Volume 98, Issue 8 pp. 1326-1332

ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

Free Access

Cutaneous B-cell lymphomas: 2023 update on diagnosis, risk-stratification, and management

Alexandra C. Hristov,

Alexandra C. Hristov

Departments of Pathology and Dermatology, University of Michigan, Ann Arbor, Michigan, USA

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Trilokraj Tejasvi,

Trilokraj Tejasvi

Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA

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Ryan A. Wilcox,

Corresponding Author

Ryan A. Wilcox

[email protected]

orcid.org/0000-0002-6420-0760

Division of Hematology/Oncology, University of Michigan Cancer Center, Ann Arbor, Michigan, USA

Correspondence

Ryan A. Wilcox, Division of Hematology/Oncology, University of Michigan Cancer Center, 1500 E. Medical Center Drive, Room 4310 CC, Ann Arbor, MI 48109-5948, USA.

Email: [email protected]

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Alexandra C. Hristov,

Alexandra C. Hristov

Departments of Pathology and Dermatology, University of Michigan, Ann Arbor, Michigan, USA

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Trilokraj Tejasvi,

Trilokraj Tejasvi

Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA

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Ryan A. Wilcox,

Corresponding Author

Ryan A. Wilcox

[email protected]

orcid.org/0000-0002-6420-0760

Division of Hematology/Oncology, University of Michigan Cancer Center, Ann Arbor, Michigan, USA

Correspondence

Ryan A. Wilcox, Division of Hematology/Oncology, University of Michigan Cancer Center, 1500 E. Medical Center Drive, Room 4310 CC, Ann Arbor, MI 48109-5948, USA.

Email: [email protected]

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First published: 22 May 2023

https://doi.org/10.1002/ajh.26968

Citations: 13

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Abstract

Disease Overview

Approximately one-fourth of primary cutaneous lymphomas are B-cell derived and are generally classified into three distinct subgroups: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT).

Diagnosis

Diagnosis and disease classification is based on histopathologic review and immunohistochemical staining of an appropriate skin biopsy. Pathologic review and an appropriate staging evaluation are necessary to distinguish primary cutaneous B-cell lymphomas from systemic B-cell lymphomas with secondary skin involvement.

Risk-Stratification

Disease histopathology remains the most important prognostic determinant in primary cutaneous B-cell lymphomas. Both PCFCL and PCMZL are indolent lymphomas that infrequently disseminate to extracutaneous sites and are associated with 5-year survival rates that exceed 95%. In contrast, PCDLBCL, LT is an aggressive lymphoma with an inferior prognosis.

Risk-Adapted Therapy

PCFCL and PCMZL patients with solitary or relatively few skin lesions may be effectively managed with local radiation therapy. While single-agent rituximab may be employed for patients with more widespread skin involvement, multiagent chemotherapy is rarely appropriate. In contrast, management of patients with PCDLBCL, LT is comparable to the management of patients with systemic DLBCL.

1 DISEASE OVERVIEW

Primary cutaneous lymphomas are a heterogeneous group of extranodal non-Hodgkin lymphomas, approximately 25% of which are B-cell derived and are classified into 3 major entities in the 2018 World Health Organization (WHO)-European Organization for Research and Treatment of Cancer (EORTC) joint classification and the International Consensus Classification (ICC): primary cutaneous follicle-center lymphoma (PCFCL), primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT), and primary cutaneous marginal zone lymphoma (PCMZL).^1-3 In addition, EBV-positive mucocutaneous ulcer (EBVMCU) is a recently described, EBV+ lymphoproliferative disorder that affects the skin and mucosa. The incidence of cutaneous B-cell lymphomas (CBCL) has been increasing and is currently ≈4 per million persons, based on Surveillance, Epidemiology, and End Results (SEER) registry data, with the highest incidence rates being reported among males, non-Hispanic whites, and adults over the age of 50.^{4, 5}

2 DIAGNOSIS

Diagnosis and classification of a CBCL requires an incisional, excisional or 4–6 mm punch biopsy which includes reticular dermis and subcutaneous fat for morphologic and immunohistochemical analysis (Table 1), and an appropriate staging evaluation to exclude systemic disease.⁶ The use of appropriate immunohistochemical stains (e.g., CD5, cyclin D1) may also aid in distinguishing CBCL from secondary skin involvement by a systemic lymphoma.

