Are You Confident of the Diagnosis?

What to be alert for in the history

Be alert for persistent skin papulonodules or tumors. The condition is often asymptomatic. Constitutional symptoms are uncommon. Skin lesions are marked by relatively slow growth, unless the patient has a large B-cell lymphoma, leg type (which has rapid growth and spread).

Characteristic findings on physical examination

Characteristic findings include pink/violaceous firm papulonodules and/or tumors, which are usually not ulcerated (if lesions are ulcerated or large, worry about large cell B-cell lymphoma, leg type). Occasionally, this may present as a subcutaneous nodule, mimicking a cast. Locations are as follows:

  • Primary cutaneous follicle center cell lymphoma (PC FCL): scalp, face, back (Figure 1,Figure 2)

  • Primary cutaneous diffuse large B-cell lymphoma, leg type (PC DLBCL, leg type): Leg (but can arise elsewhere)

  • Rarely, regional lymphadenopathy

  • Primary cutaneous marginal zone lymphoma (PC MZL): extremities, trunk (Figure 3,Figure 4)

Figure 1.

Confluent papulonodules, right frontal scalp: primary cutaneous follicle center cell lymphoma.

Figure 2.

Primary cutaneous B cell Lymphoma on the scalp. (Courtesy of Stuart Lessin, MD)

Figure 3.

Firm pink nodule, left posterior upper arm: primary cutaneous marginal zone lymphoma.

Figure 4.

Left back annular plaques, PC marginal zone lymphoma.

Expected results of diagnostic studies

Skin biopsy

Histopathology

– Follicle center cell: Nodular or diffuse infiltrates of centroblasts, centrocytes, smaller lymphocytes (follicular, diffuse or mixed patterns)

– Marginal zone: Patchy, nodular, or diffuse infiltrates of central nodular dark area with small reactive lymphocytes with or without germinal centers.

– DLBCL: Dense diffuse infiltrates dominated by large cells with round nuclei (centroblasts, immunoblasts) (Figure 5).

Figure 5.

Primary cutaenous B-cell lymphoma: Dense bottom-heavy atypical lymphocytic infiltrate. (Courtesy of Stuart Lessin, MD)

Immunohistochemistry

– Follicle center cell: CD20+, CD79a+, CD10+, BCL6+, CD5-, CD43-, BCL2- (except when secondary cutaneous), MUM-1-, MIB1/Ki67 decreased, IgM-

– Marginal zone: CD20, CD79a+, BCL2-+, CD5-, CD10-, CD43- BCL6-

– DLBCL: CD20+, CD79a+, sIg +, BCL2+, MUM-1- , Fox-P1+, IgM+, IgD+/-, BCL 6+/-

Molecular

Monoclonal rearrnagement of IgH (Immunoglobulin H) gene (in 50% of marginal zone lymphoma, slightly higher in follicle center cell, similar to DLBCL).

Bloodwork

Complete blood count (CBC) with differential

Lactate dehydrogenase

Comprehensive metabolic panel

Lyme ELISA/titer

HIV

SPEP (marginal zone lymphoma)

Hepatitis panel (if considering Rituximab treatment)

Pregnancy test (if considering chemotherapy)

Consider: Peripheral blood flow cytometry – lymphoma panel (if lymphocytosis observed on CBC)

Autoimmune assocations

Helicobacter pylori

Hepatitis panel

Throid-stimulating hormone (TSH)

Systemic evaluation

Systemic evaluation is recommended for every patient even if only a solitary lesion is present, to distinguish between primary cutaneous B-cell lymphoma versus secondary involvement of skin from an internal source. Patients may be referred to either a dermatologist specializing in cutaneous lymphomas or a hematologist/oncologist to have this work-up performed.

– Computed tomography (CT) chest/abdomen/pelvis with and without contrast

– Positron emission tomography (PET) CT scan

– Bone marrow biopsy: usually not necessary unless one suspects a secondary CBCL or patient has unexplained abnormal blood work, systemic symptoms, or patient has DLBCL.

