Primary Cutaneous Marginal Zone Lymphoma Research Articles

Diffuse Large B-cell Lymphoma, Leg Type

An 81-year-old white woman with a past medical history significant for coronary artery disease and a cerebrovascular accident presented with a large ulcerated tumor on her left ankle of 3 months duration. A skin biopsy was reported as diffuse large B-cell lymphoma. The histology revealed a diffuse infiltrate composed of a monotonous population of large round lymphocytes with features of centroblasts and immunoblasts. Immunostaining showed that the tumor cells were positive for CD20, MUM-1, FOX-P1, IgM, and BCL2 but negative for CD30. Immunostaining for Ki-67 showed that the tumor cells had a high proliferative index. The lesion was treated with radiotherapy, but the patient died 8 months later. There are 3 main types of primary cutaneous B-cell lymphoma: primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT). Primary cutaneous marginal zone lymphoma and primary cutaneous follicle center lymphoma are indolent lymphomas with a 5-year disease-specific survival greater than 95%, whereas PCLBCL-LT represents a more aggressive type of disease with a 5-year disease-specific survival of approximately 50%. PCLBCL-LT has a phenotype similar to the “activated” subtype of nodal diffuse large B-cell lymphoma, which is thought to be a reason for the poor prognosis. The treatment of patients with PCLBCL-LT should be aggressive and polychemotherapy is indicated in most cases.

XV. Primary cutaneous lymphomas

Primary cutaneous lymphomas (PCLs) are defined as non-Hodgkin lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. After the gastrointestinal lymphomas, PCL are the second most common group of extranodal non-Hodgkin lymphomas with an estimated annual incidence of 1/100 000. These PCLs must be distinguished from nodal or systemic malignant lymphomas involving the skin secondarily, which often have another clinical behavior, have a different prognosis and require a different therapeutic approach. In recent lymphoma classifications (WHO-EORTC; WHO 2008) the different types of primary cutaneous T-cell lymphoma (CTCL) and primary cutaneous B-cell lymphoma (CBCL) are therefore included as separate entities (see Table 1) [1, 2]. In the western world, CTCL constitutes 75%–80% of all PCLs and CBCL 20%–25%, but different distributions have been observed in other parts of the world. Within the group of CTCLs roughly three categories can be distinguished: (i) the group of classical CTCLs, including mycosis fungoides (MF), variants or subtypes of MF and Sezary syndrome (SS); (ii) the group of primary cutaneous CD30-positive lymphoproliferative disorders (CD30+ LPD); and (iii) a group of rare often aggressive cutaneous T/NK-cell lymphomas, including subcutaneous panniculitis-like T-cell lymphoma (SPTCL), extranodal NK/T-cell lymphoma, nasal type, and primary cutaneous peripheral T-cell lymphoma, not otherwise specified (PTCLNOS). Well-defined types of CBCL include primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT). Herein, characteristic features of the main types of CTCL and CBCL are summarized and recent observations regarding diagnosis, prognostic factors and treatment are described.

Primary cutaneous marginal zone lymphoma with subclinical cutaneous involvement and biclonality

Primary cutaneous extranodal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT) represents a monoclonal B-cell neoplasm that typically presents with papules, plaques or nodules. We describe a patient with a primary cutaneous MALT lymphoma with unusual clinical features and an unusual immunophenotype. Conventional microscopy together with immunohistochemistry and in-situ hybridization showed the presence of lymphoma in normal-appearing and minimally erythematous skin as well as in clinically involved skin. Furthermore, at least two distinct clones were shown, one of which had κ-light chain restriction, and the other of which had λ-light chain restriction. This case represents a newly described clinical appearance of primary cutaneous MZL and shows that some patients may have more than one neoplastic clone.

