Proteome-Based Analysis of Serologically Defined Tumor-Associated Antigens in Cutaneous Lymphoma

Just released through PLOS 

December 2009

Michael Forgber, Sylke Gellrich, Tumenjargal Sharav, Wolfram Sterry, and Peter Walden^*

Abstract

Information on specificities of serological responses against tumor cells in cutaneous lymphoma patients is relatively restricted. To advance the knowledge of serological immune responses against and to assess the scope of tumor antigenicity of cutaneous lymphoma, 1- and 2-dimensional Western blot analyses with sera from patients were combined with proteomics-based protein identification. Testing sera from 87 cutaneous lymphoma patients by 1-dimensional Western blot analysis, 64 cases of seroreactivity against lymphoma cells were found. The positive responses were relatively weak, restricted to few antigens in each case, and heterogeneous. To identify the antigens, proteins of the mycosis fungoides cell line MyLa and primary tumor cells were separated by 2-dimensional gel electrophoresis, Western-blotted and probed with heterogeneous and autologous patient sera. The antigens were identified from silver-stained replica gels by MALDI-TOF mass spectrometry. 14 different antigens were assigned and identified with this proteome-serological approach. Only one, vimentin, had been reported before, the other 13 are new antigens for cutaneous lymphomas.

Complete Text:

NIH - PLOS One

Cutaneous T-Cell Lymphoma in Asians

July 2012  - Just released through PubMed

Min Soo Jang, Dong Young Kang, Jong Bin Park, Sang Tae Kim, and Kee Suck Suh ^*

^Abstract

Cutaneous T-cell lymphoma describes a heterogeneous group of neoplasms of skin homing T cells that vary considerably in clinical presentation, histologic appearance, immunophenotype, and prognosis. This paper addresses the cutaneous T-cell lymphoma in Asians with respect to clinical-epidemiologic and histopathological features. Compared with Western countries, Asia usually has higher rates of cutaneous T-cell lymphomas such as extranodal NK/T-cell lymphoma, hydroa vacciniforme-like lymphoma, subcutaneous panniculitis T-cell lymphoma, and adult T-cell leukemia/lymphoma and lower rates of cutaneous B-cell lymphomas. Among many variants of mycosis fungoides, hypopigmented lesions, pityriasis lichenoides-like lesions, and ichthyosiform lesions are more prevalent in Asia than in the West. Adult T-cell leukemia/lymphoma is endemic in southwestern Japan especially in the Kyushu island. The clinicopathologic characteristics of cutaneous lymphoma vary according to geography, and this may be ascribed to genetic and environmental etiologic factors.

Complete Text with Images

NIH - ISRN Dermatology

Cutaneous EBV-positive γδ T-cell lymphoma vs. extranodal NK/T-cell lymphoma: a case report and literature review.

Nov 2012

Yu WW, Hsieh PP, Chuang SS.

Source

Department of Dermatology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Abstract

Primary cutaneous γδ T-cell lymphoma and 

extranodal natural killer (NK)/T-cell lymphoma (ENKTL), nasal type are two distinct lymphoma entities in the World Health Organization (WHO) classification. We report the case of an aggressivecutaneous lymphoma of γδ T-cell origin showing overlapping features of both lymphomas. A 78-year-old female presented with confluent erythematous plaques with ulcerations over her right thigh. Microscopically, section of the skin showed a diffuse dermal and subcutaneous lymphocytic infiltration with tumor necrosis and angioinvasion. The medium- to large-sized tumor cells expressed CD3, CD8, cytotoxic molecules and T-cell receptor (TCR)-γ but not CD4, CD20, CD30, CD56 or βF1. In situ hybridization for Epstein-Barr virus-encoded mRNA (EBER) was diffusely positive. Polymerase chain reaction-based clonality assay showed a clonal TCR-γ chain gene rearrangement. The features compatible with γδ T-cell lymphoma include dermal and subcutaneous involvements, cytotoxic phenotype, expression of TCR-γ, as well as an aggressive course. On the other hand, the diffuse EBER positivity, angioinvasion, tumor necrosis and cytotoxic phenotype may also fit in the diagnosis of an ENKTL of T-cell lineage. We review the literature on EBER-positive γδ T-cell lymphoma and discuss the diagnostic dilemma using the current WHO classification system.

