660
Correspondence Zachary D. Goodman MD, PhD Center for Liver Diseases Inova Fairfax Hospital Falls Church, VA 22042, USA Annette S.H. Gouw MD, PhD Department of Pathology and Medical Biology University Medical Center Groningen 9700 RB Groningen, The Netherlands
[3] Singhi AD, Jain D, Kakar S, Wu TT, Yeh MM, Torbenson M. Reticulin loss in benign fatty liver: an important diagnostic pitfall when considering a diagnosis of hepatocellular carcinoma. Am J Surg Pathol 2012;36:710-5. [4] Theise ND, Curado MP, Franceschi S, et al. Hepatocellular carcinoma. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon: IARC Press; 2010. p. 205-16. [5] Bioulac-Sage P, Balabaud C, Wanless I. Focal nodular hyperplasia and hepatocellular adenoma. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO Classification of Tumours of the Digestive Tract. 4th ed. Lyon: IARC Press; 2010. p. 198-204.
Stefan G. Hubscher MD Department of Cellular Pathology Level-1, Queen Elizabeth Hospital Birmingham Birmingham B15 2WB, United Kingdom Eve A. Roberts MD Division of Gastroenterology Hepatology and Nutrition The Hospital for Sick Children Toronto, Ontario M5G1X8, Canada
Well-differentiated hepatocellular neoplasm of uncertain malignant potential: proposal for a new diagnostic category—reply In reply:
Tania Roskams MD, PhD Laboratory of Histo-Cytochem Univ. Hospital St. Rafael 3000 Leuven, Belgium Luigi Terracciano MD Institute of Pathology University of Basel 4003 Basel, Switzerland Dina G. Tiniakos MD, PhD Institute of Cellular Medicine Newcastle University Newcastle upon Tyne NE2 4HH United Kingdom Michael S. Torbenson MD, PhD The Johns Hopkins University School of Medicine Baltimore, MD 21231, USA Ian R. Wanless MD Department of Pathology, Dalhousie University Queen Elizabeth II Health Sciences Centre Halifax, Nova Scotia B3H 1V8, Canada http://dx.doi.org/10.1016/j.humpath.2013.09.020
References [1] Evason KJ, Grenert JP, Ferrell LD, Kakar S. Atypical hepatocellular adenoma-like neoplasms with beta-catenin activation show cytogenetic alterations similar to well-differentiated hepatocellular carcinomas. HUM PATHOL 2013;44:750-8. [2] Roncalli M, Terracciano L, Di Tommaso L, et al. Liver precancerous lesions and hepatocellular carcinoma: the histology report. Dig Liver Dis 2011;43(Suppl. 4):S361-72.
We thank Bedossa et al for the interest in our study and endorse the proposal of creating the category of “welldifferentiated hepatocellular neoplasm of uncertain malignant potential” (HUMP). In a prior study, we proposed a similar category and labeled it as “atypical hepatocellular neoplasm” (AHN). Similar to the criteria proposed by Bedossa et al, we had categorized AHNs based on atypical clinical setting (age and sex), focal atypical morphologic features, and/or focal reticulin loss [1]. Cytogenetic studies using comparative genomic hybridization and fluorescence in situ hybridization demonstrated that most AHNs showed chromosomal gains similar to well-differentiated hepatocellular carcinoma (HCC) [1,2]. French studies have shown that hepatocellular adenoma (HCA)–like tumors with βcatenin activation often show atypical morphologic features and association with hepatocellular carcinoma [3,4]. In a recent study, we showed that HCA-like tumors with βcatenin activation often show cytogenetic features similar to HCC [2]. Although detailed follow-up was not available for most cases in our series, there were 3 cases with recurrence and/or metastasis. We also concur with Bedossa et al that some of the proposed clinical criteria (women b15 years or N50 years), cut-off for atypical morphologic features (5%) and extent of reticulin loss are somewhat arbitrary, necessitating further studies for more precise delineation of these criteria. Several immunohistochemical stains such as glypican 3 and heat shock protein 70 have been advocated for the distinction between HCA and HCC [5]. These stains can be helpful in certain instances but have low sensitivity and cannot be relied upon for the diagnosis. In a recent review of cases originally diagnosed as HCA in a large community hospital network over a 10-year period, the diagnosis was revised to HCC in some cases; this change was based largely on careful
