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Primary cutaneous large B cell lymphoma, leg type

Primary cutaneous large B cell lymphoma, leg type
Authors:
Eric Jacobsen, MD
Arnold S Freedman, MD
Rein Willemze, MD
Section Editors:
Timothy M Kuzel, MD, FACP
John A Zic, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Jan 2024.
This topic last updated: Jul 30, 2021.

INTRODUCTION — Primary cutaneous B cell lymphoma (PCBCL) refers to cases of B cell lymphoma that present in the skin when there is no evidence of extracutaneous disease at the time of diagnosis and after the completion of an initial staging evaluation. There are three main subtypes of PCBCL with differing clinical presentation, pathologic features, prognosis, and treatment approach:

●Primary cutaneous large B cell lymphoma (PCLBCL), leg type

●Primary cutaneous follicle center lymphoma (PCFCL)

●Primary cutaneous marginal zone lymphoma (PCMZL)

Since B cell lymphomas with similar pathologic features and prognosis may arise at other sites than the legs, the term PCLBCL, leg type is preferred for both lesions on the legs and similar lesions at other skin sites [1].

This topic review will discuss PCLBCL, leg type.

The other PCBCL subtypes and other forms of cutaneous lymphoma (ie, T cell lymphoma) are presented separately:

●(See "Primary cutaneous marginal zone lymphoma".)

●(See "Primary cutaneous follicle center lymphoma".)

●(See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

EPIDEMIOLOGY — Approximately 25 percent of all non-Hodgkin lymphoma cases will present at an extranodal site without systemic involvement. The skin is the second most common primary extranodal site, second in frequency only to the gastrointestinal tract [2]. The overall incidence of primary cutaneous lymphomas in Western countries is estimated to be 0.5 to 1 case per 100,000 people annually, of which approximately 20 percent represent primary cutaneous B cell lymphoma (PCBCL) [3,4].

PCLBCL, leg type comprises approximately 4 percent of all cutaneous lymphomas and 20 percent of all PCBCL [4-6]. The median age at presentation is in the mid to late seventies and is more common in females than in males with a male:female ratio of 1:3 to 4 [5,7-10].

PATHOGENESIS — There are no clearly defined risk factors for developing this disease and there is no identifiable hereditary tendency.

PCLBCL, leg type shows many genetic similarities with diffuse large B cell lymphomas (DLBCL) arising at other sites, but marked differences with primary cutaneous follicle center lymphoma (PCFCL). Interphase fluorescence in situ hybridization (FISH) analysis frequently shows translocations involving MYC, BCL6, and IgH genes in PCLBCL, leg type, but not in patients with a PCFCL [11,12]. Using array-based comparative genomic hybridization (CGH) and FISH analyses, high-level DNA amplifications of 18q21.31 to 18q21.33, including the BCL2 and MALT1 genes, were detected in 67 percent of the cases [13]. Amplification of the BCL2 gene may well explain the strong expression of BCL2 in these cases, particularly because the t(14;18) is not found in these lymphomas. Deletion of a small region on chromosome 9p21.3 containing the CDKN2A and CDKN2B gene loci has been reported in 67 percent of PCLBCL, leg type and is associated with an inferior prognosis [14]. PCLBCL, leg type have the gene expression profile of activated B cell-like DLBCL, while diffuse PCFCL have the gene expression profile of germinal center-like DLBCL [15]. Additionally, 40 percent of PCLBCL, leg type harbored translocations involving PDL1/PDL2, which lead to overexpression of PD-L1 or PD-L2 in 50 percent of the cases [16].

Constitutive activation of nuclear factor-kappa-B (NF-kB) is found consistently in PCLBCL, leg type in association with MYD88 L265P mutations (60 percent) and mutations in different components of the B cell receptor signaling pathway, including CARD11 (10 percent), CD79B (20 percent), and TNFAIP3/A20 (40 percent) [17-20]. Similarities in gene expression profile (eg, NF-kB activating mutations) and cytogenetic alterations overlap with those of ABC-type DLBCL but are most similar to primary central nervous system and primary testicular lymphomas [16,18,21].