Diagnosis confirmation

The differential diagnosis includes:

– Cutaneous lymphoid hyperplasia (CLH). (There is considerable clinical overlap between CLH and CBCL lesions so repeat skin biopsies with review by dermatopathology and/or hematopathology is important)

– Drug-induced pseudolymphoma. (Clinical history should help distinguish, heterogeneous immunohistochemistry and clonality results from different skin biopsies are often seen in drug induced processes)

– Nodular scabies (Itchy, in contrast to most cases of CBCL where patients are asymptomatic)

Who is at Risk for Developing this Disease?

Adults: males/females are equally affected. Cutaneous B-cell lymphomas comprise approximately 20-25% of all cutaneous lymphomas.

What is the Cause of the Disease?

Etiology

These lymphomas arise from B lymphocytes in various states of differentiation whose primary site is the skin. Primary cutaneous B-cell lymphomas are derived from skin associated lymphoid tissue (SALT), whereas secondary cutaneous B-cell lymphomas arise from extracutaneous (usually nodal) B-cell lymphomas.

Pathophysiology

The pathophysiology is unknown; there are no specific etiologic genetic factors. It is possibly related to chronic antigenic stimulation (analogous to MALT lymphomas). It is idiopathic in majority of cases, rarely associated with Borrelia infection, and occasionally associated with HIV infection and with with methotrexate therapy.

Systemic Implications and Complications

Indolent PC BCL

– PC FCL: 50% recurrence rate, dissemination rare

– PC MZL: No dissemination

Aggressive PC BCL

– PC DLBCL, leg type: 50% 5 yr survival

– PC DLBCL, other

– Intravascular large B-cell lymphoma

– Plasmablastic lymphoma

B-cell lymphoblastic lymphoma

Associated autoimmune disorders (thyroid disease, viral hepatitis, Helicobacter pylori, inflammatory bowel disease).

Treatment Options

Treatment options are summarized in Table I.

Table I.
Medical Surgical Physical
Indolent – Localized Intralesional steroidsTopical AldaraIntralesional interferon alphaTopical nitrogen mustard Excision Localized Radiation electron beam therapy(30-36 Gy with curative intent for single lesions)
Indolent – Generalized Watch and waitDoxycyclineRituximabInterferon alpha Excision for symptomatic lesions Radiation for symptomatic lesions (can use much lower doses for palliation, such as 2 Gy x 2 doses, instead of 30-36 Gy)
Aggressive – Localized Chemotherapy (such as R-CHOP which is rituximab, cyclophosphamide, adriamycin, vincristine, prednisone) N/A RT
Aggressive – Generalized Chemotherapy (such as R-CHOP which is rituximab, cyclophosphamide, adriamycin, vincristine, prednisone)Stem cell transplant N/A

RT

Optimal Therapeutic Approach for this Disease

Referral to a dermatology cutaneous lymphoma specialist or hematologist/oncologist is appropriate.

Indolent PC BCL

f a single lesion is present, the goal of therapy is a cure with excision or localized RT (traditional dose 20-36 Gy) or both (though patients need to be counseled that the risk of skin relapse is 40-60% even in this patient group and relapse does not necessarily portend worse prognosis). If multiple lesions are present, the goal of therapy is palliation, not cure. The choice of treatment is individualized to the given lesion, symptoms, and location of the lesion. Multifocal indolent PC BCL can be “observed” or treated with intralesional corticosteroid injection, excision, very low dose radiation therapy (2 Gy × 2), topical nitrogen mustard ointment and topical steroids, low dose interferon alpha, rituximab, or systemic chemotherapy. Indolent PC BCL with diffuse large cells generally has a similar good prognosis as above, if not on a leg. If on a leg, then it behaves more like DLBCL

Aggressive DLBCL

Even if only one lesion is present, consider radiation therapy and systemic therapy up front, given the behavior the disease.

Patient Management

Patients can be monitored every 2-3 months while on active therapy, but if in remission or with a low level of disease activity, once or twice yearly visits with a full skin and lymph node physical exam are recommended. For a low-grade indolent CBCL, complete staging including systemic scans is warranted, but repeat scans are not necessary unless the patient develops systemic symptoms or clear aggressive behavior of the skin lesions. For diffuse large BCL, patients should be referred immediately to hematology/oncology with low threshold to start systemic treatment.

