A team of researchers from the University of Michigan reviewed diagnosis, risk stratification, and management of specific subgroups of primary cutaneous lymphomas in an annual clinical update of hematologic malignancies. Their 2021 update was published in the American Journal of Hematology.

Nearly 25% of primary cutaneous lymphomas are derived from B cells, and the incidence rate of the B-cell lymphomas are approximately 4 per million persons and increasing, according to Surveillance, Epidemiology, and End Results registry data. Incidence is most prevalent in non-Hispanic, White men who are older than 50 years.

B-cell derived primary cutaneous lymphomas are generally categorized into 3 subgroups: primary cutaneous follicle center lymphoma; primary cutaneous marginal zone lymphoma; and primary cutaneous diffuse large B-cell lymphoma, leg type.

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Histopathologic analysis and immunohistochemical stating of relevant skin biopsy is essential for disease diagnosis and classification.

“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,” the authors wrote.

Primary cutaneous follicle center lymphoma commonly manifests as a solitary papule ranging in purple to pink color or as several papules, plaques, or tumors with a rim of peripheral erythema. Dermoscopy is often performed to rule out non-melanoma skin cancers. In most cases of primary cutaneous follicle center lymphoma, immunohistochemistry will indicate an absence in t(14;18) translocation involved in the bcl-locus. Additionally, bcl-2 is not strongly expressed, which is in contrast to systemic follicular lymphomas.

Risk-stratification for primary cutaneous follicle center lymphoma and primary cutaneous marginal zone lymphoma should not include a bone marrow examination, although roughly 10% of patients with follicle center lymphomas may have bone marrow involvement. For this small group of patients, the bone marrow is the only location of extracutaneous disease.

In addition, 3 independent prognostic factors for primary cutaneous follicle center lymphoma and primary cutaneous marginal zone lymphoma were identified by the International Extranodal Lymphoma Study Group: elevated lactase dehydrogenase, more than 2 skin lesions, and nodular lesions. The absence of any of these prognostic factors was linked to a 91% 5-year progression-free survival (PFS), while 2 or 3 of these factors was linked to a PFS of 48%.

Low-dose radiation therapy is a safe and significantly affective option for patients with solitary lesions with a nearly 100% complete remission rate. The investigators also noted that radiation was not inferior to multiagent chemotherapy among patients with several lesions that can be included in multiple radiation fields.

Patients who present with greater skin involvement may be effectively treated with single-agent rituximab. Following either rituximab or radiation, approximately 33% of patients may relapse; however, relapses are usually confined to skin.

Primary cutaneous marginal zone lymphoma often manifests as red-brown multifocal papules, plaques, or nodules on the trunk and arms, or as asymptomatic solitary pink papules on the trunk, arms, head, and neck.

“[Primary cutaneous marginal zone lymphomas] 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,” the authors noted.

There are 2 recent groups of primary cutaneous marginal zone lymphoma: the more common form expresses class-switched immunoglobulin and the second form expresses immunoglobulin M (IgM) and frequently recurs and spreads extracutaneously. 

“The most important factor for risk-stratification among the cutaneous B-cell lymphomas remains the histopathologic classification,” the authors wrote. Both primary cutaneous follicle center lymphoma and primary cutaneous marginal zone lymphoma are associated with a 5-year disease-specific survival rate of 95% or higher; however, a more aggressive course is linked to primary cutaneous marginal zone lymphoma with IgM expression.

Patients with this type of lymphoma may be treated with radiation therapy or surgical excision, both of which have higher response rates for patients with fewer lesions. For those with several, widespread lesions, observation is suggested until lesions are symptomatic, at which time they may be irradiated or surgically removed.

Primary cutaneous diffuse large B-cell lymphoma, leg type manifests as rapidly progressive red-brown to blue tumors in either 1 or both legs, which may be ulcerated or surrounded by smaller, satellite lesions. This type of lymphoma is most frequently reported in older women, and approximately 10% to 15% of cases may also include other cutaneous sites than the lower legs.

One significant differentiation from primary cutaneous follicle center lymphoma is the amplified expression of bcl-2; this type of lymphoma frequently presents with dual expression of bcl-2 and c-myc, which is linked to worse overall survival compared with patients in whom c-myc is not expressed.

The investigators recommended a bone marrow biopsy and that aspirate should be performed for risk stratification. Among patients with primary cutaneous diffuse large B-cell lymphoma, leg type, the presence of MYD88L265P somatic mutations are associated with reduced disease-specific and overall survival; 5-year disease-specific survival is approximately 50% in these patients and dual bcl-2 and c-myc expression with CDKN2A knockout are associated with worse survival.

“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,” the investigators noted.

As leg type closely resembles systemic diffuse large B-cell lymphoma, rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (with or without radiation therapy) may be administered to this patient population.


Hristov AC, Tejasvi T, Wilcox RA. Cutaneous B-cell lymphomas: 2021 update on diagnosis, risk-stratification, and management. Am J Hematol. Published online August 20, 2020. doi:10.1002/ajh.25970

This article originally appeared on Hematology Advisor