Anaplastic Large Cell Morphology Research Articles

Aggressive Subcutaneous Panniculitis-Like CD30+ Peripheral T-Cell Lymphoma with Diffuse EBER Expression.

T-cell lineage lymphoma with an intense membranous and paranuclear CD30 expression in the absence of ALK1 raises a differential diagnosis of peripheral T-cell lymphoma (PTCL), NOS and anaplastic large cell lymphoma (ALCL), ALK negative. However, Epstein-Barr virus is consistently negative in ALCL and is not considered an implicating factor in its pathogenesis. We describe a case of T-cell lymphoma showing anaplastic large cell morphology with scattered hallmark cells and a uniform CD30 and Epstein-Barr virus encoded early RNA (EBER) expression that primarily involved the subcutaneous tissue at presentation. On incisional biopsy, the neoplastic cells were positive for CD3, CD2, and CD30 while negative for LCA, CD20, PAX5, CD56, ALK1, and cytotoxic granules. Molecular analysis identified a positive T-cell receptor (beta and gamma) gene rearrangement by PCR. Proliferation index approached 100% and the patient had a rapidly progressive course; the subcutaneous lesions more than doubled in size within couple of weeks with new evidence for widespread systemic involvement. This case emphasizes a rare EBV association with a CD30 positive T-cell lymphoma where the morphologic and immunophenotypic findings are otherwise nondiscriminatory between PTCL, NOS and ALCL, ALK negative.

Loss of Foxp3 Is Associated With CD30 Expression in the Anaplastic Large Cell Subtype of Adult T-cell Leukemia/Lymphoma (ATLL) in US/Caribbean Patients

Adult T-cell leukemia/lymphoma (ATLL) is caused by the HTLV-1 virus, endemic to Japan and the Caribbean, and is likely derived from cells with the T-regulatory phenotype. The malignant cells express IL2 receptor α (CD25), and the majority express transcription factor Forkhead box P3 (Foxp3), in addition to T-cell markers. Occasional cases express CD30. Whereas Japanese cases are predominantly of the acute and chronic leukemic types, the less well-studied Caribbean cases are more often lymphomatous. We performed immunohistochemical analysis for CD25, Foxp3, and CD30 on samples from 42 US/Caribbean ATLL patients and correlated these markers with morphologic subtype and clinical characteristics. In the 16/42 patients who had successive biopsies, we determined the expression stability of these markers. Foxp3 was expressed in 26 of the 42 (62%) initial biopsies, and its intensity correlated with CD25 expression. It was more frequent in pleomorphic small-sized and medium-sized cell types than in large cell tumors but did not correlate with patients' clinical attributes. Foxp3 expression and morphology were unchanged in successive biopsies in 13 of 16 patients. Four initial biopsies had features of anaplastic large cell T lymphomas, all of which were Foxp3. Successive biopsies from 2 patients with pleomorphic medium cell variant showed diminishing expression of originally weak Foxp3 expression and de novo CD30 expression, whereas they showed morphologic progression to the anaplastic cell variant. A third patient's second biopsy revealed progression from pleomorphic medium to anaplastic large cell morphology with loss of Foxp3, but it remained CD30. Foxp3 expression correlates with pleomorphic small and medium cell types and may be lost with large cell transformation. The evolution of the latter type can be associated with the gain of CD30 expression; such ATLL tumors might respond to anti-CD30 monoclonal antibody therapies.

Intratumoral heterogeneity in anaplastic large cell lymphoma of non-common subtype