CLINICAL FEATURES — Most patients present with red or bluish nodules or tumors on one or both legs, preferentially the lower legs (picture 1A-B). Lesions outside of the lower extremities develop in 10 to 15 percent of cases [5]. Unlike other cutaneous B cell lymphomas, these tumors frequently disseminate to extracutaneous sites. Rare cases showing spontaneous regression have been reported [22,23].

The presence of "B" symptoms, abnormal blood counts, or an elevated lactate dehydrogenase (LDH) should raise suspicion of a systemic lymphoma [24].

PATHOLOGIC FEATURES — The diagnosis of PCLBCL, leg type is made based upon a pathologic evaluation of a skin biopsy in a patient who has no evidence of systemic lymphoma upon staging studies. (See 'Staging' below.)

Morphology — Skin biopsy specimens are characterized by a diffuse non-epidermotropic infiltrate, which often extends into the subcutaneous tissue. These infiltrates generally show a monotonous population or large confluent sheets of centroblasts (large follicle center cells with round nuclei and prominent nucleoli) and/or immunoblasts that spare the epidermis (picture 2 and picture 3). Frequent mitotic figures can be seen. Reactive T cells, which are few in number, are confined to the perivascular areas.

Immunophenotype — Evaluation of the biopsy material with immunohistochemical stains is a key component of the diagnostic evaluation of cutaneous lymphoma. At this time, flow cytometry cannot be routinely recommended as a replacement for immunohistochemical studies. This is principally because of the difficulty associated with making a single-cell suspension with this tumor type.

The normal counterpart of PCLBCL, leg type is unclear, although it has a gene expression profile similar to an activated (post-germinal center) B cell [15]. The neoplastic cells express B cell markers (eg, CD19, CD20, CD22, and CD79a) and may express surface or cytoplasmic monotypic immunoglobulin (Ig). One study has demonstrated cytoplasmic IgM expression by the tumor cells in all 40 cases of PCLBCL, leg type, but in only 5 of 53 primary cutaneous follicle center lymphomas (PCFCL) [25]. In a subsequent study, cytoplasmic IgM was expressed by all cases of PCLBCL, leg type, but not in any of the cases of PCFCL [26]. Clonal rearrangement of Ig genes has been demonstrated.

In contrast to (diffuse) PCFCL, protein expression of BCL2, MUM1, and FOXP1 is common (picture 4 and picture 3) [9,27,28], although the chromosomal translocation t(14;18) which often leads to BCL2 overexpression is not commonly seen [27,29]. However, up to 10 percent of cases may not express BCL2, MUM1, or FOXP1. BCL6 is frequently positive [28]. CD10 staining is usually negative. PCLBCL, leg type, but not PCFCL, shows strong nuclear expression of MYC [12,30]. MYC rearrangements have been demonstrated in 13 to 43 percent of PCLBCL, leg type, with a second rearrangement of the BCL6 gene in rare cases, but there is no correlation between MYC expression and MYC rearrangements [11,12,18]. In one study, the presence of a MYC rearrangement was associated with reduced survival [12].

DIAGNOSIS — The diagnosis of PCLBCL, leg type requires a representative biopsy. Excisional biopsies are preferred to punch biopsies, but if a punch biopsy is taken, the diameter should be at least 4 millimeters. The biopsy specimen is evaluated for morphology, growth pattern, and immunohistochemical studies. Immunohistochemical studies should be performed on paraffin sections and include testing for BCL2, MUM1, MYC, and both IgM and Ig light chains. We also perform immunohistochemical staining for FOXP1, when available. We do not routinely perform fluorescence in situ hybridization (FISH) studies on suspected cases of PCLBCL, leg type.

Importantly, lesions with this characteristic appearance are classified as PCLBCL, leg type regardless of their anatomic location.

DIFFERENTIAL DIAGNOSIS

Systemic lymphoma — An estimated 6 to 10 percent of patients with systemic B cell non-Hodgkin lymphoma will develop cutaneous disease at some point in their illness [31,32]. The key to differentiating systemic diffuse large B cell lymphoma from PCLBCL is a thorough staging evaluation. (See 'Staging' below and "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Diagnosis'.)

