Primary Cutaneous Follicle Center Lymphoma

Etiology

PCFCL is a low-grade lymphoma of follicle center B-cells, with no systemic or nodal involvement at diagnosis.[2]

Epidemiology

In the Western world, PCFCL is the most frequent cutaneous B-cell lymphoma and accounts for over 50% of cases. It usually affects middle-aged adults, predominance in men, with a man-to-woman ratio of 1.5 to 1.[3][4]

Pathophysiology

There are no definitive risk factors or identified hereditary predisposition for this disease. The pathogenesis is different from systemic or nodal follicular lymphoma.

Histopathology

Morphologically, PCFCL demonstrates perivascular and periadnexal to diffuse infiltration of monoclonal B-cells, which typically spares the epidermis (grenz zone). Growth patterns can be follicular, follicular diffuse, or diffuse. The growth pattern has not been found to be of clinical significance. The follicles in a follicular pattern PCFCL are commonly poorly defined, have an attenuated mantle zone, typically lack tingible body macrophages, and demonstrate a low rate of proliferation. The diffuse-type growth pattern frequently shows a sheet-like proliferation of monotonous centrocytes, which may have cleaved/multi-lobated/irregular nuclei. The proliferation rate of the diffuse growth pattern is generally high.[2][5]

History and Physical

PCFCL typically presents with solitary or grouped, firm to violaceous, painless, nonpruritic papules, plaques, or tumors. These frequently occur in the head, neck, and trunk.[2][6] The lesions are typically smooth and not ulcerated.[7] Although 60% of patients will have more than one lesion in a localized area, only a minority of patients (10%-20%) will have multifocal lesions.[2][8][9]

Evaluation

The diagnosis of PCFCL is made by histopathologic evaluation after a skin biopsy. The neoplastic cells stain positively for B-cell markers CD19, CD20, CD79a, and typically, the follicle center markers CD10 and BCL-6. CD21/23 can also help to highlight BCL-6 positive cells spreading beyond the regular meshwork. Commonly, PCFCL will be negative or weak for BCL-2. CD10 is variable and is ordinarily positive in a follicular pattern and negative in a diffuse pattern. CD5, CD43, IRF4/MUM1, and FOXP1 are negative. Ki67 can show a lower proliferation rate than regular reactive follicles.[2][10][11] Laboratory and imaging workup should include a complete blood count with differential, comprehensive metabolic panel, lactate dehydrogenase, and computed tomography (CT) with contrast, with or without positron emission tomography (PET) to exclude systemic involvement.[12][13]

Treatment / Management

Treatment is guided by the location of the lesions, the number, and the symptoms. PCFCL is effectively treated with local radiotherapy. Local radiation therapy is recommended for patients with single lesions or lesions in a single radiation field, with a complete response rate of 99% in a cumulative study review.[11] A dose of at least 30 Gray (Gy) is recommended with a margin of 1 to 1.5 cm. For small lesions, surgical excision is an acceptable alternative with a complete response rate of 99% but an increased rate of relapse (40% vs 30% for radiotherapy). For scattered or multiple lesions that can not be contained to one radiation field, local radiotherapy or observation is recommended for initial therapy. For very numerous or very thick lesions not amenable to radiotherapy, rituximab is suggested as a first-line systemic agent. If refractory, chemotherapy with R-CHOP and CHOP in older studies has been used. Fortunately, cutaneous relapses do not confer a worse prognosis and should be managed systematically with a similar approach to the initial diagnosis.[12][14](B3)

Differential Diagnosis

The following are the differential diagnoses:

• Follicular lymphoma (FL)
• Primary cutaneous diffuse large B-cell lymphoma, Leg type (PCDLBCL-LT)
• Reactive lymphoid hyperplasia (RLH)
• Primary cutaneous marginal zone lymphoma (PCMZL)

Systemic/nodal Follicular Lymphoma can secondarily involve the skin. Histology can be identical to PCFCL, but a strong expression of CD10 and BCL-2 should raise suspicion for secondary involvement of FL. Another clue to systemic FL is clinical presentations such as B symptoms and lymphadenopathy. Cytogenetics is also helpful, as t(14;18) is usually identified in FL but is not found in most cases of PCFCL.

PCDLBCL-LT is another lymphoma of large B-cells that classically involves the skin of the lower extremities of older women. However, 10-15% of cases present with non-leg lesions.[14] PCDLBCL-LT carries a much worse prognosis than PCFCL and requires a different treatment approach with multiagent chemotherapy with or without radiation therapy.[12] Histology of PCDLBCL-LT demonstrates a sheet-like proliferation of monotonous centroblasts/immunoblasts. It will strongly express BCL-2, MUM1, FOXP1, and IgM.

Skin biopsies of the head with RLH will have multiple follicles and can mimic PCFCL. Follicles in RLH will carry more of the traditional architecture with polarized germinal centers with light and dark zones, well-defined mantle zones, and tingible body macrophages. Immunohistochemistry can sometimes aid in diagnosis as BCL-6 positive cells will be well confined within the meshwork of the follicle defined by CD21/23. PCMZL with reactive follicles can also morphologically mimic PCFCL. Overall, PCMZL has a more heterogenous look with smaller, centrocyte-like, and monocytoid lymphocytes and light chain-restricted plasma cells. By immunohistochemistry, PCMZL will be positive for BCL-2 and sometimes CD43. It will be negative for BCL-6 and CD10.[2]

Prognosis

Overall, PCFCL has an excellent prognosis and follows an indolent course, with 5-year survival greater than 95%. Grading is not required because regardless of growth pattern (follicular vs diffuse), presence or absence of BCL-2 expression and/or t(14;18), multifocal lesions, or several centroblasts, there is no change in prognosis. Of note, PCFCL that presents on the legs has been shown to be more aggressive and portends a worse prognosis.[6][9]

Complications

If untreated, lesions of PCFCL will slowly increase over the years, but dissemination will only occur in 10% of cases. The generally indolent character of the disease has led to more low-morbidity modalities like radiotherapy. Surgical excision can sometimes lead to problems with cosmesis depending on the size, especially since PCFCL tends to occur on the head. Following therapy, patients are followed at regular intervals to monitor for relapse or treatment-related complications. Cutaneous relapses occur in approximately 30% of cases.[6][12]