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Li H, Matoso A. Unlocking diagnostic potential: A retrospective analysis of GPNMB immunohistochemistry in nearly 1000 surgical pathology specimens. Hum Pathol 2025; 159:105799. [PMID: 40389121 DOI: 10.1016/j.humpath.2025.105799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2025] [Revised: 05/13/2025] [Accepted: 05/16/2025] [Indexed: 05/21/2025]
Abstract
Glycoprotein non-metastatic melanoma protein B (GPNMB) is a lysosomal transmembrane protein regulated by the TSC/mTOR-TFE pathway and has been proposed as a diagnostic immunohistochemical (IHC) marker for tumors associated with TSC/mTOR-TFE pathway alterations. However, its diagnostic performance in routine surgical pathology has not been systematically evaluated on a large scale. We retrospectively reviewed 934 cases from the Johns Hopkins pathology archives (2021-2025) in which GPNMB IHC was performed. Diagnoses were categorized into TSC/mTOR-TFE-related, non-TSC/mTOR/TFE-related, or undefined molecular groups. Correlation with fluorescence in situ hybridization (FISH) results and histologic features was performed to assess diagnostic utility. GPNMB was diffusely positive in 94.8 % (218/230) of TSC/mTOR-TFE-related neoplasms, including renal cell carcinomas with TFE3/TFEB rearrangements, perivascular epithelioid cell tumors (PECOMA/AML), and other related entities. In contrast, 83.3 % of non-TSC/mTOR-TFE-related tumors were negative for GPNMB. Discordant cases were seen in both groups, likely reflecting molecular heterogeneity, limitations of FISH, or the complex regulation of GPNMB expression. GPNMB outperformed cathepsin K in sensitivity in FISH-confirmed cases with TFE3 or TFEB alterations. Patchy or equivocal staining required careful histologic and ancillary correlation for interpretation. GPNMB IHC is a valuable ancillary tool in diagnosing TSC/mTOR-TFE-related neoplasms, particularly in renal and mesenchymal tumors. While not perfectly specific or sensitive, it offers a rapid and cost-effective alternative to molecular testing and can guide further diagnostic workup. Positive GPNMB staining in tumors without known TSC/mTOR-TFE alterations may suggest secondary pathway involvement, warranting additional molecular studies.
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Affiliation(s)
- Huili Li
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Andres Matoso
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
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Nezami BG, MacLennan GT. Clear Cell Renal Cell Carcinoma: A Comprehensive Review of its Histopathology, Genetics, and Differential Diagnosis. Int J Surg Pathol 2025; 33:265-280. [PMID: 39051572 DOI: 10.1177/10668969241256111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/27/2024]
Abstract
Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal epithelial tumor, accounting for roughly 2% of all malignancies. Clinically, it often presents in the sixth to seventh decade of life, predominantly in men. Pathologically, these tumors exhibit a distinctive golden yellow cut surface, usually arising from the renal cortex. Their microscopic features are characterized by solid and nested architectures of cells with clear or eosinophilic granular cytoplasm and a prominent vascular network. A hallmark genetic feature is the inactivation of the VHL gene situated on chromosome 3p25. The majority of ccRCCs are sporadic (over 95%), typically presenting as a single mass; and a small percentage have a hereditary basis, often associated with VHL disease, characterized by multiple bilateral tumors with an earlier onset. Immunohistochemically, ccRCC tumors express PAX8, CA9 box like pattern, and CD10 but are generally negative for AMACR (35% positive) and KRT7 (15% positive). The prognosis of ccRCC is largely determined by its TNM stage, ISUP/WHO nucleolar grade, and the presence of specific aggressive features. This review article delves into the detailed gross, microscopic, molecular, and clinical features of ccRCC, offering comprehensive insights into its diagnosis, management, and prognosis.
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Affiliation(s)
- Behtash G Nezami
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Gregory T MacLennan
- Department of Pathology and Urology, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
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3
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Tekin B, Folpe AL, Dasari S, Hofich CD, McCarthy M, Alvand S, Pujari GP, Halling KC, Cheville JC, Whaley RD, Gupta S. TFE3-rearranged ossifying fibromyxoid tumors are uniquely negative for glycoprotein non-metastatic melanoma protein B: A study of 13 TFE3-rearranged mesenchymal tumors. Hum Pathol 2025; 157:105768. [PMID: 40189028 DOI: 10.1016/j.humpath.2025.105768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 04/02/2025] [Accepted: 04/03/2025] [Indexed: 04/12/2025]
Abstract
OBJECTIVES Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transcriptional target of MiTF/TFE3. Prior studies have shown that immunohistochemistry for GPNMB is a sensitive screening tool for renal cell carcinomas with alterations of TSC1/TSC2/MTOR, TFE3, and TFEB genes, as well as alveolar soft part sarcomas (ASPS) and perivascular epithelioid cell neoplasms (PEComas). However, GPNMB expression has not been systematically evaluated in a diverse group of molecularly confirmed, TFE3-rearranged mesenchymal tumors. METHODS Our archive was interrogated for TFE3-rearranged non-renal neoplasms previously assessed with our RNA NGS panel. For each case, a whole-slide section was immunostained for GPNMB, and quantified using H-scores. The methylation profiles of the included tumor types were retrieved from our database. RESULTS Thirteen TFE3-rearranged tumors were identified, including 6 ossifying fibromyxoid tumors (OFMTs) (PHF1::TFE3), 3 PEComas/PEComa-like neoplasms (ASPSCR1::TFE3, DVL2::TFE3, and PRCC::TFE3, one case each), 2 YAP1::TFE3-rearranged hemangioendotheliomas, one ASPS (ASPSCR1::TFE3), and one unclassified CBX4::TFE3-rearranged sarcoma. Tumors harboring ASPSCR1, PRCC, YAP1, and DVL2 as the fusion partner had a mean H-score of 300, 300, 290 and 280, respectively. All 6 PHF1::TFE3-rearranged OFMTs and the CBX4::TFE3-rearranged sarcoma were GPNMB-negative, despite having similar TFE3 breakpoints to the positive cases (exon 6-7). PHF1::TFE3-rearranged OFMT showed relative hypermethylation of the GPNMB promoter locus cg02203656 compared to ASPS (p = 0.027). CONCLUSIONS Although study of additional cases is necessary, these findings suggest that the downstream effects of TFE3-rearrangement are different in PHF1::TFE3-rearranged OFMTs, compared to other known TFE3-rearranged neoplasms. TFE3-rearranged OFMTs are epigenetically distinct, implying that the impact of TFE3-rearrangement may be lineage-dependent.
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Affiliation(s)
- Burak Tekin
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
| | - Andrew L Folpe
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
| | - Surendra Dasari
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
| | - Christopher D Hofich
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
| | - Michael McCarthy
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
| | - Saba Alvand
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
| | - Ganesh P Pujari
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
| | - Kevin C Halling
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
| | - John C Cheville
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
| | - Rumeal D Whaley
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
| | - Sounak Gupta
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
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Mullane PC, Qian X, Lau HD, Lowe ACY. Cytologic diagnosis of fumarate hydratase-deficient renal cell carcinoma: A single-institutional experience. Cancer Cytopathol 2025; 133:e22931. [PMID: 39804329 DOI: 10.1002/cncy.22931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/21/2024] [Accepted: 12/02/2024] [Indexed: 04/04/2025]
Abstract
BACKGROUND Fumarate hydratase-deficient renal cell carcinoma (FHRCC) is an aggressive carcinoma that typically presents as advanced-stage disease. Prompt recognition of FHRCC is critical for appropriate clinical care and genetic counseling for patients and family members. However, diagnosing FHRCC from cytology specimens is challenging, with limited characterization and no reports describing prospectively identified cases. METHODS Cytology fine-needle aspiration (FNA) cases diagnosed as FHRCC were reviewed, including two prospectively identified cases. RESULTS Five cases of FHRCC diagnosed by FNA cytology were identified in five unique patients. The cytologic samples included four FNAs with core biopsy and one FNA with cell block. Biopsy sites included kidney (n = 1), chest wall (n = 1), omentum (n = 1), lung (n = 1), and cervical lymph node (n = 1). All cases demonstrated cytologically malignant epithelial cells characterized by enlarged, round nuclei with variable pleomorphism, irregular nuclear membranes, prominent nucleoli, and moderate-to-abundant amounts of cytoplasm. Perinucleolar halos characterized by chromatin margination and pallor around macronucleoli were seen in all cases. Cytologic features not previously described included cytoplasmic macrovacuoles and eosinophilic globules, cytophagocytosis, and floral groups. Papillary architecture was rarely present on aspirate smears. Cell block sections showed variable architectural patterns. By immunohistochemistry, FH was definitively lost in three of five cases (60%), and 2-succinocysteine was positive in all 5 cases (100%). CONCLUSIONS Cytologic specimens of FHRCC demonstrate salient cytomorphologic features that can support their initial diagnosis. Confirmatory immunohistochemical testing using a dual panel of fumarate hydratase and 2-succinocysteine is recommended for the diagnosis in limited biopsy samples.
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Affiliation(s)
- Patrick C Mullane
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Xiaohua Qian
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
| | - Hubert D Lau
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
| | - Alarice Cheng-Yi Lowe
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
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Durgin JS, Smith EH, Harms PW, Brown NA, Chan MP. A case of NONO::TFE3 cutaneous epithelioid and spindle cell tumor with local recurrence after complete excision. J Cutan Pathol 2024; 51:954-958. [PMID: 39206664 DOI: 10.1111/cup.14712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/13/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024]
Abstract
Mesenchymal tumors may display morphologic and immunohistochemical overlap with melanocytic tumors, presenting a pitfall for misdiagnosis. We report a 62-year-old woman who presented with a recurrent dermal and subcutaneous tumor over the Achilles tendon 15 years following complete excision. Both the primary and the recurrent tumors were characterized by nests and sheets of epithelioid and spindle cells with eosinophilic cytoplasm and uniform ovoid nuclei. The tumor was positive for S100, SOX10, HMB45, cathepsin K, and p63 (weak), while negative for Melan-A, MiTF, smooth muscle actin, and desmin. Gene fusion analysis of the recurrent tumor revealed a NONO::TFE3 fusion which has been recently reported in two similar cutaneous cases. Our case highlights the potential of a NONO::TFE3 cutaneous epithelioid and spindle cell tumor to recur after a prolonged disease-free interval without evidence of high-grade transformation or distant metastasis. Our findings support its classification as a cutaneous mesenchymal neoplasm of intermediate malignancy.
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Affiliation(s)
- Joseph S Durgin
- Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Emily H Smith
- Department of Dermatology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
| | - Paul W Harms
- Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Noah A Brown
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - May P Chan
- Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
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Caliò A, Marletta S, Brunelli M, Antonini P, Martelli FM, Marcolini L, Stefanizzi L, Martignoni G. TFE3-Rearranged Tumors of the Kidney: An Emerging Conundrum. Cancers (Basel) 2024; 16:3396. [PMID: 39410016 PMCID: PMC11475521 DOI: 10.3390/cancers16193396] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 09/29/2024] [Accepted: 10/02/2024] [Indexed: 10/20/2024] Open
Abstract
Background: Identical translocations involving the TFE3 gene and various partners have been found in both renal and soft tissue tumors, like alveolar soft part sarcoma (ASPSCR1), ossifying fibromyxoid tumor (PHF1), epithelioid hemangioendothelioma, and the clear cell stromal tumor of the lung (YAP1). Methods: Herein, we review in detail the clinicopathologic and molecular data of TFE3-rearranged renal tumors and propose our perspective, which may shed light on this emerging conundrum. Results: Among the kidney tumors carrying TFE3 translocations, most are morphologically heterogeneous carcinomas labeling for the tubular marker PAX8. The others are mesenchymal neoplasms known as PEComas, characterized by epithelioid cells co-expressing smooth muscle actin, cathepsin-K, melanogenesis markers, and sometimes melanin pigment deposition. Over the past 30 years, numerous TFE3 fusion partners have been identified, with ASPL/ASPSCR1, PRCC, SFPQ/PSF, and NONO being the most frequent. Conclusions: It is not well understood why similar gene fusions can give rise to renal tumors with different morpho-immunophenotypes, which may contribute to the recent disagreement regarding their classification. However, as these two entities, respectively, epithelial and mesenchymal in nature, are widely recognized by the pathology community and their clinicopathologic features well established, we overall believe it is still better to retain the names TFE3-rearranged renal cell carcinoma and TFE3-rearranged PEComa.
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Affiliation(s)
- Anna Caliò
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy; (A.C.); (S.M.); (M.B.); (P.A.); (F.M.M.)
| | - Stefano Marletta
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy; (A.C.); (S.M.); (M.B.); (P.A.); (F.M.M.)
- Division of Pathology, Humanitas Istituto Clinico Catanese, 95045 Catania, Italy
| | - Matteo Brunelli
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy; (A.C.); (S.M.); (M.B.); (P.A.); (F.M.M.)
| | - Pietro Antonini
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy; (A.C.); (S.M.); (M.B.); (P.A.); (F.M.M.)
| | - Filippo Maria Martelli
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy; (A.C.); (S.M.); (M.B.); (P.A.); (F.M.M.)
| | - Lisa Marcolini
- Department of Pathology, Pederzoli Hospital, 37019 Peschiera del Garda, Italy; (L.M.); (L.S.)
| | - Lavinia Stefanizzi
- Department of Pathology, Pederzoli Hospital, 37019 Peschiera del Garda, Italy; (L.M.); (L.S.)
| | - Guido Martignoni
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy; (A.C.); (S.M.); (M.B.); (P.A.); (F.M.M.)
- Department of Pathology, Pederzoli Hospital, 37019 Peschiera del Garda, Italy; (L.M.); (L.S.)