TABLE 1. Characteristics of primary cutaneous B-cell lymphomas.

	PCMZL/LPD	PCFCL	DLBCL-LT	EBVMCU
Demographics
Male to Female	3:2	3:2	1:2	Female > Male
Age	3rd–6th decade	5–6th decade	7th decade	7th decade
Frequency (% cases of CBCL)	25–30%	30–60%	20–40%	Rare
Clinical Presentation
Location	Extremities/Trunk	Head & Neck/Trunk	Lower leg	Mucosa>Skin
Morphology	Usually solitary > multiple, erythematous papules, plaques, or nodules	Usually solitary > multiple clustered, Erythematous papules, plaques, or nodules	Usually solitary > multiple, red to blue-red nodules	Well defined ulceration of the mucosa
Associated symptoms/Additional features	None	None	Usually none	Painful ulcer Immunosuppression
Histopathology	Small, “centrocyte-like” marginal zone B cells with variable numbers of monocytoid B-cells, lymphoplasmacytic cells, plasma cells, cells resembling centroblasts and immunoblasts, and reactive T cells	Follicular, diffuse, or mixed growth of centrocytes and centroblasts	Diffuse sheets of centroblasts and immunoblasts	Shallow ulcer, mixed infiltrate of plasma cells, histiocytes, eosinophils and immunoblasts, the latter including Hodgkin-Reed-Sternberg-like forms
Immunophentoype	CD20+, bcl-2+ CD43+/− Often light chain restriction Negative for bcl-6 CD10, CD5 and CD23	CD20+, bcl-6+, bcl-2−/+, CD10−/+ MUM-1/IRF-4, FOXP1 and IgM negative	CD20+, Bcl-2+, MUM-1/IRF-4+, FOXP1+, IgM+ and bcl-6+, Negative for CD10 and EBER	Non-germinal center B-cells: CD20+, PAX5+, OCT2+, MUM-1+, CD10−. CD30+, CD15+/−, EBER+
Treatment	Low dose Radiation > excision> intralesional corticosteroids > observation	Low dose radiation > intralesional corticosteroids	As in systemic DLBCL (+/− radiation)	Spontaneous resolution to reduction in immunosuppressive agents
Treatment	Multiple sites—Low dose RT > Rituximab	Multiple sites—Low dose radiation > Rituximab
Prognosis	Indolent	Indolent	Aggressive	Indolent
Relapse rate	50%	30%	65%
5-year disease specific survival	99%	95%	30–80% (with R-CHOP)

