Early TCR-β and TCR-γ PCR detection of T-cell clonality indicates minimal tumor disease in lymph nodes of cutaneous T-cell lymphoma: diagnostic and prognostic implications

Assaf, Chalid; Hummel, Michael; Steinhoff, Matthias; Geilen, Christoph C.; Orawa, Helmut; Stein, Harald; Orfanos, Constantin E.

doi:10.1182/blood-2004-06-2220

Cited by 83 publications

(58 citation statements)

References 41 publications

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“…33 In cutaneous T-cell lymphoma, the detection of an identical monoclonal TCR gene rearrangement in skin and extracutaneous tissues has been proven to be an independent prognostic marker. 34,35 In addition, detection of the same clonal gene rearrangements in multiple skin biopsy specimens at the time of diagnosis may provide prognostic information related to disease progression. 36 Therefore, if possible, we recommend studying multiple (parallel) samples from multiple suspect localizations at initial disease presentation.…”

Section: Discussionmentioning

confidence: 99%

BIOMED-2 Multiplex Immunoglobulin/T-Cell Receptor Polymerase Chain Reaction Protocols Can Reliably Replace Southern Blot Analysis in Routine Clonality Diagnostics

Sandberg

Gastel-Mol

Verhaaf

et al. 2005

The Journal of Molecular Diagnostics

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To establish the most sensitive and efficient strategy of clonality diagnostics via immunoglobulin and Tcell receptor gene rearrangement studies in suspected lymphoproliferative disorders, we evaluated 300 samples (from 218 patients) submitted consecutively for routine diagnostics. All samples were studied using the BIOMED-2 multiplex polymerase chain reaction (PCR) protocol. In 176 samples, Southern blot (SB) data were also available, and the two types of molecular results were compared. Results of PCR and SB analysis of both T-cell receptor and immunoglobulin loci were concordant in 85% of samples. For discordant results, PCR results were more consistent with the final diagnosis in 73% of samples. No false-negative results were obtained by PCR analysis. In contrast, SB analysis failed to detect clonality in a relatively high number of samples, mainly in cases of low tumor burden. We conclude that the novel BIOMED-2 multiplex PCR strategy is of great value in diagnosing patients with suspected B-and T-cell proliferations. Because of its higher speed, efficiency, and sensitivity, it can reliably replace SB analysis in clonality diagnostics in a routine laboratory setting. In most patients with suspected lymphoproliferative disorders, discrimination between reactive and malignant cell populations can be assessed by histomorphology or cytomorphology supplemented with immunohistochemistry or flow cytometric immunophenotyping. However, in 5 to 10% of patients, diagnosis is more complicated and less straightforward. In such cases, molecular gene rearrangement studies have proved useful as an additional diagnostic tool. Molecular clonality analysis is based on the fact that, in principle, all cells of a malignancy have a common clonal origin and show clonally (identically) rearranged immunoglobulin (Ig) or T-cell receptor (TCR) genes. The diagnosis of malignant B-and T-cell proliferations is therefore supported by the finding of Ig/TCR gene clonality, whereas reactive lymphoproliferations show polyclonally rearranged Ig/TCR genes. 1 Gene rearrangement analysis can be performed by Southern blot (SB)-and polymerase chain reaction (PCR)-based techniques. Despite the high reliability of SB analysis, it is increasingly replaced by PCR techniques because of the greater efficiency and sensitivity of PCR. Moreover, PCR is relatively easy, less labor intensive, and requires much less high-molecular-weight DNA. Also, SB analysis cannot be performed on paraffinembedded tissue because the isolated DNA is often degraded. Therefore, there is a strong need to replace SB analysis with reliable PCR techniques. However, PCR studies have often suffered from false-negative results due to improper annealing of primers and/or the presence of somatic hypermutation. 2 Both SB and PCR analyses of the immunoglobulin heavy chain (IGH) locus have been demonstrated to be very useful and reliable techniques in clonality assessment of suspected B-cell malignancies. However, the most useful gene target for identifying T-cell clonality is less well e...

