Primary Cutaneous Follicle Center Lymphoma

Primary Cutaneous Follicle Center Lymphoma

Roberto N. Miranda, MD

Primary cutaneous follicle center lymphoma (PCFCL) presenting as a 1 cm erythematous nodule image in the scalp. Most cases of PCFCL are found in the head and neck region.

PCFCL displaying a dense lymphocytic infiltrate in the dermis, sparing the subepidermal layer (grenz zone image). The neoplasm contains ill-defined follicles image.



  • Primary cutaneous follicle center lymphoma (PCFCL)


  • Follicular lymphoma (FL) of skin

  • Follicular center cell lymphoma

  • Centroblastic/centrocytic lymphoma

  • PCFCL on back previously referred to as

    • Reticulohistiocytoma of the dorsum

    • Crosti disease


  • Lymphoma arising in skin composed of follicular center cells

    • Confined to skin for at least 6 months upon staging

    • Mainly centrocytes (small cleaved cells); less frequently centroblasts (large cleaved and noncleaved cells)

    • Follicular or diffuse growth pattern

  • Recently defined as entity; diagnostic criteria may require further refinement

    • Some published cases with diagnosis based on clinicopathologic findings; lack evidence of clonality

  • Subset of cases appear to be clinically and genetically distinct from nodal FL

    • BCL2 gene rearrangements less frequent than in nodal FL



  • Unknown

Cell of Origin

  • Mature germinal center B lymphocyte



  • Incidence

    • 2nd most common extranodal B-cell lymphoma after gastrointestinal lymphomas

    • 0.1-0.2 per 100,000 persons per year

  • Age

    • Affects adults; median 60 years (range 33-88 years)

  • Gender

    • Male to female ratio is 1.5:1


  • Usually in head and neck

    • Affects mainly scalp and forehead

  • Less frequent on trunk

  • Legs affected in 5% of cases


  • Usually solitary, firm, and erythematous to violaceous lesion

    • May be plaques, nodules, or tumor masses of variable size

    • Lesions range from < 1 cm to large, confluent nodules > 40 cm in diameter

  • Multifocal in 15% of patients

  • Presentation on trunk is usually preceded by erythematous papules or figurate plaques

    • This form was designated in past as “reticulohistiocytoma of the dorsum”

Natural History

  • Lesions gradually increase in size if left untreated

  • Dissemination to extracutaneous sites is uncommon (˜ 10%)

  • Recurrences occur at proximal site compared with initial site of presentation

    • Recurrences occur in 30-40% of patients


  • Local radiation or surgical excision of lesions

  • Systemic therapy required for patients with

    • Extensive disease, very thick skin tumors, or extracutaneous disease


  • Favorable, even in patients with multiple skin lesions

    • Most patients achieve complete remission with therapy

  • Survival is 95% at 5 years; not affected by presence of

    • Follicular or diffuse growth pattern or cytologic grade

    • t(14;18) or BCL2 gene rearrangements

    • Extent or relapse of disease


Histologic Features

  • Dermal infiltrate that spares epidermis (grenz zone)

  • Growth patterns

    • Pure follicular

    • Mixed follicular and diffuse

    • Pure diffuse

  • Cell composition

    • Small- to intermediate-sized centrocytes admixed with variable amount of large centroblasts

    • Grading is not recommended for PCFCL

      • Amount of large cells in follicles does not influence prognosis in patients with PCFCL

  • Lymphoid follicles and germinal centers are better appreciated in small or incipient lesions

    • Follicles are ill defined and composed of rather monotonous lymphoid population

      • Usually, tingible body macrophages are absent

      • Attenuated or absent mantle zones

  • Variable amounts of sclerosis

  • Infiltrate may reach subcutaneous tissue in ˜ 75% of cases

    • Most follicles in deep dermis (‘bottom heavy”)

  • Advanced lesions show less conspicuous follicles, if present

    • Usually composed of multilobated, cleaved, or spindle-shaped lymphocytes

    • Remnants of follicular dendritic cells (FDCs)

  • Extreme cases with many centroblasts simulate DLBCL

    • Should be considered as PCFCL if follicular component

      • Considered to share excellent prognosis of other, more typical PCFCL

    • DLBCL is diagnosed when large cells grow in pure diffuse pattern



  • Pan-B-cell antigens(+), pax-5(+)

  • CD10 is typically positive but can be negative in cases with diffuse pattern

    • CD10(+) cell clusters may be found in interfollicular areas

  • Bcl-6(+) consistently found in follicles

  • Bcl-2(+/−) in up to 60% of cases

    • When positive, Bcl-2 is often dim

      • (+) more frequently in cases with follicular pattern

  • PCFCL that are CD10(+) and Bcl-2(+) likely carry t(14;18)(q32;q21)

  • Monotypic B lymphocytes can be detected in fixed, paraffin-embedded tissue sections

    • ˜ 1-20% using routine immunohistochemistry

    • Role of mRNA expression of κ and λ in cutaneous infiltrates not established

  • IRF-4/MUM1 and FOXP1 are usually (−)

  • Cytoplasmic IgM(−), IgD(−)

  • Underlying FDC network: CD21(+), CD23(+), &/or CD35(+)

  • T-cell antigens(−)

    • Variable number of reactive small T-lymphocytes

Flow Cytometry

  • Monotypic surface Ig(+), pan-B-cell antigens(+)

  • CD10(+), CD19(+ dim), CD20(+ bright), FMC-7(+)

