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Barzilai A, Amitay-Laish I, Didkovsky E, Feinmesser M, Dalal A, Schiby G, Hodak E. New Insights into Macular Type of Primary Cutaneous B-Cell Lymphoma: Extension of the Clinical and Histopathological Patterns. Dermatology 2022; 238:1018-1025. [PMID: 35817021 DOI: 10.1159/000525439] [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: 12/05/2021] [Accepted: 04/24/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Primary cutaneous B-cell lymphoma (PCBCL) classically presents with papules, plaques, and nodules/tumors. Previous reports of PCBCL manifesting with macular lesions are scarce and focused on primary cutaneous follicle-center cell lymphoma (PCFCL). OBJECTIVES The objective of this study was to report our experience with PCBCL presenting with erythematous macules. METHODS Patients with low-grade PCBCL manifesting with erythematous patches, diagnosed and managed between January 2000 through December 2019 at 2 tertiary cutaneous-lymphoma outpatient clinics, were included. Clinical data were retrospectively collected, and biopsy specimens of the macules, and if present of the typical nodular/tumoral lesions, were reviewed. RESULTS There were 14 patients, aged 16-67 years, 8 had PCFCL and 6 marginal zone lymphoma (PCMZL). All had 1-15 cm erythematous macules, mimicking: interstitial granuloma annulare/vascular tumors/early-stage folliculotropic mycosis fungoides, or presenting with figurate erythema or livedo reticularis-like/net-like pattern. In 3 patients, macules were the presenting lesions, in 2 as the sole manifestation, whereas in 12 patients, typical PCBCL lesions were observed during disease course. The macules showed in all, superficial and deep perivascular infiltrates, and in most, periadnexal infiltrates. Micronodules were observed in 11 specimens, with nodular infiltrates also observed in 4. B cells comprised the majority of the lymphocytes in only 4. Seven of 11 cases tested showed immunoglobulin heavy chain monoclonality. CONCLUSIONS PCMZL and PCFCL may manifest with erythematous macules. Physicians should be aware of this unusual manifestation of low-grade PCBCL, which may represent a clinicopathological diagnostic pitfall.
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Affiliation(s)
- Aviv Barzilai
- Department of Dermatology, Sheba Medical Center, Tel Hashomer, Israel.,Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Iris Amitay-Laish
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, .,Division of Dermatology, Rabin Medical Center - Beilinson Hospital, Petah Tikva, Israel,
| | - Elena Didkovsky
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Institute of Pathology, Rabin Medical Center - Beilinson Hospital, Petah Tikva, Israel
| | - Meora Feinmesser
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Institute of Pathology, Rabin Medical Center - Beilinson Hospital, Petah Tikva, Israel
| | - Adam Dalal
- Department of Dermatology, Sheba Medical Center, Tel Hashomer, Israel
| | - Ginette Schiby
- Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Emmilia Hodak
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Division of Dermatology, Rabin Medical Center - Beilinson Hospital, Petah Tikva, Israel
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2
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Gaňová M, Zhang H, Zhu H, Korabečná M, Neužil P. Multiplexed digital polymerase chain reaction as a powerful diagnostic tool. Biosens Bioelectron 2021; 181:113155. [PMID: 33740540 DOI: 10.1016/j.bios.2021.113155] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 02/13/2021] [Accepted: 03/06/2021] [Indexed: 01/30/2023]
Abstract
The digital polymerase chain reaction (dPCR) multiplexing method can simultaneously detect and quantify closely related deoxyribonucleic acid sequences in complex mixtures. The dPCR concept is continuously improved by the development of microfluidics and micro- and nanofabrication, and different complex techniques are introduced. In this review, we introduce dPCR techniques based on sample compartmentalization, droplet- and chip-based systems, and their combinations. We then discuss dPCR multiplexing methods in both laboratory research settings and advanced or routine clinical applications. We focus on their strengths and weaknesses with regard to the character of biological samples and to the required precision of such analysis, as well as showing recently published work based on those methods. Finally, we envisage possible future achievements in this field.
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Affiliation(s)
- Martina Gaňová
- Central European Institute of Technology, Brno University of Technology, 612 00, Brno, Czech Republic
| | - Haoqing Zhang
- School of Mechanical Engineering, Northwestern Polytechnical University, Xi'an, 710072, PR China
| | - Hanliang Zhu
- School of Mechanical Engineering, Northwestern Polytechnical University, Xi'an, 710072, PR China
| | - Marie Korabečná
- 1st Faculty of Medicine, Institute of Biology and Medical Genetics, Charles University and General University Hospital, 12800, Prague, Czech Republic
| | - Pavel Neužil
- Central European Institute of Technology, Brno University of Technology, 612 00, Brno, Czech Republic; School of Mechanical Engineering, Northwestern Polytechnical University, Xi'an, 710072, PR China; The Faculty of Electrical Engineering and Communication, Brno University of Technology, 616 00, Brno, Czech Republic.
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3
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Durgin JS, Weiner DM, Wysocka M, Rook AH. The immunopathogenesis and immunotherapy of cutaneous T cell lymphoma: Pathways and targets for immune restoration and tumor eradication. J Am Acad Dermatol 2021; 84:587-595. [PMID: 33352267 PMCID: PMC7897252 DOI: 10.1016/j.jaad.2020.12.027] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 12/07/2020] [Accepted: 12/09/2020] [Indexed: 11/27/2022]
Abstract
Cutaneous T cell lymphomas (CTCLs) are malignancies of skin-trafficking T cells. Patients with advanced CTCL manifest immune dysfunction that predisposes to infection and suppresses the antitumor immune response. Therapies that stimulate immunity have produced superior progression-free survival compared with conventional chemotherapy, reinforcing the importance of addressing the immune deficient state in the care of patients with CTCL. Recent research has better defined the pathogenesis of these immune deficits, explaining the mechanisms of disease progression and revealing potential therapeutic targets. The features of the malignant cell in mycosis fungoides and Sézary syndrome are now significantly better understood, including the T helper 2 cell phenotype, regulatory T cell cytokine production, immune checkpoint molecule expression, chemokine receptors, and interactions with the microenvironment. The updated model of CTCL immunopathogenesis provides understanding into clinical progression and therapeutic response.
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Affiliation(s)
- Joseph S Durgin
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - David M Weiner
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Maria Wysocka
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Alain H Rook
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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4
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Mendoza H, Tormey CA, Rinder HM, Howe JG, Siddon AJ. The utility and limitations of B- and T-cell gene rearrangement studies in evaluating lymphoproliferative disorders. Pathology 2020; 53:157-165. [PMID: 33358756 DOI: 10.1016/j.pathol.2020.09.024] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 08/05/2020] [Accepted: 09/10/2020] [Indexed: 12/16/2022]
Abstract
A hallmark of lymphoid malignancies is the presence of a monoclonal lymphocyte population. Monoclonality of B- and T-cell populations can be established through immunoglobulin (IG) or T-cell receptor (TCR) gene rearrangement analysis, respectively. The biological rationale of IG and TCR gene rearrangement analysis is that due to the extensive combinatorial repertoire made possible by V(D)J recombination in lymphocytes, it is unlikely that any substantive lymphocyte population would share the same IG or TCR gene rearrangement pattern unless there is an underlying neoplastic or reactive origin. Modern IG and TCR gene rearrangement analysis is typically performed by polymerase chain reaction (PCR) using commercially available primer sets followed by gel capillary electrophoresis. This process is highly sensitive in the detection of nearly all lymphoid malignancies. Several pitfalls and limitations, both biological and technical, apply to IG/TCR gene rearrangement analysis, but these can be minimised with high quality controls, performance of assays in duplicate, and adherence to strict criteria for interpreting and reporting results. Next generation sequencing (NGS) will likely replace PCR based methods of IG/TCR gene rearrangement analysis but is not yet widespread due to the absence of standardised protocols and multicentre validation.