Keywords:

• γδ T-cell;
• γδ T-cell lymphoma;
• cutaneous lymphoma;
• extranodal natural killer,
• T-cell lymphoma;
• peripheral T-cell lymphoma;
• Taiwan

Wiley OnLine

Indolent lymphoma of the ear

Dec 2012

[Article in French]

Valois A, Bastien C, Granel-Broca F, Cuny JF, Barbaud A, Schmutz JL.

Source

Service de dermatologie, CHU de Brabois, rue du Morvan, 54500 Vandœuvre-lès-Nancy, France. Electronic address: audevalois4@yahoo.fr.

Abstract

INTRODUCTION:

In 2007, Petrella et al. identified a new entity: CD8 T-cell indolent lymphoma of the ear.

CASE REPORT:

A 40-year-old man presented a nodular erythematous and violaceous painless lesion on his right ear that had appeared four months earlier. Excision histology revealed a non-epidermotropic T-cell proliferation infiltrating the entire dermis and subcutis but with sparing of a grenz zone. The monotonous infiltrate was positive for CD8, CD3, CD5 and TIA-1, and negative for CD30, CD4, CD56, ALK and EMA. The Mib1 proliferation index was 20%. Lyme serology and PCR for EBV were negative. Additional examinations showed no extracutaneous involvement.

DISCUSSION:

CD8+ indolent lymphoma is an entity first described in 2007 and reported in the literature in 15 patients. Lesions are located on the nose or external ear. It comprises a non-epidermotropic proliferation of CD8+ T lymphocytes negative for CD4, CD30, CD56, CD57, granzyme B and perforin. The Mib1 proliferation index is low. This new entity appears neither in the 2005 World Health Organization/European Organization for Research and Treatment of Cancer (WHO/EORTC) classification of cutaneous lymphomas nor in the WHO 2008 Classification of tumours of haematopoietic and lymphoid tissues. Surgical treatment or radiotherapy is sufficient, and unlike aggressive, epidermotropic CD8+ T lymphomas chemotherapy is not required.

PubMed

Integrated Positron-Emission Tomography and Computed Tomography Manifestations of Cutaneous T-Cell Lymphoma

Dec 2012

Research letters

Mycosis fungoides (MF) and Sézary syndrome (SS) represent the most common types of primary cutaneous T-cell lymphomas (CTCLs). Current guidelines recommend [18F]-fluorodeoxyglucose positron-emission tomography (FDG-PET) plus computed tomography (CT) scan for staging purposes in all patients except in cases of early-stage disease (IA-IB). However, the application of FDG-PET in CTCL has not been widely documented. In this study, we retrospectively evaluated the findings of FDG-PET/CT scans in 41 patients with CTCL.

Complete text

Archives of Dermatology

A Cutaneous Interstitial Granulomatous Dermatitis-Like Eruption Arising in Myelodysplasia With Leukemic Progression.

Dec 2012

Cornejo KM, Lum CA, Izumi AK.

Source

*Department of Pathology, University of Massachusetts Medical School, Worcester, MA †Department of Pathology ‡Division of Dermatology, Department of Medicine, University of Hawaii, Honolulu, HI.

Abstract

Cutaneous manifestations associated with myelodysplastic syndromes (MDS) are uncommon and can occur as specific or nonspecific lesions. Recognizing these cutaneous manifestations is important as they can precede blood or bone marrow transformation to leukemia. Granulomatous reactions have rarely been described as nonspecific lesions of MDS. These rare cases histologically resembled granuloma annulare, sarcoid, and a generalized dermal interstitial granulomatous dermatitis (IGD) which were not associated with leukemic infiltration. The authors report an interesting case of an IGD-like eruption evolving over the course of MDS with eventual progression to systemic leukemia. IGD is an inflammatory reaction that refers to a varied spectrum of histologic patterns and is associated with a variety of systemic illnesses and hypersensitivity reactions, including lymphoma and leukemia. In patients with MDS, surveillance for leukemia is a critical component of their follow-up care. Normally, this surveillance occurs through serial peripheral blood smears and bone marrow studies. IGD-like eruptions are a cutaneous reaction pattern that may serve as an additional clinical indicator of leukemic progression in patients with MDS. Although primarily a reactive pattern, this entity can rarely harbor leukemic blasts.