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Collins K, Bridge JA, Mehra R, Mannan R, Dickson BC, Lotan TL, Idrees MT, Ulbright TM, Acosta AM. Renal epithelioid angiomyolipomas overexpress TFE3 and the TFE3-regulated gene TRIM63 in the absence of TFE3 rearrangement. Virchows Arch 2024; 485:471-478. [PMID: 38971946 DOI: 10.1007/s00428-024-03855-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 05/23/2024] [Accepted: 06/14/2024] [Indexed: 07/08/2024]
Abstract
Angiomyolipoma (AML) is a neoplasm within the perivascular epithelioid cell tumor family that occurs somewhat frequently in the kidney. Most are indolent and discovered incidentally, with rare tumors demonstrating malignant clinical behavior. A small subset of renal AMLs with epithelioid features are associated with aggressive behavior, and may demonstrate morphologic overlap with renal cell carcinomas (e.g., clear cell renal cell carcinoma (RCC), TFE3-rearranged RCC). Prior studies of spindle cell and epithelioid AMLs have identified rare examples with underlying TFE3 gene fusions. TFE3 protein expression (demonstrated by immunohistochemistry) with no evidence of concurrent TFE3 rearrangements has been reported previously in 4/24 AMLs (17%) (Argani et al. Am J Surg Pathol 34:1395-1406, 2010). Currently, the relationship between TFE3 protein expression, TFE3 fusions, and expression of TFE3-mediated genes remains incompletely understood in renal epithelioid AMLs. We sought to explore these relationships using TFE3 break-apart fluorescence in situ hybridization (FISH) and TRIM63 RNA in situ hybridization (ISH) on epithelioid AMLs with moderate to strong TFE3 expression by immunohistochemistry. RNA sequencing (fusion panel) was performed on two cases with negative FISH results to assess for FISH-cryptic gene fusions. The series comprised five epithelioid AMLs from four patients (three women, one man) aged 13 to 76 years. All were considered positive for TFE3 by immunohistochemistry (2 + /3 + expression). TRIM63 ISH was performed on four specimens from three patients, yielding positive results in 3/3 tumors (100%) that were successfully analyzed. TFE3 break-apart FISH was performed on all samples, demonstrating a TFE3 rearrangement in only 1/4 tumors (25%). RNA sequencing demonstrated the absence of productive TFE3 gene fusions in three tumors with negative break-apart TFE3 FISH results. This study demonstrates that renal epithelioid AMLs overexpress TFE3 and TFE3-mediated genes (TRIM63) even in the absence of TFE3 rearrangements. This finding could be explained by functional upregulation of TFE3 secondary to activation of the mammalian target of rapamycin complex 1 (mTORC1). Expression of TFE3 and TRIM63 in this tumor type represents a potential pitfall, given the morphologic and immunophenotypic overlap between epithelioid AML and TFE3-altered renal cell carcinoma.
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Affiliation(s)
- Katrina Collins
- Department of Pathology, Indiana University School of Medicine, 305 W 11 Street, Room 4080, Indianapolis, IN, USA
| | - Julia A Bridge
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
- ProPath, Division of Molecular Pathology, Dallas, TX, USA
| | - Rohit Mehra
- Department of Pathology and Michigan Center for Translational Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Rahul Mannan
- Department of Pathology and Michigan Center for Translational Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Brendan C Dickson
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Canada
| | - Tamara L Lotan
- Department of PathologyDepartment of OncologyDepartment of Urology, Johns Hopkins University School of MedicineJohns Hopkins University School of MedicineJohns Hopkins University School of Medicine, Baltimore, USA
| | - Muhammad T Idrees
- Department of Pathology, Indiana University School of Medicine, 305 W 11 Street, Room 4080, Indianapolis, IN, USA
| | - Thomas M Ulbright
- Department of Pathology, Indiana University School of Medicine, 305 W 11 Street, Room 4080, Indianapolis, IN, USA
| | - Andres M Acosta
- Department of Pathology, Indiana University School of Medicine, 305 W 11 Street, Room 4080, Indianapolis, IN, USA.
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Riddle N, Parkash V, Guo CC, Shen SS, Perincheri S, Ramirez AS, Auerbach A, Belchis D, Humphrey PA. Recent Advances in Genitourinary Tumors: Updates From the 5th Edition of the World Health Organization Blue Book Series. Arch Pathol Lab Med 2024; 148:952-964. [PMID: 38031818 DOI: 10.5858/arpa.2022-0509-ra] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2023] [Indexed: 12/01/2023]
Abstract
CONTEXT.— Urinary and Male Genital Tumours is the 8th volume of the World Health Organization Classification of Tumours series, 5th edition. Released in hard copy in September 2022, it presents an update to the classification of male genital and urinary tumors in the molecular age. Building upon previous volumes in this series, significant effort has been made to harmonize terminology across organ systems for biologically similar tumors (eg, neuroendocrine tumors). Genomic terminology has been standardized and genetic syndromes covered more comprehensively. This review presents a concise summary of this volume, highlighting new entities, notable modifications relative to the 4th edition, and elements of relevance to routine clinical practice. OBJECTIVE.— To provide a comprehensive update on the World Health Organization classification of urinary and male genital tumors, highlighting updated diagnostic criteria and terminology. DATA SOURCES.— The 4th and 5th editions of the World Health Organization Classification of Tumours: Urinary and Male Genital Tumours. CONCLUSIONS.— The World Health Organization has made several changes in the 5th edition of the update on urinary and male genital tumors that pathologists need to be aware of for up-to-date clinical practice.
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Affiliation(s)
- Nicole Riddle
- From the Department of Pathology, Tampa General Hospital, Tampa, Florida (Riddle)
- Pathology and Laboratory Medicine, Ruffolo, Hooper, and Associates, University of South Florida Health, Tampa (Riddle)
| | - Vinita Parkash
- the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut (Parkash, Perincheri, Humphrey)
| | - Charles C Guo
- the Department of Pathology, University of Texas MD Anderson Cancer Center, Houston (Guo)
| | - Steven S Shen
- the Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas (Shen)
| | - Sudhir Perincheri
- the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut (Parkash, Perincheri, Humphrey)
| | | | - Aaron Auerbach
- the Department of Hematopathology, The Joint Pathology Center, Silver Spring, Maryland (Auerbach)
| | - Deborah Belchis
- the Department of Pathology, Luminis Health, Baltimore, Maryland (Belchis)
| | - Peter A Humphrey
- the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut (Parkash, Perincheri, Humphrey)
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9
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Boroojerdi S, Weidemann S, Menz A, Lennartz M, Dwertmann Rico S, Schlichter R, Kind S, Reiswich V, Viehweger F, Bawahab AA, Höflmeyer D, Fraune C, Gorbokon N, Luebke AM, Hube-Magg C, Büscheck F, Krech T, Hinsch A, Jacobsen F, Burandt E, Sauter G, Simon R, Kluth M, Steurer S, Minner S, Marx AH, Bernreuther C, Clauditz TS, Dum D, Lebok P. Staining pattern of specific and cross-reacting Melan-A antibodies: A comparative study on 15,840 samples from 133 human tumor types. APMIS 2024; 132:479-491. [PMID: 38757248 DOI: 10.1111/apm.13408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 03/12/2024] [Indexed: 05/18/2024]
Abstract
The Melan-A (melanocyte antigen) protein, also termed 'melanoma antigen recognized by T cells 1' (MART-1) is a protein with unknown function whose expression is specific for the melanocyte lineage. Antibodies against Melan-A are thus used for identifying melanocytic tumors, but some Melan-A antibodies show an additional - diagnostically useful - cross-reactivity against an unspecified protein involved in corticosteroid hormone synthesis. To comprehensively compare the staining patterns of a specific and a cross-reactive Melan-A antibody in normal and neoplastic tissues, tissue microarrays containing 15,840 samples from 133 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry. For the Melan-A-specific antibody 'Melan-A specific' (MSVA-900M), Melan-A positivity was seen in 96.0% of 25 benign nevi, 93.0% of 40 primary and 86.7% of 75 metastatic melanomas, 82.4% of 85 renal angiomyolipomas as well as 96.4% of 84 neurofibromas, 2.2% of 46 granular cell tumors, 1.0% of 104 schwannomas, and 1.1% of 87 leiomyosarcomas. The cross-reactive antibody 'Melan-A+' (MSVA-901M+) stained 98.1% of the tumors stained by 'Melan-A specific'. In addition, high positivity rates were seen in sex-cord-stroma tumors of the ovary (35.3%-100%) and the testis (86.7%) as well as for adrenocortical neoplasms (76.3%-83.0%). Only nine further tumor groups showed Melan-A+ staining, including five different categories of urothelial carcinomas. Our data provide a comprehensive overview on the staining patterns of specific and cross-reactive Melan-A antibodies. The data demonstrate that both antibodies are highly useful for their specific purpose. It is important for pathologists to distinguish these two Melan-A antibody subtypes for their daily work.
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Affiliation(s)
- Shiva Boroojerdi
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sören Weidemann
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anne Menz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maximilian Lennartz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Ria Schlichter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Simon Kind
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Viktor Reiswich
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Florian Viehweger
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ahmed Abdulwahab Bawahab
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Pathology, Faculty of Medicine, University of Jeddah, Jeddah, Saudi Arabia
| | - Doris Höflmeyer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Natalia Gorbokon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas M Luebke
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - Andrea Hinsch
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas H Marx
- Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Christian Bernreuther
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David Dum
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
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10
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Repetto F, Sirohi D, Greipp P, Mahlow J. Incidental Detection of TFEB-Amplified Renal Cell Carcinoma by Colocated Gene Amplification of CCND3 (6p21): A Case Report and Review of the Literature. Int J Surg Pathol 2024; 32:551-555. [PMID: 37394760 DOI: 10.1177/10668969231185081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
TFEB-amplified renal cell carcinoma (RCC), which belongs to the MITF family of RCC, is characterized by genomic amplification at the 6p21.1 locus where the TFEB gene is located. The vascular endothelial growth factor A and cyclin D3 genes are also located at this same locus. When tumors lack classic morphologic features, they may be classified as "RCC not otherwise specified (NOS)." However, it is increasingly important to accurately diagnose the RCC subtype to define the patient's individual prognosis and select the subsequent therapeutic modalities, which now include targeted agents. Therefore, knowledge of the diagnostic features of TFEB-altered RCCs, such as t(6;11) RCCs and TFEB-amplified RCCs, is critical for identifying these tumors. Herein, we present an interesting case of TFEB-amplified RCC that was initially diagnosed as RCC NOS on biopsy of a renal tumor in a community practice setting with available molecular findings demonstrating CCND3 amplification. The genetic abnormality was "accidentally" detected due to the amplification of the colocated CCND3 gene at the 6p21 locus of the TFEB gene on a limited genetic sequencing panel. This case highlights the importance of molecular tests in accurately diagnosing RCC and carefully interpreting molecular findings in the context of histomorphologic features.
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Affiliation(s)
- Federico Repetto
- Favaloro University, School of Medicine, Buenos Aires, Argentina
| | - Deepika Sirohi
- University of Utah, Department of Pathology, Salt Lake City, UT, USA
| | - Patricia Greipp
- Mayo Clinic, Laboratory Medicine and Pathology, Rochester, MN, USA
| | - Jonathon Mahlow
- University of Utah, Department of Pathology, Salt Lake City, UT, USA
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11
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Wu J, Cao CZ, Cui HL, Du G, Shi HZ, Liang J, Guo L, Wang YC, Zhang J, Zhou AP, Li CL, Zheng S, Shou JZ. Prognosis and Clinicopathological Characters of Adult TFEB-Altered Renal Cell Carcinoma: A Single Center Experience of 18 Cases. Clin Genitourin Cancer 2024; 22:261-268.e3. [PMID: 38104031 DOI: 10.1016/j.clgc.2023.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/13/2023] [Accepted: 11/13/2023] [Indexed: 12/19/2023]
Abstract
INTRODUCTION TFEB-altered renal cell carcinoma (RCC) is a rare entity characterized by the rearrangement of the TFEB gene or TFEB amplified. The therapeutic implications and long-term survival of TFEB-altered RCC remain unclear, especially for metastatic cases. MATERIALS AND METHODS The current study initially enrolled 7604 consecutive RCC patients at our center and a total of 248 patients were selected for FISH and immunohistochemistry (IHC) analysis. Eventually, eighteen TFEB-altered RCC patients were identified. We then reported the clinical, morphological, IHC, and radiological features of these cases. RESULTS The median age at initial diagnosis was 45 years, ranging from 18 years to 66 years. The majority of the TFEB-altered RCC patients were male (61.1%), with localized disease (T1-2N0M0, 77.8%). The median split TFEB fluorescent signal was 24%, ranging from 15%-80%. The morphological characteristics of TFEB-altered RCC were variable, with acinar, papillary, solid, or nest patterns. IHC and magnetic resonance imaging features of TFEB-altered RCC were nonspecific. Nine patients with localized disease received partial nephrectomy and five patients with localized disease received radical nephrectomy. During the median follow-up of 67 months, no signs of recurrence or metastasis were found in these patients. Two patients had distant metastasis and received axitinib plus PD-1 immunotherapy. One of them died at 40-month follow-up and another still alive at 88-month follow-up. CONCLUSION TFEB-altered RCC is an extremely rare variant, exhibited mixed morphological characteristics. The radiological feature lack specificity, resembling clear cell RCC or papillary RCC. Genetic analyses including FISH analysis is crucial in the diagnosis of TFEB-altered RCC. For localized TFEB-altered RCC, both radical nephrectomy and partial nephrectomy conferred satisfactory prognosis. For metastatic TFEB-altered RCC, immunotherapy-based drug combinations could be a promising treatment strategy.