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Affiliation(s)
- Hadrian Mendoza
- Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA
| | | | - Henry M Rinder
- Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA; Hematology Section, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - John G Howe
- Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Alexa J Siddon
- Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA; Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
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5
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Zhang H, Gaňová M, Yan Z, Chang H, Neužil P. PCR Multiplexing Based on a Single Fluorescent Channel Using Dynamic Melting Curve Analysis. ACS OMEGA 2020; 5:30267-30273. [PMID: 33251461 PMCID: PMC7689941 DOI: 10.1021/acsomega.0c04766] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 10/29/2020] [Indexed: 06/12/2023]
Abstract
Since its invention in 1986, the polymerase chain reaction (PCR), has become a well-established method for the detection and amplification of deoxyribonucleic acid (DNA) with a specific sequence. Incorporating fluorescent probes, known as TaqMan probes, or DNA intercalating dyes, such as SYBR Green, into the PCR mixture allows real-time monitoring of the reaction progress and extraction of quantitative information. Previously reported real-time PCR product detection using intercalating dyes required melting curve analysis (MCA) to be performed following thermal cycling. Here, we propose a technique to perform dynamic MCA during each thermal cycle, based on a continuous fluorescence monitoring method, providing qualitative and quantitative sample information. We applied the proposed method in multiplexing detection of hepatitis B virus DNA and complementary DNA of human immunodeficiency virus as well as glyceraldehyde 3-phosphate dehydrogenase in different concentration ratios. We extracted the DNA melting curve and its derivative from each PCR cycle during the transition from the elongation to the denaturation temperature with a set heating rate of 0.8 K·s-1and then used the data to construct individual PCR amplification curves for each gene to determine the initial concentration of DNA in the sample. Our proposed method allows researchers to look inside the PCR in each thermal cycle, determining the PCR product specificity in real time instead of waiting until the end of the PCR. Additionally, the slow transition rate from elongation to denaturation provides a dynamic multiplexing assay, allowing the detection of at least three genes in real time.
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Affiliation(s)
- Haoqing Zhang
- Ministry
of Education Key Laboratory of Micro/Nano Systems for Aerospace, Department
of Microsystem Engineering, School of Mechanical Engineering, Northwestern Polytechnical University, 127 West Youyi Road, Xi’an, Shaanxi 710072, P. R. China
| | - Martina Gaňová
- Ministry
of Education Key Laboratory of Micro/Nano Systems for Aerospace, Department
of Microsystem Engineering, School of Mechanical Engineering, Northwestern Polytechnical University, 127 West Youyi Road, Xi’an, Shaanxi 710072, P. R. China
- Central
European Institute of Technology, Brno University
of Technology, Purkyňova 123, 612 00 Brno, Czech Republic
| | - ZhiQiang Yan
- Ministry
of Education Key Laboratory of Micro/Nano Systems for Aerospace, Department
of Microsystem Engineering, School of Mechanical Engineering, Northwestern Polytechnical University, 127 West Youyi Road, Xi’an, Shaanxi 710072, P. R. China
| | - Honglong Chang
- Ministry
of Education Key Laboratory of Micro/Nano Systems for Aerospace, Department
of Microsystem Engineering, School of Mechanical Engineering, Northwestern Polytechnical University, 127 West Youyi Road, Xi’an, Shaanxi 710072, P. R. China
| | - Pavel Neužil
- Ministry
of Education Key Laboratory of Micro/Nano Systems for Aerospace, Department
of Microsystem Engineering, School of Mechanical Engineering, Northwestern Polytechnical University, 127 West Youyi Road, Xi’an, Shaanxi 710072, P. R. China
- Central
European Institute of Technology, Brno University
of Technology, Purkyňova 123, 612 00 Brno, Czech Republic
- Department
of Microelectronics, Faculty of Electrical Engineering and Communication, Brno University of Technology, Technická 3058/10, 616 00 Brno, Czech Republic
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6
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Bolcato V, Barruscotti S, DE Silvestri A, Tomasini CF, Brazzelli V. Sézary Syndrome: a clinico-pathological study of 9 cases. Ital J Dermatol Venerol 2020; 156:73-83. [PMID: 33084262 DOI: 10.23736/s2784-8671.19.06403-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Sézary Syndrome (SS) is a rare and aggressive variant of cutaneous T-cell lymphoma characterized by erythroderma, generalized lymphadenopathy and atypical lymphocytes in peripheral blood. The aim of the study is to describe our experience with SS patients. METHODS Nine SS patients were retrospectively identified within 288 patients with cutaneous T-cell lymphomas (CTCLs) followed from 1977 to 2017 in the Unit of Dermatology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy. RESULTS Nine SS patients were described: 5 males and 4 females, mean age at diagnosis 66.1 years (49-87 y), overall survival (OS) after SS diagnosis was 2.6 years (31.5 ms). All the patients showed erythroderma, pruritus and lymphadenopathy. Palmo-plantar hyperkeratosis, nail lesions, alopecia and ectropion were also present. One patient was excluded for significative differences in management. Three lines treatment -extracorporeal photopheresis plus immunomodulator/s plus photo-photochemotherapy- was the most used first-line option for induction of remission, reached in 4 patients out of 8: 3 with Complete Remission (CR), 1 with Partial Remission (PR). Prognostic variables were investigated by univariate analysis: hypereosinophilia, highly elevated β<inf>2</inf>µglobulin >3500 µg/L, male sex and highly elevated LDH>450 U/L resulted with statistical power. CONCLUSIONS The improved comprehension of SS pathogenesis is progressively increasing the still poor survival: 38.5 months (3.2 years) considering only the 6 patients followed in the last five years, versus overall 31.5 months (2.6 years). The correct identification of SS patients remains determinant for the proper overall management. Among unfavorable prognostic markers, levels of β<inf>2</inf>µglobulin allow stratification of patients.
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Affiliation(s)
- Vittorio Bolcato
- Unit of Dermatology, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
| | - Stefania Barruscotti
- Unit of Dermatology, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
| | - Annalisa DE Silvestri
- Biometry and Statistics, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
| | - Carlo F Tomasini
- Unit of Dermatology, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
| | - Valeria Brazzelli
- Unit of Dermatology, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy -
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Fujii K, Kanekura T. Next-Generation Sequencing Technologies for Early-Stage Cutaneous T-Cell Lymphoma. Front Med (Lausanne) 2019; 6:181. [PMID: 31457014 PMCID: PMC6700355 DOI: 10.3389/fmed.2019.00181] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 07/29/2019] [Indexed: 01/09/2023] Open
Abstract
The diagnosis of early stage cutaneous T-cell lymphoma is often difficult, particularly in mycosis fungoides (MF), because the clinical presentation, histological findings, and laboratory findings of MF resemble those of inflammatory skin diseases such as atopic dermatitis, psoriasis, and parapsoriasis en plaque. Furthermore, MF sometimes occurs with or after these inflammatory skin diseases. The current diagnostic criteria heavily rely on clinical impressions along with assessments of T cell clonality. To make a diagnosis of early-stage MF, the detection of a malignant clone is critical. T cell receptor (TCR) gene rearrangements have been detected by southern blotting or polymerase chain reaction for this purpose, but the results of these methods are insufficient. High-throughput TCR sequencing has provided insights into the complexities of the immune repertoire. Accordingly, his technique is more sensitive and specific than current methods, making it useful for the detection of early lesions and monitoring responses to therapy.
