Primary cutaneous diffuse large B cell lymphoma, leg type

INTRODUCTION — 

Primary cutaneous B cell lymphoma (PCBCL) refers to cases of B cell lymphoma that present in the skin, with no evidence of extracutaneous disease after completing the initial staging evaluation. There are three main subtypes of PCBCL, which have different clinical presentations, pathologic features, prognosis, and management:

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

●Primary cutaneous follicle center lymphoma (PCFCL)

●Primary cutaneous marginal zone lymphoma (PCMZL)

PCDLBCL, leg type is the least common subtype of PCBCLs. It is usually aggressive, and it is associated with a poor prognosis. PCDLBCL, leg type presents most often on the legs, but B cell lymphomas with similar pathologic features and prognosis can arise at other cutaneous sites. The term PCDLBCL, leg type is preferred both for lesions on the legs and similar lesions at other skin sites.

This topic discusses PCDLBCL, leg type.

Related topics include:

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

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

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

EPIDEMIOLOGY — 

PCDLBCL, leg type is an uncommon subtype of cutaneous lymphoma that typically presents in older adults.

One-quarter of cases of non-Hodgkin lymphoma (NHL) present at an extranodal site without evidence of systemic involvement. The skin is the second most common primary extranodal site, second in frequency only to the gastrointestinal tract. The incidence of primary cutaneous lymphomas in Western countries is estimated to be 0.5 to 1 case per 100,000 people annually, of which 30 percent represent primary cutaneous B cell lymphomas (PCBCLs) [1-4].

PCDLBCL, leg type comprises 4 percent of all cutaneous lymphomas and up to 20 percent of all PCBCLs [2,4]. The median age at presentation is the mid to late 70s, and it is more common in females than in males (male:female ratio of 1:3 to 4) [5-9].

There is no identifiable hereditary tendency or clearly defined risk factors for development of PCDLBCL, leg type.

PATHOBIOLOGY — 

PCDLBCL, leg type is considered a type of nongerminal center B cell (non-GCB)/activated B cell (ABC) lymphoma that shares genetic similarities with diffuse large B cell lymphomas (DLBCLs) that arise at other sites.

Most cases of PCDLBCL, leg type exhibit activation of nuclear factor-kappa-B (NFkB) and/or the B cell receptor signaling pathway. The gene expression profile is like that of non-GCB/ABC DLBCL [10], but the normal counterpart of PCDLBCL, leg type is uncertain.

Processes that appear to contribute to the pathobiology of PCDLBCL, leg type include:

●NFkB activation – Constitutive activation of NFkB is found consistently in PCDLBCL, leg type in association with MYD88 L265P mutation (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) [11-15].

●Cytogenetics – Translocations involving MYC, BCL6, and IgH are frequently found by interphase fluorescence in situ hybridization (FISH) [16,17]. One-half of cases of PCDLBCL, leg type overexpress PD-L1 or PD-L2, and translocations involving PDL1/PDL2 are found in 40 percent of all cases [18].

High-level deoxyribonucleic acid (DNA) amplifications of 18q21.31 to 18q21.33 that include the BCL2 and MALT1 loci were detected in 67 percent of the cases by array-based comparative genomic hybridization (CGH) and FISH analyses [19]. Amplification of BCL2 may account for 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 PCDLBCL, leg type and is associated with an inferior prognosis [20].

●Mutational profile – PCDLBCL, leg type shares molecular/cytogenetic features with DLBCL of MCD/C5 type and lymphomas that arise in immune-privileged sites, such as the primary central nervous system and primary testicular lymphomas [12,18,21-23].

Cell of origin may be more heterogeneous than non-GCB/ABC alone. One study reported frequent mutations of MYD88 and CD79B, but this case series included a large number of unclassified or atypical cases (ie, triple positivity [CD10, BCL6, IRF4/MUM1]) by Hans algorithm or atypical gene expression profile [24]. Some cases of PCDLBCL, leg type may be TdT positive, but this should not prompt reclassification as a B lymphoblastic neoplasm [25,26].

CLINICAL PRESENTATION — 

Most patients present with red or bluish nodules or tumors on one or both legs, most often on the lower legs (picture 1 and picture 2). Lesions at sites other than the lower extremities develop in 10 to 15 percent of cases [2].