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Affiliation(s)
- Jie Wu
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chuan-Zhen Cao
- Department of Urology, China-Japan Friendship Hospital, Beijing, China
| | - Hong-Lei Cui
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Gan Du
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong-Zhe Shi
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Liang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei Guo
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yi-Cheng Wang
- Department of Imaging, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jin Zhang
- Department of Imaging, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ai-Ping Zhou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chang-Ling Li
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shan Zheng
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Jian-Zhong Shou
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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12
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Zhang R, Yang X, Shi X, Xing E, Wang L, Hao C, Zhang Z. Bortezomib modulated the autophagy-lysosomal pathway in a TFEB-dependent manner in multiple myeloma. Leuk Res 2024; 138:107455. [PMID: 38368721 DOI: 10.1016/j.leukres.2024.107455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 01/29/2024] [Accepted: 02/05/2024] [Indexed: 02/20/2024]
Abstract
OBJECTIVE To explore the involvement of TFEB-mediated autophagy-lysosomal mechanisms in multiple myeloma (MM) during bortezomib treatment. METHODS MM cells were exposed to bortezomib or subjected to TFEB knockdown. CCK assay was used to assess the cell proliferation. Western blotting and fluorescent staining were conducted to examine autophagy and lysosomes. The TFEB expression pattern was analyzed, and whole transcriptome sequencing was carried out. Additionally, TFEB target genes were predicted using the GTRD(http://gtrd.biouml.org/) website, and pathway analysis was performed. RESULTS Bortezomib demonstrated a dose-dependent and time dependent inhibition of cell proliferation. In MM cells treated with bortezomib, LC3B, Beclin-1, TFEB, and Lamp1 exhibited upregulation in a time- and concentration-dependent manner. LysoTracker dye labeling showed an increase in lysosomes in the bortezomib-treated group. Moreover, bortezomib elevated the expression of lysosome-associated factor Lamp1. Bortezomib promoted the nuclear translocation of TFEB, leading to decreased cytoplasmic TFEB and increased nuclear TFEB. TFEB gene silencing reversed bortezomib's inhibitory effect on MM cell lines, significantly reducing autophagosome expression and lysosome numbers. Furthermore, bioinformatic analysis identified the MAPK pathway as a potential downstream target of TFEB. CONCLUSION Bortezomib effectively inhibits MM cell proliferation and induces autophagy, partly through TFEB-mediated mechanisms, with potential involvement of the MAPK pathway.
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Affiliation(s)
- Rongjuan Zhang
- Department of Internal Medicine, Hebei Medical University, Shijiazhaung 050000, China
| | - Xinhong Yang
- Department of Hematology, The Affiliated Hospital of Chengde Medical College, Chengde 067000, China
| | - Xiaomin Shi
- Department of Hematology, The Affiliated Hospital of Chengde Medical College, Chengde 067000, China
| | - Enhong Xing
- Department of central laboratory, The Affiliated Hospital of Chengde Medical College, Chengde 067000, China
| | - Lihong Wang
- Department of Hematology, The Affiliated Hospital of Chengde Medical College, Chengde 067000, China
| | - Changlai Hao
- Department of Internal Medicine, Hebei Medical University, Shijiazhaung 050000, China; Department of Hematology, The Affiliated Hospital of Chengde Medical College, Chengde 067000, China.
| | - Zhihua Zhang
- Department of Hematology, The Affiliated Hospital of Chengde Medical College, Chengde 067000, China.
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13
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Zhu Y, Xia C, Ou Y, Zhang C, Li L, Yang D. TFEB-associated renal cell carcinoma: A case report and literature review. Medicine (Baltimore) 2022; 101:e31870. [PMID: 36550835 PMCID: PMC9771232 DOI: 10.1097/md.0000000000031870] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
RATIONALE TFEB-associated renal cell carcinoma is very rare and belongs to the microphthalmia - associated transcription family translocation renal cell carcinoma. PATIENT CONCERNS Hospitalized for fever, a 29-year-old male patient had a left kidney lesion without any additional discomfort. DIAGNOSES Histopathological and immunohistochemical results were corresponding with TFEB renall cell carcinoma features. INTERVENTIONS Surgical resection of the tumor was performed. OUTCOMES After 8 months of follow-up, no tumor recurrence was observed. LESSONS TFEB-associated renal cell carcinoma is rare. The diagnosis is explicit. However, the optimal treatment needs to be further explored.
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Affiliation(s)
- Yong Zhu
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Chengxing Xia
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yitian Ou
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Chao Zhang
- Department of Oncology, Qujing First People’s Hospital, Qujing, Yunnan, China
| | - Lin Li
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Delin Yang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
- * Correspondence: Delin Yang, Department of Urology, The Second Affiliated Hospital of Kunming Medical University, 374 Dianmian Avenue, Kunming, Yunnan 650101, China (e-mail: )
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14
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Taylor AS, Skala SL. Tumors masquerading as type 2 papillary renal cell carcinoma: pathologists' ever-expanding differential diagnosis for a heterogeneous group of entities. Urol Oncol 2022; 40:499-511. [PMID: 34116938 DOI: 10.1016/j.urolonc.2021.04.043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 03/22/2021] [Accepted: 04/28/2021] [Indexed: 02/07/2023]
Abstract
Although papillary renal cell carcinoma has historically been classified as either type 1 or type 2, data from The Cancer Genome Atlas (TCGA) has demonstrated significant genomic heterogeneity in tumors classified as "type 2 papillary renal cell carcinoma" (T2PRCC). Papillary renal cell carcinoma is expected to have a favorable clinical course compared to clear cell renal cell carcinoma (CCRCC). However, tumors with poor outcome more similar to CCRCC were included in the T2PRCC cohort studied by the TCGA. The differential diagnosis for T2PRCC includes a variety of other renal tumors, including aggressive entities such as TFE3 translocation-associated renal cell carcinoma, TFEB-amplified renal cell carcinoma, fumarate hydratase-deficient renal cell carcinoma, high-grade CCRCC, and collecting duct carcinoma. Accurate classification of these tumors is important for prognostication and selection of therapy.
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Affiliation(s)
- Alexander S Taylor
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI
| | - Stephanie L Skala
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI.
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15
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MiT translocation renal cell carcinoma: A review of the literature from molecular characterization to clinical management. Biochim Biophys Acta Rev Cancer 2022; 1877:188823. [DOI: 10.1016/j.bbcan.2022.188823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/17/2022] [Accepted: 10/04/2022] [Indexed: 11/23/2022]
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16
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Cathepsin K: A Versatile Potential Biomarker and Therapeutic Target for Various Cancers. Curr Oncol 2022; 29:5963-5987. [PMID: 36005209 PMCID: PMC9406569 DOI: 10.3390/curroncol29080471] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 08/15/2022] [Accepted: 08/21/2022] [Indexed: 12/11/2022] Open
Abstract
Cancer, a common malignant disease, is one of the predominant causes of diseases that lead to death. Additionally, cancer is often detected in advanced stages and cannot be radically cured. Consequently, there is an urgent need for reliable and easily detectable markers to identify and monitor cancer onset and progression as early as possible. Our aim was to systematically review the relevant roles of cathepsin K (CTSK) in various possible cancers in existing studies. CTSK, a well-known key enzyme in the bone resorption process and most studied for its roles in the effective degradation of the bone extracellular matrix, is expressed in various organs. Nowadays, CTSK has been involved in various cancers such as prostate cancer, breast cancer, bone cancer, renal carcinoma, lung cancer and other cancers. In addition, CTSK can promote tumor cells proliferation, invasion and migration, and its mechanism may be related to RANK/RANKL, TGF-β, mTOR and the Wnt/β-catenin signaling pathway. Clinically, some progress has been made with the use of cathepsin K inhibitors in the treatment of certain cancers. This paper reviewed our current understanding of the possible roles of CTSK in various cancers and discussed its potential as a biomarker and/or novel molecular target for various cancers.
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17
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Kmeid M, Akgul M. TFE3 Rearrangement and Expression in Renal Cell Carcinoma. Int J Surg Pathol 2022:10668969221108517. [PMID: 35912477 DOI: 10.1177/10668969221108517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
TFE3 rearranged Renal cell carcinoma (RCC) is not very common, and demonstrates unique heterogenous morphological features overlapping other recognized entities and distinct immunoprofile. It can be seen in any age group, therefore practicing pathologists should be aware of the distinctive clinical settings and histologic findings associated with these tumors and subsequently employ an adequate panel of ancillary studies in order to confirm the diagnosis. Recognizing these entities remains crucial for future clinical trials and development of novel therapies.
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Affiliation(s)
- Michel Kmeid
- Department of Pathology and Laboratory Medicine, 138207Albany Medical Center, Albany, NY, USA
| | - Mahmut Akgul
- Department of Pathology and Laboratory Medicine, 138207Albany Medical Center, Albany, NY, USA
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18
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Simonaggio A, Ambrosetti D, Verkarre V, Auvray M, Oudard S, Vano YA. MiTF/TFE Translocation Renal Cell Carcinomas: From Clinical Entities to Molecular Insights. Int J Mol Sci 2022; 23:ijms23147649. [PMID: 35886994 PMCID: PMC9324307 DOI: 10.3390/ijms23147649] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 07/07/2022] [Accepted: 07/08/2022] [Indexed: 12/30/2022] Open
Abstract
MiTF/TFE translocation renal cell carcinoma (tRCC) is a rare and aggressive subtype of RCC representing the most prevalent RCC in the pediatric population (up to 40%) and making up 4% of all RCCs in adults. It is characterized by translocations involving either TFE3 (TFE3-tRCC), TFEB (TFEB-tRCC) or MITF, all members of the MIT family (microphthalmia-associated transcriptional factor). TFE3-tRCC was first recognized in the World Health Organization (WHO) classification of kidney cancers in 2004. In contrast to TFEB-tRCC, TFE3-tRCC is associated with many partners that can be detected by RNA or exome sequencing. Both diagnoses of TFE3 and TFEB-tRCC are performed on morphological and immunohistochemical features, but, to date, TFE break-apart fluorescent in situ hybridization (FISH) remains the gold standard for diagnosis. The clinical behavior of tRCC is heterogeneous and more aggressive in adults. Management of metastatic tRCC is challenging, especially in the younger population, and data are scarce. Efficacy of the standard of care-targeted therapies and immune checkpoint inhibitors remains low. Recent integrative exome and RNA sequencing analyses have provided a better understanding of the biological heterogeneity, which can contribute to a better therapeutic approach. We describe the clinico-pathological entities, the response to systemic therapy and the molecular features and techniques used to diagnose tRCC.
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Affiliation(s)
- Audrey Simonaggio
- Department of Medical Oncology, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP. Centre—Université Paris-Cité, F-75015 Paris, France; (A.S.); (M.A.); (S.O.)
| | - Damien Ambrosetti
- Department of Pathology, CHU Nice, Université Côte d’Azur, F-06107 Nice, France;
- Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR 7284, INSERM U1081, University Côte d’Azur, F-06107 Nice, France
| | - Virginie Verkarre
- Department of Pathology, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP. Centre—Université Paris-Cité, F-75015 Paris, France;
- INSERM UMR-970, PARCC, Université Paris-Cité, F-75015 Paris, France
| | - Marie Auvray
- Department of Medical Oncology, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP. Centre—Université Paris-Cité, F-75015 Paris, France; (A.S.); (M.A.); (S.O.)
| | - Stéphane Oudard
- Department of Medical Oncology, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP. Centre—Université Paris-Cité, F-75015 Paris, France; (A.S.); (M.A.); (S.O.)
- INSERM UMR-970, PARCC, Université Paris-Cité, F-75015 Paris, France
| | - Yann-Alexandre Vano
- Department of Medical Oncology, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP. Centre—Université Paris-Cité, F-75015 Paris, France; (A.S.); (M.A.); (S.O.)
- INSERM UMR-970, PARCC, Université Paris-Cité, F-75015 Paris, France
- Centre de Recherche des Cordeliers, INSERM, Université Paris-Cité, Sorbonne Université, F-75006 Paris, France
- Correspondence: ; Tel.: +33-624281311
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19
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Tretiakova MS. Chameleon TFE3-translocation RCC and How Gene Partners Can Change Morphology: Accurate Diagnosis Using Contemporary Modalities. Adv Anat Pathol 2022; 29:131-140. [PMID: 35180736 DOI: 10.1097/pap.0000000000000332] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Translocation renal cell carcinoma (tRCC) with TFE3 gene rearrangements has been born as a distinct entity 20 years ago. These relatively rare tumors were notable among other RCC subtypes because of their disproportionally high incidence among children and young adults. Initial reports were focused on describing unifying morphologic criteria and typical clinical presentation. Follow-up studies of ancillary immunohistochemical and hybridization techniques provided additional diagnostic tools allowing recognition of tRCC tumors in practice. However, a growing body of literature also expanded the clinicomorphologic spectrum of tRCCs, to include a significant morphologic overlap with other RCC variants thus blurring the diagnostic clarity of this entity. More recent molecular studies utilizing next-generation sequencing technology accelerated recognition of numerous novel gene partners fusing at different breakpoints with the TFE3 gene. Accumulating data indicates that morphologic and clinical heterogeneity of tRCC could be explained by fusion subtypes, and knowledge of TFE3 partnering genes may be important in predicting tumor behavior. Herein we provided a comprehensive analysis of ∼400 tRCC cases with known TFE3 fusion partners, estimated their relative incidence and summarized clinicomorphologic features associated with most common fusion subtypes. Our data was based on an extensive literature review and had a special focus on comparing immunohistochemistry, fluorescent in situ hybridization and contemporary molecular studies for the accurate diagnosis of tRCC.