Correspondence review of morphology and reticulin stain [6]. Apart from establishing β-catenin activation, immunohistochemistry currently has a limited role in HUMP. We agree that the term HUMP is preferable to AHN as it clearly embodies the uncertain natural history of these tumors. HUMP is not a distinct entity but reflects doubt about the diagnosis of HCA versus HCC based on currently accepted criteria. A tumor classified as HUMP on biopsy may show diagnostic features of HCC on resection. Further studies on natural history and outcome will be most useful by analysis of HUMP cases diagnosed on resection specimens. Bedossa et al have proposed that HCA in the setting of anabolic steroid use be categorized as HUMP. Tumors resembling HCA also occur in other settings such as glycogen storage disease, tyrosinemia, galactosemia, and congenital hepatic fibrosis [7-9]. More recently, inflammatory HCA-like nodules with positive staining for serum amyloid–associated protein have been described in cirrhosis [10]. The category of HUMP can also be considered for HCA-like tumors arising in these settings, especially if the diagnosis is being made on a biopsy. Sanjay Kakar MD Department of Anatomic Pathology 113B UCSF and VA Medical Centers, 4150 Clement St San Francisco, CA 94121, USA E-mail address: [email protected] Kimberley J. Evason MD, PhD Linda D. Ferrell MD Department of Anatomic Pathology University of California San Francisco, San Francisco CA 94143, USA http://dx.doi.org/10.1016/j.humpath.2013.09.019
References [1] Kakar S, Chen X, Ho C, et al. Chromosomal abnormalities determined by comparative genomic hybridization are helpful in the diagnosis of atypical hepatocellular neoplasms. Histopathology 2009;55:197-205. [2] Evason KJ, Grenert JP, Ferrell LD, Kakar S. Atypical hepatocellular adenoma-like neoplasms with beta-catenin activation show cytogenetic alterations similar to well-differentiated hepatocellular carcinomas. HUM PATHOL 2013;44:750-8. [3] Zucman-Rossi J, Jeannot E, Nhieu JT, et al. Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology 2006;43:515-24. [4] Bioulac-Sage P, Rebouissou S, Thomas C, et al. Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry. Hepatology 2007;46:740-8. [5] Lagana SM, Salomao M, Bao F, Moreira RK, Lefkowitch JH, Remotti HE. Utility of an immunohistochemical panel consisting of glypican-3, heat-shock protein-70, and glutamine synthetase in the distinction of low-grade hepatocellular carcinoma from hepatocellular adenoma. Appl Immunohistochem Mol Morphol 2013;21: 170-6.
661 [6] Genrich G, Shafizadeh N, Ferrell L, Kakar S. Hepatocellular adenomas in a large community population 2000-2010: reclassification per current WHO classification and long-term follow-up. Mod Pathol 2013;26:401A-2A [abstract]. [7] Kishnani PS, Chuang TP, Bali D, et al. Chromosomal and genetic alterations in human hepatocellular adenomas associated with type Ia glycogen storage disease. Hum Mol Genet 2009;18:4781-90. [8] Calderaro J, Labrune P, Morcrette G, et al. Molecular characterization of hepatocellular adenomas developed in patients with glycogen storage disease type I. J Hepatol 2013;58:350-7. [9] Bioulac-Sage P, Cubel G, Balabaud C. Pathological diagnosis of hepatocellular adenoma in clinical practice. Diagn Histopathol (Oxf) 2011;17:521-9. [10] Sasaki M, Kondo F, Sawai Y, et al. Serum amyloid A–positive hepatocellular neoplasms in the resected livers from 3 patients with alcoholic cirrhosis. Histol Histopathol 2013;28:1499-505.