ALK-positive anaplastic large cell lymphoma (ALCL) with identical primary genetic aberration present with variable morphology. The eponymous anaplastic large cell morphology can be detected in the majority cases which are described as being of common type morphology. However, morphological variants displaying small tumor cells that are barely distinguishable from reactive lymphocytes occur often in combination with classical large tumor cells and characterize so-called non-common type ALCL. This subgroup has recently been shown to be associated with a weak immune response to the ALK1 protein and a poorer outcome in children. Expression of T cell markers like CD3 is often reduced or absent in these lymphomas, probably as a direct effect of the ALK1 protein. In non-common type ALCL, the expression of ALK is restricted to the nucleus, suggesting reduced activity of the enzyme. The goal of the present study was to gain insight into the intratumoral heterogeneity of these lymphomas and to understand how T cell marker expression is distributed among tumor cells. We analyzed the immunophenotype of ALK1-positive ALCL in 41 pediatric patients by fluorescence multi-staining and subsequent digital image analysis. The small tumor cells in non-common type ALCL expressed larger amounts of T cell surface markers such as CD3, CD5, and CD8 but less CD30 compared to the large tumor cells. Expression of ALK1 and phosphorylated STAT3 as well as cell proliferation measured by positivity for Ki67 was reduced in the small cells of non-common type ALCL. These data demonstrate heterogeneity of the immunophenotype of tumor cells within non-common type ALCL suggestive for differentiation of small tumor cells, thereby providing a possible first explanation for the reduced immunogenicity of non-common type ALCL.

Activation of mTORC1 Signaling Pathway in AIDS-Related Lymphomas

Using immunohistochemistry with antibodies against the phosphoserine residues in both S6rp and 4E binding protein 1, we identified the activation of the mammalian target of rapamycin (mTORC)1 pathway in 29 cases of AIDS-related lymphoma. These cases represented a diverse spectrum of histological types of non-Hodgkin lymphoma (24 cases) and classic Hodgkin lymphoma (five cases). mTORC1 was also activated in the hyperplastic but not involuted follicles of HIV-associated lymphadenopathy in eight cases, supporting the notion that mTORC1 activation is a common feature of transformed lymphocytes irrespective of either their reactive or malignant phenotype. We also found that in B-cell lines that represent diffuse large B-cell lymphoma, Burkitt lymphoma, Epstein-Barr virus-infected lymphocytes, and human herpesvirus 8-positive primary effusion lymphoma, inhibitors of Syk, MEK, and, seemingly, phosphoinositide 3 kinases suppressed mTORC1 activation, in particular when these inhibitors were used in combination. These findings indicate that AIDS-related lymphoma and other histologically similar types of lymphomas that are derived from transformed B lymphocytes may display clinical responses to inhibitors that directly target mTORC1 or, possibly, upstream activators of the mTORC1 pathway.

Plasmablastic lymphoma: One or more entities?