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Affiliation(s)
- Maria S Tretiakova
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA
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20
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Bennett JA, Ordulu Z, Pinto A, Wanjari P, Antonescu CR, Ritterhouse LL, Oliva E. Uterine PEComas: correlation between melanocytic marker expression and TSC alterations/TFE3 fusions. Mod Pathol 2022; 35:515-523. [PMID: 34131293 PMCID: PMC8671557 DOI: 10.1038/s41379-021-00855-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/19/2021] [Accepted: 06/01/2021] [Indexed: 11/09/2022]
Abstract
Uterine PEComas often present a diagnostic challenge as they share morphological and immunohistochemical features with smooth muscle tumors. Herein we evaluated a series of 19 uterine PEComas to compare the degree of melanocytic marker expression with their molecular profile. Patients ranged from 32-77 (median 48) years, with six tumors classified as malignant based on the modified gynecologic-specific prognostic algorithm. All patients with malignant PEComas were alive with disease or dead of disease at last follow-up, while all those of uncertain malignant potential were alive and well (median follow-up, 47 months).Seventeen of 19 (89%) PEComas harbored either a TSC1 or TSC2 alteration. One of the two remaining tumors showed a TFE3 rearrangement, but the other lacked alterations in all genes evaluated. All showed at least focal (usually strong) positivity for HMB-45, with 15/19 (79%) having >50% expression, while the tumor lacking TSC or TFE3 alterations was strongly positive in 10% of cells. Melan-A and MiTF were each positive in 15/19 (79%) tumors, but staining extent and intensity were much more variable than HMB-45. Five of six (83%) malignant PEComas also harbored alterations in TP53, ATRX, or RB1, findings not identified in any tumors of uncertain malignant potential. One malignant PEComa was microsatellite-unstable/mismatch repair protein-deficient.In summary, TSC alterations/TFE3 fusions and diffuse (>50%) HMB-45 expression are characteristic of uterine PEComas. In morphologically ambiguous mesenchymal neoplasms with myomelanocytic differentiation, especially those with metastatic or recurrent disease, next-generation sequencing is recommended to evaluate for TSC alterations; as such, patients can be eligible for targeted therapy.
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Affiliation(s)
| | - Zehra Ordulu
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | | | | | | | | | - Esther Oliva
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
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21
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Munari E, Settanni G, Caliò A, Segala D, Lonardi S, Sandrini S, Vacca P, Tumino N, Marconi M, Brunelli M, Gobbo S, Netto GJ, Moretta L, Zamboni G, Martignoni G. TSC loss is a clonal event in eosinophilic solid and cystic renal cell carcinoma: a multiregional tumor sampling study. Mod Pathol 2022; 35:376-385. [PMID: 33990704 DOI: 10.1038/s41379-021-00816-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/30/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022]
Abstract
Eosinophilic, solid and cystic (ESC) renal cell carcinoma (RCC) is characterized by a solid and cystic architecture with cells showing abundant eosinophilic cytoplasm with hobnail arrangement and a cytokeratin 7-negative/cytokeratin 20-positive immunophenotype. Recent studies have suggested that bi-allelic events affecting TSC genes might play an important role for such tumors. However, only indirect evidence of the clonal origin of TSC mutation has been gathered so far. Therefore, in this paper we aimed to perform multi-regional tumor sampling molecular analysis in four ESC RCC cases that had been completely embedded, three sporadic and one occurring in a patient with tuberous sclerosis complex (TSC). Histologically, the 4 cases showed cystic and solid architecture and cells with abundant eosinophilic cytoplasm with cytoplasmic stippling and round to oval nuclei. Immunohistochemistry showed at least focal expression of cytokeratin 20 in all tissue samples and negative cytokeratin 7, as well as diffuse positivity for S100A1 and at least focal expression of cathepsin K in three out of four cases. The sporadic cases showed the same somatic TSC1 mutations in all tissue samples analyzed, while the TSC-associated case showed the same TSC1 alteration in both normal tissue and all tumor samples analyzed, proving the germline nature of the alteration. In conclusion, our data demonstrate that clonal TSC loss is a key event in ESC RCC and support considering ESC RCC as an entity given its distinct morphologic, immunophenotypical and molecular characteristics.
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Affiliation(s)
- Enrico Munari
- Department of Pathology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy.,Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Giulio Settanni
- Department of Pathology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy
| | - Anna Caliò
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Diego Segala
- Pathology Unit, ASST-Spedali Civili, Brescia, Italy
| | - Sara Lonardi
- Department of Pathology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy
| | - Silvia Sandrini
- Department of Pathology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy
| | - Paola Vacca
- Immunology Area, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Nicola Tumino
- Immunology Area, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Marcella Marconi
- Department of Pathology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy
| | - Matteo Brunelli
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Stefano Gobbo
- Pathology Unit, Pederzoli Hospital, Peschiera del Garda, Verona, Italy
| | - George J Netto
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Lorenzo Moretta
- Immunology Area, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Giuseppe Zamboni
- Department of Pathology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy.,Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Guido Martignoni
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy. .,Pathology Unit, Pederzoli Hospital, Peschiera del Garda, Verona, Italy.
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22
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Caliò A, Marletta S, Brunelli M, Martignoni G. WHO 2022 Classification of Kidney Tumors: what is relevant? An update and future novelties for the pathologist. Pathologica 2022; 115:23-31. [PMID: 36645397 DOI: 10.32074/1591-951x-814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 10/21/2022] [Indexed: 01/17/2023] Open
Abstract
Classification systems reflect our technical abilities in the investigation of tumors and our current theories on tumor development. Herein, by providing a historical perspective on the evolution of classifying renal tumors, we assess the current WHO classification highlighting the novelties and the implications of these changes in daily clinical practice.
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Affiliation(s)
- Anna Caliò
- Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Italy
| | - Stefano Marletta
- Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Italy.,Department of Pathology, Pederzoli Hospital, Peschiera, Italy
| | - Matteo Brunelli
- Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Italy
| | - Guido Martignoni
- Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Italy.,Department of Pathology, Pederzoli Hospital, Peschiera, Italy
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23
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Salles DC, Asrani K, Woo J, Vidotto T, Liu HB, Vidal I, Matoso A, Netto GJ, Argani P, Lotan TL. GPNMB
expression identifies
TSC1
/2/
mTOR
‐associated and
MiT
family translocation‐driven renal neoplasms. J Pathol 2022; 257:158-171. [PMID: 35072947 PMCID: PMC9310781 DOI: 10.1002/path.5875] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 12/21/2021] [Accepted: 01/22/2022] [Indexed: 11/20/2022]
Abstract
GPNMB (glycoprotein nonmetastatic B) and other TFE3/TFEB transcriptional targets have been proposed as markers for microphthalmia (MiT) translocation renal cell carcinomas (tRCCs). We recently demonstrated that constitutive mTORC1 activation via TSC1/2 loss leads to increased activity of TFE3/TFEB, suggesting that the pathogenesis and molecular markers for tRCCs and TSC1/2‐associated tumors may be overlapping. We examined GPNMB expression in human kidney and angiomyolipoma (AML) cell lines with TSC2 and/or TFE3/TFEB loss produced using CRISPR–Cas9 genome editing as well as in a mouse model of Tsc2 inactivation‐driven renal tumorigenesis. Using an automated immunohistochemistry (IHC) assay for GPNMB, digital image analysis was employed to quantitatively score expression in clear cell RCC (ccRCC, n = 87), papillary RCC (papRCC, n = 53), chromophobe RCC (chRCC, n = 34), oncocytoma (n = 4), TFE3‐ or TFEB‐driven tRCC (n = 56), eosinophilic solid and cystic RCC (ESC, n = 6), eosinophilic vacuolated tumor (EVT, n = 4), and low‐grade oncocytic tumor (LOT, n = 3), as well as AML (n = 29) and perivascular epithelioid cell tumors (PEComas, n = 8). In cell lines, GPNMB was upregulated following TSC2 loss in a MiT/TFE‐ and mTORC1‐dependent fashion. Renal tumors in Tsc2+/− A/J mice showed upregulation of GPNMB compared with normal kidney. Mean GPNMB expression was significantly higher in tRCC than in ccRCC (p < 0.0001), papRCC (p < 0.0001), and chRCC (p < 0.0001). GPNMB expression in TSC1/2/MTOR alteration‐associated renal tumors (including ESC, LOT, AML, and PEComa) was comparable to that in tRCC. The immunophenotype of tRCC and TSC1/2/MTOR alteration‐associated renal tumors is highly overlapping, likely due to the increased activity of TFE3/TFEB in both, revealing an important caveat regarding the use of TFE3/TFEB‐transcriptional targets as diagnostic markers. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Daniela C. Salles
- Department of Pathology Johns Hopkins University School of Medicine Baltimore MD USA
| | - Kaushal Asrani
- Department of Pathology Johns Hopkins University School of Medicine Baltimore MD USA
| | - Juhyung Woo
- Department of Pathology Johns Hopkins University School of Medicine Baltimore MD USA
| | - Thiago Vidotto
- Department of Pathology Johns Hopkins University School of Medicine Baltimore MD USA
| | - Hans B. Liu
- Department of Pathology Johns Hopkins University School of Medicine Baltimore MD USA
| | - Igor Vidal
- Department of Pathology Johns Hopkins University School of Medicine Baltimore MD USA
| | - Andres Matoso
- Department of Pathology Johns Hopkins University School of Medicine Baltimore MD USA
| | - George J. Netto
- Department of Pathology University of Alabama Birmingham Alabama USA
| | - Pedram Argani
- Department of Pathology Johns Hopkins University School of Medicine Baltimore MD USA
| | - Tamara L. Lotan
- Department of Pathology Johns Hopkins University School of Medicine Baltimore MD USA
- Department of Urology Johns Hopkins University School of Medicine Baltimore MD USA
- Department of Oncology Johns Hopkins University School of Medicine Baltimore MD USA
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24
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TFE3 and TFEB-rearranged renal cell carcinomas: an immunohistochemical panel to differentiate from common renal cell neoplasms. Virchows Arch 2022; 481:877-891. [PMID: 35980471 PMCID: PMC9734233 DOI: 10.1007/s00428-022-03380-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/08/2022] [Accepted: 07/15/2022] [Indexed: 01/22/2023]
Abstract
TFE3/TFEB-rearranged renal cell carcinomas are characterized by translocations involving TFE3 and TFEB genes. Despite the initial description of typical morphology, their histological spectrum is wide, mimicking common subtypes of renal cell tumors. Thus, the diagnosis is challenging requiring the demonstration of the gene rearrangement, usually by FISH. However, this technique is limited in most laboratories and immunohistochemical TFE3/TFEB analysis is inconsistent. We sought to identify a useful immunohistochemical panel using the most common available markers to recognize those tumors. We performed an immunohistochemical panel comparing 27 TFE3-rearranged and 10 TFEB-rearranged renal cell carcinomas to the most common renal cell tumors (150 clear cell, 100 papillary, 50 chromophobe renal cell carcinomas, 18 clear cell papillary renal cell tumors, and 50 oncocytomas). When dealing with neoplasms characterized by cells with clear cytoplasm, CA9 is a helpful marker to exclude clear cell renal cell carcinoma. GATA3, AMACR, and CK7 are useful to rule out clear cell papillary renal cell tumor. CK7 is negative in TFE3/TFEB-rearranged renal cell carcinoma and positive in papillary renal cell carcinoma, being therefore useful in this setting. Parvalbumin and CK7/S100A1 respectively are of paramount importance when TFE3/TFEB-rearranged renal cell carcinoma resembles oncocytoma and chromophobe renal cell carcinoma. Moreover, in TFEB-rearranged renal cell carcinoma, cathepsin K and melanogenesis markers are constantly positive, whereas TFE3-rearranged renal cell carcinoma stains for cathepsin K in roughly half of the cases, HMB45 in 8% and Melan-A in 22%. In conclusion, since TFE3/TFEB-rearranged renal cell carcinoma may mimic several histotypes, an immunohistochemical panel to differentiate them from common renal cell tumors should include cathepsin K, CA9, CK7, and parvalbumin.
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25
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Argani P. Translocation carcinomas of the kidney. Genes Chromosomes Cancer 2021; 61:219-227. [PMID: 34704642 DOI: 10.1002/gcc.23007] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 10/24/2021] [Indexed: 01/19/2023] Open
Abstract
The MiT subfamily of transcription factors includes TFE3, TFEB, TFEC, and MITF. Gene fusions involving two of these transcription factors have been well-characterized in renal cell carcinoma (RCC). The TFE3-rearranged RCC (also known as Xp11 translocation RCC) was first officially recognized in the 2004 World Health Organization (WHO) renal tumor classification. The TFEB-rearranged RCC, which typically harbor a t(6;11)(p21;q12) translocation which results in a MALAT1-TFEB gene fusion, were first officially recognized in the 2016 WHO renal tumor classification. These two subtypes of translocation RCC have many similarities. Both disproportionately involve young patients, although adult translocation RCC overall outnumber pediatric cases. Both often have unusual and distinctive morphologies; the TFE3-rearranged RCCs frequently have clear cells with papillary architecture and abundant psammoma bodies, while the TFEB-rearranged RCCs frequently have a biphasic appearance with both small and large epithelioid cells and nodules of basement membrane material. However, the morphology of these two neoplasms can overlap, with one mimicking the other or other more common renal neoplasms. Both of these RCC underexpress epithelial immunohistochemical markers, such as cytokeratin and epithelial membrane antigen, relative to most other RCC. Unlike other RCC, both frequently express the cysteine protease cathepsin k and often express melanocytic markers like HMB45 and Melan A. Finally, TFE3 and TFEB have overlapping functional activity as these two transcription factors frequently heterodimerize and bind to the same targets. Therefore, these two neoplasms are now grouped together under the heading of "MiT family translocation RCC." Approximately 50 renal cell carcinomas with gene fusions involving the anaplastic lymphoma kinase (ALK) gene have now been reported. While those with a Vinculin-ALK fusion have distinctive features (predilection to affect children with sickle cell trait and to show solid architecture with striking cytoplasmic vacuolization), other ALK-fusion RCCs have more varied clinical presentations and pathologic features. This review summarizes our current knowledge of these recently described RCC.