Atypical teratoid/rhabdoid tumor with ganglioglioma-like differentiation To the Editor, The recently published article by Krishnan et al [1] describes an interesting case of atypical teratoid/rhabdoid tumor (AT/RT) featuring ganglioglioma (GG)-like differentiation arising within the fourth ventricle in a 4-year-old girl. The tumor histology demonstrates 2 components including a cellular element with small cell embryonal phenotype arranged in a sheet-like pattern constituting less than 5% and with a high proliferative index. Remarkably, the tumor features extensive areas of gangliogliomatous differentiation with the presence of typical dysmorphic ganglion cells often with binucleation and admixed astrocytic component. Neoplastic cells with rhabdoid phenotype were rarely identified as described by the authors. The diagnosis of AT/RT with gangliogliomatous differentiation is confirmed by demonstrating the unique molecular signature of AT/RT —loss of nuclear expression of INI-1 protein in both the morphologic components, abnormal karyotype with monosomy 22 by cytogenetics, and hemizygous deletion of SMARCB1 gene locus on chromosome 22q11.3 by fluorescence in situ hybridization. True to its polyphenotypic nature with morphologic heterogeneity, AT/RT exhibits a diverse pattern, with rare examples arising with pleomorphic xanthoastrocytoma [2] and also evolving from GG [3]. Although the frequency of BRAF V600E mutation in supratentorial GG as reported in recent studies by sequencing and immunohistochemistry shows a wide range from 18% to 58% [4,5], this tumor may also be evaluated for the presence of BRAF V600E mutation both by sequencing the 2 components separately and by performing immunohistochemistry with mutation-specific antibody. Recent study has indicated the presence of mutated protein both in the neuronal and glial components of GG as detected by the monoclonal antibody VE1 [5]. Immunohistochemistry would especially
Correspondence Zachary D. Goodman MD, PhD Center for Liver Diseases Inova Fairfax Hospital Falls Church, VA 22042, USA Annette S.H. Gouw MD, PhD Department of Pathology and Medical Biology University Medical Center Groningen 9700 RB Groningen, The Netherlands
[3] Singhi AD, Jain D, Kakar S, Wu TT, Yeh MM, Torbenson M. Reticulin loss in benign fatty liver: an important diagnostic pitfall when considering a diagnosis of hepatocellular carcinoma. Am J Surg Pathol 2012;36:710-5. [4] Theise ND, Curado MP, Franceschi S, et al. Hepatocellular carcinoma. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon: IARC Press; 2010. p. 205-16. [5] Bioulac-Sage P, Balabaud C, Wanless I. Focal nodular hyperplasia and hepatocellular adenoma. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO Classification of Tumours of the Digestive Tract. 4th ed. Lyon: IARC Press; 2010. p. 198-204.
Stefan G. Hubscher MD Department of Cellular Pathology Level-1, Queen Elizabeth Hospital Birmingham Birmingham B15 2WB, United Kingdom Eve A. Roberts MD Division of Gastroenterology Hepatology and Nutrition The Hospital for Sick Children Toronto, Ontario M5G1X8, Canada
Well-differentiated hepatocellular neoplasm of uncertain malignant potential: proposal for a new diagnostic category—reply In reply:
Tania Roskams MD, PhD Laboratory of Histo-Cytochem Univ. Hospital St. Rafael 3000 Leuven, Belgium Luigi Terracciano MD Institute of Pathology University of Basel 4003 Basel, Switzerland Dina G. Tiniakos MD, PhD Institute of Cellular Medicine Newcastle University Newcastle upon Tyne NE2 4HH United Kingdom Michael S. Torbenson MD, PhD The Johns Hopkins University School of Medicine Baltimore, MD 21231, USA Ian R. Wanless MD Department of Pathology, Dalhousie University Queen Elizabeth II Health Sciences Centre Halifax, Nova Scotia B3H 1V8, Canada http://dx.doi.org/10.1016/j.humpath.2013.09.020
References [1] Evason KJ, Grenert JP, Ferrell LD, Kakar S. Atypical hepatocellular adenoma-like neoplasms with beta-catenin activation show cytogenetic alterations similar to well-differentiated hepatocellular carcinomas. HUM PATHOL 2013;44:750-8. [2] Roncalli M, Terracciano L, Di Tommaso L, et al. Liver precancerous lesions and hepatocellular carcinoma: the histology report. Dig Liver Dis 2011;43(Suppl. 4):S361-72.