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Section: Discussionmentioning

confidence: 99%

BIOMED-2 Multiplex Immunoglobulin/T-Cell Receptor Polymerase Chain Reaction Protocols Can Reliably Replace Southern Blot Analysis in Routine Clonality Diagnostics

Sandberg

Gastel-Mol

Verhaaf

et al. 2005

The Journal of Molecular Diagnostics

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“…In contrast, patients with tumor stage disease (T3), erythroderma (T4), nodal involvement characterized by partial or complete architectural effacement (N3), visceral metastases (M1), or significant leukemic involvement (B2) have ''advanced-stage'' disease. Detection of a clonal TCR gene rearrangement by PCR, which has been incorporated into the revised ISCL/EORTC node(N) and blood(B) staging classification, is an adverse prognostic factor [7,[185][186][187][188]. Unfortunately, median survivals from 1-5 years are observed in these patients with more extensive disease [7].…”

Section: Risk-stratification Stagingmentioning

confidence: 99%

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

Wilcox

2011

American J Hematol

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Disease overview: Cutaneous T‐cell lymphomas are a heterogenous group of T‐cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis fungoides (MF) or Sézary syndrome (SS).Diagnosis: The diagnosis of MF or SS requires the integration of clinical and histopathologic data.Risk‐adapted therapy: Tumor, node, metastasis, and blood (TNMB) staging remains the most important prognostic factor in MF/SS and forms the basis for a “risk‐adapted,” multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin‐directed therapies is preferred, as both disease‐specific and overall survival for these patients is favorable. In contrast, patients with advanced‐stage disease with significant nodal, visceral, or blood involvement are generally approached with biologic‐response modifiers, denileukin diftitox, and histone deacetylase inhibitors before escalating therapy to include systemic, single‐agent chemotherapy. Multiagent chemotherapy may be used for those patients with extensive visceral involvement requiring rapid disease control. In highly‐selected patients with disease refractory to standard treatments, allogeneic stem‐cell transplantation may be considered. Am. J. Hematol., 2011. © 2011 Wiley‐Liss, Inc.

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“…Erst kürzlich konnten wir anhand einer gröûeren Fallzahl mittels TCR-b-und TCR-g-PCR in Kombination mit der Genescan-Technik zeigen, dass sich eine klonale T-Zell-Population in 50 % der klinisch ver- gröûerten und histologisch als dermatopathisch klassifizierten Lymphknoten eine klonale T-Zell-Population nachweisen lässt. Darüber hinaus konnten wir erstmals anhand Gröûen-und Sequenzvergleich der PCR-Produkte zeigen, dass dieser T-Zell-Klon identisch mit dem malignen T-Zell-Klon in der korrespondierenden befallenen Hautläsion ist [39]. Dies beweist, dass die klonale T-Zell-Population im Lymphknoten eine Infiltration des Primär-tumor, d. h. des kutanen Lymphoms repräsentiert (Abb.…”

Section: Bedeutung Der Klonalität In Der Ausbreitungsdiagnostikunclassified

“…Darü-ber hinaus zeigen diese Patienten mit nachweisbarem T-ZellKlon im Lymphknoten eine reduzierte Überlebensrate, auch wenn der Befall histologisch nicht manifest ist. Im Gegensatz dazu konnten in dermatopathischen Lymphknoten bei Patienten mit chronischen entzündlichen Dermatosen keine klonalen T-Zell-Populationen nachgewiesen werden [39]. Zusammenfassend belegen die bisherigen Southern-blot-Daten sowie insbesondere unsere Ergebnisse, dass die TCR-Klonalitätsanalysen eine wichtige Hilfe in der schwierigen Diagnostik bei suspektem Lymphknotenbefall durch ein kutanes T-Zell-Lymphom sind und dadurch ein akkurates Staging von Lymphompatienten ermögli-chen.…”

Section: Bedeutung Der Klonalität In Der Ausbreitungsdiagnostikunclassified

Diagnostischer Stellenwert und klinische Bedeutung der Analyse von T-Zellrezeptor-Genumlagerungen beim kutanen T-Zell-Lymphom

