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
662 be interesting because it would highlight the distribution pattern of mutated protein within various components in this tumor. Although loss of INI-1 protein expression within both tumor components aligns its classification more within the spectrum of AT/RT, evaluation of BRAF V600E mutation in this tumor may still be worthwhile. Although central nervous system tumors with loss of INI-1 protein expression besides AT/RT are rare, cribriform neuroepithelial tumor (CRINET) is a recently described intraventricular tumor arising in infants with primitive neuroectodermal, nonrhabdoid morphology [6]. The tumor is typically characterized by small undifferentiated cells arranged in cribriform strands and trabeculae. The primitive undifferentiated cells in CRINET are polyphenotypic with immunoreactivity for epithelial membrane antigen, vimentin, and synaptophysin and focally with cytokeratin and smooth muscle actin. There is variable reactivity for glial fibrillary acidic protein. Consistent in all reported examples is complete lack of nuclear INI-1 protein expression within tumor cells. Although exceedingly rare with only 4 reported cases in the literature [6], this tumor is described to have a relatively favorable prognosis. As the classification of these primitive neuroectodermal tumors in infants is still evolving, CRINET deserves a mention here. The tumor described by the authors is unusual and illustrates the challenges often encountered in accurately classifying many of the high-grade childhood brain tumors.
Correspondence Neuroblastoma or not neuroblastoma To the Editor: Vali et al [1] reported a case of a 14-year-old girl presenting with a retroperitoneal tumor composed of 2 distinct histologies. In this case, the first and predominant component was conventional primitive neuroectodermal tumor (PNET)/Ewing sarcoma (ES) genotypically and phenotypically. The second component, making multiple microscopic foci distributed in the tumor tissue, was genotypically PNET/ES but showed morphologic/cytologic as well as immunohistochemical characteristics similar to neuroblastoma. Tumor cells in the latter component had active neuropil formation, and some of them demonstrated an appearance of differentiating neuroblasts with both nuclear and cytoplasmic enlargement. In the report, the case is described as “extraosseous Ewing sarcoma with foci of neuroblastoma-like differentiation.” To support the diagnosis and interpretation, we performed an additional immunohistochemical study using antibodies against tyrosine hydroxylase (TH; Leica, Buffalo Grove, IL; 1B5, mouse monoclonal, 1:200) and trkA (Abcam,
Kirti Gupta MD Post Graduate Institute of Medical Education and Research Chandigarh 160012, India Presently on Fellowship at St. Jude Children's Research Hospital, Memphis, USA E-mail address: [email protected] http://dx.doi.org/10.1016/j.humpath.2013.11.006
References [1] Krishnan C, Vogel H, Perry A. Atypical teratoid/rhabdoid tumor with ganglioglioma-like differentiation: case report and review of the literature. HUM PATHOL 2014;45:185-8. [2] Chacko G, Chacko AG, Dunham CP, Judkins AR, Biegel JA, Perry A. Atypical teratoid/rhabdoid tumor arising in the setting of a pleomorphic xanthoastrocytoma. J Neuro Oncol 2007;84:217-22. [3] Allen JC, Judkins AR, Rosenblum MK, Biegel JA. Atypical teratoid/rhabdoid tumor evolving from an optic pathway ganglioglioma: case study. Neuro Oncol 2006;8:79-82. [4] Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011;121: 397-405. [5] Koelsche C, Wohrer A, Jeibmann A, et al. Mutant BRAF V600E protein in ganglioglioma is predominantly expressed by neuronal tumor cells. Acta Neuropathol 2013;125:891-900. [6] Hasselblatt M, Oyen F, Gesk S, et al. Cribriform neuroepithelial tumor (CRINET): a nonrhabdoid ventricular tumor with INI1 loss and relatively favorable prognosis. J Neuropathol Exp Neurol 2009;68:1249-55.
Fig A, TH is totally negative for the cells in both conventional PNET/ES area and neuroblastoma-like area. B, TrkA is positive for the cells and their neuropil in the neuroblastoma-like area, but negative in the PNET/ES area. Immunostaining, original magnification ×100.