We thank Bedossa et al for the interest in our study and endorse the proposal of creating the category of “welldifferentiated hepatocellular neoplasm of uncertain malignant potential” (HUMP). In a prior study, we proposed a similar category and labeled it as “atypical hepatocellular neoplasm” (AHN). Similar to the criteria proposed by Bedossa et al, we had categorized AHNs based on atypical clinical setting (age and sex), focal atypical morphologic features, and/or focal reticulin loss [1]. Cytogenetic studies using comparative genomic hybridization and fluorescence in situ hybridization demonstrated that most AHNs showed chromosomal gains similar to well-differentiated hepatocellular carcinoma (HCC) [1,2]. French studies have shown that hepatocellular adenoma (HCA)–like tumors with βcatenin activation often show atypical morphologic features and association with hepatocellular carcinoma [3,4]. In a recent study, we showed that HCA-like tumors with βcatenin activation often show cytogenetic features similar to HCC [2]. Although detailed follow-up was not available for most cases in our series, there were 3 cases with recurrence and/or metastasis. We also concur with Bedossa et al that some of the proposed clinical criteria (women b15 years or N50 years), cut-off for atypical morphologic features (5%) and extent of reticulin loss are somewhat arbitrary, necessitating further studies for more precise delineation of these criteria. Several immunohistochemical stains such as glypican 3 and heat shock protein 70 have been advocated for the distinction between HCA and HCC [5]. These stains can be helpful in certain instances but have low sensitivity and cannot be relied upon for the diagnosis. In a recent review of cases originally diagnosed as HCA in a large community hospital network over a 10-year period, the diagnosis was revised to HCC in some cases; this change was based largely on careful
Correspondence review of morphology and reticulin stain [6]. Apart from establishing β-catenin activation, immunohistochemistry currently has a limited role in HUMP. We agree that the term HUMP is preferable to AHN as it clearly embodies the uncertain natural history of these tumors. HUMP is not a distinct entity but reflects doubt about the diagnosis of HCA versus HCC based on currently accepted criteria. A tumor classified as HUMP on biopsy may show diagnostic features of HCC on resection. Further studies on natural history and outcome will be most useful by analysis of HUMP cases diagnosed on resection specimens. Bedossa et al have proposed that HCA in the setting of anabolic steroid use be categorized as HUMP. Tumors resembling HCA also occur in other settings such as glycogen storage disease, tyrosinemia, galactosemia, and congenital hepatic fibrosis [7-9]. More recently, inflammatory HCA-like nodules with positive staining for serum amyloid–associated protein have been described in cirrhosis [10]. The category of HUMP can also be considered for HCA-like tumors arising in these settings, especially if the diagnosis is being made on a biopsy. Sanjay Kakar MD Department of Anatomic Pathology 113B UCSF and VA Medical Centers, 4150 Clement St San Francisco, CA 94121, USA E-mail address: [email protected] Kimberley J. Evason MD, PhD Linda D. Ferrell MD Department of Anatomic Pathology University of California San Francisco, San Francisco CA 94143, USA http://dx.doi.org/10.1016/j.humpath.2013.09.019
References [1] Kakar S, Chen X, Ho C, et al. Chromosomal abnormalities determined by comparative genomic hybridization are helpful in the diagnosis of atypical hepatocellular neoplasms. Histopathology 2009;55:197-205. [2] Evason KJ, Grenert JP, Ferrell LD, Kakar S. Atypical hepatocellular adenoma-like neoplasms with beta-catenin activation show cytogenetic alterations similar to well-differentiated hepatocellular carcinomas. HUM PATHOL 2013;44:750-8. [3] Zucman-Rossi J, Jeannot E, Nhieu JT, et al. Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology 2006;43:515-24. [4] Bioulac-Sage P, Rebouissou S, Thomas C, et al. Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry. Hepatology 2007;46:740-8. [5] Lagana SM, Salomao M, Bao F, Moreira RK, Lefkowitch JH, Remotti HE. Utility of an immunohistochemical panel consisting of glypican-3, heat-shock protein-70, and glutamine synthetase in the distinction of low-grade hepatocellular carcinoma from hepatocellular adenoma. Appl Immunohistochem Mol Morphol 2013;21: 170-6.
