CD30-positive Large Cell Lymphoma Research Articles

IRF8 as a Novel Marker to Differentiate Between CD30-Positive Large Cell Lymphomas.

Interferon regulatory factor 8 (IRF8) is a new biomarker shown to be positive in monocytic leukemias as well as in B cells. As a transcription factor, it plays a critical role in pre-B-cell differentiation and induction of tolerance pathways, among other functions. Given the frequent diagnostic dilemma in CD30-positive large cell lymphomas that could resemble both Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL), we sought to determine whether IRF8 can be useful in distinguishing between these neoplasms that require different treatment strategies. In this retrospective study, 74 cases of classic Hodgkin lymphoma (CHL) and 7 cases of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) on a tissue microarray (TMA), as well as 15 individual cases of ALK-negative ALCL and 4 cases of ALK-positive ALCL, were stained for IRF8. Paired box 5 (PAX5) immunostaining of the TMA was also performed and compared alongside since that marker is occasionally the only marker to help clinically differentiate between T- and B-cell lymphomas with anaplastic/Hodgkin-like cytology. None (0%) of the ALCLs were positive for IRF8 while all (100%) of the NLPHLs and 85% of the CHLs were positive for IRF8. Six (8%) cases of CHL were PAX5 negative but IRF8 positive. Conversely, seven (10%) cases of CHL were PAX5 positive but IRF8 negative. Four (6%) cases of CHL were negative for both PAX5 and IRF8. There is significant morphologic and immunophenotypic (CD30 positive and CD45 and CD20 negative) overlap between CHL and ALCL. Since many ALCLs show downregulation of lineage-specific T-cell markers or are "null cell" type, only PAX5 has been a reliable marker to differentiate between borderline cases. This is further confounded by positivity of PAX5 in some ALCLs due to amplification of PAX5. On the basis of recent discoveries of IRF8 function as well as performance as an immunostain, we tested this marker in human lymphoma samples and found that it aids in the discrimination between these tumors.

Primary Cutaneous CD30-Positive Large T-Cell Lymphoma in an 80-Year-Old Man: A Case Report

Primary cutaneous CD30-positive large cell lymphoma (CD30+ PCLCL) is a rare subtype of cutaneous T-cell lymphoma (CTCL) that can present in a variety of ways. We report a patient with a three-month history of an enlarging, exophytic mass with two smaller satellite lesions on the left forearm. Biopsy of the skin stained positive for CD30, and, after thorough systemic evaluation, a diagnosis of CD30+ PCLCL was made. When PCLCL is suspected, it is important to perform immunohistological studies for CD30 types and conduct a thorough workup to rule out systemic LCL. These measures will reduce the use of unnecessarily aggressive chemotherapy regimens for CD30+ PCLCL, an indolent disease with a favorable prognosis.

CD30 (Ki-1)-positive large-cell cutaneous T-cell lymphoma with secondary xanthomatous changes after radiation therapy

A 72-year-old woman with a large mass on her forehead was found to have primary cutaneous CD30-positive large T-cell lymphoma and was treated with radiation therapy. Five weeks after the completion of radiation therapy, a large, yellow plaque developed on the forehead. Histopathologic examination showed numerous xanthoma-like cells with clear and foamy cytoplasm that infiltrated the upper and mid dermis with no residual lymphoma. To our knowledge, this is the first report of xanthomatous change after radiation therapy for primary cutaneous CD30-positive large cell lymphoma. We believe that the xanthomatous change after radiation therapy probably was caused by lysis of radiosensitive lymphoma cells and histiocytic scavenging of lipid-membrane debris. (J Am Acad Dermatol 2003;48:S28-30.)

Response of CD30+ Large Cell Lymphoma of Skin to Bexarotene

According to the REAL classification, CD30+ anaplastic large cell lymphoma of the skin is a distinct clinicopathologic entity characterized by an indolent clinical course. Mycosis fungoides are predominantly small cells with cerebriform nuclei and propensity to infiltrate the epidermis or epidermotropism. CD30+ lymphoid cells are not generally observed in mycosis fungoides except in late or terminal stage. To distinguish between CD30 positive anaplastic large cell lymphoma and CD30 positive mycosis fungoides may be difficult. We describe a case of CD30 positive large cell lymphoma of skin that responded to bexarotene that is recently approved for refractory mycosis fungoides.

MUC1 (EMA) is preferentially expressed by ALK positive anaplastic large cell lymphoma, in the normally glycosylated or only partly hypoglycosylated form.