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Affiliation(s)
- Kazuyasu Fujii
- Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Takuro Kanekura
- Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
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Tetzlaff MT, Tang S, Duke T, Grabell DA, Cabanillas ME, Zuo Z, Yao JC, Nagarajan P, Aung PP, Torres‐Cabala CA, Duvic M, Prieto VG, Huen A, Curry JL. Lichenoid dermatitis from immune checkpoint inhibitor therapy: An immune‐related adverse event with mycosis‐fungoides‐like morphologic and molecular features. J Cutan Pathol 2019; 46:872-877. [DOI: 10.1111/cup.13536] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 06/21/2019] [Accepted: 06/24/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Michael T. Tetzlaff
- Department of Pathology, Section of DermatopathologyThe University of Texas MD Anderson Cancer Center Houston Texas
- Department of Translational Molecular PathologyThe University of Texas MD Anderson Cancer Center Houston Texas
| | - Sherry Tang
- Department of Pathology, Section of DermatopathologyThe University of Texas MD Anderson Cancer Center Houston Texas
| | - Taylor Duke
- Department of DermatologyThe University of Texas Health Science Houston Texas
| | - Daniel A. Grabell
- Department of DermatologyThe University of Texas Health Science Houston Texas
| | - Maria E. Cabanillas
- Department of Endocrine Neoplasia and Hormonal DisordersThe University of Texas MD Anderson Cancer Center Houston Texas
| | - Zhuang Zuo
- Department of HematopathologyThe University of Texas MD Anderson Cancer Center Houston Texas
| | - James C. Yao
- Department of GI Medical OncologyThe University of Texas MD Anderson Cancer Center Houston Texas
| | - Priyadharsini Nagarajan
- Department of Pathology, Section of DermatopathologyThe University of Texas MD Anderson Cancer Center Houston Texas
| | - Phyu P. Aung
- Department of Pathology, Section of DermatopathologyThe University of Texas MD Anderson Cancer Center Houston Texas
| | - Carlos A. Torres‐Cabala
- Department of Pathology, Section of DermatopathologyThe University of Texas MD Anderson Cancer Center Houston Texas
- Department of DermatologyThe University of Texas MD Anderson Cancer Center Houston Texas
| | - Madeleine Duvic
- Department of DermatologyThe University of Texas MD Anderson Cancer Center Houston Texas
- Department of DermatologyThe University of Texas Health Science Houston Texas
| | - Victor G. Prieto
- Department of Pathology, Section of DermatopathologyThe University of Texas MD Anderson Cancer Center Houston Texas
- Department of DermatologyThe University of Texas MD Anderson Cancer Center Houston Texas
| | - Auris Huen
- Department of DermatologyThe University of Texas MD Anderson Cancer Center Houston Texas
- Department of DermatologyThe University of Texas Health Science Houston Texas
| | - Jonathan L. Curry
- Department of Pathology, Section of DermatopathologyThe University of Texas MD Anderson Cancer Center Houston Texas
- Department of Translational Molecular PathologyThe University of Texas MD Anderson Cancer Center Houston Texas
- Department of DermatologyThe University of Texas MD Anderson Cancer Center Houston Texas
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Kutane Lymphome. MEDIKAMENTÖSE TUMORTHERAPIE IN DER DERMATO-ONKOLOGIE 2019. [PMCID: PMC7121154 DOI: 10.1007/978-3-662-58012-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Kutane Lymphome (cutaneous lymphomas: CL) umfassen die Gruppe der kutanen T-Zell-Lymphome (cutaneous T-cell lymphomas: CTCL), kutanen B-Zell-Lymphome (cutaneous B-cell lymphomas: CBCL) und die sog. hämatodermischen Neoplasien (HN). CL gehören zur Gruppe der Non-Hodgkin-Lymphome (NHL) und stellen in der Subgruppe der extranodalen NHL die zweithäufigste Gruppe hinter den gastrointestinalen Lymphomen dar (Jaffe et al. 2009). Man unterscheidet zwischen primären und sekundären CL. Primäre CL haben ihren Ursprung in der Haut und bleiben in der Regel darauf auch längere Zeit beschränkt, während sekundäre CL kutane Manifestationen von primär nodalen oder extranodalen Lymphomen darstellen (Willemze 2005). Die primären CL unterscheiden sich hinsichtlich klinischem Verlauf, Therapieoptionen und Prognose erheblich von nodalen und extrakutanen Lymphomen. So zeigen z. B. die primär kutanen CD30+-T-Zell-Lymphome einen gutartigen Verlauf, wogegen die nodalen Varianten als aggressiv eingestuft werden. Da die CL zumeist weniger aggressiv sind, werden sie auch weniger aggressiv behandelt.
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Yuki A, Shinkuma S, Hayashi R, Fujikawa H, Kato T, Homma E, Hamade Y, Onodera O, Matsuoka M, Shimizu H, Iwata H, Abe R. CADM1 is a diagnostic marker in early-stage mycosis fungoides: Multicenter study of 58 cases. J Am Acad Dermatol 2018; 79:1039-1046. [DOI: 10.1016/j.jaad.2018.06.025] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 05/30/2018] [Accepted: 06/06/2018] [Indexed: 12/11/2022]
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Marks E, Wang Y, Shi Y, Susa J, Jacobson M, Goldstein DY. Specific TCR gene rearrangements in mycosis fungoides: does advanced clinical stage show a preference? J Clin Pathol 2018; 71:1072-1077. [PMID: 30171087 DOI: 10.1136/jclinpath-2018-205324] [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: 06/07/2018] [Revised: 08/01/2018] [Accepted: 08/08/2018] [Indexed: 11/04/2022]
Abstract
AIMS The relationship between the presence of specific T-cell receptor (TCR) gene rearrangements and clinical stage in mycosis fungoides (MF) has not been studied. We analysed a cohort of patients with a diagnosis of MF to determine the different types of specific TCR gene rearrangements present and their relationship to disease stage. METHODS A retrospective chart review was used to select patients with a diagnosis of MF who had a skin biopsy and a positive TCR gene rearrangement study in either blood or tissue and at least 2 years of clinical follow-up. RESULTS 43 patients were identified and divided into two groups. The first group consisted of 23 patients with early stage disease (IA-IIA) that was either stable or went into partial or complete remission with minimal intervention. None of these patients advanced to late stage disease. The second group consisted of 20 patients who had either late stage disease at diagnosis or progressed to late stage disease at some point in time. In the first group, only 4/23 (17%) patients had a single TCR gene rearrangement in the Vɣ1-8 region. In contrast, the second group had 13/20 (65%) patients with a single TCR gene rearrangement in the Vɣ1-8 region (p=0.002). CONCLUSION The presence of a single TCR gene rearrangement in the Vɣ1-8 region could possibly be related to a more advanced stage of MF. However, more comprehensive studies, such as next generation sequencing, with a larger cohort is necessary for a more definitive conclusion.