American Journal of HematologyVolume 83, Issue 10 p. 763-764 CommentaryFree Access Plasmablastic lymphoma: One or more entities?† Antonino Carbone, Corresponding Author Antonino Carbone [email protected] Department of Pathology, National Cancer Institute of Milan, Milan, ItalyDepartment of Pathology, Fondazione IRCCS, Istituto Nazionale Tumori, Via Venezian, 1, 20133 Milano, ItalySearch for more papers by this authorAnnunziata Gloghini, Annunziata Gloghini Department of Pathology, National Cancer Institute of Milan, Milan, ItalySearch for more papers by this author Antonino Carbone, Corresponding Author Antonino Carbone [email protected] Department of Pathology, National Cancer Institute of Milan, Milan, ItalyDepartment of Pathology, Fondazione IRCCS, Istituto Nazionale Tumori, Via Venezian, 1, 20133 Milano, ItalySearch for more papers by this authorAnnunziata Gloghini, Annunziata Gloghini Department of Pathology, National Cancer Institute of Milan, Milan, ItalySearch for more papers by this author First published: 22 July 2008 https://doi.org/10.1002/ajh.21259Citations: 29 † Conflict of Interest: Nothing to report. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 ES Jaffe, NL Harris, H Stein, JW Vardiman, Editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001. 2 Delecluse HJ,Anagnostopoulos I,Dallenbach F, et al. Plasmablastic lymphomas of the oral cavity: A new entity associated with the human immunodeficiency virus infection. Blood 1997; 89: 1413– 1420. 3 Castillo J,Pantanowithz L,Dezube BJ. HIV-associated plasmablastic lymphoma: A literature review of 112 cases. Am J Hematol, in press. 4 Nador RG,Cesarman E,Chadburn A, et al. Primary effusion lymphoma: A distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood 1996; 88: 645– 656. 5 Dupin N,Diss TL,Kellam P, et al. HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood 2000; 95: 1406– 1412. 6 Deloose ST,Smit LA,Pals FT, et al. High incidence of Kaposi sarcoma-associated herpesvirus infection in HIV-related solid immunoblastic/plasmablastic diffuse large B-cell lymphoma. Leukemia 2005; 19: 851– 855. 7 Carbone A,Gloghini A,Vaccher E, et al. KSHV/HHV-8 associated lymph node based lymphomas in HIV seronegative subjects: Report of two cases with anaplastic large cell morphology and plasmablastic immunophenotypes. J Clin Pathol 2005; 58: 1039– 1045. 8 Klein U,Gloghini A. Gaidano G, et al. Gene expression profile analysis of AIDS related primary effusion lymphoma (PEL) suggest a plasmablastic derivation and identifies PEL-specific transcripts. Blood 2003; 101: 4115– 4121. 9 Carbone A,Gloghini A,Larocca LM, et al. Human immunodeficiency virus-associated Hodgkin's disease derives from post-germinal center B cells. Blood 1999; 93: 2319– 2326. 10 Klein U,Dalla-Favera R. Germinal centres: Role in B-cell physiology and malignancy. Nat Rev Immunol 2008; 8: 22– 33. 11 Vockerodt M,Morgan S,Kuo M, et al. The Epstein-Barr virus oncoprotein, latent membrane protein-1, reprograms germinal centre B cells towards a Hodgkin's Reed-Sternberg-like phenotype. J Pathol, [Epub ahead of print]. 12 Colomo L,Loong F,Rives S, et al. Diffuse large B-cell lymphomas with plasmablastic differentiation represent a heterogeneous group of disease entities. Am J Surg Pathol 2004; 28: 223– 228. 13 Petitjean B,Jardin F,Joly B, et al. Pyothorax-associated lymphoma: A peculiar clinicopathologic entity derived from B-cells at late stage of differentiation and with occasional aberrant dual B- and T-cell phenotype. Am J Surg Pathol 2002; 26: 724– 732. 14 Carbone A,Gloghini A.Vaccher E, et al. Kaposi's sarcoma-associated herpes virus/human herpes virus type 8-positive solid lymphoma. A tissue-based variant of primary effusion lymphoma. J Mol Diagn 2005; 7: 17– 27. Citing Literature Volume83, Issue10October 2008Pages 763-764 ReferencesRelatedInformation

Integration of HIV-1 caused STAT3-associated B cell lymphoma in an AIDS patient

Signal transducer and activator of transcription 3 (STAT3) is a DNA-binding transcription factor activated by multiple cytokines and interferons. High expression of STAT3 has also been implicated in cancer and lymphoma. Here, we show a case of B cell lymphoma in which a defective human immunodeficiency virus 1 (HIV-1) integrated upstream of the first STAT3 coding exon. The lymphoma cells with anaplastic large cell morphology formed multiple nodular lesions in the lung of an acquired immunodeficiency syndrome (AIDS) patient with Kaposi's sarcoma. The provirus had a 5′ long terminal repeat (LTR) deletion, but the 3′ LTR had stronger promoter activity than the STAT3 promoter in reporter assays. Immunohistochemistry showed increased expression of STAT3 in the nuclei of lymphoma cells. Transfection of STAT3 resulted in transient cell proliferation in primary B cells in vitro. Although this is a very rare case of HIV-1-integrated lymphoma, these data suggest that up-regulation of STAT3 caused by HIV-1 integration resulted in the development of B cell lymphoma in this special case.