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Affiliation(s)
- Pedram Argani
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Departments of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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26
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Lobo J, Ohashi R, Helmchen BM, Rupp NJ, Rüschoff JH, Moch H. The Morphological Spectrum of Papillary Renal Cell Carcinoma and Prevalence of Provisional/Emerging Renal Tumor Entities with Papillary Growth. Biomedicines 2021; 9:1418. [PMID: 34680535 PMCID: PMC8533532 DOI: 10.3390/biomedicines9101418] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/04/2021] [Accepted: 10/06/2021] [Indexed: 12/11/2022] Open
Abstract
Renal cell carcinoma (RCC) represents a heterogeneous disease, encompassing an increasing number of tumor subtypes. Post-2016, the World Health Organization (WHO) classification recognized that the spectrum of papillary renal cell carcinoma is evolving and has long surpassed the dichotomic simplistic "type 1 versus type 2" classification. The differential diagnosis of pRCC includes several new provisional/emerging entities with papillary growth. Type 2 tumors have been cleared out of several confounding entities, now regarded as independent tumors with specific clinical and molecular backgrounds. In this work we describe the prevalence and characteristics of emerging papillary tumor entities in two renal tumor cohorts (one consisting of consecutive papillary tumors from a single institute, the other consisting of consultation cases from several centers). After a review of 154 consecutive pRCC cases, 58% remained type 1 pRCC, and 34% type 2 pRCC. Papillary renal neoplasm with reversed polarity (1.3%), biphasic hyalinizing psammomatous RCC (1.3%), and biphasic squamoid/alveolar RCC (4.5%) were rare. Among 281 consultation cases, 121 (43%) tumors had a dominant papillary growth (most frequently MiT family translocation RCCs, mucinous tubular and spindle cell carcinoma and clear cell papillary RCC). Our data confirm that the spectrum of RCCs with papillary growth represents a major diagnostical challenge, frequently requiring a second expert opinion. Papillary renal neoplasm with reversed polarity, biphasic hyalinizing psammomatous RCC, and biphasic squamoid/alveolar RCC are rarely sent out for a second opinion, but correct classification and knowledge of these variants will improve our understanding of the clinical behavior of renal tumors with papillary growth.
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Affiliation(s)
- João Lobo
- Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal;
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), R. Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
- Department of Pathology and Molecular Immunology, ICBAS—School of Medicine and Biomedical Sciences, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal
| | - Riuko Ohashi
- Histopathology Core Facility, Faculty of Medicine, Niigata University, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata 951-8510, Japan;
- Division of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata 951-8510, Japan
| | - Birgit M. Helmchen
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland; (B.M.H.); (N.J.R.); (J.H.R.)
| | - Niels J. Rupp
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland; (B.M.H.); (N.J.R.); (J.H.R.)
| | - Jan H. Rüschoff
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland; (B.M.H.); (N.J.R.); (J.H.R.)
| | - Holger Moch
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland; (B.M.H.); (N.J.R.); (J.H.R.)
- Faculty of Medicine, University of Zurich, Rämistrasse 71, 8006 Zurich, Switzerland
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27
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Wang XM, Zhang Y, Mannan R, Skala SL, Rangaswamy R, Chinnaiyan A, Su F, Cao X, Zelenka-Wang S, McMurry L, Xiao H, Spratt DE, Sangoi A, Shao L, Betz BL, Brown N, Tickoo SK, McKenney JK, Argani P, Gupta S, Reuter VE, Chinnaiyan AM, Dhanasekaran SM, Mehra R. TRIM63 is a sensitive and specific biomarker for MiT family aberration-associated renal cell carcinoma. Mod Pathol 2021; 34:1596-1607. [PMID: 33854184 PMCID: PMC8298271 DOI: 10.1038/s41379-021-00803-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 03/19/2021] [Accepted: 03/20/2021] [Indexed: 12/20/2022]
Abstract
Microphthalmia-associated transcription factor (MiT) family aberration-associated renal cell carcinoma (MiTF-RCC) is a subtype of renal cell carcinoma harboring recurrent chromosomal rearrangements involving TFE3 or TFEB genes. MiTF-RCC is morphologically diverse, can histologically resemble common RCC subtypes like clear cell RCC and papillary RCC, and often poses a diagnostic challenge in genitourinary clinical and pathology practice. To characterize the MiTF-RCC at the molecular level and identify biomarker signatures associated with MiTF-RCC, we analyzed RNAseq data from MiTF-RCC, other RCC subtypes and benign kidney. Upon identifying TRIM63 as a cancer-specific biomarker in MiTF-RCC, we evaluated its expression independently by RNA in situ hybridization (RNA-ISH) in whole tissue sections from 177 RCC cases. We specifically included 31 cytogenetically confirmed MiTF-RCC cases and 70 RCC cases suspicious for MiTF-RCC in terms of clinical and morphological features, to evaluate and compare TRIM63 RNA-ISH results with the results from TFE3/TFEB fluorescence in situ hybridization (FISH), which is the current clinical standard. We confirmed that TRIM63 mRNA was highly expressed in all classes of MiTF-RCC compared to other renal tumor categories, where it was mostly absent to low. While the TRIM63 RNA-ISH and TFE3/TFEB FISH results were largely concordant, importantly, TRIM63 RNA-ISH was strongly positive in TFE3 FISH false-negative cases with RBM10-TFE3 inversion. In conclusion, TRIM63 can serve as a diagnostic marker to distinguish MiTF-RCC from other renal tumor subtypes with overlapping morphology. We suggest a combination of TFE3/TFEB FISH and TRIM63 RNA-ISH assays to improve the accuracy and efficiency of MiTF-RCC diagnosis. Accurate diagnosis of MiTF-RCC and other RCC subtypes would enable effective targeted therapy and avoid poor therapeutic response due to tumor misclassification.
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Affiliation(s)
- Xiao-Ming Wang
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI,Michigan Center for Translational Pathology, Ann Arbor, MI
| | - Yuping Zhang
- Michigan Center for Translational Pathology, Ann Arbor, MI
| | - Rahul Mannan
- Michigan Center for Translational Pathology, Ann Arbor, MI
| | - Stephanie L. Skala
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI
| | | | | | - Fengyun Su
- Michigan Center for Translational Pathology, Ann Arbor, MI
| | - Xuhong Cao
- Michigan Center for Translational Pathology, Ann Arbor, MI
| | - Sylvia Zelenka-Wang
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI,Michigan Center for Translational Pathology, Ann Arbor, MI
| | - Lisa McMurry
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI
| | - Hong Xiao
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI
| | - Daniel E. Spratt
- Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI
| | - Ankur Sangoi
- Department of Pathology, El Camino Hospital, Mountain View, CA
| | - Lina Shao
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI
| | - Bryan L. Betz
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI
| | - Noah Brown
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI
| | - Satish K. Tickoo
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jesse K. McKenney
- Robert J Tomsich Pathology and Laboratory Medicine Institute, Anatomic Pathology, Cleveland Clinic, Cleveland, OH
| | - Pedram Argani
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
| | | | - Victor E. Reuter
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Arul M. Chinnaiyan
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI,Michigan Center for Translational Pathology, Ann Arbor, MI,Rogel Cancer Center, Michigan Medicine, Ann Arbor, MI,Department of Urology, University of Michigan Medical School, Ann Arbor, MI,Howard Hughes Medical Institute, Ann Arbor, MI
| | - Saravana M. Dhanasekaran
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI,Michigan Center for Translational Pathology, Ann Arbor, MI
| | - Rohit Mehra
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. .,Michigan Center for Translational Pathology, Ann Arbor, MI, USA. .,Rogel Cancer Center, Michigan Medicine, Ann Arbor, MI, USA.
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28
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Baniak N, Barletta JA, Hirsch MS. Key Renal Neoplasms With a Female Predominance. Adv Anat Pathol 2021; 28:228-250. [PMID: 34009777 DOI: 10.1097/pap.0000000000000301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Renal neoplasms largely favor male patients; however, there is a growing list of tumors that are more frequently diagnosed in females. These tumors include metanephric adenoma, mixed epithelial and stromal tumor, juxtaglomerular cell tumor, mucinous tubular and spindle cell carcinoma, Xp11.2 (TFE3) translocation-associated renal cell carcinoma, and tuberous sclerosis complex (somatic or germline) associated renal neoplasms. The latter category is a heterogenous group with entities still being delineated. Eosinophilic solid and cystic renal cell carcinoma is the best-described entity, whereas, eosinophilic vacuolated tumor is a proposed entity, and the remaining tumors are currently grouped together under the umbrella of tuberous sclerosis complex/mammalian target of rapamycin-related renal neoplasms. The entities described in this review are often diagnostic considerations when evaluating renal mass tissue on biopsy or resection. For example, Xp11.2 translocation renal cell carcinoma is in the differential when a tumor has clear cell cytology and papillary architecture and occurs in a young or middle-aged patient. In contrast, tuberous sclerosis complex-related neoplasms often enter the differential for tumors with eosinophilic cytology. This review provides an overview of the clinical, gross, microscopic, immunohistochemical, genetic, and molecular alterations in key renal neoplasms occurring more commonly in females; differential diagnoses are also discussed regardless of sex predilection.
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Affiliation(s)
- Nicholas Baniak
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Justine A Barletta
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Michelle S Hirsch
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
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29
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New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia. Mod Pathol 2021; 34:1392-1424. [PMID: 33664427 DOI: 10.1038/s41379-021-00779-w] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 02/11/2021] [Accepted: 02/11/2021] [Indexed: 12/28/2022]
Abstract
The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.
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30
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Zhang ZH, Zhang RJ, Han N, Li C, Wang LL, Xing EH, Gu CH, Hao CL. [Transcription factor EB related autophagy in the treatment of multiple myeloma and its mechanism]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2021; 42:407-414. [PMID: 34218584 PMCID: PMC8292998 DOI: 10.3760/cma.j.issn.0253-2727.2021.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Indexed: 11/19/2022]
Abstract
Objective: To clarify the effects of bortezomib combined with or without siramesine on the proliferation of multiple myeloma cell lines, the expression changes of transcription factor EBC (TFEB) nuclear translocation and the level of autophagy, and to provide basis for further exploring the regulation mechanism of transcription factor TFEB on autophagy. Methods: The multiple myeloma cell lines RPMI8226 and U266 were cultured in vitro, and the multiple myeloma cells were treated with a certain concentration of bortezomib and siramesine. The changes of cell proliferation inhibition were detected by CCK-8 method. Real time PCR and Western blot were used to detect the relative expression of TFEB, autophagy-related factor LC3B, Beclin1, p62, LAMP1 mRNA and protein. Results: As the concentration of bortezomib increased and the duration of action increased, the proliferation inhibition rates of the two cell lines gradually increased (P<0.05) . The combination of the two drugs has a synergistic inhibitory effect on the proliferation of the above-mentioned multiple myeloma cell lines (P<0.05) . In the blank control group, single drug group, and combination drug group, the relative expression of TFEB mRNA and protein in the cytoplasm decreased sequentially (P<0.05) , and the relative expression of TFEB mRNA and protein in the nucleus increased sequentially (P<0.05) . The relative expression of autophagy-related factors LC3B, Beclin1, LAMP1 mRNA and protein increased sequentially, and the relative expression of p62 mRNA and protein decreased sequentially (P<0.05) . Conclusion: Bortezomib and siramesine can synergistically inhibit the growth of multiple myeloma cells, which is related to the increased autophagy expression in multiple myeloma cell lines and the expression of TFEB with nuclear translocation is also enhanced.
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Affiliation(s)
- Z H Zhang
- Affiliated Hospital of Chengde Medical College, Chengde 067000, China
| | - R J Zhang
- Affiliated Hospital of Chengde Medical College, Chengde 067000, China
| | - N Han
- Affiliated Hospital of Chengde Medical College, Chengde 067000, China
| | - C Li
- Affiliated Hospital of Chengde Medical College, Chengde 067000, China
| | - L L Wang
- Affiliated Hospital of Chengde Medical College, Chengde 067000, China
| | - E H Xing
- Affiliated Hospital of Chengde Medical College, Chengde 067000, China
| | - C H Gu
- Affiliated Hospital of Chengde Medical College, Chengde 067000, China
| | - C L Hao
- Affiliated Hospital of Chengde Medical College, Chengde 067000, China
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31
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Contemporary Characterization and Recategorization of Adult Unclassified Renal Cell Carcinoma. Am J Surg Pathol 2021; 45:450-462. [PMID: 33239504 DOI: 10.1097/pas.0000000000001629] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Our recent study of early-onset unclassified eosinophilic renal cell carcinoma (RCC) demonstrated that two third of cases could be reclassified by performing a limited number of immunohistochemistry stains. Following the same approach, we aimed to investigate what proportion of adult unclassified RCC could be reclassified. We identified 79 cases. The mean age at presentation was 58 years (range, 29 to 84 y). Tumors were grouped based on their predominant morphologic features as oncocytic (n=23); papillary (n=22); clear cell (n=22); mucinous tubular and spindle cell (MTSC; n=5); rhabdoid (n=4); or lacking a dominant pattern (n=3). By reviewing the morphologic features and performing ancillary studies, we were able to reclassify 10 cases (13%). Four cases were positive for CK20 and showed morphologic features consistent with eosinophilic solid and cystic RCC. Four cases were reclassified as MTSC based on VSTM2A expression by RNA in situ hybridization. One case was negative for SDHB and reclassified as succinate dehydrogenase-deficient RCC. None of the cases showed loss of expression of fumarate hydratase. One case was diffusely positive for CK7 and negative for CD117 and reclassified as a low-grade oncocytic tumor. Four cases were positive for both cathepsin-K and TFE3 by immunohistochemistry, although fluorescence in situ hybridization failed to identify rearrangement in either TFE3 or TFEB genes. Of the tumors that remained unclassified, those with oncocytic features were less likely to be a high grade (odds ratio [OR]=0.22, P=0.013) or advanced stage (OR=0.19, P=0.039) and were more common in women (OR=3.4, P=0.05) compared with those without oncocytic features. Tumors with rhabdoid morphology were associated with advanced stage (relative risk=3.6, P=0.009), while tumors with clear cell or papillary features had a wide range of grades and stages at presentation. In summary, the most frequent reclassified entity is eosinophilic solid and cystic RCC. Investigation of expression of succinate dehydrogenase or fumarate hydratase in individuals older than 35 years with unclassifiable tumors is low yield in the absence of specific morphologic features. A subset of MTSC without well-developed morphologic features can be reclassified by using RNA-ISH for VSTM2A. Recognition of more-recently described RCC subtypes allows for their distinction from the unclassified subtype and improves the prognostic information provided.