2.1 PCFCL

PCFCL commonly present as a solitary purple to pink colored papule (often biopsied to rule out a non-melanoma skin cancer) or as multiple papules, plaques or tumors with a rim of peripheral erythema occurring on the forehead, neck and upper back in middle-aged adults. While grouped lesions may be observed, multifocal disease is less common, as are less common presentations, including rhinophyma and scarring alopecia with tumid pink plaques. Dermoscopy may help differentiate these cutaneous lymphomas from more common non-melanoma skin cancers.⁷ Histopathologically, PCFCL are characterized by a follicular, diffuse, or mixed growth pattern comprised of large centrocytes and variable centroblasts derived from germinal-center B-cells.^8-10 In contrast to systemic follicular lymphomas, the majority of PCFCL do not harbor the t(14;18) translocation involving the bcl-2 locus, and do not strongly express bcl-2 by immunohistochemistry, although expression may be observed in a minority of cases.^11-15 Strong expression of bcl-2 and CD10 may suggest secondary cutaneous involvement by follicular lymphoma. PCFCLs express bcl-6, variably express CD10, and are MUM-1/IRF-4, FOXP1 and IgM negative, consistent with their origin from germinal-center B cells.¹⁶ Zhou et al. performed whole-exome sequencing in both PCFCL (n = 30) and in systemic FL with secondary cutaneous involvement (n = 10).¹⁵ Consistent with prior observations, most (i.e., 73%) PCFCL did not express bcl-2, and when compared with secondary cutaneous FL were more proliferative, as determined by Ki67 expression. Notably, recurrent mutations in the epigenetic modifiers CREBBP, KMT2D, EZH2, or EP300 were recurrently observed in secondary cutaneous FL, but were rarely observed in PCFCL. Consequently, mutations in at least two of these genes were observed in 63% of secondary cutaneous FL cases, but were rarely observed in PCFCL.¹⁵ In contrast, TNFRSF14 is frequently mutated in PCFCL.¹⁷ Therefore, the genetic landscape may help distinguish PCFCL from secondary cutaneous FL. A novel variant involving the lower female genital tract (cervix and/or vagina) was recently described,¹⁸ sharing immunophenotypic (e.g., >80% Bcl-2 negative), genetic (e.g., no CREBBP, KMT2D mutations were identified), and clinical characteristics (localized disease with 100% 5-year overall survival) with PCFCL.

2.2 PCDLBCL, LT

PCDLBCL, leg type commonly affects elderly women and presents with rapidly progressive red brown to blue tumors involving either one or both lower legs.^{14, 19} Tumors may be ulcerated, and larger tumors may be surrounded by smaller satellite lesions. Less common presentations include verrucous and multicolored nodules. Population-based studies suggest that involvement restricted to the legs is less common than the designation “leg type” would suggest, as involvement of other cutaneous sites is fairly common.^{14, 20} These lymphomas are characterized by diffuse sheets of centroblasts and immunoblasts that spare the epidermis, but frequently extend deep into the dermis and subcutaneous tissue. In contrast to PCFCL, lymphoma cells highly express bcl-2, likely due to gene amplification,^{21, 22} as t(14;18) is not observed in PCDLBCL, LT. Bcl-2 overexpression, or dual expression of both bcl-2 and c-myc, is associated with inferior overall survival compared.^22-24 C-myc and bcl-2 translocations (“double hits”) are observed in <20% of PCDLBCL, LT.^{22, 23} Most cases are MUM-1/IRF-4, FOXP1, IgM and bcl-6 positive, CD10 negative, and have a gene expression profile resembling activated B cells.¹⁰ EBV in situ hybridization (EBER) is negative. Perhaps not surprisingly, the genetic landscape observed in PCDLBCL, LT is similar to that observed in activated B-cell-type diffuse large B-cell lymphoma (ABC-DLBCL), with NF-κB-activating mutations being observed in CD79B, CARD11, and MYD88.^25-28 Of these, somatic MYD88 L265P mutations appear most common with a prevalence of ≈75%.^{22, 26-28} Despite the use of somatically hypermutated immunoglobulin heavy-chain variable (IGHV) regions, Staphylococcal superantigen binding sites within the IGHV are preserved, thus implicating superantigen-dependent B-cell receptor signaling in disease pathogenesis.²⁹