American Journal of Dermatopathology

Cutaneous CD30-positive lymphoproliferative disorders with CD8 expression: a clinicopathologic study of 21 cases.

Nov 2012

Plaza JA, Feldman AL, Magro C.

Source

Department of Dermatopathology, The Medical College of Wisconsin, Milwaukee, WI, USA.

Abstract

Lymphomatoid papulosis (LyP) and cutaneous anaplastic large cell lymphoma (ALCL) belong to the spectrum ofcutaneous CD30+ lymphoproliferative disorders, an indolent form of T-cell lymphoproliferative disease. We reviewed 21 cases of CD30+ lymphoproliferative lesions expressing cytotoxic profile (CD8+). Seven cases of cutaneous ALCL, 2 cases of systemic ALCL involving the skin, and 12 cases of LyP. The cases of LyP were predominated by small lymphocytes exhibiting a prominent epidermotropic pattern consistent with either type B or type D LyP. Four cases showed co-expression of CD56. The ALCL cases included myxoid features, pseudoepitheliomatous change, and an intravascular component. In all cases that were primary in the skin an indolent clinical course was seen while one patient with systemic myxoid ALCL is in remission following systemic multiagent chemotherapy. The paucity of other neutrophils and eosinophils and concomitant granulomatous inflammation were distinctive features in cases of type B and type D LyP. CD30 and CD45 Ro positivity and a clinical course typical of LyP were useful differentiating features from an aggressive cytotoxic CD8+ T cell lymphoma. In all cases that were primary in the skin an indolent clinical course was observed. CD30 and CD45 Ro positivity and a clinical course typical of LyP were useful in preventing a misdiagnosis of an aggressive cytotoxic CD8+ T cell lymphoma.

Wiley OnLine

The role of AHI1 and CDKN1C in cutaneous T-cell lymphoma progression.

Nov 2012

Litvinov IV, Kupper TS, Sasseville D.

Source

Division of Dermatology, McGill University Health Centre, Montréal, QC, Canada.

Abstract

Cutaneous T-cell lymphoma (CTCL) is the most common lymphoma of the skin. Recent reports suggest that AHI1 is overexpressed in a subset of CTCL-derived cell lines, where it downregulates the expression of CDKN1C tumor suppressor gene. In the current work, we test the expression of these genes in 60 patients with Mycosis Fungoides and Sezary Syndrome by RT-PCR and correlate our findings with 6 years of clinical follow-up. These findings reveal that AHI1 and CDKN1C exhibit opposite expression patterns, where AHI1 is expressed in poor and intermediate prognosis patients, while CDKN1C is expressed in favourable prognosis patients. Kaplan-Meier analysis documents that downregulation of CDKN1C is associated with poor disease outcome in patients with CTCL, while upregulation of AHI1 shows a weak association with aggressive disease course.

Wiley Online

The role of molecular analysis in cutaneous lymphomas.

Dec 2012

Deonizio JM, Guitart J.

Source

Department of Dermatology, Northwestern University, Chicago, IL.

Abstract

The purpose of this review is to summarize the most important molecular techniques for the diagnosis of cutaneous lymphomas. When making a diagnosis, we are looking for the solid clinicopathological correlation. Molecular analysis includes immunophenotyping and clonality analysis, and is important for 2 principal reasons: (1) to confirm the diagnosis in cases where the clinical and/or pathological presentations are nondiagnostic, and (2) to further characterize the nature of the lymphoma. More specifically, we are trying to discern whether the lymphoma is primarily cutaneous or systemic with secondary skin involvement, and we are also attempting to subclassify the tumor. Recently, many techniques have provided a more accurate diagnosis of cutaneous lymphomas and some prognostic implications, including polymerase chain reaction, fluorescence in situ hybridization, and flow cytometry. Fluorescence in situ hybridization is not routinely used in the diagnosis of cutaneous lymphoma, but many studies have shown potential future applications in various areas. Other techniques, such as comparative genomic hybridization, are still confined to the research arena, but have added some insight into the molecular pathogenesis of cutaneous T-cell lymphoma.