Unlike other cutaneous B cell lymphomas, these tumors frequently disseminate to extracutaneous sites. Rare cases showing spontaneous regression have been reported [27,28].

The presence of constitutional "B" symptoms (ie, unexplained fever, drenching sweats, weight loss), abnormal blood counts, or an elevated lactate dehydrogenase should raise suspicion of a systemic lymphoma [29].

EVALUATION — 

The patient is evaluated clinically, a diagnostic skin biopsy specimen is obtained, and staging studies are used to exclude other categories of lymphomas.

Clinical and laboratory

●Clinical – History should include the duration of skin lesions and presence of constitutional symptoms (ie, unexplained fevers, drenching sweats, weight loss). Physical examination includes a complete skin examination for skin nodules and an evaluation for lymphadenopathy and/or organomegaly.

●Laboratory studies

•Hematology – Complete blood count (CBC) with differential count

•Serum chemistries – Comprehensive metabolic panel, including lactate dehydrogenase

•Infectious – Hepatitis B, hepatitis C, human immunodeficiency virus (HIV) testing

•Other

-Flow cytometry of peripheral blood should be performed if there is lymphocytosis on CBC.

-Bone marrow examination is generally reserved for patients with equivocal results from positron emission tomography (PET)/computed tomography (CT) or to evaluate unexplained cytopenias.

-Pregnancy test, if clinically applicable.

Imaging — PET/CT is obtained to confirm that disease is limited to skin, thereby excluding other categories of lymphoma.

Contrast-enhanced CT of chest/abdomen/pelvis is obtained, if clinically indicated.

Skin biopsy — An adequate biopsy specimen is required for diagnosis. Excisional biopsies are preferred, but if a punch biopsy is taken, the diameter should be ≥4 millimeters. Shave biopsies are inadequate for diagnosis.

The skin biopsy specimen is evaluated for:

●Microscopy – Morphology and growth pattern.

●Immunohistochemistry – Immunohistochemical studies should be performed on paraffin sections. Flow cytometry is not routinely used because it is difficult to make single-cell suspensions with this tumor type.

Immunohistochemical studies should include BCL2, MUM1, MYC, FOXP1, immunoglobulin M (IgM), and Ig light chains.

●Cytogenetics/mutation analysis – Fluorescence in situ hybridization studies are performed to evaluate for MYC, BCL6, and BCL2 translocations.

Pathologic findings of PCDLBCL, leg type are described below. (See 'Pathology' below.)

PATHOLOGY

Morphology — Skin lesions are characterized by a diffuse nonepidermotropic infiltrate, which often extends into the subcutaneous tissue.

Skin infiltrates generally show large confluent sheets or a monotonous population of centroblasts (large follicle center cells with round nuclei and prominent nucleoli) and/or immunoblasts that spare the epidermis (picture 3 and picture 4). Frequent mitotic figures can be seen. Reactive T cells, which are few in number, are confined to the perivascular areas.

Immunophenotype — The immunophenotype demonstrates B cell lineage.

The neoplastic cells express B cell markers (eg, CD19, CD20, CD22, and CD79a) and may express monotypic surface or cytoplasmic immunoglobulin (Ig). One study demonstrated tumor cell expression of cytoplasmic IgM in all 40 cases of PCDLBCL, leg type [30]; another study reported cytoplasmic IgM in all 10 cases of PCDLBCL, leg type [31].

There is strong nuclear expression of MYC [17,32].

Protein expression of BCL2, MUM1, and FOXP1 is common (picture 5 and picture 4), but up to 10 percent of cases may not express these antigens [8,33,34]. BCL6 is frequently positive, while CD10 staining is usually negative [34].

Cytogenetics — Many cases have rearrangements of MYC.

MYC rearrangements have been demonstrated in 13 to 43 percent of PCDLBCL, leg type, but there is no correlation between MYC rearrangements and MYC expression; rarely, second rearrangements of BCL6 are seen [12,16,17]. In one study, the presence of a MYC rearrangement was associated with reduced survival [17].

A high prevalence of MYD88 L265P mutation has been reported in patients with PCDLBCL, leg type and is associated with inferior clinical outcomes [13,35].