To investigate whether MUC1 mucin, a high molecular weight transmembrane glycoprotein, also known as epithelial membrane antigen (EMA), differs in its expression and degree of glycosylation between anaplastic large cell lymphoma (ALCL) and classic Hodgkin's disease (HD), and whether MUC1 immunostaining can be used to differentiate between CD30 positive large cell lymphomas. Using five different monoclonal antibodies (E29/anti-EMA, DF3, 139H2, VU-4H5, and SM3) that distinguish between various MUC1 glycoforms, high MUC1 expression (50-95% of tumour cells positive) was found in 13 of 17 anaplastic lymphoma kinase (ALK) positive systemic nodal ALCLs, and in one of 20 cases of classic HD. Scattered or focal staining (< 25% of tumour cells) was seen in two additional ALK positive systemic ALCLs, two additional classic HD cases, and in three of 20 cases of ALK negative systemic nodal ALCL. Primary cutaneous ALCL showed no staining with the anti-MUC1 antibodies. Antibodies detecting hypoglycosylated MUC1 were found to be absent in all lymphomas (SM3) or present in only six of 15 ALK positive ALCLs (VU-4H5). MUC1 is preferentially expressed by a subtype of systemic nodal ALCL, characterised by ALK expression, but is found in only a few cases of classic HD and ALK negative ALCL. Therefore, although MUC1 could be used in a panel of markers for CD30 positive lymphomas, it is probably not a valuable tool to differentiate between ALK negative CD30 positive large cell lymphomas. Finally, the degree of MUC1 glycosylation in lymphomas is relatively high, compared with the aberrant hypoglycosylation found in adenocarcinomas.

Allelic Deletion at 9p21–22 in Primary Cutaneous CD30+ Large Cell Lymphoma

The genetic alterations responsible for the development of cutaneous lymphoma are largely unknown. Chromosome region 9p21 contains a gene locus encoding an inhibitor of cyclin-dependent kinase 4, and heterozygous deletions of this tumor suppressor gene (p16) have been shown in a variety of malignant tumors. We studied 11 randomly selected cutaneous CD30-positive large cell lymphomas. Several areas containing 20-50 CD30-positive lymphocytes were microdissected in each case and subjected to single-step DNA extraction. Loss of heterozygosity analysis was performed using polymorphic markers at 9p21 (IFNA, D9S171, D9S169) and 17p13 (TP53). Samples from normal cells apart from CD30-positive lymphocytes, e.g., CD30-negative lymphohistiocytic infiltrates and normal epidermal layer, were also obtained in all cases from the same slide for comparison with the tumor samples. Expression of CD30 and T-lineage antigens (CD3, CD45Ro) was confirmed in all cases. Immunohistochemical staining for p16 and p53 was performed using the monoclonal antibodies sc-1661 and DO-7, respectively. Of the 11 informative cases, seven (64%) exhibited loss of heterozygosity at least for one marker at 9p21 (p16), whereas no allelic deletions were found for the polymorphic marker at 17p13 (p53). On immunohistochemistry loss of the p16 protein was detected in two of 11 cases. Nuclear staining for p53 protein was found in four of 11 cases. Here, we provide the first evidence of the involvement of the tumor suppressor gene p16 in primary cutaneous large cell lymphoma. Whether p16 deletion in these lymphomas is associated with disease progression and whether this method could serve as an early marker to detect lymphomas at an early stage needs to be addressed in future studies. J Invest Dermatol 115:1104-1107 2000

Immunohistochemical Analysis of CD30-Positive Lymphoproliferative Disorders for Expression of CD95 and CD95L

Primary cutaneous (PC) CD30-positive large cell lymphoma and lymphomatoid papulosis (LyP) represent the spectrum of PC CD30-positive lymphoproliferative disorders (LPDs) associated with a favorable prognosis. Noncutaneous CD30-positive anaplastic large cell lymphoma (ALCL), although morphologically similar to PC CD30-positive LPDs, seems to be a biologically distinct entity. Cell lines derived from noncutaneous ALCL express CD95 and undergo CD95-induced apoptosis. Little is known about expression or function of CD95/CD95L in cutaneous lesions. We examined a series of PC CD30-positive LPDs and noncutaneous ALCL for expression of CD95/CD95L to investigate possible differences between these histologically similar but biologically distinct entities.Paraffin-embedded, formalin-fixed tissue sections from 25 cases of CD30-positive LPDs (10 noncutaneous ALCL, 15 PC CD30-positive LPDs) were immunostained for CD3, CD20 (L26), CD43 (Leu22), CD30 (BerH2), anaplastic lymphoma kinase (ALK-1), CD95, and CD95L (C-33). One hundred large atypical cells and 100 small lymphocytes were counted to determine the percentage of CD95/CD95L-positive cells. Statistical analysis using the Mann-Whitney U test was performed.CD95 expression was slightly higher in the large atypical cells of noncutaneous ALCL compared with PC CD30-positive LPDs (median, 100% versus 94%; P =.003) because of the lower expression of CD95 in LyP. CD95L expression was higher in the surrounding small lymphocytes in PC CD30-positive LPDs (median, 3% versus 13%; P =.002). Expression of CD95 in the small lymphocytes and CD95L in the large atypical cells was not significantly different.These results support the biologic distinction between cutaneous and noncutaneous CD30-positive LPDs and may have implications in the differing clinical behavior of these entities. Further study of expression and function of apoptosis-related proteins in these entities is warranted.