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TFEB rearranged renal cell carcinoma. A clinicopathologic and molecular study of 13 cases. Tumors harboring MALAT1-TFEB, ACTB-TFEB, and the novel NEAT1-TFEB translocations constantly express PDL1. Mod Pathol 2021; 34:842-850. [PMID: 33208882 DOI: 10.1038/s41379-020-00713-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/19/2020] [Accepted: 10/19/2020] [Indexed: 02/06/2023]
Abstract
Renal cell carcinomas with t(6;11) chromosome translocation has been classically characterized by the rearrangement of the TFEB gene, located on chromosome 6, and MALAT1 gene, located on chromosome 11. Recently, a few other genes have been described as fusion partners in TFEB rearranged renal cell carcinomas. Although most of TFEB rearranged renal cell carcinomas have an indolent behavior, in the rare cases of advanced metastatic disease targeted therapy and predictive markers remain lacking. In the present study, we collected 13 TFEB rearranged renal cell carcinomas, confirmed by FISH, analyzing their morphology and exploring the novel gene partners. Looking for predictive markers, we have also performed PDL1 immunohistochemical analysis by using four different assays (E1L3N, 22C3, SP142, and SP263). MALAT1 gene rearrangement has been found in ten tumors, five cases showing classical biphasic morphology with "rosettes", five cases without "rosettes" mimicking other renal cell carcinomas or epithelioid angiomyolipoma/pure epithelioid PEComa. We identified two different partner genes, ACTB and NEAT1, the latter previously unreported and occurring in a tumor with an unusual solid and cystic appearance. In both cases, the "rosettes" were absent. In one case no gene partner was identified. Overall, in 12 of 13 TFEB-rearranged renal cell carcinomas staining for PDL1 SP263 was observed, whereas the other antibodies were less reliable or more difficult to interpret. In conclusion, we described the third case of ACTB-TFEB rearranged renal cell carcinoma and a novel NEAT1-TFEB rearranged renal cell carcinoma, both without the distinctive biphasic morphology typical of t(6;11) renal cell carcinoma. Finally, PDL1 SP263 was constantly expressed in TFEB rearranged renal cell carcinoma with possible clinical benefit which requires further investigations.
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Iakymenko OA, Delma KS, Jorda M, Kryvenko ON. Cathepsin K (Clone EPR19992) Demonstrates Uniformly Positive Immunoreactivity in Renal Oncocytoma, Chromophobe Renal Cell Carcinoma, and Distal Tubules. Int J Surg Pathol 2021; 29:600-605. [PMID: 33764165 DOI: 10.1177/1066896921991588] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Introduction. Cathepsin K is overexpressed in several tumors associated with microphthalmia transcription factor (MiTF) family or mechanistic target of rapamycin (mTOR) upregulation. Among renal neoplasms, MiTF translocation renal cell carcinoma (RCC), perivascular epithelioid cell neoplasms (PEComa), and eosinophilic solid and cystic RCC have demonstrated Cathepsin K immunoreactivity. In this study, we demonstrate a uniform Cathepsin K expression in oncocytoma, chromophobe RCC (CHRCC), and distal tubules. Design. We stained 13 oncocytomas, 13 CHRCC, 14 clear cell RCC (CCRCC), 9 papillary RCC (PRCC), 9 PEComas, and 5 MiTF RCC. Additionally, we assessed immunoreactivity for Cathepsin K in non-neoplastic renal parenchyma. Immunolabeling was performed on regularly charged slides from formalin-fixed paraffin-embedded tissue with monoclonal anti-rabbit antibodies to human Cathepsin K (clone EPR19992, Abcam). Results. All oncocytomas demonstrated diffuse strong cytoplasmic immunolabeling. CHRCC demonstrated uniform less intense immunolabeling in all cases with membranous accentuation. The assessment of the non-neoplastic renal parenchyma in all cases showed strong cytoplasmic immunoreaction in distal tubules and proximal tubules stained faintly. Mesangial cells were not immunoreactive. All MiTF RCC and PEComas were immunoreactive for Cathepsin K, whereas CCRCC and PRCC were negative in all cases. Conclusions. In this study, we expand the spectrum of renal neoplasms reactive with a particular clone of Cathepsin K (EPR19992). Distal tubules are strongly immunoreactive for Cathepsin K. Our conclusions need to be taken into consideration when differential diagnosis includes MiTF RCC or PEComa and this Cathepsin K clone is included in the immunohistochemical panel. This newer antibody clone was not tested in prior publications, potentially explaining the difference in conclusions.
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Affiliation(s)
| | - Katiana S Delma
- 12235University of Miami Miller School of Medicine, Miami, FL, USA
| | - Merce Jorda
- 12235University of Miami Miller School of Medicine, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, 12235University of Miami Miller School of Medicine, Miami, FL, USA
| | - Oleksandr N Kryvenko
- 12235University of Miami Miller School of Medicine, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, 12235University of Miami Miller School of Medicine, Miami, FL, USA
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Morphologic and Immunohistochemical Characteristics of Fluorescent In Situ Hybridization Confirmed TFE3-Gene Fusion Associated Renal Cell Carcinoma: A Single Institutional Cohort. Am J Surg Pathol 2020; 44:1450-1458. [PMID: 32701515 DOI: 10.1097/pas.0000000000001541] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
TFE3-fusion associated renal cell carcinoma (TFE3-RCC) accounts for up to 5% adults and 40% of childhood RCC. Their comprehensive immunohistochemical (IHC) profile in correlation to fluorescence in situ hybridization (FISH) testing and their role in the diagnostic approach are not well documented because of lacking published data. FISH confirmed TFE3-RCC between years 2010 and 2020 were identified from institutional electronic database and retrospectively reviewed. Eighty-five TFE3-RCC were identified. Seventy-six of 85 (89.4%) TFE3-RCC cases had positive TFE3 expression, with diffuse and strong/moderate TFE3 expression in 45 (54.2%). Three (3.5%) TFE3-RCC had negative TFE3 expression whereas 6 (7%) cases had equivocal TFE3 expression. On the other hand, positive TFE3-IHC expression was observed in 17/29 (58.6%) TFE3-FISH negative RCC cases, although only 8 (27.5%) had diffuse and moderate/strong TFE3 expression. Diffuse and strong TFE3-IHC expression was statistically significant in predicting TFE3-FISH positivity (P<0.0001) regardless of morphologic features. After univariate and multivariate analyses, TFE3-IHC was the only parameter with significant predictive value for detecting positive TFE3-FISH (P<0.0001). On univariate analysis, sex, classic morphology, age, negative AE1/AE3 or cytokeratin 7 were not predictive of TFE3-FISH positivity. Diffuse and strong nuclear TFE3-IHC expression is significantly associated with TFE3-FISH positivity and can be used as a surrogate marker to confirm translocation associated cases. TFE3-rearranged RCCs show variable histomorphologic features and TFE3-FISH should be performed in cases presenting at a younger age or, regardless of the age, tumors with unusual morphology. Despite previous reports, negative pancytokeratin and positive cathepsin K expression may not be reliable markers for TFE3-RCC.
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Akgul M, Cheng L, Idrees M. A Simplified Diagnostic Approach on TFE3 Gene Fusion-Associated Renal Cell Carcinoma. Arch Pathol Lab Med 2020; 145:447008. [PMID: 33147320 DOI: 10.5858/arpa.2020-0360-ed] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/14/2020] [Indexed: 11/06/2022]
Affiliation(s)
- Mahmut Akgul
- From the Department of Pathology (Akgul, Cheng, Idrees), Indiana University, Indianapolis
| | - Liang Cheng
- From the Department of Pathology (Akgul, Cheng, Idrees), Indiana University, Indianapolis
- Department of Urology (Cheng), Indiana University, Indianapolis
| | - Muhammad Idrees
- From the Department of Pathology (Akgul, Cheng, Idrees), Indiana University, Indianapolis
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Abstract
Molecular characterization has led to advances in the understanding of pediatric renal tumors, including the association of pediatric cystic nephromas with DICER1 tumor syndrome, the metanephric family of tumors with somatic BRAF mutations, the characterization of ETV6-NTRK3-negative congenital mesoblastic nephromas, the expanded spectrum of gene fusions in translocation renal cell carcinoma, the relationship of clear cell sarcoma of the kidney with other BCOR-altered tumors, and the pathways affected by SMARCB1 alterations in rhabdoid tumors of the kidney. These advances have implications for diagnosis, classification, and treatment of pediatric renal tumors.
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Kuthi L, Somorácz Á, Micsik T, Jenei A, Hajdu A, Sejben I, Imre D, Pósfai B, Kóczián K, Semjén D, Bajory Z, Kulka J, Iványi B. Clinicopathological Findings on 28 Cases with XP11.2 Renal Cell Carcinoma. Pathol Oncol Res 2020; 26:2123-2133. [PMID: 31955345 PMCID: PMC7471254 DOI: 10.1007/s12253-019-00792-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 12/30/2019] [Indexed: 02/07/2023]
Abstract
Xp11.2 translocation carcinoma is a distinct subtype of renal cell carcinoma characterized by translocations involving the TFE3 gene. Our study included the morphological, immunohistochemical and clinicopathological examination of 28 Xp11.2 RCCs. The immunophenotype has been assessed by using CA9, CK7, CD10, AMACR, MelanA, HMB45, Cathepsin K and TFE3 immunostainings. The diagnosis was confirmed by TFE3 break-apart FISH in 25 cases. The ages of 13 male and 15 female patients, without underlying renal disease or having undergone chemotherapy ranged from 8 to 72. The mean size of the tumors was 78.5 mm. Forty-three percent of patients were diagnosed in the pT3/pT4 stage with distant metastasis in 6 cases. Histological appearance was branching-papillary composed of clear cells with voluminous cytoplasm in 13 and variable in 15 cases, including one tumor with anaplastic carcinoma and another with rhabdoid morphology. Three tumors were labeled with CA9, while CK7 was negative in all cases. Diffuse CD10 reaction was observed in 17 tumors and diffuse AMACR positivity was described in 14 tumors. The expression of melanocytic markers and Cathepsin K were seen only in 7 and 6 cases, respectively. TFE3 immunohistochemistry displayed a positive reaction in 26/28 samples. TFE3 rearrangement was detected in all the analyzed cases (25/25), including one with the loss of the entire labeled break-point region. The follow-up time ranged from 2 to 300 months, with 7 cancer-related deaths. In summary, Xp11.2 carcinoma is an uncommon form of renal cell carcinoma with a variable histomorphology and rather aggressive clinical course.
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Affiliation(s)
- Levente Kuthi
- Department of Pathology, University of Szeged, 1 Állomás Street, Szeged, H-6725, Hungary.
| | - Áron Somorácz
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Tamás Micsik
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Alex Jenei
- Department of Pathology, University of Szeged, 1 Állomás Street, Szeged, H-6725, Hungary
| | - Adrienn Hajdu
- Department of Pathology, University of Szeged, 1 Állomás Street, Szeged, H-6725, Hungary
| | - István Sejben
- Department of Pathology, Bács-Kiskun County Teaching Hospital, Kecskemét, Hungary
| | - Dániel Imre
- Department of Pathology, Hetényi Géza County Hospital, Szolnok, Hungary
| | - Boglárka Pósfai
- Department of Oncotherapy, University of Szeged, Szeged, Hungary
| | - Katalin Kóczián
- Surgical and Molecular Tumor Pathology Centre, National Institute of Oncology, Budapest, Hungary
| | - Dávid Semjén
- Department of Pathology, Clinical Center and Medical School, University of Pécs, Pécs, Hungary
| | - Zoltán Bajory
- Department of Urology, University of Szeged, Szeged, Hungary
| | - Janina Kulka
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Béla Iványi
- Department of Pathology, University of Szeged, 1 Állomás Street, Szeged, H-6725, Hungary
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Silveri M, Natali GL, Cobellis G, Roberti A, Rossi S, Gregori L, Torino G. Individualized robotic organ-sparing surgery in a paediatric case of renal perivascular epithelioid cell tumour. Int J Med Robot 2020; 16:1-4. [PMID: 32721101 DOI: 10.1002/rcs.2142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 05/19/2020] [Accepted: 06/24/2020] [Indexed: 01/06/2023]
Abstract
BACKGROUND Perivascular epithelioid cell tumours (PEComas) represent a rare group of mesenchymal tumours with an unpredictable outcome. They are usually observed in middle-aged women whilst they are very rare in children, with limited cases described. Due to the rare anatomical location in kidneys, a correct diagnosis and treatment is really challenging. METHODS We observed and treated a case of kidney's PEComa in a 14-year-old boy. RESULTS An individualized approach based on anatomical (3D CT-reconstructions) and histopathological (US-guided preliminary biopsy) features lead us to perform a successful robotic-sparing surgery enabling the preservation of two-thirds of the kidney involved. CONCLUSIONS A meticulous preoperative planning in selected patients can lead to a minimally invasive approach even in some paediatric kidney's neoplasms.