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Affiliation(s)
- Etan Marks
- Department of Pathology, NYU Langone Medical Center, New York, USA
| | - Yanhua Wang
- Department of Pathology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA
| | - Yang Shi
- Department of Pathology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA
| | - Joseph Susa
- Division of Dermatopathology, Cockerell Dermatopathology, Dallas, Texas, USA
| | - Mark Jacobson
- Department of Pathology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA
| | - D Yitzchak Goldstein
- Department of Pathology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA
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12
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Ranugha PSS, Betkerur J. Antihypertensives in dermatology Part II - Cutaneous adverse reactions to antihypertensives. Indian J Dermatol Venereol Leprol 2018; 84:137-147. [DOI: 10.4103/ijdvl.ijdvl_992_16] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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13
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Comfere N, Sundram U, Hurley MY, Swick B. Views of dermatopathologists about clonality assays in the diagnosis of cutaneous T-cell and B-cell lymphoproliferative disorders. J Cutan Pathol 2017; 45:39-47. [DOI: 10.1111/cup.13072] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 09/01/2017] [Accepted: 10/26/2017] [Indexed: 12/11/2022]
Affiliation(s)
- Nneka Comfere
- Department of Dermatology and Laboratory Medicine and Pathology; Mayo Clinic; Rochester Minnesota
| | - Uma Sundram
- Department of Pathology; Oakland University William Beaumont School of Medicine and Beaumont Health Systems; Royal Oak Michigan
| | | | - Brian Swick
- Department of Dermatology; University of Iowa; Iowa City Iowa
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15
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Bouthemy C, Beldi-Ferchiou A, Ortonne N, Delfau-Larue MH, Ingen-Housz-Oro S, Molinier-Frenkel V. [The value of blood immunophenotyping and clonality testing in the management of cutaneous T-cell lymphomas]. Ann Dermatol Venereol 2017; 144:315-322. [PMID: 28242099 DOI: 10.1016/j.annder.2016.12.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 12/12/2016] [Accepted: 12/19/2016] [Indexed: 10/20/2022]
Affiliation(s)
- C Bouthemy
- Laboratoire d'immunologie biologique, hôpital Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France
| | - A Beldi-Ferchiou
- Laboratoire d'immunologie biologique, hôpital Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France
| | - N Ortonne
- Département de pathologie, hôpital Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France
| | - M-H Delfau-Larue
- Laboratoire d'immunologie biologique, hôpital Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France
| | - S Ingen-Housz-Oro
- Service de dermatologie, hôpital Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France.
| | - V Molinier-Frenkel
- Laboratoire d'immunologie biologique, hôpital Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France
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Cordel N, Tressières B, D'Incan M, Machet L, Grange F, Estève É, Dalac S, Ingen-Housz-Oro S, Bagot M, Beylot-Barry M, Joly P. Frequency and Risk Factors for Associated Lymphomas in Patients With Lymphomatoid Papulosis. Oncologist 2015; 21:76-83. [PMID: 26668250 DOI: 10.1634/theoncologist.2015-0242] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 10/09/2015] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Lymphomatoid papulosis (LyP) is classified as an indolent cutaneous lymphoma, but outcome dramatically worsens if LyP is associated with lymphoma. The frequency of this association remains unclear in the literature. Here, we assess the frequency and risk factors of association between LyP and another lymphoma in an 11-year retrospective study conducted in 8 dermatology departments belonging to the French Study Group on Cutaneous Lymphoma (FSGCL). PATIENTS AND METHODS Patients with LyP were identified and data extracted from the FSGCL registry between 1991 and 2006. Patients were followed up to January 2014. Age, sex, number of skin lesions, histologic subtype, and genotype were recorded at baseline. Risk factors were determined using univariate and multivariate analysis. Cumulative probability of association was calculated using the Kaplan-Meier method. RESULTS We observed 52 cases of lymphomas (cutaneous, n = 38; systemic, n = 14) in 44 of 106 patients (41%). Lymphoma diagnosis was concomitant with or prior to LyP diagnosis in 31 cases and occurred during the course of LyP in 21 cases (cutaneous, n = 14; systemic, n = 7; median delay: 5 years; interquartile range: 1.5-7 years). In multivariate analysis, main prognostic factors for association between LyP and another lymphoma were older age (odds ratio [OR]: 1.05 per year; 95% confidence interval [CI]: 1.01-1.08; p = .011) and presence of a T-cell clone in LyP lesions (OR: 7.55; 95% CI: 2.18-26.18; p = .001). CONCLUSION Older age and presence of a T-cell clone in LyP lesions are risk factors for associated lymphomas in patients with LyP. These findings should help to identify patients who require close management in clinical practice. IMPLICATIONS FOR PRACTICE The management of lymphomatoid papulosis (LyP) is that of an indolent cutaneous lymphoma, based on its excellent prognosis. However, this good prognosis is altered if LyP is associated with lymphoma. Furthermore, risk factors for and frequency of this association remain unclear in the literature. The results presented here demonstrate a high rate of association between LyP and other lymphomas (41%) as well as a long median delay of occurrence (5 years), which emphasizes the need for prolonged follow-up of patients with LyP. Moreover, two main risk factors (i.e., older age and presence of a T-cell clone in LyP lesions) are highlighted, which should help clinical practitioners to identify patients who require close management.
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Affiliation(s)
- Nadège Cordel
- Unit of Dermatology and Internal Medicine, Guadeloupe University Hospital and EA 4546, Antilles University, Pointe-à-Pitre, Guadeloupe
| | - Benoît Tressières
- Centre d'investigation clinique Antilles-Guyane, INSERM CIC 1424, Pointe-à-Pitre, Guadeloupe
| | - Michel D'Incan
- Department of Dermatology, Clermont-Ferrand University Hospital, University of Auvergne, Clermond-Ferrand, France
| | - Laurent Machet
- Department of Dermatology, Tours University Hospital and François Rabelais University, Tours, France
| | - Florent Grange
- Department of Dermatology, Robert Debré Hospital and EA 7319, University of Reims Champagne-Ardennes, Reims, France
| | - Éric Estève
- Department of Dermatology, Orléans Regional Hospital, Orléans, France
| | - Sophie Dalac
- Department of Dermatology, Dijon University Hospital, Dijon, France
| | | | - Martine Bagot
- Department of Dermatology, Paris University Hospitals-St Louis and INSERM U 976, Denis Diderot University, Sorbonne Paris Cité, Paris, France
| | - Marie Beylot-Barry
- Department of Dermatology, Bordeaux University Hospital and EA 2406, University of Bordeaux, Bordeaux, France
| | - Pascal Joly
- Department of Dermatology, Rouen University Hospital and INSERM U 519, Institute for Research and Innovation in Biomedicine, Rouen University, Rouen, Normandy, France
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‘Could it be mycosis fungoides?’: an approach to diagnosing patch stage mycosis fungoides. J Hematop 2015. [DOI: 10.1007/s12308-015-0247-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
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Hurabielle C, Ingen-Housz-Oro S, Ortonne N, Cornillet-Lefèbvre P, Merah A, D'Incan M, Joly P, Franck N, Estève E, Maubec E, Grange F, Machet L, Laroche L, Barete S, Dalac S, Mortier L, Michel C, Quereux G, Saiag P, Ram-Wolff C, Lenormand B, Wechsler J, Bastuji-Garin S, Bagot M, Delfau-Larue M. Frequency and prognostic value of cutaneous molecular residual disease in mycosis fungoides: a prospective multicentre trial of the Cutaneous Lymphoma French Study Group. Br J Dermatol 2015; 173:1015-23. [DOI: 10.1111/bjd.14017] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2015] [Indexed: 11/27/2022]
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Abstract
Primary cutaneous CD30⁺ lymphoproliferative disorders (LPDs) account for approximately 25% of cutaneous lymphomas. Although these LPDs are clinically heterogeneous, they can be indistinguishable histologically. Lymphomatoid papulosis rarely requires systemic treatment; however, multifocal primary cutaneous anaplastic large cell cutaneous lymphoma and large cell transformation of mycosis fungoides are typically treated systemically. As CD30⁺ LPDs are rare, there is little published evidence to support a specific treatment algorithm. Most studies are case reports, small case series, or retrospective reviews. This article discusses various treatment choices for each of the CD30⁺ disorders and offers practical pearls to aid in choosing an appropriate regimen.
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Affiliation(s)
- Lauren C Hughey
- University of Alabama at Birmingham, 1530 3rd Avenue South, EFH 414, Birmingham, AL 35294, USA.