Assaf¹

2004

Akt Dermatol

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ZusammenfassungKutane T-Zell-Lymphome (CTCL) stellen eine Gruppe lymphoproliferativer Hauterkrankungen dar, die durch klonale Akkumulation von T-Lymphozyten-Populationen charakterisiert sind. Die Diagnose wird in der Regel aufgrund klinischer und histologischer charakteristischer Eigenschaften der CTCL gestellt. Schwierigkeiten bereitet die Diagnosestellung insbesondere in frühen Stadien, aber auch in seltenen Varianten der CTCL. In diesen Fällen ist der Nachweis klonaler T-Zell-Populationen durch identisch umgelagerte T-Zellrezeptor-Gene eine wertvolle Hilfe. So zeigen PCR-basierende Techniken zum Nachweis klonaler T-Zell-Populationen eine hohe Sensitivität von 70 ± 90 % in Hautbiopsien früher CTCL-Stadien. Nach Diagnosestellung ist der nächste wichtige Schritt die Ausbreitungsdiagnostik des CTCL, sinkt doch die Überlebensrate drastisch bei Auftreten extrakutaner Manifestationen wie z.B. bei Infiltration der Lymphknoten oder viszeraler Organe. Ein Stadienwechsel, d.h. die Progression der Erkrankung, wird in der Regel klinisch erst spät entdeckt. Insbesondere der Lymphknotenbefall, der erfahrungsgemäû als erste extrakutane Manifestation des CTCL gilt, stellt sowohl den Kliniker als auch den Histologen vor diagnostische Probleme. Hier konnten wir in einer aktuellen Studien zeigen, dass in ca. 50 % der dermatopathischen Lymphknoten identische klonale T-ZellPopulationen wie in den CTCL-Läsionen der Haut nachweisbar sind. Des Weiteren zeigte sich, dass diese Patienten eine reduzierte Überlebensrate haben, ähnlich denen, die eine histologisch manifeste Lymphknoteninfiltration durch das CTCL haben. Diese Daten belegen, dass T-Zellrezeptor-Umlagerungsanalysen bei Patienten mit CTCL sowohl eine diagnostische als auch prognostische Bedeutung haben und somit ein akkurates Staging ermöglichen. AbstractCutaneous T-cell lymphoma (CTCL) is a clonal lymphoproliferative malignancy primarily involving the skin. Routine diagnosis of CTCL is based on its characteristic clinical and histopathologic features. However, the broad clinical and histological spectrum of the disease, especially of its early stages and rare variants, often complicates the differentiation between malignant CTCL and benign lymphoproliferative or reactive skin diseases. In these cases demonstration of a clonal T-cell population by detection of identically rearranged T-cell receptor genes (TCR) provides an adjunct. Using this approach clonality could be demonstrated in 70-90 % in CTCL biopsies of early stages by recent PCR-based studies, indicating a high sensitivity. After achieving the correct diagnosis the next important step is to stage the disease in CTCLpatients. Patients with CTCL usually have an indolent course with a 5-year survival of approximately 87%. However, in a significant number of patients the disease may progress and disseminated extracutaneous manifestations may develop involving the lymph nodes, blood and visceral organs. The prognosis for patients with widespread manifestation of CTCL beyond the skin is poor. Therefore, accurate evaluatio...

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Early TCR-β and TCR-γ PCR detection of T-cell clonality indicates minimal tumor disease in lymph nodes of cutaneous T-cell lymphoma: diagnostic and prognostic implications

Cited by 83 publications

References 41 publications

BIOMED-2 Multiplex Immunoglobulin/T-Cell Receptor Polymerase Chain Reaction Protocols Can Reliably Replace Southern Blot Analysis in Routine Clonality Diagnostics

BIOMED-2 Multiplex Immunoglobulin/T-Cell Receptor Polymerase Chain Reaction Protocols Can Reliably Replace Southern Blot Analysis in Routine Clonality Diagnostics

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

Diagnostischer Stellenwert und klinische Bedeutung der Analyse von T-Zellrezeptor-Genumlagerungen beim kutanen T-Zell-Lymphom

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