PubMed

Radiographically negative, asymptomatic, sentinel lymph node positive cutaneous T-cell lymphoma in a 3-year-old male: a case report.

2012

Carson J, Bedrnicek J, Abdessalam S.

Source

Department of General Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Abstract

We present a case of a 3-year-old male originally diagnosed with a CD30+ anaplastic cutaneous T-cell lymphoma with no evidence of systemic disease after CT scan, PET scan, and bone marrow aspiration. Sentinel lymph node biopsy (SLNB) was performed as an additional step in the workup and showed microscopic disease. Current management/recommendations for cutaneous T-cell lymphoma do not include SLNB. Medical and surgical management of cutaneous malignancies is dramatically different for local versus advanced disease. Therefore adequate evaluation is necessary to properly stage patients for specific treatment. Such distinction in extent of disease suggests more extensive therapy including locoregional radiation and systemic chemotherapy versus local excision only. Two international case reports have described SLNB in cutaneous T-cell lymphoma with one demonstrating evidence of node positive microscopic disease despite a negative metastatic disease workup. This case is being presented as a novel case in a child with implications including lymphoscintigraphy and SLNB as a routine procedure for evaluation and staging of cutaneous T-cell lymphoma if the patient does not demonstrate evidence of metastatic disease on routine workup.

NIH

Advanced/aggressive CTCL: improving the efficacy of treatment.

Dec 2012

Zinzani PL.

Source

"L. e A. Seràgnoli" Institute of Hematology, University of Bologna, Bologna, Italy.

Abstract

Treatment regimens of patients with cutaneous T-cell lymphoma (CTCL) vary widely based on clinician preference and patient tolerance. Skin directed therapies are recommended for patients with early stage IA and IB MF, with combinations used in refractory cases. While no regimen has been proven to prolong survival in advanced stages, immunomodulatory regimens should be used initially to reduce the need for cytotoxic therapies. In more advanced stages of disease, treatment efforts should strive for palliation and improvement of quality of life. With many new therapies and strategies on the horizon, the future looks promising for CTCL patients.

PubMedC

Cutaneous peripheral T-cell lymphomas, unspecified/NOS and rare subtypes: a heterogeneous group of challenging cutaneous lymphomas.

Dec 2012

Kempf W, Rozati S, Kerl K, French LE, Dummer R.

Source

Department of Dermatology, University Hospital Zürich, Zürich, Switzerland - werner.kempf@access.unizh.ch.

Abstract

Cutaneous peripheral T-cell lymphoma, unspecified/not otherwise specified (PTL NOS) represents a phenotypically and prognostically heterogenous group of cutaneous T-cell lymphomas (CTCL) that do not fit into any of well defined defined CTCL subtypes. In the WHO-EORTC classification as well as the WHO classification, three entities have been delineated as provisional rare subtypes of PTL based on their characteristic clinico-pathological, immunophenotypic and prognostic features and have been separated out from PTL, NOS: Primary cutaneous CD4-positive small/medium T-cell lymphoma(CD4+ SMTL), primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma (CD8+ AECTCL), and primarycutaneous gamma/delta T-cell lymphoma (CGD-TCL). CD4+ SMTL manifests in most patients with a solitary nodule in the head and neck area and nodular infiltrates of CD4+ small to medium-sized lymphocytes with nuclear pleomorphism. The prognosis of this lymphoproliferation is excellent in patients with a solitary lesion, but may be impaired in patients with multifocal disease. Rapidly evolving erosive or necrotic plaques and nodules with an epidermotropic infiltrate of CD8+ atypical lymphocytes are the hallmark of CD8+ AECTCL, which exhibits a poor prognosis. CGD-TCL displays a broad spectrum of clinical and histological manifestations with expression of the T-cell receptor gamma/delta chain as the common denominator and diagnostic marker. As most of other forms of PTL, CGD-TCL carries a poor prognosis. Despite the rarity of PTL NOS, clinicians as well as dermatopathologists and pathologists should be familiar with these rare CTC, especially since most of these lymphomas exhibit an unfavourable prognosis. Immediate intense treatment with multiagent chemotherapy and hematopoietic stem cell transplantation is indicated in patients with PTL NOS. This review focuses on the clinicopathological aspects, the diagnostic criteria and the classification of the rare subtypes of PTL and PTL NOS.