2.3 PCMZL/LPD

Patients with PCMZL/LPD frequently present with solitary asymptomatic pink papule on the trunk, arm and head and neck area, or as red brown multifocal papules, plaques or nodules involving the trunk and arms. While an association with Borrelia burgdorferi has been observed in Europe, a similar association has not been observed in cases from the United States.^30-33 PCMZL/LPD are composed of a variably mixed infiltrate of small, “centrocyte-like” marginal zone B cells, monocytoid B-cells, lymphoplasmacytic cells, plasma cells, cells resembling centroblasts and immunoblasts, and reactive T cells. Marginal zone B cells characteristically express bcl-2 and may express CD43, but lack bcl-6, CD10, CD5 and CD23 expression. Recently, two groups of PCMZL/LPD have been identified.^34-36 The majority of PCMZL/LPD express class-switched immunoglobulin and have an indolent course. A recent classification system recommends that this type of PCMZL should be considered a lymphoproliferative disorder (LPD) to reflect its clinical and histopathologic overlap with atypical reactive B-cell infiltrates (pseudo B-cell lymphomas) and extremely favorable prognosis.³ This group is characterized by collections of B-cells with peripheral plasma cells, numerous intermixed T-cells and reactive follicles.³⁷ A second group expresses IgM and shows a behavior similar to extracutaneous extranodal marginal zone lymphomas, with frequent recurrences and extracutaneous spread. This group often shows a diffuse infiltrate with intermixed rather than peripheral plasma cells and frequent follicular colonization and is more likely to involve the subcutis.³⁷ PCMZL/LPD often harbor FAS, SLAMF1, SPEN and NCOR mutations and IGH translocations involving FOXP1 and BCL10.^{38, 39}

2.4 EBVMCU

EBVMCU typically presents as a solitary, painful and well-circumscribed ulcer on the skin or mucosa, the latter including the oropharynx, genital mucosa, or the gastrointestinal tract.^40-45 Patients are generally immunosuppressed, either due to age-related immunosenescence, iatrogenic immunosuppression (particularly with methotrexate), solid organ transplantation, HIV, or primary immunodeficiency. They do not have other symptoms and are without bone marrow involvement, lymphadenopathy, or hepatosplenomegaly. In addition, EBV is not increased in the peripheral blood.⁴⁴ Histopathologically, EBVMCU demonstrates a shallow ulcer with an underlying mixed infiltrate that includes numerous plasma cells, histiocytes and eosinophils and a base composed of numerous CD8+ T-cells.^40-45 Scattered throughout, there are variably-sized B-cell immunoblasts, some with a Hodgkin-Reed-Sternberg-like (HRS-like) appearance. Apoptotic plasmacytoid cells may also be present.^{40, 45} Immunohistochemical studies demonstrate that the immunoblasts are non-germinal center B-cells that express CD20, PAX5, OCT2 and MUM-1 and are negative for CD10. They are CD30 positive and may express CD15. Plasma cells may be light chain restricted.⁴¹ EBV in situ hybridization (EBER) marks the immunoblasts, including the HRS-like cells, as well as smaller lymphoid cells. Angioinvasion and necrosis are often present. B-cell receptor gene rearrangement studies show a clonal B-cell population in less than half of cases; T-cell receptor gene rearrangement studies may be oligoclonal or clonal.^{40-42, 44}