Primary cutaneous follicle center lymphoma (PCFCL) — PCFCL may show a follicular (less than 5 percent), follicular and diffuse (30 percent), or diffuse growth pattern (65 percent) [9]. In particular, differentiation between diffuse PCFCL and PCLBCL, leg type may sometimes be difficult but is extremely important because of the therapeutic and prognostic consequences. Differentiation should always be based on a combination of histological, immunophenotypical, and clinical criteria (table 1). In contrast to PCLBCL, leg type, PCFCL characteristically show a proliferation of large cleaved cells (large centrocytes), which generally do not express BCL2, MUM1, FOXP1, MYC, and cytoplasmic IgM, and 85 percent of patients present with localized skin lesions on the head (in particular the scalp) or trunk. Additional histological criteria favoring a diagnosis of PCFCL include a considerable proportion of admixed T cells, the presence of a stromal reaction and demonstration of (remnants of) follicular dendritic cell networks. (See "Primary cutaneous follicle center lymphoma".)

Primary cutaneous marginal zone lymphoma (PCMZL) — PCMZL can be distinguished from PCLBCL, leg type histologically. While PCMZL consists primarily of small cells with irregular nuclei, PCLBCL, leg type has a large component of centroblasts or large cells (table 1). (See "Primary cutaneous marginal zone lymphoma".)

Cutaneous T cell lymphoma — Cutaneous T cell lymphomas can be distinguished from cutaneous B cell lymphomas through their expression of T cell markers such as CD2, CD3, and CD5. Aberrant expression of B cell markers (CD20, CD79a) can occasionally be found in advanced stages of mycosis fungoides and may raise confusion. In such cases, lineage analysis by immunoglobulin or T cell receptor (TCR) gene rearrangement studies may facilitate a correct diagnosis. This is discussed in more detail separately. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Diagnosis'.)

Intravascular lymphoma — Intravascular large B cell lymphoma, formerly also known as malignant angioendotheliomatosis, is a distinctly uncommon non-Hodgkin lymphoma variant that typically presents as multiple, erythematous tender nodules, tumors, or telangiectasias in older patients. Isolated involvement of the skin does occur, but the disease more frequently affects multiple organ systems, including the central nervous system (CNS), producing a wide variety of symptoms, ranging from confusion or dementia to focal motor and sensory deficits. This is discussed in more detail separately. (See "Intravascular large B cell lymphoma".)

Iatrogenic immunodeficiency-associated lymphoproliferative disorders — The 2016 revision of the World Health Organization (WHO) classification includes the diagnosis, "other iatrogenic immunodeficiency-associated lymphoproliferative disorders," which includes lymphoid proliferations or lymphomas that develop in patients treated with immunosuppressive drugs (eg, methotrexate) for the management of autoimmune diseases or conditions other than transplantation [1,5]. These lymphoproliferative disorders commonly involve extranodal sites, including the skin. Diffuse large B cell lymphoma is the most common histology in this setting. Primary cutaneous large B cell lymphomas that develop in this setting often express CD20 and CD30 (but not CD15) and variably demonstrate positivity for Epstein-Barr virus [30].

STAGING — Patients with suspected PCLBCL should undergo staging with history, physical examination, and positron emission tomography (PET)/computed tomography (CT) to exclude involvement of other sites and guide treatment. This staging evaluation is described in more detail separately. (See "Primary cutaneous follicle center lymphoma", section on 'Staging'.)

We generally reserve bone marrow aspiration and biopsy for patients with equivocal results from PET/CT or to evaluate unexplained cytopenias.

TREATMENT — PCLBCL, leg type is a rare disorder; accordingly, large trials regarding therapy are lacking. The published data regarding treatment consist entirely of retrospective reviews and anecdotal reports.

PCLBCL, leg type is widely reported to have a more aggressive clinical course than other categories of primary cutaneous B cell lymphoma (PCBCL). In contrast to primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous marginal zone lymphoma (PCMZL), which have estimated five-year survival rates of over 95 percent [9,33,34], PCLBCL, leg type has an estimated five-year survival rate of between 41 and 66 percent, with higher rates reported since the more routine incorporation of rituximab [7,9,10,35-37]. While a watch-and-wait approach or treatment with localized therapy is often appropriate for other types of PCBCL, patients with PCLBCL, leg type require a more aggressive approach with combination chemotherapy.