Unusual Clinical Scenarios to Consider in Patient Management

Follicle center cell lymphoma, diffuse type, can histologically have overlap with diffuse large B-cell lymphoma, leg type. Accurate clinicopathologic diagnosis is needed to avoid overtreating this group unnecessarily. Of note, follicle center cell lymphoma, diffuse type that appears on the legs, has a rapid course.

What is the Evidence?

Brandenburg, A, Humme, D, Terhorst, D, Gellrich, S, Sterry, W, Beyer, M. “Long-term outcome of intravenous therapy with rituximab in patients with primary cutaneous B-cell lymphomas”. Br J Dermatol. vol. 169. 2013. pp. 1126-1132. (Review of response rates and duration of response of IV rituximab in CBCL).

Cerroni, L, Gatter, K, Kerl, H. “Cutaneous B-cell lymphomas (Section 2). In: Skin Lymphoma: The Illustrated Guide”. Wiley-Blackwell. 2009. pp. 127-172. (Definitive textbook chapter on primary cutaneous B-cell lymphomas, as defined by the 2005 WHO-EORTC classification system.)

Kerl, H, Cerroni, L. “Primary cutaneous B-cell lymphomas: then and now”. J Cutan Pathol. vol. 33. 2006. pp. 1-5. (Historical perspective of CBCLs and impact of new staging system discussed.)

Neelis, KJ, Schimmel, EC, Vermeer, MH. “Low-dose palliative radiotherapy for cutaneous B- and T-cell lymphomas”. Int J Radiat Oncol Biol Phys. vol. 74. 2009. pp. 154-158. (Describes efficacy of palliative low dose radiation therapy 2 Gy × 2 for CBCL.)

Magro, CM, Crowson, AN. “Marginal zone lymphoma and other low-grade B-cell Lymphoproliferative disorders of the skin (Chapter 7), Primary cutaneous follicle center cell lymphoma (Chapter 8), Primary cutaneous diffuse large B-cell lymphoma and precursor lymphoblastic lymphoma (Chapter 9)”. The Cutaneous Lymphoid Proliferations. 2007. pp. 141-225. (A thorough review of these variants of cutaneous B cell lymphomas.)

Senff, NJ, Hoeffnagel, JJ, Jansen, PF. “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”. J Clin Oncol. vol. 25. 2007. pp. 1581-1587. (Complicated review and update on the classification of cutaneous B-cell lymphomas.)

Suárez, AL, Pulitzer, M, Horwitz, S, Moskowitz, A, Querfeld, C, Myskowski, PL. “Primary cutaneous B-cell lymphomas: part I. Clinical features, diagnosis, and classification”. J Am Acad Dermatol. vol. 69. 2013. pp. 329.e1-13.

Suárez, AL, Querfeld, C, Horwitz, S, Pulitzer, M, Moskowitz, A, Myskowski, PL. “Primary cutaneous B-cell lymphomas: part II. Therapy and future directions”. J Am Acad Dermatol. vol. 69. 2013. pp. 343.e1-11. (Excellent review of CBCL from Memorial Sloan Kettering cutaneous lymphoma group.)

Zelenetz, AD, Abramson, JS, Advani, RH. “Primary Cutaneous B-cell Lymphomas, NCCN Clinical practice guidelines in oncology in non-Hodgkin's lymphomas”. pp. v2014(This collaborative effort has resulted in standardizing diagnosis, staging and treatment of primary cutaneous B-cell lymphoma. Recommendations are updated yearly.)

Willemze, R, Jaffe, ES, Burg, G, Cerroni, L, Berti, E, Swerdlow, SH. “WHO-EORTC classification of cutaneous lymphomas”. Blood. vol. 105. 2005. pp. 3768-3785. (In this landmark paper, primary cutaneous lymphomas are reclassified based on both clinical and histopathologic characteristics. Primary cutaneous B-cell lymphomas are separated into indolent and aggressive categories.)

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