The t(14;18) chromosomal translocation, which is often associated with BCL2 overexpression in other lymphomas, is not commonly seen in PCDLBCL, leg type [33,36].

There is clonal rearrangement of Ig genes.

STAGING — 

Careful staging of PCDLBCL, leg type is required to exclude other types of lymphoma.

Staging is based on history, physical examination, laboratory studies, and imaging, including positron emission tomography (PET)/CT.

Some experts perform bone marrow examination in all patients with PCDLBCL, leg type; others perform bone marrow examination only in patients with equivocal results from PET/CT or to evaluate unexplained cytopenias.

Details of the staging evaluation are discussed above. (See 'Evaluation' above.)

DIAGNOSIS — 

PCDLBCL, leg type should be suspected in patients with cutaneous nodules or tumors on legs or at other sites.

Diagnosis is based on a skin biopsy that demonstrates the characteristic morphology and immunophenotype of a large B cell lymphoma in a patient with no evidence of systemic lymphoma after completion of initial staging. Regardless of their anatomic location, lesions with these characteristics are classified as PCDLBCL, leg type.

Both the World Health Organization 5^th edition (WHO5) and the International Consensus Classification (ICC) classify PCDLBCL, leg type as a distinct category of lymphoma and apply the same diagnostic criteria [37,38].

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of PCDLBCL, leg type includes systemic lymphomas and other categories of cutaneous B cell and T cell lymphomas.

Systemic lymphoma — PCDLBCL, leg type is distinguished from systemic lymphomas by the absence of extracutaneous involvement after a thorough staging evaluation.

An estimated 6 to 10 percent of patients with systemic B cell non-Hodgkin lymphoma (NHL) develop cutaneous disease at some point in their illness [39,40]. PCDLBCL, leg type shows morphologic, immunophenotypic, and cytogenetic similarities with diffuse large B cell lymphomas (DLBCLs) arising at other sites. Staging evaluation to exclude other sites of involvement is described above. (See 'Staging' above.)

Primary cutaneous follicle center lymphoma — Primary cutaneous follicle center lymphoma (PCFCL) must be distinguished from PCDLBCL, leg type because of important therapeutic and prognostic differences.

These cutaneous B cell lymphomas share certain histologic features, but they can be distinguished by clinical, immunophenotypic, and molecular findings, including (table 1):

●Clinical – Approximately 85 percent of patients with PCFCL present with localized skin lesions on the head (scalp, face, or forehead) or trunk; by contrast, most cases of PCDLBCL, leg type present on one or both legs.

PCFCL is generally indolent or slow growing, whereas PCDLBCL, leg type is more aggressive and associated with a poor prognosis and extracutaneous relapse in up to one-half of patients [8].

●Histology – PCFCL may show a follicular (<5 percent), follicular and diffuse (30 percent), or diffuse growth pattern (65 percent) [8]. By contrast to PCDLBCL, leg type, PCFCL histology characteristically shows proliferation of large cleaved cells (large centrocytes). Other features that favor a diagnosis of PCFCL include a considerable proportion of admixed T cells, a stromal reaction, and remnants of follicular dendritic cell networks.

●Immunophenotype – Malignant cells of PCFCL generally do not express BCL2, MUM1, FOXP1, MYC, and cytoplasmic IgM. By contrast, protein expression of BCL2, MUM1, and FOXP1 is common with PCDLBCL, leg type [8,33,34].

One study demonstrated cytoplasmic IgM expression by tumor cells in all 40 cases of PCDLBCL, leg type but in only 5 of 53 cases of PCFCL [30]. In another study, cytoplasmic IgM was expressed by all cases of PCDLBCL, leg type but in none of the cases of PCFCL [31].

●Molecular – Mutations of MYD88 and/or CD79B are uncommon with PCFCL, whereas these mutations are common in PCDLBCL, leg type.

The gene expression profiles differ between PCFCL and PCDLBCL, leg type [10].

Further details of the diagnosis of PCFCL are presented separately. (See "Primary cutaneous follicle center lymphoma".)

Primary cutaneous marginal zone lymphoma — Primary cutaneous marginal zone lymphoma (PCMZL) is distinguished from PCDLBCL, leg type based on histology.

