Primary Cutaneous Follicle Center Lymphoma



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 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.


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

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