Primary Cutaneous Follicle Center Lymphoma

Roberto N. Miranda, MD

Key Facts

Terminology

Lymphoma arising in skin composed of follicular center cells
Subset of cases appear to be clinically and genetically distinct from nodal FL

Clinical Issues

Usually solitary, erythematous lesion in head and neck
Therapy with local radiation or surgical excision
Prognosis favorable, even in patients with multiple skin lesions
5-year survival rate is 95%

Microscopic Pathology

Dermal lymphoid follicular infiltrate that spares epidermis

Ancillary Tests

CD10(+) in cases with follicular pattern
Bcl-6(+); Bcl-2(+/-) in up to 60% of cases
PCFCL that is CD10(+), Bcl-2(+) likely carries t(14;18) (q32;q21)
˜ 30% of PCFCL cases have t(14;18) by FISH

Top Differential Diagnoses

Secondary follicular lymphoma of skin
- Usually strongly CD10(+) and Bcl-2(+)
- BCL2 gene rearrangements in ˜ 80-90% of cases
Cutaneous marginal zone B-cell lymphoma
Primary cutaneous diffuse large B-cell lymphoma (PCLBCL), leg type
PCLBCL, other (non-leg type)
Cutaneous follicular hyperplasia

Primary cutaneous follicle center lymphoma (PCFCL) presenting as a 1 cm erythematous nodule

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

). The neoplasm contains ill-defined follicles

TERMINOLOGY

Abbreviations

Primary cutaneous follicle center lymphoma (PCFCL)

Synonyms

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

Definitions

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

ETIOLOGY/PATHOGENESIS

Etiology

Unknown

Cell of Origin

Mature germinal center B lymphocyte

CLINICAL ISSUES

Epidemiology

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

Site

Usually in head and neck
- Affects mainly scalp and forehead
Less frequent on trunk
Legs affected in 5% of cases

Presentation

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

Treatment

Local radiation or surgical excision of lesions
Systemic therapy required for patients with
- Extensive disease, very thick skin tumors, or extracutaneous disease

Prognosis

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

MICROSCOPIC PATHOLOGY

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

ANCILLARY TESTS

Immunohistochemistry

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

DIFFERENTIAL DIAGNOSIS

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

DIAGNOSTIC CHECKLIST

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

SELECTED REFERENCES

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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