Our treatment approach is largely based upon observations from the largest literature review that reported outcomes of 164 patients with PCLBCL, leg type treated with different modalities as described below [38]. In addition, we integrate high-quality evidence from the treatment of systemic diffuse large B cell lymphoma (DLBCL) discussed separately. (See "Initial treatment of advanced stage diffuse large B cell lymphoma".)

●Multiagent chemotherapy – Twenty-six of 32 patients with PCLBCL reported in the literature treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CHOP-like, or COP (cyclophosphamide, vincristine, and prednisone) regimens achieved a complete response. Of those, a little over half have relapsed at an undefined length of follow-up.

Another series of 12 patients treated with rituximab plus anthracycline-containing chemotherapy (eg, CHOP) reported a complete response in all but one patient (92 percent) with only one reported relapse.

●Rituximab – Cumulative data on 13 patients treated with systemic single-agent rituximab, mostly in the setting of relapsed disease, demonstrates complete response rates of 40 to 50 percent. Long-term follow-up on relapse rates is not available.

●Radiation therapy – Compilation of data on 101 patients treated with radiation revealed an 88 percent complete response rate. Relapses were seen in 52 patients (58 percent); extracutaneous progression was seen in approximately 30 percent.

We treat patients with PCLBCL in a similar fashion to patients with limited stage systemic DLBCL. For patients with PCLBCL, we suggest treatment with rituximab plus an anthracycline-based combination chemotherapy regimen (eg, R-CHOP) (table 2) followed by involved-field radiation therapy rather than either of these modalities alone. The data supporting this approach in DLBCL is presented separately. (See "Initial treatment of advanced stage diffuse large B cell lymphoma".)

This approach is generally consistent with those proposed by the International Society for Cutaneous Lymphoma, International Lymphoma Radiation Oncology Group, and the National Comprehensive Cancer Network (NCCN) [38-41].

ASSESSING DISEASE RESPONSE — We evaluate and restage patients 8 to 12 weeks after the completion of therapy. Restaging should consist of repeating all laboratory, clinical, and radiographic examinations used to stage the disease at presentation though we typically do not repeat a bone marrow biopsy unless there is suspicion of new bone marrow involvement such as an abnormal complete blood count.

Following the completion of therapy, restaging, and documentation of complete remission, patients are seen at periodic intervals to monitor for treatment complications and assess for possible relapse. The frequency and extent of these visits depends upon the comfort of both the patient and physician. When planning the post-treatment surveillance strategy, care should be taken to limit the number of CT scans, particularly in younger individuals, given concerns about radiation exposure and the risk for second malignancies. (See "Radiation-related risks of imaging".)

For patients who are in complete remission, we typically re-evaluate with a physical examination, complete blood count, lactate dehydrogenase, and comprehensive metabolic profile every three months for the first two years following therapy. The frequency of clinic visits is then decreased thereafter. We do not pursue routine radiographic restaging after a patient has attained a complete remission in order to limit the number of CT scans, particularly in younger individuals, given concerns about radiation exposure and the risk for second malignancies. Unlike systemic diffuse large B cell lymphoma, relapse of PCLBCL, leg type almost invariably occurs in the leg of initial involvement with or without regional lymph node involvement. More widespread nodal involvement without skin lesions is exceptional.

TREATMENT AT RELAPSE — More than half of patients will relapse. The median length of remission is largely unknown. In one large series of PCLBCL, leg type 27 of 58 patients had developed extracutaneous disease and 26 of 58 patients had died as a result of lymphoma after a median follow-up of 26 months [9]. The overall and disease-specific five-year survival rates were 37 and 50 percent, respectively. Lenalidomide and ibrutinib show activity in relapsed PCLBCL, leg type but experience is limited [42-44]. Relapsed disease should be approached in much the same way as relapsed diffuse large B cell lymphoma as discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