Integration of HIV-1 Caused STAT3-Associated B Cell Lymphoma in an AIDS Patient

B cell lymphomas remain a significant cause of morbidity in AIDS but the pathophysiology of this disease is unclear. We report a case of B cell lymphoma in which HIV-1 integrated into the host genome. The lymphoma cells with anaplastic large cell morphology formed multiple nodular lesions in the lung of a homosexual AIDS patient. The lymphoma cells did not express KSHV-LANA and EBVEBER or HIV-1 p24 but did express high levels of nuclear localized STAT3. The provirus had a 5'LTR deletion and the 3'LTR was inserted just before the first coding exon of STAT3. Reporter gene assay demonstrated that the 3'LTR had a strong promoter activity especially when co-transfected with HIV Tat. These data suggest HIV-1 integration resulted in induction of STAT3 and possibly promoted lymphoma formation. This suggests that HIV-1 insertional mutagenesis may be associated with some cases of AIDS lymphoma. from 2005 International Meeting of The Institute of Human Virology Baltimore, USA, 29 August – 2 September 2005

Intravascular large T-cell lymphoma: a case report of CD30-positive and ALK-negative anaplastic type with cytotoxic molecule expression

We reported a case of intravascular T-cell lymphoma (T-IVL) with anaplastic large cell morphology, the hemophagocytic syndrome, and an aggressive clinical course. Phenotypic analysis of the tumor cells revealed CD2+, CD3-, CD4+, CD5-, CD8-, CD30+, CD56-, T-cell receptor alpha/beta-, ALK-, TIA1+, granzyme B+, and perforin+. No association with Epstein-Barr virus was found by in situ hybridization. A review revealed that 25 cases of T-IVL have been reported in the available literature, only two of which were of CD30+ anaplastic large cell or cytotoxic T-cell type. The findings in the present case may highlight the unique clinicopathologic aspects of a subset of CD30-positive T-IVLs with an ALK-negative cytotoxic phenotype.

KSHV/HHV-8 associated lymph node based lymphomas in HIV seronegative subjects. Report of two cases with anaplastic large cell morphology and plasmablastic immunophenotype

Background: Kaposi sarcoma associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8) associated lymphomas, which often develop in human immunodeficiency virus (HIV) infected patients with advanced AIDS, present predominantly as primary effusion lymphoma...

Leucocyte-specific protein (LSP1) in malignant lymphoma and Hodgkin's disease.

Biopsies from 319 haematopoietic neoplasms were immunostained for intracellular leucocyte-specific protein 1 (LSP1) to assess its distribution and to compare its diagnostic value with that of CD45 (leucocyte common antigen: LCA). Most small B-cell neoplasms expressed LSP1, but one third of diffuse large B-cell lymphomas (DLBCL) were LSP1 negative. Among the cases with DLBCL (76 samples) tested for both LSP1 and CD45, one fifth expressed only CD45, but five samples were LSP1-positive and negative for CD45. The latter pattern was also seen in four of nine myelomas. Five out of 14 T-lymphoblastic lymphomas co-expressed LSP1 and CD45, and three cases were LSP1 negative and CD45-positive. Most peripheral T-cell lymphomas co-expressed LSP1 and CD45. All anaplastic lymphoma kinase (ALK)-negative lymphomas of anaplastic large cell morphology (T and null phenotype) expressed LSP1 although the percentage of LSP1-positive tumour cells was variable, however, only seven out of 30 cases with ALK-positive lymphoma were LSP1 positive. LSP1 was expressed on Reed-Sternberg cells in 60 out of 66 cases with classic Hodgkin's disease but neoplastic cells were usually negative in lymphocyte predominant Hodgkin's. This study confirms the wide expression of LSP1 within haematopoietic neoplasms and its diagnostic value for a minority of lymphoid tumours that have lost CD45 expression. Furthermore, the strong expression of LSP1 in classic Hodgkin's disease, contrasting with its heterogeneous expression in ALK-negative anaplastic lymphomas, may help to distinguish the latter lymphomas from patients with tumour cell-rich Hodgkin's disease.

Rapidly Progressive Human Herpesvirus 8-associated Solid Anaplastic Lymphoma in a Patient with AIDS—Associated Kaposi Sarcoma

We report a case of rapidly progressive solid lymphoma with anaplastic large cell morphology, followed by systemic Kaposi sarcoma in an adult patient with AIDS. The lymphoma cells expressed human herpesvirus 8 (HHV-8)-encoded latent and lytic proteins and Epstein-Barr virus -encoded small RNA, suggesting that this case could be categorized into HHV-8-associated solid lymphoma, a recently identified disease entity.