PubMed

MDx/CDx Focus: Phase III Adcetris Trial in Hodgkin Lymphoma; FDA Priority Review for Roche's T-DM1

MDx/CDx Focus: Phase III Adcetris Trial in Hodgkin Lymphoma; FDA Priority Review for Roche's T-DM1

November 07, 2012

Millennium, Seattle Genetics Launch Phase III Adcetris Trial in Hodgkin Lymphoma

Millennium and Seattle Genetics earlier this month initiated a Phase III trial to investigate the efficacy and safety of Adcetris, a drug being developed for the treatment of advanced Hodgkin lymphoma.

Adcetris targets the cell membrane protein CD30, which is expressed in Hodgkin lymphoma. The trial, being conducted under a special protocol agreement with the US Food and Drug Administration, will study Adcetris (brentuximab vedotin) in combination with chemotherapy as a first-line treatment for previously untreated Hodgkin lymphoma patients.

“This is a key step in our efforts to explore the potential of this targeted therapy as part of a front-line treatment regimen,” Karen Ferrante, chief medical officer of Millennium, a subsidiary of Takeda Pharmaceuticals' oncology division, said in a statement.

This trial is part of Millennium and Seattle's ongoing program to identify patient populations with CD30-expressing malignancies that might benefit from Adcetris treatment.

Earlier this year, Millennium and Seattle Genetics launched a Phase III study evaluating Adcetris in previously treated patients with CD30-expressing cutaneous T-cell lymphoma. In this study, the partners are also evaluating a companion test to identify patients with CD30-expressing malignancies. Millennium and Seattle Genetics have inked a deal with Ventana Medical Systems to develop the molecular companion diagnostic test accompanying Adcetris (PGx Reporter 5/9/2012).

Seattle Genetics Chief Medical Officer Thomas Reynolds noted in a statement that there is an unmet medical need for new treatments for Hodgkin lymphoma. This Phase III trial might lead to the development of a new front-line treatment for Hodgkin lymphoma patients, but it also may yield data that the companies can submit to the FDA to garner accelerated approval for Adcetris in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma patients.

The randomized, open-label study will compare Adcetris plus combination chemotherapy (adriamycin, vinblastine, dacarbazine) versus just chemotherapy (adriamycin, bleomycin, vinblastine, dacarbazine) in more than 1,000 patients with advanced, classical Hodgkin lymphoma. Researchers will investigate whether the Adcetris plus chemo regimen improves progression-free survival in patients compared to only chemo based on the Revised Response Criteria for malignant lymphoma. Other endpoints that will be studied include overall survival, complete remission, and safety.

Pharmacogenomics Reporter

HDAC inhibitor-based therapies: Can we interpret the code?

Oct 2012

New M, Olzscha H, La Thangue NB.

Source

Department of Oncology, Laboratory of Cancer Biology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford OX3 7DQ, UK.