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
662 be interesting because it would highlight the distribution pattern of mutated protein within various components in this tumor. Although loss of INI-1 protein expression within both tumor components aligns its classification more within the spectrum of AT/RT, evaluation of BRAF V600E mutation in this tumor may still be worthwhile. Although central nervous system tumors with loss of INI-1 protein expression besides AT/RT are rare, cribriform neuroepithelial tumor (CRINET) is a recently described intraventricular tumor arising in infants with primitive neuroectodermal, nonrhabdoid morphology [6]. The tumor is typically characterized by small undifferentiated cells arranged in cribriform strands and trabeculae. The primitive undifferentiated cells in CRINET are polyphenotypic with immunoreactivity for epithelial membrane antigen, vimentin, and synaptophysin and focally with cytokeratin and smooth muscle actin. There is variable reactivity for glial fibrillary acidic protein. Consistent in all reported examples is complete lack of nuclear INI-1 protein expression within tumor cells. Although exceedingly rare with only 4 reported cases in the literature [6], this tumor is described to have a relatively favorable prognosis. As the classification of these primitive neuroectodermal tumors in infants is still evolving, CRINET deserves a mention here. The tumor described by the authors is unusual and illustrates the challenges often encountered in accurately classifying many of the high-grade childhood brain tumors.
Correspondence Neuroblastoma or not neuroblastoma To the Editor: Vali et al [1] reported a case of a 14-year-old girl presenting with a retroperitoneal tumor composed of 2 distinct histologies. In this case, the first and predominant component was conventional primitive neuroectodermal tumor (PNET)/Ewing sarcoma (ES) genotypically and phenotypically. The second component, making multiple microscopic foci distributed in the tumor tissue, was genotypically PNET/ES but showed morphologic/cytologic as well as immunohistochemical characteristics similar to neuroblastoma. Tumor cells in the latter component had active neuropil formation, and some of them demonstrated an appearance of differentiating neuroblasts with both nuclear and cytoplasmic enlargement. In the report, the case is described as “extraosseous Ewing sarcoma with foci of neuroblastoma-like differentiation.” To support the diagnosis and interpretation, we performed an additional immunohistochemical study using antibodies against tyrosine hydroxylase (TH; Leica, Buffalo Grove, IL; 1B5, mouse monoclonal, 1:200) and trkA (Abcam,
Kirti Gupta MD Post Graduate Institute of Medical Education and Research Chandigarh 160012, India Presently on Fellowship at St. Jude Children's Research Hospital, Memphis, USA E-mail address: [email protected] http://dx.doi.org/10.1016/j.humpath.2013.11.006
References [1] Krishnan C, Vogel H, Perry A. Atypical teratoid/rhabdoid tumor with ganglioglioma-like differentiation: case report and review of the literature. HUM PATHOL 2014;45:185-8. [2] Chacko G, Chacko AG, Dunham CP, Judkins AR, Biegel JA, Perry A. Atypical teratoid/rhabdoid tumor arising in the setting of a pleomorphic xanthoastrocytoma. J Neuro Oncol 2007;84:217-22. [3] Allen JC, Judkins AR, Rosenblum MK, Biegel JA. Atypical teratoid/rhabdoid tumor evolving from an optic pathway ganglioglioma: case study. Neuro Oncol 2006;8:79-82. [4] Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011;121: 397-405. [5] Koelsche C, Wohrer A, Jeibmann A, et al. Mutant BRAF V600E protein in ganglioglioma is predominantly expressed by neuronal tumor cells. Acta Neuropathol 2013;125:891-900. [6] Hasselblatt M, Oyen F, Gesk S, et al. Cribriform neuroepithelial tumor (CRINET): a nonrhabdoid ventricular tumor with INI1 loss and relatively favorable prognosis. J Neuropathol Exp Neurol 2009;68:1249-55.
Fig A, TH is totally negative for the cells in both conventional PNET/ES area and neuroblastoma-like area. B, TrkA is positive for the cells and their neuropil in the neuroblastoma-like area, but negative in the PNET/ES area. Immunostaining, original magnification ×100.