Human Herpesvirus 8–Associated Solid Lymphomas that Occur in AIDS Patients Take Anaplastic Large Cell Morphology

Human herpesvirus type 8 (HHV-8; Kaposi's sarcoma–associated herpesvirus) is a recently isolated human herpesvirus frequently identified in Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Here we report three cases of HHV-8–bearing solid lymphomas that occurred in AIDS patients (Cases 1–3). All three patients were homosexual men presenting extranodal masses in the lungs (Case 1) or skin (Cases 2 and 3), together with the presence of Kaposi's sarcoma (Case 1), primary effusion lymphoma (Case 2), or multicentric Castleman's disease (Case 3). These solid lymphomas exhibited anaplastic large cell morphology and expressed CD30, corresponding to the recent diagnostic criteria of anaplastic large cell lymphoma (ALCL). The chromosomal translocation t(2;5)-associated chimeric protein p80NPM/ALK was not observed in any of these cases. HHV-8 was detected in all of these cases by polymerase chain reaction, immunohistochemistry of HHV-8–encoded ORF73 protein, and in situ hybridization of T1.1. Epstein-Barr virus was detected only in Cases 2 and 3 by in situ hybridization. It is interesting that inoculation of a cell line obtained from a primary effusion lymphoma cell in Case 2 to severe combined immunodeficiency mice produced HHV-8–positive and Epstein-Barr virus–negative tumors in inoculated sites. These tumor cells exhibited phenotypes of ALCL that were identical to the subcutaneous tumor cells of this particular patient. These findings clearly show that HHV-8 can associate with solid lymphomas and that it can take anaplastic large cell morphology. Those lymphomas should be distinguished from the classical ALCL as were defined by the revised European-American classification of lymphoid neoplasms even though morphology and a part of immunophenotype mimic that of classical ALCL.

Chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone in patients with refractory cutaneous T-cell lymphoma

This Phase II study was undertaken to assess the efficacy and toxicity of chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone (EPOCH regimen) in patients with advanced, refractory cutaneous T-cell lymphoma (CTCL). Fifteen patients were treated with a 96-hour continuous infusion of etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone, followed by granulocyte-colony stimulating factor support and trimethoprim/sulfamethoxazole prophylaxis. The median age of the patients was 53 years (range, 17-82 years). Six patients had Sézary syndrome (SS), four patients had visceral involvement, and four patients had anaplastic large cell morphology, three with Ki-1 (CD30) positivity. All patients had disease that was refractory to prior chemotherapy or electron beam irradiation and eight of these patients had received cyclophosphamide, doxorubicin, vincristine, and prednisone. Seven patients had received prior interferon therapy and nine patients had received fludarabine and/or 2-CDA. After a median of 5 cycles (range, 1-9 cycles), 4 patients achieved a complete response (27%) and 8 patients achieved a partial response (53%) for an overall response rate of 80% (95% confidence interval, 52-96%). Three patients with visceral involvement, two of three patients with anaplastic large cell morphology, and one patient with human T-cell lymphoma virus leukemia/lymphoma did not respond. All 12 responders had improvement in skin disease; 2 of 6 patients with SS had complete disappearance of circulating Sézary cells. The median progression free survival was 8.0 months (range, 3-22 months). After a median follow-up of 11.4 months (range, 2-56+ months), the median patient survival was 13.5 months. Grade 3 or 4 hematologic toxicity occurred in 8 patients (61%); 5 of these 8 patients had febrile neutropenia. Six patients developed staphylococcal bacteremia, two patients had disseminated herpes infection, and one patient had Pneumocystis carinii pneumonia. Grade 3 neurotoxicity occurred in one patient. Two patients had a significant decrease in left ventricular ejection fraction and one patient had supraventricular tachycardia. EPOCH chemotherapy has a high response rate with acceptable toxicity in patients with advanced and refractory CTCL.