Diagnostik primär kutaner B-Zell-Lymphome

Primär kutane B-Zell-Lymphome (PCBCL) sind seltene Erkankungen der Haut. Die drei wichtigsten Subtypen sind die indolent verlaufenden primär kutanen follikulären Lymphome (PCFCL) und die primär kutanen Marginalzonenlymphome (PCMZL) sowie das deutlich aggressiver verlaufende primär kutane diffus großzellige B-Zell-Lymphom des Beines (PCLBCL, LT). Bei der Verdachtsdiagnose PCBCL muss zunächst ein nodales Lymphom mit sekundärer Hautbeteiligung durch entsprechende Staginguntersuchungen ausgeschlossen werden. Die Differenzierung zwischen den einzelnen Subtypen ist in den meisten Fällen mittels Anamnese, Klinik und (Immun)-Histologie möglich. In Einzelfällen erscheinen molekular-biologische Untersuchungen gerechtfertigt.

Simultaneous aberrations of single CDKN2A network components and a high Rb phosphorylation status can differentiate subgroups of primary cutaneous B-cell lymphomas

The cyclin-dependent kinase inhibitor 2A (CDKN2A) gene on chromosome 9p21 encodes p16 (INK4A), the inhibitor of the CDK4/retinoblastoma (Rb) cell proliferation pathway, as well as p14 (ARF), which controls p53-dependent pathways. Inactivation of p16 has previously been associated with the prognostically unfavourable primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT). In this work, we analysed 22 tumors [nine primary cutaneous follicle centre lymphomas (PCFCL), seven primary cutaneous marginal zone lymphomas (PCMZL) and six PCLBCL, LT] not only for alterations of the p16 gene but also for p14, p53 and Rb by fluorescence in situ hybridization (FISH) and immunohistochemistry. In most PCLBCL, LT (4/6) alterations of CDKN2A (two biallelic deletions, one monoallelic deletion and one trisomy 9) and in addition the highest frequency of deletions of p53 (3/6) and Rb (3/6) were detected. p16 was not expressed but very high levels of phosphorylated Rb, indicating a functional effect of genomic CDKN2A alterations on the protein level in PCLBCL, LT. Regarding the p14/p53 axis, PCLBCL, LT showed a variable expression. Neither PCFCL nor PCMZL showed alterations of CDKN2A and also deletions of p53 or Rb were extremely rare in these subtypes. Exclusively in PCMZL, p53 protein was consistently lacking. In conclusion, only PCLBCL, LT is characterized by a high frequency of aberrations of the CDKN2A network components in both important tumor suppressor pathways regulated by the CDKN2A gene. Moreover, PCLBCL, LT appears to be distinguishable from PCMZL not only by its level of p53 expression but also by its stage of Rb phosphorylation. The latter may also apply to a subgroup of PCFCL.

Survival Data for 299 Patients with Primary Cutaneous Lymphomas: A Monocentre Study

The aim of this study was retrospectively to assess the validity of the 2005 WHO-EORTC classification for primary cutaneous lymphomas (PCL) in a large cohort of patients of a single German skin cancer unit. All patients with PCLs consecutively visiting our hospital between January 1980 and December 2005 were included in a retrospective monocentre study, analysing their histological and clinical data. A total of 312 patients fulfilled the inclusion criteria for PCL. In 299 patients clinical information and paraffin material were sufficient for detailed classification. Of the 299 patients, 63% expressed a T-cell and 37% a B-cell phenotype. Mycosis fungoides was the entity with the highest frequency (30.9%), followed by primary cutaneous follicle centre lymphomas (16.9%) and lymphomatoid papulosis (15.9%). The mean follow-up period was 38.4 months. Five-year disease-specific survival was 80.5% for mycosis fungoides, 92.5% in primary cutaneous anaplastic large cell lymphoma, 100% in lymphomatoid papulosis, 98.1% in primary cutaneous follicle center lymphoma, 100% in primary cutaneous marginal zone lymphoma and 63.2% in diffuse large B-cell lymphoma, leg type. Our data are in line with the data collected by the WHO-EORTC. This is further evidence for the reliability of the WHO-EORTC classification and staging system.