Abstract

Abnormal epigenetic control is a common early event in tumour progression, and aberrant acetylation in particular has been implicated in tumourigenesis. One of the most promising approaches towards drugs that modulate epigenetic processes has been seen in the development of inhibitors of histone deacetylases (HDACs). HDACs regulate the acetylation of histones in nucleosomes, which mediates changes in chromatin conformation, leading to regulation of gene expression. HDACs also regulate the acetylation status of a variety of other non-histone substrates, including key tumour suppressor proteins and oncogenes. Histone deacetylase inhibitors (HDIs) are potent anti-proliferative agents which modulate acetylation by targeting histone deacetylases. Interest is increasing in HDI-based therapies and so far, two HDIs, vorinostat (SAHA) and romidepsin (FK228), have been approved for treating cutaneous T-cell lymphoma (CTCL). Others are undergoing clinical trials. Treatment with HDIs prompts tumour cells to undergo apoptosis, and cell-based studies have shown a number of other outcomes to result from HDI treatment, including cell-cycle arrest, cell differentiation, anti-angiogenesis and autophagy. However, our understanding of the key pathways through which HDAC inhibitors affect tumour cell growth remains incomplete, which has hampered progress in identifying malignancies other than CTCL which are likely to respond to HDI treatment.

PubMed

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma: Transformation from indolent to aggressive phase in association with CCR7-positive conversion.

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma: Transformation from indolent to aggressive phase in association with CCR7-positive conversion.

Oct 2012

Kasuya A, Hirakawa S, Tokura Y.

Source

Hamamatsu University School of Medicine Hamamatsu, Shizuoka, Japan.

Abstract

We report a case of primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma that transformed from the indolent phase to the aggressive phase. In the aggressive phase, the patient developed numerous subcutaneous lesions on the trunk, limbs, and face. The involvement of muscle, right testis, and pharynx were also found. We immunohistochemically analyzed the expression of chemokine receptors, before and after the transformation of aggressive epidermotropic CD8+ T-cell lymphoma. The transformation was accompanied by positive conversion of CCR7. CCR7 is crucial in lymphatic cell migration and chemotaxis to lymph nodes. Therefore, its expression is likely associated with the disseminated behavior of T-cell lymphoma.

PubMed

Mycosis fungoides palmaris et plantaris.

Nov 2012

[Article in German]

Pfaff S, Megahed M.

Source

Klinik für Dermatologie und Allergologie, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Deutschland, spfaff@ukaachen.de.

Abstract

Mycosis fungoides (MF) is a low-grade cutaneous T-cell lymphoma characterized by skin-homing CD4- positive helper T cells. Mycosis fungoides palmaris et plantaris is an uncommon variant primarily involving the palms and soles. An 80-year old man presented with hyperkeratotic erythematous palmoplantar changes. Clinical and histopathologic criteria led to the diagnosis mycosis fungoides palmaris et plantaris. Tumor staging using sonography of the abdomen and lymph nodes, chest x-ray and blood examination is recommended, because extracutaneous manifestations may be present.

Springerlink

PML-IRIS IN A PATIENT TREATED WITH BRENTUXIMAB.

Oct 2012

von Geldern G, Pardo CA, Calabresi PA, Newsome SD.

Source

From the Departments of Neurology (G.v.G., C.A.P., P.A.C., S.D.N.) and Pathology (C.A.P.), The Johns Hopkins Hospital, Baltimore, MD.

Abstract

A 38-year-old woman was diagnosed with cutaneous anaplastic T-cell lymphoma that proved refractory to methotrexate, bexarotene, denileukin diftitox, interferon γ-1b, interferon α-2b, vorinostat, and pralatrexate. She was therefore started on the newly approved monoclonal anti-CD30 antibody brentuximab vedotin. Treatment with brentuximab 1.8 mg/kg IV every 3 weeks quickly led to disappearance of her cutaneous tumors. The day after her second brentuximab infusion she developed word-finding difficulties and unsteady gait. Due to further neurologic deterioration, she was admitted to an outside hospital. Brain MRI revealed multifocal enhancing white matter lesions throughout bilateral cerebral hemispheres and posterior fossa (figure, A-C). Brain biopsy was performed 15 days after her last brentuximab dose to rule out metastases and she was diagnosed with progressive multifocal leukoencephalopathy (PML) (figure, J). The patient was discharged home with hospice care. Upon discharge, she was started on prednisone 50 mg daily to help treat her eczema. Her family brought her to our clinic for a second opinion.

Neurology