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Affiliation(s)
| | - Gian Luigi Natali
- Department of Imaging, Bambino Gesù Children's Hospital, Rome, Italy
| | - Giovanni Cobellis
- Pediatric Urology and Surgery Unit, G. Salesi Children's Hospital, Ancona, Italy
| | - Agnese Roberti
- Pediatric Urology Unit, Santobono-Pausilipon Children's Hospital, Naples, Italy
| | - Sabrina Rossi
- Department of Pathology, Bambino Gesù Children's Hospital, Rome, Italy
| | - Lorenzo Gregori
- Department of Imaging, Bambino Gesù Children's Hospital, Rome, Italy
| | - Giovanni Torino
- Pediatric Urology and Surgery Unit, G. Salesi Children's Hospital, Ancona, Italy
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Ross J, Li G, Yang XJ. Application and Pitfalls of Immunohistochemistry in Diagnosis of Challenging Genitourinary Cases. Arch Pathol Lab Med 2020; 144:290-304. [PMID: 32101059 DOI: 10.5858/arpa.2019-0550-ra] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Immunohistochemistry (IHC) has become increasingly important in the evaluation of pathologic conditions in the genitourinary (GU) organs. In addition to careful evaluation of hematoxylin-eosin sections and generation of a differential diagnosis, choosing the optimal panel of IHC markers becomes even more important when the biopsy material is very limited. The following summary of our experience supplemented with relevant literature review exemplifies how to use IHC to facilitate pathologic diagnosis in the GU system. OBJECTIVE.— To describe our experience with the most common immunohistochemical markers used in GU pathology. DATA SOURCES.— Institutional experience and literature search comprise our data sources. CONCLUSIONS.— Application of IHC provides enormous benefits to the interpretation of GU pathologic conditions, including benign and malignant lesions. However, both insufficient and excessive types of use of IHC, as well as incorrect interpretations in common and rare GU conditions, could present pitfalls in diagnosis.
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Affiliation(s)
- Jenny Ross
- From the Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Guangyuan Li
- From the Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Ximing J Yang
- From the Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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40
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Williamson SR, Gill AJ, Argani P, Chen YB, Egevad L, Kristiansen G, Grignon DJ, Hes O. Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers: III: Molecular Pathology of Kidney Cancer. Am J Surg Pathol 2020; 44:e47-e65. [PMID: 32251007 PMCID: PMC7289677 DOI: 10.1097/pas.0000000000001476] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Renal cell carcinoma (RCC) subtypes are increasingly being discerned via their molecular underpinnings. Frequently this can be correlated to histologic and immunohistochemical surrogates, such that only simple targeted molecular assays, or none at all, are needed for diagnostic confirmation. In clear cell RCC, VHL mutation and 3p loss are well known; however, other genes with emerging important roles include SETD2, BAP1, and PBRM1, among others. Papillary RCC type 2 is now known to include likely several different molecular entities, such as fumarate hydratase (FH) deficient RCC. In MIT family translocation RCC, an increasing number of gene fusions are now described. Some TFE3 fusion partners, such as NONO, GRIPAP1, RBMX, and RBM10 may show a deceptive fluorescence in situ hybridization result due to the proximity of the genes on the same chromosome. FH and succinate dehydrogenase deficient RCC have implications for patient counseling due to heritable syndromes and the aggressiveness of FH-deficient RCC. Immunohistochemistry is increasingly available and helpful for recognizing both. Emerging tumor types with strong evidence for distinct diagnostic entities include eosinophilic solid and cystic RCC and TFEB/VEGFA/6p21 amplified RCC. Other emerging entities that are less clearly understood include TCEB1 mutated RCC, RCC with ALK rearrangement, renal neoplasms with mutations of TSC2 or MTOR, and RCC with fibromuscular stroma. In metastatic RCC, the role of molecular studies is not entirely defined at present, although there may be an increasing role for genomic analysis related to specific therapy pathways, such as for tyrosine kinase or MTOR inhibitors.
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MESH Headings
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Renal Cell/diagnosis
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/metabolism
- Carcinoma, Renal Cell/pathology
- Humans
- Immunohistochemistry
- In Situ Hybridization, Fluorescence
- Kidney Neoplasms/diagnosis
- Kidney Neoplasms/genetics
- Kidney Neoplasms/metabolism
- Kidney Neoplasms/pathology
- Mutation
- Neoplasm Metastasis
- Neoplastic Syndromes, Hereditary/diagnosis
- Neoplastic Syndromes, Hereditary/genetics
- Neoplastic Syndromes, Hereditary/metabolism
- Neoplastic Syndromes, Hereditary/pathology
- Pathology, Clinical
- Pathology, Molecular
- Prognosis
- Societies, Medical
- Urology
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Affiliation(s)
- Sean R Williamson
- Department of Pathology and Laboratory Medicine and Henry Ford Cancer Institute, Henry Ford Health System
- Department of Pathology, Wayne State University School of Medicine, Detroit, MI
| | - Anthony J Gill
- NSW Health Pathology, Department of Anatomical Pathology
- Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards
- Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Pedram Argani
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ying-Bei Chen
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Lars Egevad
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | | | - David J Grignon
- Department of Pathology, Indiana University School of Medicine, Indianapolis, IN
| | - Ondrej Hes
- Department of Pathology, Charles University, Medical Faculty and Charles University Hospital Plzen, Pilsen, Czechia
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Comprehensive analysis of 34 MiT family translocation renal cell carcinomas and review of the literature: investigating prognostic markers and therapy targets. Pathology 2020; 52:297-309. [PMID: 32107074 DOI: 10.1016/j.pathol.2019.11.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 11/21/2019] [Accepted: 11/28/2019] [Indexed: 12/14/2022]
Abstract
Recently cabozantinib, a tyrosine kinase inhibitor with activity against VEGF, MET, AXL, and downregulating cathepsin K in vitro, has been proposed for the treatment of advanced clear and non-clear renal cell carcinomas. Since it is well known that cathepsin K is expressed in the majority of MiT family translocation renal cell carcinomas, we investigated cathepsin K, MET, AXL, and VEGF in a large series of those tumours, looking for possible predictive markers. We collected the clinicopathological features of 34 genetically confirmed MiT family translocation renal cell carcinomas [26 Xp11 and 8 t(6;11) renal cell carcinomas] and studied them using an immunohistochemical panel including PAX8, cathepsin K, HMB45, Melan-A, CD68 (PG-M1), CK7, CA9, MET, AXL and by FISH for VEGFA and MET. Cathepsin K was expressed in 14 of 26, HMB45 in 8 of 25, and Melan-A in 4 of 23 Xp11 renal cell carcinomas, whereas labelling for CK7 and CA9 was minimal. In t(6;11) renal cell carcinoma, cathepsin K and melanogenesis markers were constantly positive, whereas CK7 and CA9 were negative. None of the 34 carcinomas showed CD68 (PG-M1) and AXL expression. One aggressive Xp11 renal cell carcinoma showed increased VEGFA gene copy number (4-5 copies) with concurrent gains of TFE3 and TFEB. None of the 34 carcinomas showed MET gene amplification, whereas staining for MET was found in 7 of 8 t(6;11) and in 16 of 24 Xp11 renal cell carcinomas, and in the latter cases, when the expression was >50%, correlated with aggressiveness (p=0.0049). In Xp11 renal cell carcinomas, the aggressiveness was also correlated with larger tumour size (p=0.0008) and the presence of necrosis (p=0.027) but not nucleolar grading (p=1). Interestingly, in patients with tumours exhibiting two of three parameters (necrosis, larger tumour size and MET immunolabelling >50%) an aggressive clinical behaviour was observed in 88% of cases. In conclusion, cathepsin K, CD68 (PG-M1), CK7, CA9, and PAX8 is a useful panel for the diagnosis. Larger tumour size, the presence of necrosis and MET immunohistochemical expression correlate with aggressive behaviour in Xp11 renal cell carcinomas, especially in combination. VEGF, MET, cathepsin K but not AXL may be potential predictive markers for targeted therapy in MiT family translocation renal cell carcinomas.
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Kim M, Joo JW, Lee SJ, Cho YA, Park CK, Cho NH. Comprehensive Immunoprofiles of Renal Cell Carcinoma Subtypes. Cancers (Basel) 2020; 12:cancers12030602. [PMID: 32150988 PMCID: PMC7139472 DOI: 10.3390/cancers12030602] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 02/25/2020] [Accepted: 03/03/2020] [Indexed: 12/13/2022] Open
Abstract
In recent years, renal epithelial tumors have been among the fastest reclassifying tumors, requiring updates to the tumor classification system. Nonetheless, immunohistochemistry (IHC) remains the most widely used tool for renal epithelial tumors. In this proposal, we aimed to create the most efficient IHC panel for categorizing the diverse subtypes of renal tumors, and to find out more specific immunohistochemical results in each subtype or each antibody. A total of 214 renal tumors were analyzed using 10 possible IHC markers to differentiate subtypes, including three major renal cell carcinoma (RCC) subtypes, clear-cell type (50 cases), papillary type (50 cases), and chromophobe type (20 cases), and minor subtypes (MiT RCC, 13 cases; collecting duct carcinoma, 5 cases; and oncocytoma, 10 cases). A triple immunomarker (cytokeratin 7 (CK7)-carbonic anhydrase IX (CAIX)- alpha-methylacyl-CoA racemase (AMACR)) panel is useful in particular high-grade clear-cell tumors. If IHC remains ambiguous, the use of an adjunctive panel can be suggested, including CD10, epithelial membrane antigen, cathepsin K, c-kit, hepatocyte nuclear factor 1-β, and E-cadherin. For an efficient immunohistochemical strategy for subtyping of RCC, we conclude that the CK7-CAIX-AMACR panel is the best primary choice for screening subtyping.
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Affiliation(s)
- Moonsik Kim
- Deptartment of Pathology, Yonsei University College of Medicine, Seoul 03722, Korea; (M.K.); (J.W.J.); (S.J.L.)
| | - Jin Woo Joo
- Deptartment of Pathology, Yonsei University College of Medicine, Seoul 03722, Korea; (M.K.); (J.W.J.); (S.J.L.)
| | - Seok Joo Lee
- Deptartment of Pathology, Yonsei University College of Medicine, Seoul 03722, Korea; (M.K.); (J.W.J.); (S.J.L.)
| | - Yoon Ah Cho
- Deptartment of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea;
| | - Cheol Keun Park
- Deptartment of Pathology, Armed Forces Capital Hospital, Seongnam 13574, Korea;
| | - Nam Hoon Cho
- Deptartment of Pathology, Yonsei University College of Medicine, Seoul 03722, Korea; (M.K.); (J.W.J.); (S.J.L.)
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 03722, Korea
- Correspondence: ; Tel.: +82-2-2228-1767; Fax: +82-2-362-0860
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43
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Herrscher H, Boilève A, Lindner V, Barthélémy P, Hutt É, Pierard L, Kurtz JE, Rioux-Leclercq N, Lang H, Malouf GG. [MiT family translocation renal cell carcinomas: Natural history, molecular features and multidisciplinary management]. Bull Cancer 2020; 107:272-280. [PMID: 32044098 DOI: 10.1016/j.bulcan.2019.11.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 11/10/2019] [Accepted: 11/16/2019] [Indexed: 10/25/2022]
Abstract
MiT family translocation renal cell carcinomas (tRCC) represent a rare subtype of renal cell carcinomas. These tumors have been introduced for the first time in the World Health Classification (WHO) classification of kidney cancers in 2004. tRCC are characterized by reccurent translocations involving members of the MiT family transcription factors, mainly TFE3 and TFEB. The estimated incidence of these tumors is ∼1-5 % among all renal cell carcinomas, with female prodominance. tRCC were initially described in children, and the spectrum has been expanded over time to encompass adolescents and adults. TFE3- and TFEB-rearranged RCC harbor characteristic clinicopathological and immunohistochemical features and fluorescent hybridization in situ is considered the gold standard for their diagnosis, although it has some limitations especially when the partners are located in the vicinity of TFE3. Nephron-sparing surgery is an efficient treatment of localized cases when achievable. In metastatic setting, targeted agents and immunotherapy showed modest efficacy, with response rates and median overall survival inferior to those observed in clear-cell renal cell carcinomas. Management of tRCC necessite a multidisciplinary team and accrual in clinical trials have to be encouraged when possible. Novel biological insights are urgently awaited to better understand the mechanisms associated with kidney oncogenesis in this setting, and ultimately help to identify therapeutic targets.
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Affiliation(s)
- Hugo Herrscher
- Hôpitaux universitaires de Strasbourg, service d'oncologie médicale, 67200 Strasbourg, France
| | - Alice Boilève
- Institut Gustave-Roussy, département de médecine, 67200 Villejuif, France
| | - Véronique Lindner
- Hôpitaux universitaires de Strasbourg, département de pathologie, 67200 Strasbourg, France
| | - Philippe Barthélémy
- Hôpitaux universitaires de Strasbourg, service d'oncologie médicale, 67200 Strasbourg, France
| | - Émilie Hutt
- Hôpitaux universitaires de Strasbourg, service d'oncologie médicale, 67200 Strasbourg, France
| | - Laure Pierard
- Hôpitaux universitaires de Strasbourg, service d'oncologie médicale, 67200 Strasbourg, France
| | - Jean-Emmanuel Kurtz
- Hôpitaux universitaires de Strasbourg, service d'oncologie médicale, 67200 Strasbourg, France
| | - Nathalie Rioux-Leclercq
- Université de Rennes, service d'anatomie et cytologie pathologiques, Centre Hospitalier Universitaire de Rennes, IRSET, 67200 Rennes, France
| | - Hervé Lang
- Hôpitaux universitaires de Strasbourg, service d'urologie, 35033 Strasbourg, France
| | - Gabriel G Malouf
- Hôpitaux universitaires de Strasbourg, service d'oncologie médicale, 67200 Strasbourg, France.