PROGNOSIS — PCLBCL, leg type is widely reported to have a more aggressive clinical course than other categories of primary cutaneous B cell lymphoma. Unlike other cutaneous B cell lymphomas, these tumors frequently disseminate to extracutaneous sites. Retrospective analyses have reported estimated five-year survival rates of between 41 and 66 percent, with the higher rates reported since the more routine incorporation of rituximab [7,9,10,35-37]. No difference in survival is found between PCLBCL, leg type presenting on the leg(s) and PCLBCL, leg type arising at other sites, nor between cases with or without expression of BCL2 and/or MUM1/IRF4 [9,45]. The presence of multiple skin lesions at diagnosis is, however, a significant adverse risk factor [7,9]. In analyses that included 58 patients with a PCLBCL, leg type, patients presenting with solitary, localized, or generalized skin lesions had estimated rates of five-year disease-specific survival of 75, 49, and 0 percent, respectively, and five-year overall survival of 70, 27, and 0 percent, respectively [9,46]. Inactivation of CDKN2A either by deletion or hypermethylation and the presence of MYD88 L265P mutation has been found to be an unfavorable prognostic factor [14,19].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary cutaneous lymphoma".)

SUMMARY AND RECOMMENDATIONS

●Primary cutaneous B cell lymphoma (PCBCL) refers to those cases of B cell lymphoma that present in the skin when there is no evidence of extracutaneous disease at the time of diagnosis and after the completion of an initial staging evaluation. Primary cutaneous large B cell lymphoma (PCLBCL), leg type is the most aggressive form of PCBCL. (See 'Introduction' above and 'Epidemiology' above.)

●Most patients with PCLBCL, leg type present with red or bluish nodules on one or both legs (picture 1A-B). Ten to 15 percent will develop outside of the lower extremities. This terminology could understandably be confusing, since a patient can sometimes be diagnosed with PCLBCL, leg type without having any lesions on the leg. (See 'Clinical features' above.)

●The diagnosis of PCLBCL, leg type requires a representative biopsy of involved skin and the exclusion of non-cutaneous disease in the appropriate clinical setting. Lesions with a diffuse pattern or a monotonous proliferation of large cells with round nuclei (centroblasts and immunoblasts) (picture 2) and expression of BCL2 (picture 4) and MUM1 are classified as PCLBCL, leg type regardless of their anatomic location. (See 'Pathologic features' above and 'Diagnosis' above and 'Differential diagnosis' above.)

●The staging evaluation confirms the diagnosis by excluding involvement of other sites and provides information to guide treatment. (See "Primary cutaneous follicle center lymphoma", section on 'Staging'.)

●PCLBCL, leg type is a rare disorder; accordingly, large trials are lacking. The published data regarding treatment consist entirely of retrospective reviews and anecdotal reports.

●We treat patients with PCLBCL, leg type in a similar fashion to patients with limited stage systemic diffuse large B cell lymphoma (DLBCL). For patients with PCLBCL, leg type, we suggest treatment with rituximab plus an anthracycline-based combination chemotherapy regimen (eg, R-CHOP) (table 2) followed by involved-field radiation therapy rather than any of these modalities alone (Grade 2B). Given the aggressive nature of this disease, neither surgical excision nor observation is an appropriate treatment modality. (See 'Treatment' above.)

●More than half of patients will relapse and extracutaneous relapses are not uncommon. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

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Topic 4715 Version 28.0

References

1 : The 2016 revision of the World Health Organization classification of lymphoid neoplasms.

2 : Some statistical data, diagnosis, and staging of cutaneous B-cell lymphomas.

3 : Cutaneous lymphomas reported to the National Cancer Institute's surveillance, epidemiology, and end results program: applying the new WHO-European Organisation for Research and Treatment of Cancer classification system.

4 : The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas.

5 : The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas.

6 : Cutaneous lymphoma incidence patterns in the United States: a population-based study of 3884 cases.

7 : Primary cutaneous diffuse large B-cell lymphoma, leg type: clinicopathologic features and prognostic analysis in 60 cases.

8 : Primary cutaneous large B-cell lymphoma of the leg: histogenetic analysis of a controversial clinicopathologic entity.

9 : Reclassification of 300 primary cutaneous B-Cell lymphomas according to the new WHO-EORTC classification for cutaneous lymphomas: comparison with previous classifications and identification of prognostic markers.