While PCMZL consists primarily of small cells with irregular nuclei, PCDLBCL, leg type has a large component of centroblasts or large cells (table 1). Other aspects of the diagnosis of PCMZL are presented separately. (See "Primary cutaneous marginal zone lymphoma".)

Cutaneous T cell lymphoma — Cutaneous T cell lymphomas (CTCLs) are distinguished from PCDLBCL, leg type by expression of characteristic T cell markers.

CTCLs generally express T cell markers, such as CD2, CD3, and CD5, and have T cell receptor (TCR) rearrangements. Some cases of mycosis fungoides (MF) express CD30, which is not expressed by cutaneous B cell lymphomas.

Aberrant expression of B cell markers (CD20, CD79a) can occasionally be found in advanced stages of MF and may raise confusion. In such cases, lineage analysis of Ig versus TCR can facilitate a correct diagnosis, as discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Diagnosis'.)

Intravascular lymphoma — Intravascular large B cell lymphoma (formerly called malignant angioendotheliomatosis) is a rare B cell NHL that typically presents in older adults as multiple, erythematous, tender nodules, tumors, or telangiectasias.

Intravascular large B cell lymphoma can affect multiple organ systems, including the central nervous system, producing a wide variety of symptoms, ranging from confusion or dementia to focal motor and sensory deficits. It is distinguished from PCDLBCL, leg type by the location of lymphoma cells in intravascular spaces.

Isolated involvement of the skin occurs in one-quarter of cases of intravascular lymphoma. Cases of skin-only intravascular lymphoma are reported to have a better prognosis than the systemic variant, as discussed separately. (See "Intravascular large B cell lymphoma".)

B cell lymphoproliferative disorders — There are various categories of B cell lymphoproliferative disorders related to viral infections, immunodeficiencies, and iatrogenic causes that should be distinguished from PCDLBCL, leg type.

The most common histology is that of DLBCL, and these disorders commonly involve extranodal sites, including skin. Primary cutaneous DLBCLs that develop in that setting often express CD20 and CD30 (but not CD15) and variably demonstrate positivity for Epstein-Barr virus (EBV) [32]. Lymphomatoid granulomatosis is a rare angiocentric and angiodestructive lymphoproliferative disease composed of a variable number of EBV-positive B cells admixed with reactive T cells; pulmonary involvement is required for the diagnosis [41]. EBV-positive mucocutaneous ulcer manifests as a solitary lesion (usually of oropharyngeal mucosa); cutaneous presentations are usually associated with iatrogenic immunosuppression [42,43]. Other lymphoproliferative disorders are associated with HIV or KSHV (Kaposi sarcoma-associated herpesvirus)/HHV8 (human herpesvirus 8) infection [37,38].

It should be noted that these lymphoproliferative disorders have modest differences in labels and diagnostic criteria by the World Health Organization 5^th edition (WHO5) and the International Consensus Classification (ICC) systems [37,38].

MANAGEMENT — 

For most patients with PCDLBCL, leg type, we suggest R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) (table 2), with or without radiation therapy (RT), rather than observation, surgery alone, other chemoimmunotherapy regimens, or RT alone. This approach is extrapolated from the management of advanced systemic diffuse large B cell lymphoma (DLBCL).

We generally treat with six cycles of R-CHOP. Administration of R-CHOP is like that for systemic DLBCL, as discussed separately. (See "Initial treatment of advanced-stage diffuse large B cell lymphoma".)

●Limited stage – For patients with limited-stage PCDLBCL, leg type, we suggest adding RT to involved sites after completing chemotherapy.

●Advanced stage – Treatment is with R-CHOP alone.

PCDLBCL, leg type is rare disorder, and data regarding treatment outcomes are primarily derived from retrospective reviews and small cohort series. No randomized clinical trials have directly compared R-CHOP versus chemotherapy without rituximab, other chemotherapy regimens, RT alone, or evaluated the optimal number of treatment cycles.

There are no reports of treating PCDLBCL, leg type using R-pola-CHP (rituximab, polatuzumab, cyclophosphamide, doxorubicin, prednisone).

Our approach is largely based on a study that reported outcomes of 164 patients with PCDLBCL, leg type who received various treatment modalities [44].