Within European margins

In June, 2008, an 88-year-old woman presented to us with a 4-month history of dark red, partly ulcerated cutaneous nodules and plaques on both feet (fi gure A). We suspected large B-cell lymphoma of the leg, cutaneous follicle centre lymphoma, or merkel-cell carcinoma. Full blood count was normal. Serum protein electrophoresis suggested a monoclonal IgG λ band. No antibodies to lymphotropic viruses, Toxoplasma gondii, or Helicobacter pylori were detected, but IgG antibodies to Borrelia burgdorferi were found. Sonography, chest radiography, and whole-body CT were normal. Biopsy samples from the plaques showed dense infi ltrates with CD20-positive lymphocytes mixed with lympho plasmacytoid plasma cells and small reactive lymphocytes (fi gure B). Dutcher bodies (PAS-positive, diastaseresistant nuclear pseudoinclusions found in malignant plasma cells) were observed, and also a monoclonal κ light-chain restriction of plasma cells. The presence of B burgdorferi DNA was shown by PCR targeting of the OspA gene. Sequence analysis of the amplifi ed DNA showed that the strain belonged to the Borrelia afzelii genospecies. Our patient did not recall a tick bite, and she had no history of erythema migrans, borrelia lymphocytoma, acrodermatitis chronica atrophicans, or other symptoms of Lyme borreliosis. Primary cutaneous marginal-zone lymphoma with plasmacytic diff erentiation induced by B afzelii was diagnosed. Ceftriaxone 2 g intravenously for 3 weeks was started. 2 months after the start of treatment, the plaques had substantially regressed. After 18 months, red, scaling, hyperpigmented eczematous lesions persisted only on the left foot. On histological examination, Dutcher bodies were greatly reduced. B burgdorferi antibody titres had decreased. On serum electrophoresis, there was a switch from λ to κ light chain, which was in line with the histological fi ndings of monoclonal κ light chain proliferation. Our patient’s lesions regressed gradually, but erythema was still present after 24 months. This phenomenon of slow regression is also seen in late Lyme borreliosis and suggests that the eff ectiveness of antibiotics might be misinterpreted. Antibiotic therapy should be considered as a fi rst-line treatment option in patients with cutaneous marginalzone lymphoma, in the presence of B burgdorferi infection, or local radiotherapy in doses of 10–50 Gy. We did not give radiotherapy because of our patient’s age and stable disease state. B burgdorferi sensu lato has been shown by PCR in cutaneous B-cell lymphomas in European, but not in American, or Asian patients. Response to antibiotic treatment has been reported. The phylogenetic link to the B afzelii genospecies has not been made for skin lymphomas. In our patient, B afzelii specifi c DNA was reported for the fi rst time in skin lymphoma. The predominant species isolated from acrodermatitis chronica atrophicans and borrelia lymphocytoma in Europe is B afzelii. Since B afzelii is not present in the USA, cutaneous B-cell lymphoma induced by this genospecies is probably a European phenomenon. B burgdorferi serology can be borderline or negative, even in patients with lymphoma with B burgdorferi positive PCR. Acrodermatitis chronica atrophicans is a polyclonal lymphocytic proliferation, but clonal B-cell proliferation has been observed in erythema migrans. Further studies are needed to show whether malignant lympho proliferation is a unique phenomenon of B afzelii or is also induced by other B burgdorferi genotypes.

Primary cutaneous marginal zone lymphoma as a complication of radiation therapy: Case report and review

The occurrence of primary cutaneous B-cell lymphoma at the site of radiation therapy is exceptional. We report herein the case of a primary cutaneous marginal zone lymphoma arising at the site of radiotherapy for breast cancer. A seventy-year-old woman was diagnosed in 2005 with an invasive ductal carcinoma of the left breast, which was treated with surgery, adjuvant chemotherapy, and radiation therapy. Three years later she developed several cutaneous nodules on her left breast, followed by similar lesions on her back. Histologic, immunohistochemistry, and molecular findings were consistent with the diagnosis of cutaneous marginal zone lymphoma. Physical examination was otherwise negative, as well as mammography, total body CT, bone marrow biopsy, and Borrelia serology. To our knowledge, this is the first published case of primary cutaneous marginal zone lymphoma occurring at the site of radiotherapy. Cutaneous surveillance is proposed from the first year after irradiation in order to detect new primary malignancies, including this rare cutaneous neoplasm.