10 : Primary cutaneous large B-cell lymphomas of the legs. A distinct type of cutaneous B-cell lymphoma with an intermediate prognosis. Dutch Cutaneous Lymphoma Working Group.

11 : Molecular cytogenetic analysis of chromosomal breakpoints in the IGH, MYC, BCL6, and MALT1 gene loci in primary cutaneous B-cell lymphomas.

12 : High Incidence and Clinical Significance of MYC Rearrangements in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type.

13 : Array-based comparative genomic hybridization analysis reveals recurrent chromosomal alterations and prognostic parameters in primary cutaneous large B-cell lymphoma.

14 : Fine-mapping chromosomal loss at 9p21: correlation with prognosis in primary cutaneous diffuse large B-cell lymphoma, leg type.

15 : Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling.

16 : Genomic Analyses Identify Recurrent Alterations in Immune Evasion Genes in Diffuse Large B-Cell Lymphoma, Leg Type.

17 : MYD88 somatic mutation is a genetic feature of primary cutaneous diffuse large B-cell lymphoma, leg type.

18 : Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma.

19 : High frequency and clinical prognostic value of MYD88 L265P mutation in primary cutaneous diffuse large B-cell lymphoma, leg-type.

20 : Nuclear factor-κB pathway-activating gene aberrancies in primary cutaneous large B-cell lymphoma, leg type.

21 : Identification of Somatic Mutations in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type by Massive Parallel Sequencing.

22 : Spontaneous regression of primary cutaneous diffuse large B-cell lymphoma, leg type with significant T-cell immune response.

23 : Spontaneous Regression of Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg Type.

24 : Prognostic factors in primary cutaneous lymphomas other than mycosis fungoides and the Sézary syndrome. The French Study Group on Cutaneous Lymphomas.

25 : IgM expression on paraffin sections distinguishes primary cutaneous large B-cell lymphoma, leg type from primary cutaneous follicle center lymphoma.

26 : The expression of IgM is helpful in the differentiation of primary cutaneous diffuse large B cell lymphoma and follicle center lymphoma.

27 : Bcl-2 protein expression is the strongest independent prognostic factor of survival in primary cutaneous large B-cell lymphomas.

28 : New prognostic relevant factors in primary cutaneous diffuse large B-cell lymphomas.

29 : bcl-2 protein expression in primary cutaneous large B-cell lymphoma is site-related.

30 : Methotrexate-associated B-cell lymphoproliferative disorders presenting in the skin: A clinicopathologic and immunophenotypical study of 10 cases.

31 : Skin involvement of malignant B-cell lymphomas.

32 : Primary cutaneous diffuse large B-cell lymphoma, leg type and secondary cutaneous involvement by testicular B-cell lymphoma share identical clinicopathological and immunophenotypical features.

33 : EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer.

34 : Primary cutaneous lymphomas: applicability of current classification schemes (European Organization for Research and Treatment of Cancer, World Health Organization) based on clinicopathologic features observed in a large group of patients.

35 : Primary cutaneous B-cell lymphoma: review and current concepts.

36 : Treatment of primary cutaneous B-cell lymphomas of follicle center cell origin: a clinical follow-up study of 55 patients treated with radiotherapy or polychemotherapy.

37 : Improvement of survival in patients with primary cutaneous diffuse large B-cell lymphoma, leg type, in France.

38 : European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas.

39 : Primary cutaneous B-cell lymphomas: part II. Therapy and future directions.

40 : Modern radiation therapy for primary cutaneous lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group.

41 : Modern radiation therapy for primary cutaneous lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group.

42 : Excellent Outcome of Immunomodulation or Bruton's Tyrosine Kinase Inhibition in Highly Refractory Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type.

43 : A Single-Arm Phase II Trial of Lenalidomide in Relapsing or Refractory Primary Cutaneous Large B-Cell Lymphoma, Leg Type.

44 : Molecular Mechanisms of Disease Progression in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type during Ibrutinib Therapy.

45 : Primary cutaneous large B-cell lymphomas: clinicopathologic features, classification, and prognostic factors in a large series of patients.

46 : 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.

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