal HE and 40 had comorbidities that could contribute or fully explain their profiles. Thus, 95/177 patients (54%) with overt or subclinical alterations had comorbidities other than HE that could contribute to these alterations. Comorbidities and confounders included recent alcohol misuse (n 5 15), cerebrovascular disease (17), malnutrition (6), severe hyponatremia (2) or hypoglycemia (1), hypothyroidism (2), infection/sepsis (5), psychoactive drugs (4), and various combinations of the above in a single patient. Several of these comorbidities are unlikely to benefit from a new liver. Patients with comorbidities/confounders were significantly older than those without (59.8 6 10.8 versus 56.8 6 11.5 years, P 5 0.04). Short, stand-alone tests for HE diagnosis such as CFF, brief sets of questions, and quick computerized tests have long been advocated for use in the clinic or at the bedside, and may be adequate for screening purposes. However, considerably more comprehensive evaluations seem necessary as a second step, especially for patients on a transplant list. In the same way as we do not expect an ECG, an echocardiogram, or an angiogram to provide us with comprehensive information on cardiac function as standalone tests, we should not expect one test to provide us with comprehensive information on cerebral function in cirrhosis. It is our impression that for the time being the HE quick diagnosis
HEPATOLOGY, January 2015
remains fiction, and the specificity of any neurological/psychiatric test a myth. SARA MONTAGNESE, PH.D. SAMI SCHIFF, PH.D. PIERO AMODIO, M.D. Department of Medicine University of Padova Italy
References 1. Montagnese S, Merkel C, Amodio P. Encephalopathy or hepatic encephalopathy? J Hepatol 2012;57:928-929. 2. Amodio P, Marchetti P, Del Piccolo F, de Tourtchaninoff M, Varghese P, Zuliani C, et al. Spectral versus visual EEG analysis in mild hepatic encephalopathy. Clin Neurophysiol 1999;110:1334-1344. 3. Weissenborn K, Ennen JC, Schomerus H, R€ uckert N, Hecker H. Neuropsychological characterization of hepatic encephalopathy. J Hepatol 2001;34:768-7673. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27127 Potential conflict of interest: Nothing to report.
Is Segmental Transarterial Yttrium 90 Radiation a Curative Option for Solitary Hepatocellular Carcinoma £5 cm? To the Editor: Recently, Vouche et al.1 reported their experience with segmental transarterial yttrium 90 radiation (STAY90R) as a potential curative option for unresectable solitary hepatocellular carcinomas (HCCs) 5 cm not amenable to radiofrequency ablation (RFA). However, careful analysis of the study’s results calls for some comments. First, almost half of the patients were Child-Pugh-B and onethird underwent liver transplantation (LT) a short time after STAY90R. In this setting, relevant comparison of overall and local tumor progression-free survivals after STAY90R with those reported after RFA should require a specific analysis in Child-Pugh-A patients censored to LT (no more risk of local recurrence after LT). Beyond the difficulty to assess the response to STAY90R with imaging, the question is how to know if such a method has enough reliable and predictable antitumor effects to be used like RFA for curative purposes. Vouche et al. pointed out that 51% of HCC 5 cm showed complete necrosis (CN) at histopathological examinations after STAY90R, a result that they assume is quite similar to after RFA. Mazzaferro et al.2 have nicely shown that time to transplantation (TTT) was strongly associated with a dramatic increase in the probability to find viable tumor in the ablation zone (30%/3 months of waiting time). The TTT was shorter in the Vouche et al. study (6.3 months [3.6-9.7]) compared to the RFA studies of Mazzaferro et al. (9.5 months [2-47]) and Lu et al. (7.5 months [0.5-21.1]).2,3 Therefore, the direct comparison based on CN between STAY90R and RFA made by Vouche et al. appears spurious. Moreover, focusing on HCCs 3 cm, 54.1% of CN are reported by Vouche et al., while it was up to 63% in the Mazzaferro et al. and 83% in Lu et al. studies. The superiority of RFA in achieving CN of small HCCs becomes more obvious when one considers no-touch multipolar RFA, which achieved up to 89.6% of CN of HCC 5 cm with 8.4 months median TTT.4 In addition, as Vouche et al. did not report histologic data concerning the
nontumorous liver, the comparison of the method to segmentectomy appears to be somewhat overstated. Finally, for nonresectable small HCC, a clear definition of tumors not amenable to RFA is critical because such a judgment leads to treatments with a higher risk of incomplete response. Vouche et al. pointed out the potential technical limitations of RFA related to specific locations. However, currently most of these limitations could be overcome and therefore are no longer regarded as definite contraindications in expert centers.5 Only a central location abutting primary main bile ducts remains a common contraindication for thermotherapy like RFA. In conclusion, Vouche et al. showed that STAY90R can induce CN in roughly 50% of HCC 5 cm. Thus, STAY90R could be regarded only as one of the second-line intraarterial treatments in the very rare cases of small HCCs not amenable to resection or RFA.
OLIVIER SEROR, M.D., PH.D. JEAN-CHARLES NAULT, M.D., PH.D. PIERRE NAHON, M.D., PH.D. GISELE N’KONTCHOU, M.D. JEAN-CLAUDE TRINCHET, M.D., PH.D. H^ opital Jean Verdier Groupe des Hopitaux Universitaires Paris Saint Denis Assistance Publique H^ opitaux de Paris, Radiology Bondy, France
References 1. Vouche M, Habib A, Ward TJ, Kim E, Kulik L, Ganger D, et al. Unresectable solitary HCC not amenable to RFA. Multicenter radiologypathology correlation and survival of radiation segmentectomy. HEPATOLOGY 2014;60:192-201.