●Chemoimmunotherapy

•A literature survey reported that among 32 patients treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CHOP-like regimens, or COP (cyclophosphamide, vincristine, prednisone), with or without rituximab, the rate of complete response (CR) was 81 percent; however, 52 percent of those who achieved CR subsequently relapsed [44].

•Another study reported 92 percent CR among 12 patients treated with anthracycline-based chemoimmunotherapy plus rituximab; relapse was reported in 9 percent [6].

●Rituximab – Treatment of 13 patients using single-agent rituximab (mostly for relapsed disease) reported 40 to 50 percent CR, but the follow-up of these patients was short [44].

●Radiation therapy – Among 101 patients who were treated with RT, the CR rate was 88 percent; relapses were seen in 58 percent, while extracutaneous progression was seen in one-third of patients [44].

Our management approach is consistent with those proposed by the International Society for Cutaneous Lymphomas, the International Lymphoma Radiation Oncology Group, and the National Comprehensive Cancer Network [44-46].

MONITORING — 

Patients are restaged after completing therapy and subsequently monitored for relapse.

Restaging — We evaluate and restage patients 8 to 12 weeks after the completion of therapy.

Restaging consists of repeating all laboratory, clinical, and imaging studies that were used for staging at presentation. However, we typically do not repeat a bone marrow examination unless there is suspicion of new marrow involvement (eg, new abnormalities in blood counts).

Patients with complete response (CR) are monitored, as described below. (See 'Surveillance' below.)

Patients with less than CR are managed as relapsed or refractory disease. (See 'Relapsed or refractory disease' below.)

Surveillance — Following documentation of CR, patients are seen periodically to monitor for possible relapse and treatment complications. The frequency and nature of visits depend on clinical needs and the comfort of the patient and clinician.

For patients in CR, we typically re-evaluate with a physical examination, complete blood count, comprehensive metabolic profile, and lactate dehydrogenase every three months for the first two years. The frequency of follow-up visits can decrease thereafter. To limit radiation exposure and reduce risk for second cancers, we do not obtain routine surveillance imaging, particularly in younger individuals.

RELAPSED OR REFRACTORY DISEASE — 

More than one-half of patients with PCDLBCL, leg type will relapse, but the median duration of complete response (CR) is not well-defined. Relapse 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.

We manage relapsed or refractory (r/r) PCDLBCL, leg type like r/r systemic diffuse large B cell lymphoma (DLBCL). There is no consensus approach, but treatment is informed by prior treatments and relapses, medical fitness, and patient preference.

The efficacy and adverse effects of allogeneic hematopoietic cell transplantation and various immunotherapy approaches, including chimeric antigen receptor T cell therapy, are not well defined in this setting. Lenalidomide and ibrutinib show activity in relapsed PCDLBCL, leg type, but experience is limited [47-49]. Although PCDLBCL, leg type often has PDL-1/PDL-2 overexpression, the activity of checkpoint inhibitors in this disease has not been well studied and is best reserved for clinical trials.

Management and outcomes with r/r DLBCL are discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

PROGNOSIS — 

PCDLBCL, leg type has a more aggressive clinical course than other categories of primary cutaneous B cell lymphoma (PCBCL).

Unlike other types of PCBCL, these tumors frequently disseminate to extracutaneous sites. Five-year overall survival (OS) was estimated at 41 to 66 percent in retrospective studies, with the higher rates reported since the incorporation of rituximab into treatment plans [6,8,9,50-52]. A retrospective review of 161 cases of PCBCL reported that PCDLBCL, leg type had the worst prognosis among the PCBCL categories; OS after two and five years was 59 and 52 percent, respectively [53]. By contrast, primary cutaneous follicle center lymphoma and primary cutaneous marginal zone lymphoma were associated with >95 percent five-year OS [8,54,55].

The presence of multiple skin lesions at diagnosis is an adverse prognostic feature [6,8]. Analysis that included 58 patients with PCDLBCL, leg type reported that presentation with solitary, localized, or generalized skin lesions was associated with five-year OS of 70, 27, and 0 percent, respectively; five-year rates of disease-specific survival were 75, 49, and 0 percent [8,56]. Inactivation of CDKN2A by deletion or hypermethylation and MYD88 L265P mutation are also associated with an unfavorable prognosis [13,20].