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Symmetrical primary cutaneous marginal zone lymphoma associated with rheumatoid arthritis

Primary cutaneous marginal zone B-cell lymphoma (PCMZL) is an indolent low grade B cell lymphoma of the skin, with lack of extracutaneous involvement at the time of diagnosis. Herein we report the case of a patient with rheumatoid arthritis (RA) who developed symmetrical PCMZL lesions on both ear lobes. Lesions occurring symmetrically on ear lobes are more specific for cutaneous lymphoid hyperplasia (CLH) and this kind of symmetrical localization hasn't been reported for PCMZL before. PCMZL is considered to arise from a background of reactive lymphoid hyperplasia and this case point out the concept of CLH and PCMZL spectrum. Association of marginal zone lymphoma with rheumatoid arthritis and resolution of lesions together with the resolution of symptoms due to rheumatoid arthritis after rituximab therapy is another interesting point for this case. To the best of our knowledge PCMZL associated with RA has not been reported previously.

Characteristics of Cutaneous Marginal Zone Lymphomas With Marked Plasmacytic Differentiation and a T Cell–Rich Background

Primary cutaneous marginal zone lymphoma (MZL) is a common B-cell lymphoma of skin and is characterized by an infiltrate of neoplastic marginal zone B cells typically within the marginal zones of reactive lymphoid follicles and the interfollicular region. However, in our experience, many cases have underemphasized features such as marked plasmacytic differentiation and/or a prominent T-cell component, which may obscure the neoplastic B cells and lead to misdiagnosis. We wanted to draw attention to these features and have studied 15 cases of MZL with marked plasmacytic differentiation, 10 of which had numerous T cells, some with cytologic atypia, and few B cells in the interfollicular region. Plasma cells were monotypic in all cases by in situ hybridization. By polymerase chain reaction, 6 of 8 T cell-rich cases had an IGH gene rearrangement, and none were clonal for T-cell receptor gene. We discuss the terminology, morphologic features, molecular profile, behavior, and differential diagnosis of cutaneous MZL.

Cutaneous Non-Hodgkin's Lymphoma of the Foot: A Rare Case Report

Lymphomas comprise a heterogeneous group of cancers originating in cells of the immune system at different stages of differentiation. Primary cutaneous non-Hodgkin lymphoma of the foot is a rare occurrence. We present a case involving a primary cutaneous marginal zone lymphoma of the foot, and highlight the clinical recognition and treatment of this condition. 4.

Castleman’s disease with numerous mantle zone lymphocytes with clear cytoplasm involving the skin: case report

Castleman's disease (CD) is an unusual lymphoid hyperplasia occurring in the mediastinal lymph nodes and, less frequently, in the neck lymph nodes. CD is classified clinically into a unicentric and a multicentric type, whereas three histomorphological variants are recognized: the hyaline vascular type, the intermediate type and the plasma cell type. We report the clinical and pathological features of a 54-year-old female suffering with multiple sclerosis and developing a lymph node hyaline-vascular type CD relapsing in the skin after 24 months. Histological features showed a nodular dermatitis with atrophic germinal centers and an 'onion skin' rimming of lymphocytes in the mantle zone with numerous mantle zone lymphocytes with clear cytoplasm, with a CD20+, CD79a+, IgM+, IgG-, IgA-, CD5-, CD10-, CD43-, CD45RO-, bcl-2+ and bcl-6- phenotype with polytypic nature supporting the diagnosis of lymphoid variant of hyaline-vascular CD. This case shows that skin CD recapitulates all the histological variants of lymph node CD. Considering the many similarities between the present case and the primary cutaneous marginal zone lymphoma, it is important to bear in mind this atypical lymphoproliferative disorder in order to avoid overdiagnosis and overtreatment.