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Argani P, Zhang L, Sung YS, White MJ, Miller K, Hopkins M, Small D, Pratilas CA, Swanson D, Dickson B, Antonescu CR. A novel RBMX-TFE3 gene fusion in a highly aggressive pediatric renal perivascular epithelioid cell tumor. Genes Chromosomes Cancer 2020; 59:58-63. [PMID: 31408245 PMCID: PMC7057291 DOI: 10.1002/gcc.22801] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 08/09/2019] [Accepted: 08/10/2019] [Indexed: 01/24/2023] Open
Abstract
We report an Xp11 translocation perivascular epithelioid cell tumor (PEComa) with a novel RBMX-TFE3 gene fusion, resulting from a paracentric X chromosome inversion, inv(X)(p11;q26). The neoplasm occurred in an otherwise healthy 12-year-old boy who presented with a large left renal mass with extension into the inferior vena cava. The patient was found to have multiple pulmonary metastases at diagnosis and died of disease 3 months later. The morphology (epithelioid clear cells with alveolar and nested architecture) and immunophenotype (TFE3 and HMB45 strongly positive; actin, desmin, and PAX8 negative) was typical of an Xp11 translocation PEComa; however, TFE3 rearrangement was initially not detected by routine TFE3 break-apart fluorescence in situ hybridization (FISH). Further RNA sequencing revealed a novel RBMX-TFE3 gene fusion, which was subsequently confirmed by fusion assay FISH, using custom design RBMX and TFE3 come-together probes. This report describes a novel TFE3 gene fusion partner, RBMX, in a pediatric renal PEComa patient associated with a fulminant clinical course. As documented in other intrachromosomal Xp11.2 inversions, such as fusions with NONO, RBM10, or GRIPAP1 genes, the TFE3 break-apart might be below the FISH resolution, resulting in a false negative result.
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Affiliation(s)
- Pedram Argani
- Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA,Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Lei Zhang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Yun-Shao Sung
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Marissa J. White
- Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Karin Miller
- Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Mark Hopkins
- Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Donald Small
- Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | | | - David Swanson
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Brendan Dickson
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
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Deng FM, Zhai QJ. Application of Immunohistochemistry in Diagnosis of Renal Cell Neoplasms. KIDNEY CANCER 2020. [DOI: 10.1007/978-3-030-28333-9_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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46
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Ye H, Qin S, Li N, Lin M, Xu Y, Li X. A Rare Partner of TFE3 in the Xp11 Translocation Renal Cell Carcinoma: Clinicopathological Analyses and Detection of MED15-TFE3 Fusion. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5974089. [PMID: 31828108 PMCID: PMC6881588 DOI: 10.1155/2019/5974089] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 09/29/2019] [Accepted: 10/16/2019] [Indexed: 01/09/2023]
Abstract
Xp11 translocation renal cell carcinoma (RCC), a member of the microphthalmia-associated transcription factor (MiTF) family, is a rare renal tumor characterized by different translocations involving the TFE3 gene. Here, we reported a case of Xp11 translocation RCC with a rare MED15-TFE3 gene fusion by RNA sequencing. Morphologically, the tumor cells were arranged in a solid and small nest pattern. The cytoplasm was voluminous, flocculent eosinophilic, and vacuolated. The nuclei were round or polygon with fine granular chromatin, and the nucleoli were unconspicuous. Psammoma bodies were observed in mesenchyma. Immunohistochemically, the tumor cells were diffuse moderately or strongly positive for CD10, P504S, vimentin, PAX8, RCC, AE1/AE3, and SDHB and focally positive for CK7 and CA IX while negative for cathepsin K, HMB45, Melan-A, Ksp-cadherin, and CD117. The Ki67 proliferation index was approximately 3%. However, TFE3 labeling showed an uncertainly weak nuclear staining and been considered negative. Fluorescence in situ hybridization (FISH) demonstrated a positive result that splits signals with a distance of > 2 signal diameters. Subsequently, RNA sequencing confirmed a fusion of MED15 gene exon 11 on chromosome 22 with TFE3 gene exon 6 in the tumor. The patient was alive with no evidence of recurrence. Our report contributes to the understanding on MED15-TFE3 RCC.
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MESH Headings
- Adult
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics
- Biomarkers, Tumor/genetics
- Carcinoma, Renal Cell/diagnostic imaging
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/pathology
- Chromosomes, Human, X/genetics
- Female
- Humans
- In Situ Hybridization, Fluorescence
- Male
- Mediator Complex/genetics
- Middle Aged
- Neoplasm Proteins/genetics
- Neoplasm Recurrence, Local/diagnostic imaging
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/pathology
- Oncogene Proteins, Fusion/genetics
- Sequence Analysis, RNA
- Tomography, X-Ray Computed
- Translocation, Genetic/genetics
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Affiliation(s)
- Hong Ye
- Department of Pathology, Tai'an Central Hospital, Tai'an 271000, China
| | - Shuming Qin
- Department of Pathology, Tai'an Central Hospital, Tai'an 271000, China
| | - Ning Li
- Department of Pathology, Tai'an Central Hospital, Tai'an 271000, China
| | - Min Lin
- Department of Pathology, Tai'an Central Hospital, Tai'an 271000, China
| | - Yanmei Xu
- Department of Pathology, Shanxian Central Hospital, Heze 274300, China
| | - Xiaomei Li
- Department of Pathology, Tai'an Central Hospital, Tai'an 271000, China
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Gandhi JS, Malik F, Amin MB, Argani P, Bahrami A. MiT family translocation renal cell carcinomas: A 15th anniversary update. Histol Histopathol 2019; 35:125-136. [PMID: 31489603 DOI: 10.14670/hh-18-159] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Microphthalmia (MiT) family translocation renal cell carcinomas (RCCs) are a heterogeneous category of renal tumors which all express MiT transcription factors, typically from chromosomal translocation and rarely from gene amplification. This tumor family has two major subtypes [i.e., Xp11 translocation RCC and t(6;11) RCC] and several related neoplasms (i.e., TFEB amplification RCC and melanotic Xp11 translocation renal cancers). Increased understanding of the clinical, pathological, molecular and prognostic heterogeneity of these tumors, since their official recognition in 2004, provides the opportunity to identify prognostic biomarkers and to understand the reasons for tumor aggression. We will review the literature from the past 15 years and highlight the need for a greater understanding of the molecular mechanisms underpinning heterogeneous tumor behavior.
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Affiliation(s)
- Jatin S Gandhi
- Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Faizan Malik
- Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Mahul B Amin
- Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Pedram Argani
- Department of Pathology, John Hopkins University, Baltimore, MD, USA
| | - Armita Bahrami
- Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, USA.,Departments of Pathology and Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
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Abstract
Uterine perivascular epithelioid cell tumors (PEComas) are rare neoplasms that may show overlapping morphology and immunohistochemistry with uterine smooth muscle tumors. In this study, we evaluated the morphologic, immunohistochemical, and molecular features of 32 PEComas, including 11 with aggressive behavior. Two distinct morphologies were observed: classic (n=30) and those with a lymphangioleiomyomatosis appearance (n=2). In the former, patients ranged from 32 to 77 (mean: 51) years and 13% had tuberous sclerosis. Tumors ranged from 0.2 to 17 (mean: 5.5) cm with 77% arising in the corpus. Epithelioid cells were present in 100% and a spindled component was seen in 37%. Nuclear atypia was low (53%), intermediate (17%), or high (30%). Mitoses ranged from 0 to 36 (mean: 6) and 0 to 133 (mean: 19) per 10 and 50 high-power fields, with atypical mitoses present in 30%. Thin and delicate vessels were noted in 100%, clear/eosinophilic and granular cytoplasm in 93%, stromal hyalinization in 73%, necrosis in 30%, and lymphovascular invasion in 10%. All tumors were positive for HMB-45, cathepsin K, and at least one muscle marker, with most expressing melan-A (77%) and/or MiTF (79%). A PSF-TFE3 fusion was identified in one while another showed a RAD51B-OPHN1 fusion. Follow-up ranged from 2 to 175 (mean: 41) months, with 63% of patients alive and well, 20% dead of disease, 13% alive with disease, and 3% dead from other causes. In the latter group (n=2), patients were 39 and 49 years old, one had tuberous sclerosis, while the other had pulmonary lymphangioleiomyomatosis. Both tumors expressed HMB-45, cathepsin K, and muscle markers, but lacked TFE3 and RAD51B rearrangements. The 2 patients are currently alive and well. Application of gynecologic-specific criteria (≥4 features required for malignancy: size ≥5 cm, high-grade atypia, mitoses >1/50 high-power fields, necrosis, and lymphovascular invasion) for predicting outcome misclassified 36% (4/11) of aggressive tumors; thus, a modified algorithm with a threshold of 3 of these features is recommended to classify a PEComa as malignant.
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Caliò A, Segala D, Munari E, Brunelli M, Martignoni G. MiT Family Translocation Renal Cell Carcinoma: from the Early Descriptions to the Current Knowledge. Cancers (Basel) 2019; 11:E1110. [PMID: 31382581 PMCID: PMC6721505 DOI: 10.3390/cancers11081110] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 07/29/2019] [Accepted: 07/30/2019] [Indexed: 12/27/2022] Open
Abstract
The new category of MiT family translocation renal cell carcinoma has been included into the World Health Organization (WHO) classification in 2016. The MiT family translocation renal cell carcinoma comprises Xp11 translocation renal cell carcinoma harboring TFE3 gene fusions and t(6;11) renal cell carcinoma harboring TFEB gene fusion. At the beginning, they were recognized in childhood; nevertheless, it has been demonstrated that these neoplasms can occur in adults as well. In the nineties, among Xp11 renal cell carcinoma, ASPL, PRCC, and SFPQ (PSF) were the first genes recognized as partners in TFE3 rearrangement. Recently, many other genes have been identified, and a wide spectrum of morphologies has been described. For this reason, the diagnosis may be challenging based on the histology, and the differential diagnosis includes the most common renal cell neoplasms and pure epithelioid PEComa/epithelioid angiomyolipoma of the kidney. During the last decades, many efforts have been made to identify immunohistochemical markers to reach the right diagnosis. To date, staining for PAX8, cathepsin K, and melanogenesis markers are the most useful identifiers. However, the diagnosis requires the demonstration of the chromosomal rearrangement, and fluorescent in situ hybridization (FISH) is considered the gold standard. The outcome of Xp11 translocation renal cell carcinoma is highly variable, with some patients surviving decades with indolent disease and others dying rapidly of progressive disease. Despite most instances of t(6;11) renal cell carcinoma having an indolent clinical course, a few published cases demonstrate aggressive behavior. Recently, renal cell carcinomas with TFEB amplification have been described in connection with t(6;11) renal cell carcinoma. Those tumors appear to be associated with a more aggressive clinical course. For the aggressive cases of MiT family translocation carcinoma, the optimal therapy remains to be determined; however, new target therapies seem to be promising, and the search for predictive markers is mandatory.
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Affiliation(s)
- Anna Caliò
- Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Verona 37134, Italy
| | - Diego Segala
- Department of Pathology, Pederzoli Hospital, Peschiera del Garda 37019, Italy
| | - Enrico Munari
- Department of Pathology, Sacro Cuore Hospital, Negrar 37024, Italy
| | - Matteo Brunelli
- Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Verona 37134, Italy
| | - Guido Martignoni
- Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Verona 37134, Italy.
- Department of Pathology, Pederzoli Hospital, Peschiera del Garda 37019, Italy.
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Magers MJ, Cheng L. Practical Molecular Testing in a Clinical Genitourinary Service. Arch Pathol Lab Med 2019; 144:277-289. [PMID: 31373513 DOI: 10.5858/arpa.2019-0134-ra] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Molecular testing is increasingly playing a key role in the diagnosis, prognosis, and treatment of neoplasms of the genitourinary system. OBJECTIVE.— To provide a general overview of the clinically relevant molecular tests available for neoplasms of the genitourinary tract. DATA SOURCES.— Relevant medical literature indexed on PubMed. CONCLUSIONS.— Understanding of the molecular oncology of genitourinary neoplasms is rapidly advancing, and the pathologist must be aware of the practical implications of molecular testing. While many genomic abnormalities are not yet clinically relevant, there is an increasing library of ancillary tests that may guide diagnosis, prognosis, and/or treatment of many neoplasms. Recurrent genomic abnormalities have been identified in many types of renal cell carcinoma, and some types of renal cell carcinoma are specifically defined by the molecular abnormality. Two major routes of developing urothelial carcinoma have been molecularly described. Recurrent translocations involving ETS family genes are found in approximately half of prostate cancer cases. Testicular germ cell tumors typically harbor i(12p). Penile neoplasms are often high-risk human papillomavirus-driven cancers. Nonetheless, even as genitourinary neoplasms are increasingly better understood at the molecular level, further research with eventual clinical validation is needed for optimal diagnosis, prognosis, and treatment of aggressive malignancies in the genitourinary tract.
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Affiliation(s)
- Martin J Magers
- From the Departments of Pathology and Laboratory Medicine (Drs Magers and Cheng) and Urology (Dr Cheng), Indiana University School of Medicine, Indianapolis, Indiana
| | - Liang Cheng
- From the Departments of Pathology and Laboratory Medicine (Drs Magers and Cheng) and Urology (Dr Cheng), Indiana University School of Medicine, Indianapolis, Indiana
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