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20
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Abstract
Pseudo-Sezary syndrome is a benign lymphoproliferative disorder, which clinically and pathologically mimics true Sezary syndrome. In this article, a case of pseudo-Sezary syndrome and review the literature has been reported. The patient was a 51-year-old man who developed erythroderma and palmoplantar keratoderma. The patient's medication history included fosinopril and combination metoprolol/hydrochlorothiazide. Flow cytometry showed a population of 2500 "Sezary-like" CD4726 T cells per microliter in the peripheral blood. Skin biopsy showed numerous atypical lymphocytes with epidermotropism, and there was matching dominant T-cell clonality in the skin and peripheral blood. After stopping all antihypertensive medications, the eruption resolved in its entirety.
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21
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Sufficool KE, Lockwood CM, Abel HJ, Hagemann IS, Schumacher JA, Kelley TW, Duncavage EJ. T-cell clonality assessment by next-generation sequencing improves detection sensitivity in mycosis fungoides. J Am Acad Dermatol 2015; 73:228-36.e2. [PMID: 26048061 DOI: 10.1016/j.jaad.2015.04.030] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 04/05/2015] [Accepted: 04/16/2015] [Indexed: 11/17/2022]
Abstract
BACKGROUND T-cell receptor (TCR) clonality assessment is a principal diagnostic test in the management of mycosis fungoides (MF). However, current polymerase chain reaction-based methods may produce ambiguous results, often because of low abundance of clonal T lymphocytes, resulting in weak clonal peaks that cannot be size-resolved by contemporary capillary electrophoresis (CE). OBJECTIVE We sought to determine if next-generation sequencing (NGS)-based detection has increased sensitivity for T-cell clonality over CE-based detection in MF. METHODS Clonality was determined by an NGS-based method in which the TCR-γ variable region was polymerase chain reaction amplified and the products sequenced to establish the identity of rearranged variable and joining regions. RESULTS Of the 35 MF cases tested, 29 (85%) showed a clonal T-cell rearrangement by NGS, compared with 15 (44%) by standard CE detection. Three patients with MF had follow-up testing that showed identical, clonal TCR sequences in subsequent skin biopsy specimens. LIMITATIONS Clonal T-cell populations have been described in benign conditions; evidence of clonality alone, by any method, is not sufficient for diagnosis. CONCLUSION TCR clonality assessment by NGS has superior sensitivity compared with CE-based detection. Further, NGS enables tracking of specific clones across multiple time points for more accurate identification of recurrent MF.
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Affiliation(s)
| | | | - Haley J Abel
- Washington University School of Medicine, Saint Louis, Missouri
| | - Ian S Hagemann
- Washington University School of Medicine, Saint Louis, Missouri
| | | | - Todd W Kelley
- University of Utah School of Medicine, Salt Lake City, Utah
| | - Eric J Duncavage
- Washington University School of Medicine, Saint Louis, Missouri.
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22
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Hu SCS. Mycosis fungoides and Sézary syndrome: Role of chemokines and chemokine receptors. World J Dermatol 2015; 4:69-79. [DOI: 10.5314/wjd.v4.i2.69] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 03/16/2015] [Accepted: 04/09/2015] [Indexed: 02/06/2023] Open
Abstract
Mycosis fungoides is the most common form of cutaneous T-cell lymphoma (CTCL), and is characterized by a clonal expansion of malignant CD4+ T lymphocytes with skin-homing properties. Clinically and pathologically, mycosis fungoides can be categorized into patch, plaque and tumor stages. The clinical course of mycosis fungoides is usually chronic and indolent, but a proportion of patients may develop progressive disease with peripheral blood, lymph node and visceral organ involvement. Sézary syndrome is an aggressive leukemic form of CTCL characterized by a clonal population of malignant T cells in the peripheral blood. Various forms of skin-directed and systemic treatments are available for mycosis fungoides and Sézary syndrome. However, current treatments are generally not curative, and can only control the disease. Currently, the etiology and pathogenesis of mycosis fungoides and Sézary syndrome are not well defined. Proposed mechanisms include chronic antigenic stimulation by infectious agents, expression of specific adhesion molecules, altered cytokine production, mutations of oncogenes and tumor suppressor genes, and avoidance of apoptosis. In recent years, a number of chemokine receptors and their corresponding chemokine ligands have been found to contribute to the migration and survival of lymphoma cells in mycosis fungoides and Sézary syndrome, including CC chemokine receptor 4 (CCR4), CCR10, C-X-C chemokine receptor type 4 (CXCR4), CCR7, CCR3 and CXCR3. Since chemokines and chemokine receptors have been found to play important roles in the pathophysiology of mycosis fungoides and Sézary syndrome, they may be potentially useful targets for the development of new treatments for these diseases in the future.
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T-Cell Receptor Gene Rearrangement Studies Using the GeneScan Technique as an Adjunct to the Histopathological Diagnosis of Mycosis Fungoides. Am J Dermatopathol 2015; 37:210-3. [DOI: 10.1097/dad.0000000000000204] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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24
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Juvenile mycosis fungoides: Cutaneous T-cell lymphoma with frequent follicular involvement. J Am Acad Dermatol 2014; 70:993-1001. [DOI: 10.1016/j.jaad.2013.12.029] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2013] [Revised: 12/11/2013] [Accepted: 12/19/2013] [Indexed: 11/19/2022]
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25
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T-cell receptor gene rearrangement detection in suspected cases of cutaneous T-cell lymphoma. J Invest Dermatol 2014; 134:1-5. [PMID: 24646806 DOI: 10.1038/jid.2014.73] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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26
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Jawed SI, Myskowski PL, Horwitz S, Moskowitz A, Querfeld C. Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome). J Am Acad Dermatol 2014; 70:205.e1-16; quiz 221-2. [DOI: 10.1016/j.jaad.2013.07.049] [Citation(s) in RCA: 171] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 06/25/2013] [Accepted: 07/01/2013] [Indexed: 02/08/2023]
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27
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Molluscum contagiosum with CD30+ cell infiltration in a patient with mycosis fungoides. Am J Dermatopathol 2014; 36:685-7. [PMID: 24423931 DOI: 10.1097/dad.0000000000000056] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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28
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Kutane Lymphome. MEDIKAMENTÖSE TUMORTHERAPIE IN DER DERMATO-ONKOLOGIE 2014. [PMCID: PMC7122836 DOI: 10.1007/978-3-642-24837-5_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Kutane Lymphome (cutaneous lymphomas: CL) umfassen die Gruppe der kutanen T-Zell-Lymphome (cutaneous T-cell lymphomas: CTCL), kutanen B-Zell-Lymphome (cutaneous B-cell lymphomas: CBCL) und die sog. hämatodermischen Neoplasien (HN). CL gehören zur Gruppe der Non-Hodgkin-Lymphome (NHL) und stellen in der Subgruppe der extranodalen NHL die zweithäufigste Gruppe hinter den gastrointestinalen Lymphomen dar (Jaffe et al. 2009). Man unterscheidet zwischen primären und sekundären CL. Primäre CL
haben ihren Ursprung in der Haut und bleiben in der Regel darauf auch längere Zeit beschränkt, während sekundäre LymphomekutaneCL kutane Manifestationen von primär nodalen oder extranodalen Lymphomen darstellen (Willemze 2005). Die primären CL unterscheiden sich hinsichtlich klinischem Verlauf, Therapieoptionen und Prognose erheblich von nodalen und extrakutanen Lymphomen. So zeigen z. B. die primär kutanen CD30+ Lymphome einen gutartigen Verlauf, wogegen die nodalen Varianten als aggressiv eingestuft werden. Da die CL zumeist weniger aggressiv sind, werden sie weniger aggressiv behandelt.