Applying the new TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome in primary cutaneous marginal zone lymphoma

Applying the new TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome in primary cutaneous marginal zone lymphoma

Persistent CD20-negative primary cutaneous marginal zone lymphoma after treatment with intralesional rituximab therapy

Persistent CD20-negative primary cutaneous marginal zone lymphoma after treatment with intralesional rituximab therapy

Applying the new TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome in primary cutaneous marginal zone lymphoma

Primary cutaneous marginal zone lymphoma is recognized as a unique subset of low-grade cutaneous B-cell lymphoma with indolent course in the current World Health Organization-European Organization on Research and Treatment of Cancer classification system. However, few large series on this entity have been reported, including the new TNM (tumor, (lymph) node, metastasis) classification for non-mycosis fungoides cutaneous lymphomas. We aimed to characterize the clinical features including new TNM classification for non-mycosis fungoides cutaneous lymphomas, as well as outcomes and responses to therapy in 30 patients with primary cutaneous marginal zone lymphoma. Primary cutaneous marginal zone lymphoma typically presents with deep-seated nodular or papular lesions on the upper extremities or trunk (25/30). Disease course is indolent and none of 30 patients died of disease. Sustainable complete remissions were obtained only in patients with T1a (n = 3) and T2a (n = 1) disease. Most patients have persistent stable disease independent of treatment. Two patients developed systemic disease and 5 developed large cell transformation. The average follow-up time was 63 months (range, 3-204 months). Longer follow-up time is needed to determine whether patients with untreated persistent stable disease are at greater risk relative to patients treated aggressively early in the disease course. Primary cutaneous marginal zone lymphoma is a distinct subtype of marginal zone lymphoma with an indolent disease course. Patients with T1a or T2a disease (ie, single lesions or a localized cluster of lesions) may achieve sustained complete remission, whereas patients with multiple nonlocalized lesions are unlikely to maintain complete remission independent of treatment modality. Systemic involvement is typically preceded by large cell transformation and may be an indication for more systemic therapy. Death from disease is rare.

Inactivation of p16 INK4a /CDKN2A gene may be a diagnostic feature of large B cell lymphoma leg type among cutaneous B cell lymphomas

The World Health Organization-European Organization for Research and Treatment of Cancer has individualized three main categories among the primary cutaneous B cell lymphoma (PCBCL): leg-type primary cutaneous large B cell lymphoma (PCLBCL leg type), primary cutaneous follicle center lymphoma (PCFCL), and primary cutaneous marginal zone lymphoma (PCMZL). The genetic features of 21 PCBCL cases (six PCLBCL leg type four PCFCL large cells, seven PCFCL small cells, and four PCMZL) were investigated by comparative genomic hybridization (CGH array). Fluorescent in situ hybridization (FISH) analysis was performed to confirm CGH array data and to detect lymphoma-associated gene rearrangements. p14(ARF)/p16(INK4a) CDKN2A gene quantification, methylation analysis, and immunohistochemical detection were also performed. CGH array showed a higher number of recurrent genetic imbalances in PCLBCL leg type (mean 62) than in PCFCL large cells (mean 34). PCFCL small cells and PCMZL exhibited fewer chromosomal alterations (mean 24 and 9). FISH analysis provided concordant results with CGH array data in 97% (98 of 101) assays and demonstrated a t(8;14)(q24;q32) in two of six PCLBCL leg type. Recurrent deletions in 9p21 (p14(ARF)/p16(INK4a)CDKN2A) were a constant finding in PCLBCL leg type (six of six). Conversely, PCFCL large cells exhibited recurrent 1p36 deletions (four of four) without deletion in 9p21 (zero of four). The diagnostic and prognostic impact of the p16(INK4a)CDKN2A gene status in PCBCL should therefore be confirmed on a larger series.

Results of Radiotherapy in 153 Primary Cutaneous B-Cell Lymphomas Classified According to the WHO-EORTC Classification