3 RISK-STRATIFICATION

The International Society for Cutaneous Lymphomas (ISCL) and EORTC recently proposed staging recommendations for cutaneous lymphomas other than mycosis fungoides and Sezary syndrome.⁶ Staging should include a history, physical examination, and imaging (either CT, PET, or increasingly PET/CT) of the chest, abdomen, pelvis, and neck (in cases with involvement of the head or neck). A bone marrow biopsy and aspirate should be performed in cases of PCDLBCL, LT. The joint ISCL/EORTC does not endorse routine bone marrow examination in cases of PCFCL or PCMZL, although approximately 10% of patients with follicle center lymphomas have bone marrow involvement and in most of these patients, the bone marrow is the only site of extracutaneous disease.⁴⁶ Bone marrow involvement was associated with significantly inferior disease-specific survival. While the TNM staging classification describes the extent of disease, staging in CBCL is of limited prognostic value, as the disease histopathology is the major determinant in risk-stratification. This is highlighted by a population-based study which identified histopathology and the site of skin involvement as important prognostic factors.⁴⁷ In contrast, the International Extranodal Lymphoma Study Group identified three independent prognostic factors (i.e., elevated LDH, >2 skin lesions, and nodular lesions) among patients with PCFCL and PCMZL. These factors were combined to form the cutaneous lymphoma international prognostic index (CLIPI). The absence of any adverse prognostic factor was associated with a 5-year progression-free survival of 91%. In contrast, the presence of 2 or 3 adverse prognostic factors was associated with a 5-year progression-free survival of 48%. As the vast majority of relapses were confined to the skin, the CLIPI was unable to risk-stratify patients by overall survival. The presence of multiple skin lesions was associated with inferior disease-free survival in a European series,⁴⁸ but was not associated with disease-free survival in a large North American series.⁴⁹ The most important factor for risk-stratification among the cutaneous B-cell lymphomas remains the histopathologic classification. Indolent CBCL (PCFCL and PCMZL) are associated with 5-year disease-specific survival ≥95%,^{8, 49} though PCMZL with IgM expression have been associated with a more aggressive course. Neither the presence of a matching B-cell clone in the skin and the blood nor a paraproteinemia are associated with cutaneous relapse or prognosis in PCMZL/LPD.⁵⁰ Differences in growth pattern, the density of centroblasts, and cytogenetic findings do not appear to provide meaningful prognostic information in PCFCL. While rare, a subset of systemic FL may initially present with cutaneous involvement, but with extracutaneous disease that is below the threshold of radiographic detection. The presence of mutations in CREBBP, KMT2D, EZH2, EP300 (as observed in systemic FL), rearrangements involving the bcl-2 gene, and a low proliferation rate (Ki67 < 30%) may identify these patients.¹⁵ In contrast, PCDLBCL, LT is associated with a 5-year disease-specific survival of approximately 50%, and dual bcl-2 and c-myc expression^{8, 22, 26, 51} and loss of CDKN2A are associated with inferior survival.⁵² The presence of a somatic MYD88^L265P mutation is also associated with inferior disease-specific and overall survival.²⁶ In contrast to patients presenting with only a single tumor, involvement of multiple sites, on one or both legs, is associated with a significantly inferior disease-specific survival.⁵³

While EBVMCU may spread or recur locally, distant dissemination is exceedingly rare, and if observed, ought to prompt consideration of alternative EBV-associated lymphoproliferative neoplasms. Thankfully, EBVMCU are generally localized and associated with a favorable prognosis, as most cases regress following a reduction in immunosuppression.^{54, 55}

4 TREATMENT

As no randomized controlled trials are available, treatment recommendations for CBCL are largely based on small retrospective studies and institutional experience. The EORTC and ISCL have published consensus treatment recommendations that are consistent with NCCN guidelines.⁵⁶ In most cases, optimal patient management requires a multidisciplinary approach, including dermatology, medical oncology and radiation oncology.

4.1 PCFCL

For patients with solitary lesions, low-dose radiation therapy is safe and highly affective, with a complete remission rate approaching 100%. Radiation does not appear inferior to multiagent chemotherapy among patients with multiple lesions that can be included in multiple radiation fields.⁵⁷ In a large North American series, the rate of local control for indolent CBCL with radiation alone was 98%.⁴⁹ In the same series, a local recurrence requiring radiation therapy was observed in 25% of patients who had undergone surgical excision alone. Reserving radiation until disease recurrence did not appear to compromise disease-specific or overall survival.⁴⁹ Therefore, complete excision alone, deferring radiation until disease recurrence, is also reasonable. Intralesional [e.g., corticosteroids or rituximab^58-60] or topical therapies including corticosteroids, nitrogen mustard and bexarotene may also be considered.^{61, 62} While radiation therapy is generally recommended for patients with a solitary lesion, radiation therapy or observation (i.e., “watch and wait”) are reasonable options for those patients with multiple lesions. Rarely, patients with PCFCL may show a locally aggressive course and some have suggested the possibility of transformation to DLBCL,^{63, 64} suggesting that “watch and wait” patients require close clinical follow-up. Patients with more extensive skin involvement are effectively managed with single-agent rituximab.⁵⁶ Approximately one-third of patients may relapse following either radiation or single-agent rituximab, but relapses are usually confined to the skin and are approached in a manner similar to that described for the initial management of PCFCL.