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29
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Lai PJ, Hsiao YP, Hsu JD, Wey SJ. Early stage mycosis fungoides with focal CD30-positive large cell transformation. DERMATOL SIN 2013. [DOI: 10.1016/j.dsi.2012.06.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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30
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Herrmann JL, Hughey LC. Recognizing large-cell transformation of mycosis fungoides. J Am Acad Dermatol 2012; 67:665-72. [DOI: 10.1016/j.jaad.2011.12.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2011] [Revised: 11/30/2011] [Accepted: 12/09/2011] [Indexed: 10/14/2022]
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EuroClonality/BIOMED-2 guidelines for interpretation and reporting of Ig/TCR clonality testing in suspected lymphoproliferations. Leukemia 2012; 26:2159-71. [PMID: 22918122 PMCID: PMC3469789 DOI: 10.1038/leu.2012.246] [Citation(s) in RCA: 360] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
PCR-based immunoglobulin (Ig)/T-cell receptor (TCR) clonality testing in suspected lymphoproliferations has largely been standardized and has consequently become technically feasible in a routine diagnostic setting. Standardization of the pre-analytical and post-analytical phases is now essential to prevent misinterpretation and incorrect conclusions derived from clonality data. As clonality testing is not a quantitative assay, but rather concerns recognition of molecular patterns, guidelines for reliable interpretation and reporting are mandatory. Here, the EuroClonality (BIOMED-2) consortium summarizes important pre- and post-analytical aspects of clonality testing, provides guidelines for interpretation of clonality testing results, and presents a uniform way to report the results of the Ig/TCR assays. Starting from an immunobiological concept, two levels to report Ig/TCR profiles are discerned: the technical description of individual (multiplex) PCR reactions and the overall molecular conclusion for B and T cells. Collectively, the EuroClonality (BIOMED-2) guidelines and consensus reporting system should help to improve the general performance level of clonality assessment and interpretation, which will directly impact on routine clinical management (standardized best-practice) in patients with suspected lymphoproliferations.
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Beaufils N, Ben Lassoued A, Essaydi A, Dales JP, Formisano-Tréziny C, Bonnet N, Grob JJ, Gabert J. Analysis of T-cell receptor-γ gene rearrangements using heteroduplex analysis by high-resolution microcapillary electrophoresis. Leuk Res 2012; 36:1119-23. [PMID: 22738890 DOI: 10.1016/j.leukres.2012.06.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Revised: 05/31/2012] [Accepted: 06/06/2012] [Indexed: 01/28/2023]
Abstract
Determination of T-cell clonality has an important additional value for diagnosis of T-cell lymphomas. Various molecular methods have been developed, including polymerase chain reaction (PCR) of T-cell receptor γ (TCRγ). The detection of PCR products usually relies commonly on either GeneScan (GS) analysis or heteroduplex (HD) analysis by polyacrylamide gel electrophoresis (PAGE). These techniques have their disadvantages, being relatively time-consuming and laborious or requiring expensive equipment. Here, we propose an alternative method that combines multiplex PCR and HD analysis by microcapillary electrophoresis (ME) on the Agilent 2100 Bioanalyzer. The sensitivity of the method was determined with clonal PEER T-cell line DNA dilution in polyclonal DNA and was evaluated as 1-5%. Fifty-three samples from patients with T-cell lymphoproliferative disorders were analyzed by HD analysis using ME and GS analyses. Comparison of the two techniques showed them to be highly concordant (93% similarity). The rate of clonality detection by GS analysis was higher than HD analysis by ME, but none of the discordant patients (n=5) has yet developed lymphoma. HD analysis by ME to reveal TCRγ gene rearrangements in clinical specimens was consistent with clinical data and the outcome of patients. Detection of T-cell clonality by HD analysis with ME is sensitive, practical, safe and represents a potential alternative to PAGE and GS analysis.
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Affiliation(s)
- Nathalie Beaufils
- Département de Biochimie et Biologie Moléculaire, Assistance Publique des Hôpitaux de Marseille, Marseille, France.
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Yang H, Xu C, Tang Y, Wan C, Liu W, Wang L. The significance of multiplex PCR/heteroduplex analysis-based TCR-γ gene rearrangement combined with laser-capture microdissection in the diagnosis of early mycosis fungoides. J Cutan Pathol 2012; 39:337-46. [PMID: 22335593 DOI: 10.1111/j.1600-0560.2011.01842.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND The diagnosis of early mycosis fungoides (MF) is a big challenge to dermatologists and dermatopathologists because it lacks specific clinicopathologic features. METHODS Fifty-two paraffin-embedded skin samples from 50 patients, including 31 with suspected MF, 10 with typical MF and 9 with benign inflammatory dermatosis (BID), were obtained from our archives. DNA was extracted both by traditional phenol-chloroform method and by the laser-capture microdissection (LCM)-proteinase K approach. The T(VG) /T(JG) , V(2-5) /V(8-12) /JGT(1) and BIOMED-2-TCR-γ primers were used to assess TCR-γ monoclonal rearrangement as measured by polymerase chain reaction (PCR). RESULTS In the suspected MF group, clonal TCR-γ gene rearrangements were detected in 11/31 cases (35.5%) by phenol-chloroform DNA extraction and in 25/31 cases (80.7%) by LCM-proteinase K extraction (p < 0.05). While T-cell clonality was detected in 8/10 cases (80%) by the phenol-chloroform method and 10/10 cases (100%) by LCM (p > 0.05) in the typical MF group, no TCR-γ monoclonal rearrangement was detected in the BID group. CONCLUSIONS The strategy of multiple PCR/heteroduplex analysis for TCR-γ gene rearrangement combined with LCM increases the detection rate of clonal TCR-γ gene rearrangement in early MF cases and could provide strong evidence to confirm the diagnosis of early MF.
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Affiliation(s)
- Hanjun Yang
- Department of Dermatovenerology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
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34
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Sproul AM, Goodlad JR. Clonality testing of cutaneous lymphoid infiltrates: practicalities, pitfalls and potential uses. J Hematop 2012. [DOI: 10.1007/s12308-012-0145-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
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Abstract
The histological discrimination of granulomatous cutaneous T-cell lymphomas (CTCLs) from reactive granulomatous disorders such as sarcoidosis and granuloma annulare (GA) may be difficult due to overlapping histological features. We analyzed the T-cell receptor gene rearrangement in sarcoidosis and GA to investigate the value of the detection of clonal T cells as an adjunctive diagnostic marker in the differentiation between sarcoidosis and GA versus granulomatous CTCLs. Rearrangement of T-cell receptor γ genes was examined by the use of automated high-resolution polymerase chain reaction fragment analysis in 35 cases of sarcoidosis and 15 cases of GA and compared with a series of 19 cases of granulomatous CTCLs. A monoclonal T-cell population was found in none of the cases of sarcoidosis and in 2 of 15 cases of GA (13%). In granulomatous CTCLs, a neoplastic T-cell clone was detected in 94%. Presence of clonal T cells argues in favour of a granulomatous CTCL, while a polyclonal T-cell population makes the presence of a sarcoidosis or a GA more likely. The analysis of T-cell clonality is a useful diagnostic adjunct in the differentiation between sarcoidosis and GA from granulomatous CTCLs.