To evaluate the results of radiotherapy in patients with primary cutaneous B-cell lymphoma (CBCL) classified according to the criteria of the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification. Multicenter, 20-year, retrospective, cohort analysis. Eight dermatology departments collaborating in the Dutch Cutaneous Lymphoma Group. From 1985 until 2005, a total of 153 patients with CBCL were initially treated with radiotherapy with curative intent. These cases were classified according to the WHO-EORTC classification and consisted of 25 primary cutaneous marginal zone lymphomas (PCMZLs), 101 primary cutaneous follicle center lymphomas (PCFCLs), and 27 primary cutaneous large B-cell lymphomas, leg type (PCLBCLs, LT). Interventions Local radiotherapy with a median dose of 40 Gy (range, 20-46 Gy) applied to all visible skin lesions. Complete remission rate, relapse rate, 5-year relapse-free survival, 5-year overall survival, and 5-year disease-specific survival. Complete remission was reached in 151 of 153 patients (99%). Relapse rates for PCMZL, PCFCL, and PCLBCL, LT were 60%, 29%, and 64%, and the 5-year disease-specific survival was 95%, 97%, and 59%, respectively. The PCFCLs presenting on the legs had a higher relapse rate (63%) and a much lower 5-year disease-specific survival (44%) than PCFCLs at other sites (relapse rate, 25%; 5-year disease-specific survival, 99%). Radiotherapy is a suitable treatment for a large group of patients with CBCL. However, patients with PCFCL presenting with lesions on the leg and patients with PCLBCL, LT display a more unfavorable clinical course and should therefore be treated with more aggressive treatment modalities.

The applicability and prognostic value of the new TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome: results on a large cohort of primary cutaneous B-cell lymphomas and comparison with the system used by the Dutch Cutaneous Lymphoma Group

Recently, a consensus proposal was published for a TNM classification system for all primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome, meant to document extent of disease in a consistent manner. The applicability and the prognostic significance of this system have not been investigated thus far. To test the applicability and prognostic relevance of the proposed TNM classification system on a cohort of primary cutaneous B-cell lymphomas (CBCL). The study group included 71 primary cutaneous marginal zone lymphomas (PCMZL), 171 primary cutaneous follicle centre lymphomas (PCFCL) and 58 primary cutaneous diffuse large B-cell lymphomas, leg type (PCLBCL, LT). As only patients with primary cutaneous lymphoma were included (T1-3, N0M0), only the T-rating was scored. The results were compared with the scoring as applied by the Dutch Cutaneous Lymphoma Group. The system was easily applicable to all cases. In PCMZL and PCFCL no correlation was found between T-score and survival (5-year disease-specific survival: T1, 100% and 98%; T2, 94% and 93%; T3, 100% and 88%, respectively). In PCLBCL, LT there was a clear, although statistically not significant, association between increasing T-score and reduced survival (5-year disease-specific survival: T1, 75%; T2, 49%; T3, 0%; P = 0.077). Comparing the TNM system with the Dutch Cutaneous Lymphoma Group system, there was a discrepancy in the classification of 20 cases. The new TNM system is a useful tool to document disease extent in patients with CBCL and provides prognostic information in the group of patients with PCLBCL, LT.

High frequency of primary cutaneous lymphomas associated with lymphoproliferative disorders of different lineage

In patients suffering from primary cutaneous lymphomas, secondary malignancies of various origin may develop. However, the frequency of a second neoplasm deriving from another lymphoid lineage is still unclear and may be underestimated. We screened all our patients with primary cutaneous lymphomas from a 4-year recruitment period for a coexisting secondary lymphoproliferative disorder. The cohort comprised of a total of 82 patients with primary cutaneous lymphomas, 62 with primary cutaneous T-cell lymphoma (CTCL), 18 with primary cutaneous B-cell lymphomas, and two with CD4+/CD56+ hematodermic neoplasm/blastic lymphomas. Seven patients (8.5%) were identified with a coexisting lymphoma of a different lymphoid lineage. Four patients with Sézary syndrome (SS) suffered from systemic B-cell lymphoma. Two of these developed SS after chemotherapy of their B-cell lymphoma. The other three patients with various types of skin lymphomas (SS, Mycosis fungoides [MF], primary cutaneous marginal zone lymphoma) developed Hodgkin's disease (hairy cell leukemia). Our data indicate that patients with primary cutaneous lymphomas have an elevated risk for the development of a secondary lymphoproliferative disorder even without previous chemotherapy. Possible explanations for this association include a genetic predisposition, alterations in early progenitor cells, underlying viral infections, and/or stimulation of a B-cell clone by the malignant helper T cells of the primary CTCL and vice versa.