661 [6] Genrich G, Shafizadeh N, Ferrell L, Kakar S. Hepatocellular adenomas in a large community population 2000-2010: reclassification per current WHO classification and long-term follow-up. Mod Pathol 2013;26:401A-2A [abstract]. [7] Kishnani PS, Chuang TP, Bali D, et al. Chromosomal and genetic alterations in human hepatocellular adenomas associated with type Ia glycogen storage disease. Hum Mol Genet 2009;18:4781-90. [8] Calderaro J, Labrune P, Morcrette G, et al. Molecular characterization of hepatocellular adenomas developed in patients with glycogen storage disease type I. J Hepatol 2013;58:350-7. [9] Bioulac-Sage P, Cubel G, Balabaud C. Pathological diagnosis of hepatocellular adenoma in clinical practice. Diagn Histopathol (Oxf) 2011;17:521-9. [10] Sasaki M, Kondo F, Sawai Y, et al. Serum amyloid A–positive hepatocellular neoplasms in the resected livers from 3 patients with alcoholic cirrhosis. Histol Histopathol 2013;28:1499-505.
Atypical teratoid/rhabdoid tumor with ganglioglioma-like differentiation To the Editor, The recently published article by Krishnan et al [1] describes an interesting case of atypical teratoid/rhabdoid tumor (AT/RT) featuring ganglioglioma (GG)-like differentiation arising within the fourth ventricle in a 4-year-old girl. The tumor histology demonstrates 2 components including a cellular element with small cell embryonal phenotype arranged in a sheet-like pattern constituting less than 5% and with a high proliferative index. Remarkably, the tumor features extensive areas of gangliogliomatous differentiation with the presence of typical dysmorphic ganglion cells often with binucleation and admixed astrocytic component. Neoplastic cells with rhabdoid phenotype were rarely identified as described by the authors. The diagnosis of AT/RT with gangliogliomatous differentiation is confirmed by demonstrating the unique molecular signature of AT/RT —loss of nuclear expression of INI-1 protein in both the morphologic components, abnormal karyotype with monosomy 22 by cytogenetics, and hemizygous deletion of SMARCB1 gene locus on chromosome 22q11.3 by fluorescence in situ hybridization. True to its polyphenotypic nature with morphologic heterogeneity, AT/RT exhibits a diverse pattern, with rare examples arising with pleomorphic xanthoastrocytoma [2] and also evolving from GG [3]. Although the frequency of BRAF V600E mutation in supratentorial GG as reported in recent studies by sequencing and immunohistochemistry shows a wide range from 18% to 58% [4,5], this tumor may also be evaluated for the presence of BRAF V600E mutation both by sequencing the 2 components separately and by performing immunohistochemistry with mutation-specific antibody. Recent study has indicated the presence of mutated protein both in the neuronal and glial components of GG as detected by the monoclonal antibody VE1 [5]. Immunohistochemistry would especially