Papulosis lymphomatoides evolving into a cutaneous CD30-positive large cell lymphoma

Papulosis lymphomatoides evolving into a cutaneous CD30-positive large cell lymphoma

Construction of a YAC contig and a STS map spanning at least seven megabasepairs in chromosome 5q34-35.

We have constructed a YAC contig containing 54 clones and a minimum of 7 Mbp of human DNA, that maps to bands q34-35 on chromosome 5. The contig was nucleated using FISH mapped cosmid clones shown to flank the t(2;5)(p23;q35) translocation breakpoint in a CD30-positive large cell lymphoma cell line. Thirty of the 54 YAC clones are non-chimeric and six span the translocation breakpoint, as determined by FISH analysis. A total of 28 YAC clone end fragments, 14 non-polymorphic YAC end STS probes and 13 polymorphic microsatellite STS markers have been used to order clones within the contig. The most distal genetic markers (D5S498 and D5S619) are separated by 15 cM based on multipoint linkage analysis. This map of overlapping clones and the set of densely spaced physical markers will promote our understanding of the 5q34-35 region and its associated genes.

Primary cutaneous CD30-positive large cell lymphoma: Definition of a new type of cutaneous lymphoma with a favorable prognosis.A European multicenter study of 47 patients

CD30 (Ki-1)-positive anaplastic large cell lymphoma (LCL) has been described as a morphologically distinct group of LCL that generally are associated with a poor prognosis. Recent studies indicate that these lymphomas, when confined to the skin, have a favorable prognosis. However, there is no consensus regarding the definition of these primary cutaneous CD30-positive LCL. Reported patients have been selected variously on the basis of morphologic (anaplastic cytology) or immunophenotypical (expression of CD30 antigen) criteria. At two recent workshops aimed to achieve consensus on the definition and terminology of these lymphomas, the clinical, histologic, and immunophenotypical data of 47 patients with primary cutaneous CD30-positive LCL from five collaborating European centers were analyzed. Characteristic clinical features were presentation with solitary or localized skin lesions (42 of 47 patients), frequent cutaneous relapses (15 patients), and partial or complete spontaneous remission of skin lesions (11 patients). Twelve of 47 (25%) patients developed extracutaneous disease. The favorable prognosis of these lymphomas is indicated by the follow-up data that show that 36 of 47 patients are alive and in complete remission, only four disease-related deaths have occurred, and the overall median survival is 42 months (range, 2-130 months). There were no differences in clinical presentation, course, or prognosis between anaplastic and nonanaplastic CD30-positive LCL. The results of this study indicate that primary cutaneous CD30-positive LCL, regardless of their morphologic classification (anaplastic or nonanaplastic) can be considered as a distinct type of cutaneous T-cell lymphoma. Recognition of this type of cutaneous lymphoma is important because it may prevent patients from unnecessary aggressive treatment.

Diagnostic difficulties in 'non-mycotic' cutaneous lymphoproliferative diseases.

The diagnosis of cutaneous lymphoproliferative diseases is an area of bewildering complexity to many histopathologists. This article concentrates on 'non-mycotic' cutaneous diseases. The 'current state of the diagnostic art' is critically assessed. Cutaneous 'pseudolymphoma' is relegated to the position of an aid-memoire and is not a diagnosis. Inadequacies in the classification of cutaneous lymphoma are discussed and the non-specificity of many histopathological features is highlighted. The status of specific entities is analysed and the contribution of modern investigative techniques in diagnosis is evaluated. This includes cutaneous T-cell lymphomas with a detailed consideration of large cell lymphoma heterogeneity. Cutaneous B-cell diseases are shown to be an unresolved diagnostic maze and the necessity for new clearly defined diagnostic criteria is emphasized. Evidence is presented to show that many cutaneous lymphoproliferative diseases lie on continuous spectra that, initially, are probably antigenically driven, and that a diagnosis is best achieved by a multifaceted approach. This is exemplified by cutaneous diseases that have origins from both B- (cutaneous lymphoid hyperplasia/lymphoma) and T-cells (lymphomatoid papulosis, lymphomatoid granulomatosis and mycosis fungoides). The future diagnostic role of the polymerase chain reaction and cytogenetic analysis is discussed. Intriguingly, recent molecular evidence has shown that lymphomatoid papulosis, cutaneous T-cell lymphoma, CD30 positive large cell lymphoma and Hodgkin's disease can originate from a single T-cell clone and display an identical chromosomal translocation and T-cell receptor rearrangement. Careful clinico-pathological correlation combined with prolonged patient follow-up remains the gold standard for diagnosis.