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Abstract
The skin, the body's largest organ, helps to secure the integrity of the host and, at the same time, allows the individual to communicate with the outside world. This finely tuned balance between protection from harmful pathogens (mostly microorganisms) and bidirectional signal exchange is provided by a network of structural, cellular, and molecular elements that are collectively referred to as the skin barrier. This "gateway" has a physical, chemical, and immunologic component. The role of the latter is to elicit a powerful defense reaction in the case of danger and, at the same time, to prevent such a reaction against innocuous substances. Immune responses originating in the skin are mounted and executed by cells and molecules of the innate or the adaptive immune system. Innate reactions are typically rapid, poorly discriminating, and do not exhibit memory. Adaptive responses, in contrast, show a high degree of specificity as well as memory but need a protracted time for their development. As a consequence, innate and adaptive responses are consecutive events influencing each other. In fact, we now know that the type and magnitude of the innate reactions govern and often determine the quality and quantity of adaptive responses.
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Affiliation(s)
- Christine Bangert
- Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria
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Sidorova JV, Biderman BV, Nikulina EE, Sudarikov AB. A simple and efficient method for DNA extraction from skin and paraffin-embedded tissues applicable to T-cell clonality assays. Exp Dermatol 2011; 21:57-60. [PMID: 21995276 DOI: 10.1111/j.1600-0625.2011.01375.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
PCR-based clonality assay of rearranged T-cell receptor genes gamma and beta (TCRG and TCRB) in a number of cases could be essential to discriminate between cutaneous T-cell lymphomas and reactive lymphoproliferative lesions in the skin. However, extraction of good-quality DNA from skin specimens (especially formalin-fixed paraffin-embedded) remains a challenge. Common procedures, being labour-intensive and time-consuming and requiring toxic solvents such as phenol and chloroform, still may end up with DNA sample of insufficient quality. We herewith present a simple and efficient method for DNA isolation based on ammonia extraction of tissue, followed by neutralization and simultaneous salting out of proteins with acetic acid. We have analysed 30 samples - 24 fresh (16 skin, two spleen and six lymph node) and six paraffin-embedded. Standard procedure (proteinase K digestion, followed by phenol/chloroform extraction) has been carried out simultaneously. We observed good PCR signal for TCRG rearrangements in 30 samples processed with the new protocol and only in 20 extracted with proteinase K/phenol/chloroform. For TCRB, the success rate was 29 of 30 with the new protocol, compared to 11 of 30 with conventional protocol. The proposed method of DNA extraction should improve the value of T-cell clonality assay, because insufficient DNA quality and quantity may bias analysis towards monoclonality and therefore cause false-positive results.
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Affiliation(s)
- Julia V Sidorova
- Department of Molecular Hematology, National Hematology Research Center, Moscow, Russia
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Moshkovskii SA, Sokolova EE, Brattseva EV, Karpova MA, Pyatnitskiy MA, Kubanova AA, Archakov AI. Proteome and cytokine serum profiling to diagnose a mycosis fungoides. Proteomics Clin Appl 2011; 5:432-9. [DOI: 10.1002/prca.201000165] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2010] [Revised: 04/20/2011] [Accepted: 05/04/2011] [Indexed: 11/08/2022]
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Histopathologic diagnosis of lymphomatous versus inflammatory erythroderma: a morphologic and phenotypic study on 47 skin biopsies. Am J Dermatopathol 2011; 32:755-63. [PMID: 20559121 DOI: 10.1097/dad.0b013e3181cfbfbf] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Erythroderma may be secondary to a cutaneous T-cell lymphoma (CTCL) and various other erythrodermic inflammatory dermatoses (EID), and their histopathologic distinction is often difficult. The aim of this study was to determine if morphological parameters, namely: the presence of b-catenin, and JunB (previously shown to be expressed by CTCL cells), the epidermal CD8:CD3 ratio, and CD30 expression may help in the histopathologic diagnosis of erythroderma, especially in differentiating CTCL and EID. We retrospectively reviewed a series of 47 skin biopsies from patients with erythroderma (18 CTCL and 29 EID). The diagnosis of each case was established using clinical, biological and histopathologic data. After a blind assessment of the hematoxylin--eosin--safran stained slides, a correct diagnosis of the underlying cause of erythroderma was made only in 31% of cases. A correct differential diagnosis between lymphoma and EID was done with certainty in 57% of cases. Various morphologic and phenotypic parameters were then recorded and we compared their frequency in the CTCL versus the EID group. With the exception of atypical lymphocytes, the moderate to high density of dermal infiltrates and Pautrier microabcesses, only found in CTCL, no morphologic parameter was found to be specific of CTCL, although single lymphocytes epidermotropism, telangiectasias, and slight lymphocytic dermal infiltrate were significantly more frequent in EID. A low (<10%) CD8:CD3 ratio in the epidermal lymphocytic infiltrate and dermal CD30+ lymphocytes were significantly more frequent in CTCL. JunB expression by lymphocytes was specific of CTCL, but was inconstant in our series (17%). We found β-catenin expression in a minority of cases from both the CTCL and EID groups. Among EID, dermal suprapapillary thinning was specific of psoriasis. Neutrophils exocytosis and edema of papillary dermis were significantly more frequent in psoriasis, and spongiosis was more frequent in eczema. In conclusion, few morphological and phenotypical parameters are helpful in making a differential diagnosis between erythrodermic CTCL and EID using paraffin embedded skin biopsies.
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Cho-Vega JH, Tschen JA, Duvic M, Vega F. Early-stage mycosis fungoides variants: case-based review. Ann Diagn Pathol 2011; 14:369-85. [PMID: 20850703 DOI: 10.1016/j.anndiagpath.2010.06.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2010] [Accepted: 06/22/2010] [Indexed: 02/04/2023]
Abstract
Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma. The diagnosis of classic MF is based on a combination of clinical presentation, histopathology, and T-cell monoclonality detected by molecular studies. However, the diagnosis can be difficult in cases of early MF because of the subtle nature of histologic findings and, in cases of variants of MF, because of the unusual clinical and/or pathologic features. In this review, we presented the most frequent variants of MF at early stage including hypopigmented, folliculotropic, pagetoid reticulosis, unilesional, granulomatous, and ichthyosis forms. This case-based clinicopathologic review provides the notion that a comprehensive clinicopathologic correlation is of substantial importance to render the diagnosis of MF. In addition, we discuss the role of molecular studies, which are highly sensitive and recently more applicable to routinely processed skin biopsy specimens in the diagnosis of MF.
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High-scatter T cells: a reliable biomarker for malignant T cells in cutaneous T-cell lymphoma. Blood 2010; 117:1966-76. [PMID: 21148332 DOI: 10.1182/blood-2010-05-287664] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
In early-stage cutaneous T-cell lymphoma (CTCL), malignant T cells are confined to skin and are difficult to isolate and discriminate from benign reactive cells. We found that T cells from CTCL skin lesions contained a population of large, high-scatter, activated skin homing T cells not observed in other inflammatory skin diseases. High-scatter T (T(HS)) cells were CD4(+) in CD4(+) mycosis fungoides (MF), CD8(+) in CD8(+) MF, and contained only clonal T cells in patients with identifiable malignant Vβ clones. T(HS) cells were present in the blood of patients with leukemic CTCL, absent in patients without blood involvement, and contained only clonal malignant T cells. The presence of clonal T(HS) cells correlated with skin disease in patients followed longitudinally. Clonal T(HS) cells underwent apoptosis in patients clearing on extracorporeal photopheresis but persisted in nonresponsive patients. Benign clonal T-cell proliferations mapped to the normal low-scatter T-cell population. Thus, the malignant T cells in both MF and leukemic CTCL can be conclusively identified by a unique scatter profile. This observation will allow selective study of malignant T cells, can be used to discriminate patients with MF from patients with other inflammatory skin diseases, to detect peripheral blood involvement, and to monitor responses to therapy.