In Situ Hybridization

  • ˜ 30% of PCFCL cases have t(14;18) by FISH

Array CGH

  • Chromosomal imbalances in minority of cases

Molecular Genetics

  • Monoclonal Ig gene rearrangements

    • Detected by PCR in 40-50% of cases

    • Somatic hypermutation of Ig genes is common

  • IgH-BCL2 fusion occurs at variable frequency in PCFCL

Gene Expression Profiling

  • Gene expression profile similar to germinal center-like large B-cell lymphoma

    • REL gene amplification is common


Secondary Follicular Lymphoma (FL) of Skin

  • Evidence of systemic FL elsewhere

    • Head and neck are most frequent sites

  • Immunophenotype

    • Bcl-6(+), CD10(+), Bcl-2(+)

  • IgH-BCL2/t(14;18)(q32;q21) in ˜ 80-90% of cases

Marginal Zone B-cell Lymphoma of Skin

  • Usually multifocal

    • Previous nomenclature included

      • B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)

      • Cutaneous immunocytoma

      • Cutaneous follicular lymphoid hyperplasia with monotypic plasma cells

  • Indolent low-grade lymphoma, 99% 5-year survival

  • Association with Borrelia burgdorferi, mostly in Europe

  • Marginal zone and interfollicular distribution

  • Mixed cell composition

    • Marginal zone (centrocyte-like) cells

    • Monocytoid cells or small round lymphocytes

    • Scattered large cells, centroblast-like

    • ± plasma cell differentiation

      • Subepidermal or at advancing edge of tumor

  • Immunophenotype

    • B-cell antigens(+), CD10(−), Bcl-6(−)

    • Monotypic cytoplasmic Ig in cases with plasmacytoid differentiation

    • Clusters of reactive CD123(+) plasmacytoid dendritic cells are common

  • Underlying disrupted and colonized germinal centers highlighted by FDC markers

    • Residual germinal center cells are CD10(+) and Bcl-6(+)

Primary Cutaneous Diffuse Large B-cell Lymphoma (PCLBCL), Leg Type

  • Disease of elderly

  • Rapidly growing tumors with 50% 5-year survival

  • Primarily affects lower extremities; occasionally occurs at other body sites

  • Diffuse and monotonous infiltrate composed of large centroblasts or immunoblasts

    • Absence of neoplastic follicles and small or large centrocytes

    • Distinct from DLBCL with centrocytes or neoplastic follicles

  • Non-germinal center cell (activated B-cell) immunophenotype

    • B-cell antigens(+), cytoplasmic IgM(+), Bcl-6(+)

    • Bcl-2(+), IRF-4/MUM1(+), FOXP1(+)

    • CD10(−), CD138(−)

Primary Cutaneous Diffuse Large B-cell Lymphoma (PCLBCL), Other (Non-Leg Type)

  • Includes DLBCL that does not fit with

    • PCLBCL leg type

    • PCFCL with diffuse large cells

    • Also encompasses T cell-rich large B-cell lymphoma and plasmablastic lymphoma

  • Large neoplastic cells are admixed with inflammatory reactive infiltrate

  • Phenotype may be germinal and non-germinal center type

  • Lymphoma of adults with slightly better prognosis than PCLBCL leg type

Cutaneous Follicular Hyperplasia

  • Lesions of variable ages; may be associated with

    • Insect or tick bites

    • Hair follicle inflammation

  • Well-defined follicles with distinct germinal centers and mantle zones

    • Most follicles are in superficial dermis (‘top heavy”)

  • Frequent tingible body macrophages

  • Immunophenotype

    • Mixture of B cells and T cells; often in compartments

    • Germinal centers are Bcl-6(+), Bcl-2(−)

  • No evidence of monoclonal Ig gene rearrangements


Clinically Relevant Pathologic Features

  • FL confined to skin for at least 6 months upon staging

Pathologic Interpretation Pearls

  • Grading is not recommended for PCFCL

  • Lower frequency of t(14;18)/IgH-BCL2 than in nodal FL


1. Koens L et al: IgM expression on paraffin sections distinguishes primary cutaneous large B-cell lymphoma, leg type from primary cutaneous follicle center lymphoma. Am J Surg Pathol. 34(7):1043-8, 2010

2. Dijkman R et al: Array-based comparative genomic hybridization analysis reveals recurrent chromosomal alterations and prognostic parameters in primary cutaneous large B-cell lymphoma. J Clin Oncol. 24(2):296-305, 2006

3. Hoefnagel JJ et al: Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling. Blood. 105(9):3671-8, 2005

4. Kim BK et al: Clinicopathologic, immunophenotypic, and molecular cytogenetic fluorescence in situ hybridization analysis of primary and secondary cutaneous follicular lymphomas. Am J Surg Pathol. 29(1):69-82, 2005

5. Kodama K et al: Primary cutaneous large B-cell lymphomas: clinicopathologic features, classification, and prognostic factors in a large series of patients. Blood. 106(7):2491-7, 2005

6. Willemze R et al: WHO-EORTC classification for cutaneous lymphomas. Blood. 105(10):3768-85, 2005

7. Goodlad JR et al: Primary cutaneous diffuse large B-cell lymphoma: prognostic significance of clinicopathological subtypes. Am J Surg Pathol. 27(12):1538-45, 2003

8. Goodlad JR et al: Primary cutaneous follicular lymphoma: a clinicopathologic and molecular study of 16 cases in support of a distinct entity. Am J Surg Pathol. 26(6):733-41, 2002

9. Mirza I et al: Primary cutaneous follicular lymphoma: an assessment of clinical, histopathologic, immunophenotypic, and molecular features. J Clin Oncol. 20(3):647-55, 2002

10. Aguilera NS et al: Cutaneous follicle center lymphoma: a clinicopathologic study of 19 cases. Mod Pathol. 14(9):828-35, 2001

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Primary Cutaneous Follicle Center Lymphoma

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