Diffuse Large Cell, B-cell Type Lymphoma with a Novel Translocation (2;22)(p23;q11.2)

We observed a translocation (2;22)(p23;q11.2) in the bone marrow cells of a patient with multiple subcutaneous nodules. Tumor histology and immunohistochemical staining demonstrated a malignant lymphoma, diffuse large cell type, displaying a CD30 negative B cell immunophenotype. To our knowledge, this is the first report of this specific translocation in lymphoma, which may join the site of the anaplastic lymphoma kinase (ALK) gene at 2p23 to the region of the immunoglobulin lambda light chain gene at 22q11.2. The ALK gene was initially identified through its involvement in the t(2;5)(p23;q35) found most commonly in anaplastic large cell lymphoma. This observation in a CD30 negative large cell lymphoma of B cell lineage further extends the relationship of anaplastic large cell morphology, ALK activation, lymphoid lineage, and expression of the CD30 antigen.

Long term prognostic importance of primary Ki-1 (CD30) antigen expression and anaplastic morphology in adult patients with diffuse large-cell lymphoma

We retrospectively assessed the long-term prognostic importance of primary CD30 antigen expression and of anaplastic large-cell morphology (ALCL) in adult patients with previously untreated diffuse large-cell lymphoma (DLCL), including cases of immunoblastic lymphoma, and identified their clinical features. We examined available archival paraffin-embedded or frozen pathologic material and medical records of adult patients with previously untreated DLCL seen at M.D. Anderson Cancer Center (MDACC) between January 1978 and May 1989. Sixty-seven cases of DLCL and seven cases of IBL (a total of seventy-four heretofore referred to as DLCL) were identified. Twenty-two of the 74 patients were positive for the CD 30 antigen. For these 22 patients the rates of complete remission, survival, and time to treatment failure (TTF) were 86%, 82%, and 77%, respectively, at 81 months. When compared with the group of 54 patients which stained negative for CD 30, the long term survival of CD 30-positive DLCL was favorable (82% vs. 49%, p = 0.08). ALCL morphology was present in two-thirds of the patients with CD 30-positive DLCL but did not affect survival and TTF rates. Among patients with CD 30-positive DLCL, 16 patients without skin involvement were younger and had a low failure rate (13%) compared with six patients with skin involvement who were older and had a high failure rate (50%); however, the latter group had a more indolent course after failure and thus both groups had similar survival rates. Primary CD 30 positivity is associated with a favorable long-term prognosis in adult patients with DLCL treated with doxorubicin-containing chemotherapy. ALCL morphology among these patients does not affect the outcome. Patients with CD30-positive DLCL and skin involvement have a higher failure rate than those without skin involvement, but similar overall survival.

Primary gastric CD30 (Ki-1)-positive large cell non-Hodgkin's lymphomas. A clinicopathologic analysis of six cases

The CD30/Ki-1 antigen characterizes a series of non-Hodgkin's lymphomas (NHL) predominantly showing anaplastic large cell (ALCL) morphology and frequently involving the skin and other extranodal sites. In cutaneous large cell lymphomas, the CD30 expression was indicated as a favorable prognostic marker independently from cytology, anaplastic versus nonanaplastic. The stomach is the most common site of extranodal lymphomas in the adult population, but primary gastric CD30+ lymphomas have been reported rarely. The clinical, morphologic, and immunohistochemical features of six cases with primary CD30/Ki-1+ gastric large cell lymphomas were analyzed. The mean age of patients was 64 years with a prevalence of women (M:F ration = 1:2). Patients were assigned to Stage IE or IIE. Three of them died of disease, whereas the others are still alive (mean follow-up, 18 months). Three of six cases had ALCL morphology, whereas other cases had centroblastic, immunoblastic, and high-grade mucosa-associated lymphoid tissue lymphoma. Immunohistochemistry revealed a B-cell phenotype in three of six cases; a T-cell phenotype in one of six cases; and a null, non-B, non-T phenotype in two of six cases. Within CD30+ primary gastric large cell lymphomas, cytology, anaplastic versus nonanaplastic, did not affect clinical presentation and/or prognosis. The survival rate of the patients studied is in keeping with literature reports regarding prognosis of primary high-grade gastric NHL. The findings suggest that clinical behavior of this extranodal lymphoma is more closely related to clinical symptoms and initial stage of disease than to CD30 expression.