No difference in survival is found between PCDLBCL, leg type presenting on the leg(s) and PCDLBCL, leg type arising at other sites, nor between cases with or without expression of BCL2 and/or MUM1/IRF4 [8,57].

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

●Description – Primary cutaneous B cell lymphoma (PCBCL) refers to B cell lymphomas that present in skin, with no extracutaneous disease after completion of staging.

There are three subtypes of PCBCL:

•Primary cutaneous diffuse large B cell lymphoma (PCDLBCL), leg type

•Primary cutaneous follicle center lymphoma (PCFCL)

•Primary cutaneous marginal zone lymphoma (PCMZL)

●Epidemiology – Presentation is generally in the mid to late 70s, and it is more common in females. (See 'Epidemiology' above.)

●Clinical presentation – Most patients present with red or bluish nodules on one or both legs (picture 1), but presentation at other sites is seen in 10 to 15 percent of cases. It is called PCDLBCL, leg type even without lesions on the legs. (See 'Clinical presentation' above.)

●Evaluation

•Clinical – Duration and location of skin lesions, constitutional symptoms, and complete skin examination for skin nodules, lymphadenopathy, and/or organomegaly are evaluated. (See 'Clinical and laboratory' above.)

•Imaging – Positron emission tomography (PET)/CT must confirm that disease is limited to skin.

Contrast-enhanced CT of the chest/abdomen/pelvis is obtained, if clinically indicated. (See 'Imaging' above.)

•Skin biopsy – Excisional biopsy is preferred, but an adequate punch biopsy is acceptable. Morphology, immunophenotype, and cytogenetic studies are performed. (See 'Skin biopsy' above.)

●Pathology – Characteristic pathologic findings include:

•Microscopy – Monotonous population or large confluent sheets of centroblasts with round nuclei and prominent nucleoli and/or immunoblasts that spare the epidermis (picture 3). (See 'Morphology' above.)

•Immunophenotype – B cell markers (eg, CD19, CD20, CD22, CD79a), surface or cytoplasmic immunoglobulin, and nuclear MYC are expressed. BCL2 is often overexpressed (picture 5). (See 'Immunophenotype' above.)

•Cytogenetics – MYC rearrangement and MYD88 L265P may be seen; BCL2 rearrangement is uncommon. (See 'Cytogenetics' above.)

●Staging – Clinical evaluation and PET exclude systemic involvement; bone marrow examination is not generally needed. (See 'Staging' above.)

●Diagnosis – PCDLBCL, leg type should be suspected with cutaneous nodules or tumors on leg(s) or other sites.

Diagnosed by characteristic pathology findings, with no systemic involvement. (See 'Diagnosis' above.)

●Differential diagnosis – Systemic lymphomas and other cutaneous B and T cell lymphomas are excluded by clinical, morphologic, immunophenotypic, and cytogenetic findings. (See 'Differential diagnosis' above.)

PCFCL is especially challenging to exclude; distinguishing features are described above. (See 'Primary cutaneous follicle center lymphoma' above.)

●Management – For most patients, we suggest R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) (table 2), with or without radiation therapy (RT), rather than observation, surgery alone, other chemotherapy regimens, or rituximab alone (Grade 2C). (See 'Management' above.)

•For limited-stage disease, we suggest adding involved site RT after completing R-CHOP (Grade 2C).

•Advanced-stage disease is treated with R-CHOP alone.

●Monitoring

•Restaging – Repeat PET to document response after completing therapy. (See 'Restaging' above.)

•Surveillance – Follow for relapse with clinical evaluation and laboratory studies; we limit imaging to reduce radiation exposure. (See 'Surveillance' above.)

●Relapsed or refractory disease – More than one-half of patients relapse, but there is no consensus treatment. (See 'Relapsed or refractory disease' above.)

Management is like that for relapsed or refractory systemic diffuse large B cell lymphoma and is guided by prior treatments and relapses, medical fitness, and patient preference. Lenalidomide and ibrutinib have some activity, but there is only limited experience with allogeneic hematopoietic cell transplantation, chimeric antigen receptor T cell therapy, and immune checkpoint inhibitors. (See 'Relapsed or refractory disease' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Arnold S Freedman, MD, who contributed to earlier versions of this topic review.