4.2 PCMZL

Patients with PCMZL are approached in a manner analogous to that described in the initial management of PCFCL. Radiation therapy or surgical excision are associated with high response rates for patients with a single or few lesions.⁵⁶ Those with more widespread skin involvement may be observed. Once symptomatic, culprit lesions may be irradiated or surgically excised.⁶⁵ As for PCFCL, single-agent rituximab may be utilized in patients with symptomatic, widespread skin lesions. An initial trial of antibiotics for those with B. burgdorferi-associated PCMZL has been recommended,⁶⁶ but is less relevant for North American patients.

4.3 PCDLBCL, LT

As previously noted, the natural history of PCDLBCL, LT more closely resembles that of systemic DLBCL. Therefore, R-CHOP (with or without radiation therapy) is utilized in these patients. While few reports are available in the literature, the use of R-CHOP in these patients is associated with disease-free survival rates rivaling those reported for patients with high-risk systemic DLBCL.^{14, 19, 49, 56} Many patients present with disease confined to a single site and are managed like patients with limited stage systemic DLBCL with R-CHOP and involved field radiation therapy. The management of relapsed disease is comparable to that for relapsed systemic ABC-DLBCL [e.g., lenalidomide,⁶⁷ ibrutinib,⁶⁸ or tafasitamab/lenalidomide⁶⁹]. In a small phase II study (n = 19), the 6-month overall response rate with single-agent lenalidomide in relapsed/refractory PCDLBCL, LT was 26%, but was significantly higher in patients without the MYD88^L265P mutation.⁷⁰ The efficacy of checkpoint (PD-1) blockade was recently suggested, as 3 out of 5 patients with relapsed/refractory disease achieved durable responses upon PD-1 blockade.⁷¹

4.4 EBVMCU

Among EBVMCU associated with immunosuppression, the vast majority spontaneously regress upon discontinuation or reduction of immunosuppression. For those associated with age-related immunosenescence, and those with a relapse and remitting course following reduction of immunosuppression, either focal radiation therapy or single-agent rituximab are highly effective.^{54, 55}

FUNDING INFORMATION

This was supported by R37CA233476, R01CA236722, and R01CA265929 (Ryan A. Wilcox).

CONFLICT OF INTEREST STATEMENT

Nothing to report.

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Volume98, Issue8

August 2023

Pages 1326-1332

Cutaneous B-cell lymphomas: 2023 update on diagnosis, risk-stratification, and management

Abstract

Disease Overview

Diagnosis

Risk-Stratification

Risk-Adapted Therapy

1 DISEASE OVERVIEW

2 DIAGNOSIS

2.1 PCFCL

2.2 PCDLBCL, LT

2.3 PCMZL/LPD

2.4 EBVMCU

3 RISK-STRATIFICATION

4 TREATMENT

4.1 PCFCL

4.2 PCMZL

4.3 PCDLBCL, LT

4.4 EBVMCU

FUNDING INFORMATION

CONFLICT OF INTEREST STATEMENT

REFERENCES

Citing Literature

References

Information

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Cutaneous B-cell lymphomas: 2023 update on diagnosis, risk-stratification, and management

Abstract

Disease Overview

Diagnosis

Risk-Stratification

Risk-Adapted Therapy

1 DISEASE OVERVIEW

2 DIAGNOSIS

2.1 PCFCL

2.2 PCDLBCL, LT

2.3 PCMZL/LPD

2.4 EBVMCU

3 RISK-STRATIFICATION

4 TREATMENT

4.1 PCFCL

4.2 PCMZL

4.3 PCDLBCL, LT

4.4 EBVMCU

FUNDING INFORMATION

CONFLICT OF INTEREST STATEMENT

REFERENCES

Citing Literature

References

Related

Information