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TCRγ-Chain Gene Rearrangement by GeneScan: Incidence and Significance of Clonal Heterogeneity in Sézary Syndrome. J Invest Dermatol 2010; 130:2312-9. [DOI: 10.1038/jid.2010.97] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Patel KP, Pan Q, Wang Y, Maitta RW, Du J, Xue X, Lin J, Ratech H. Comparison of BIOMED-2 versus laboratory-developed polymerase chain reaction assays for detecting T-cell receptor-gamma gene rearrangements. J Mol Diagn 2010; 12:226-37. [PMID: 20181819 DOI: 10.2353/jmoldx.2010.090042] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Detecting clonal T-cell receptor (TCR)-gamma gene rearrangements (GRs) is an important adjunct test for diagnosing T-cell lymphoma. We compared a recently described assay (BIOMED-2 protocol), which targets multiple variable (V) gene segments in two polymerase chain reaction (PCR) reactions (multi-V), with a frequently referenced assay that targets a single V gene segment in four separate PCR reactions (mono-V). A total of 144 consecutive clinical DNA samples were prospectively tested for T-cell clonality by PCR using laboratory-developed mono-V and commercial multi-V primer sets for TCR-gamma GR. The combination of TCR-beta, mono-V TCR-gamma and multi-V TCR-gamma detected more clonal cases (68/144, 47%) than any individual PCR assay. We detected clonal TCR-beta GR in 47/68 (69%) cases. Using either mono-V or multi-V TCR-gamma primers, the sensitivities for detecting clonality were 52/68 (76%) or 51/68 (75%). Using both mono-V and multi-V TCR-gamma primers improved the sensitivity for detecting clonality, 60/68 (88%). Combining either mono-V or multi-V TCR-gamma primers with TCR-beta primers also improved the sensitivity, 64/68 (94%). Significantly, TCR-gamma V11 GRs could only be detected using the mono-V-PCR primers. We conclude that using more than one T-cell PCR assay can enhance the overall sensitivity for detecting T-cell clonality.
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Affiliation(s)
- Keyur P Patel
- Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, 111 E. 210th Street, Bronx, NY 10467, USA
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Kummalue T, Chuphrom A, Sukpanichanant S, Pongpruttipan T, Sukpanichanant S. Detection of monoclonal immunoglobulin heavy chain gene rearrangement (FR3) in Thai malignant lymphoma by High Resolution Melting curve analysis. Diagn Pathol 2010; 5:31. [PMID: 20482846 PMCID: PMC2886000 DOI: 10.1186/1746-1596-5-31] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2009] [Accepted: 05/19/2010] [Indexed: 11/10/2022] Open
Abstract
UNLABELLED Malignant lymphoma, especially non-Hodgkin lymphoma, is one of the most common hematologic malignancies in Thailand. The diagnosis of malignant lymphoma is often problematic, especially in early stages of the disease. Detection of antigen receptor gene rearrangement including T cell receptor (TCR) and immunoglobulin heavy chain (IgH) by polymerase chain reaction followed by heteroduplex has currently become standard whereas fluorescent fragment analysis (GeneScan) has been used for confirmation test. In this study, three techniques had been compared: thermocycler polymerase chain reaction (PCR) followed by heteroduplex and polyacrylamide gel electrophoresis, GeneScan analysis, and real time PCR with High Resolution Melting curve analysis (HRM). The comparison was carried out with DNA extracted from paraffin embedded tissues diagnosed as B- cell non-Hodgkin lymphoma. Specific PCR primers sequences for IgH gene variable region 3, including fluorescence labeled IgH primers were used and results were compared with HRM. In conclusion, the detection IgH gene rearrangement by HRM in the LightCycler System showed potential for distinguishing monoclonality from polyclonality in B-cell non-Hodgkin lymphoma. INTRODUCTION Malignant lymphoma, especially non-Hodgkin lymphoma, is one of the most common hematologic malignancies in Thailand. The incidence rate as reported by Ministry of Public Health is 3.1 per 100,000 population in female whereas the rate in male is 4.5 per 100,000 population 1. At Siriraj Hospital, the new cases diagnosed as malignant lymphoma were 214.6 cases/year 2. The diagnosis of malignant lymphoma is often problematic, especially in early stages of the disease. Therefore, detection of antigen receptor gene rearrangement including T cell receptor (TCR) and immunoglobulin heavy chain (IgH) by polymerase chain reaction (PCR) assay has recently become a standard laboratory test for discrimination of reactive from malignant clonal lymphoproliferation 34. Analyzing DNA extracted from formalin-fixed, paraffin-embedded tissues by multiplex PCR techniques is more rapid, accurate and highly sensitive. Measuring the size of the amplicon from PCR analysis could be used to diagnose malignant lymphoma with monoclonal pattern showing specific and distinct bands detected on acrylamide gel electrophoresis. However, this technique has some limitations and some patients might require a further confirmation test such as GeneScan or fragment analysis 56.GeneScan technique or fragment analysis reflects size and peak of DNA by using capillary gel electrophoresis. This technique is highly sensitive and can detect 0.5-1% of clonal lymphoid cells. It measures the amplicons by using various fluorescently labeled primers at forward or reverse sides and a specific size standard. Using a Genetic Analyzer machine and GeneMapper software (Applied Bioscience, USA), the monoclonal pattern revealed one single, sharp and high peak at the specific size corresponding to acrylamide gel pattern, whereas the polyclonal pattern showed multiple and small peak condensed at the same size standard. This technique is the most sensitive and accurate technique; however, it usually requires high technical experience and is also of high cost 7. Therefore, rapid and more cost effective technique are being sought.LightCycler PCR performs the diagnostic detection of amplicon via melting curve analysis within 2 hours with the use of a specific dye 89. This dye consists of two types: one known as SYBR-Green I which is non specific and the other named as High Resolution Melting analysis (HRM) which is highly sensitive, more accurate and stable. Several reports demonstrated that this new instrument combined with DNA intercalating dyes can be used to discriminate sequence changes in PCR amplicon without manual handling of PCR product 1011. Therefore, current investigations using melting curve analysis are being developed 1213.In this study, three different techniques were compared to evaluate the suitability of LightCycler PCR with HRM as the clonal diagnostic tool for IgH gene rearrangement in B-cell non-Hogdkin lymphoma, i.e. thermocycler PCR followed by heteroduplex analysis and PAGE, GeneScan analysis and LightCycler PCR with HRM.
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Affiliation(s)
- Tanawan Kummalue
- Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Bangkok 10700, Thailand.
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Furmanczyk PS, Wolgamot GM, Kussick SJ, Sabath DE, Olerud JE, Argenyi ZB. Diagnosis of mycosis fungoides with different algorithmic approaches. J Cutan Pathol 2010; 37:8-14. [DOI: 10.1111/j.1600-0560.2009.01289.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Goeldel A, Cornillet-Lefebvre P, Durlach A, Birembaut P, Bernard P, Nguyen P, Grange F. T-cell receptor γ gene rearrangement in cutaneous T-cell lymphoma: comparative study of polymerase chain reaction with denaturing gradient gel electrophoresis and GeneScan analysis. Br J Dermatol 2009; 162:822-9. [DOI: 10.1111/j.1365-2133.2009.09575.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Bachelez H. The Uncertain Status of Cutaneous Pseudolymphoma. ACTAS DERMO-SIFILIOGRAFICAS 2009; 100 Suppl 1:33-7. [DOI: 10.1016/s0001-7310(09)73166-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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Gubler B, Marty-Grès S, Guillot B, Eliaou JF, Dereure O. Molecular identity of skin and blood T-cell clones in cutaneous T-cell lymphoma patients as determined from the migration pattern of the T-cell receptor-γ gene by capillary electrophoresis. Electrophoresis 2009; 30:999-1007. [DOI: 10.1002/elps.200800198] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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