Primary cutaneous follicle-center lymphoma
Primary cutaneous follicle center lymphoma (PCFCL)
is defined as a tumor of neoplastic follicle center cells, usually a
mixture of centrocytes (small and large cleaved follicle center
cells) and variable numbers of centroblasts (large noncleaved
follicle center cells with prominent nucleoli), with a follicular, a
follicular and diffuse, or a diffuse growth pattern, which generally
present on the head or trunk. Lymphomas with a diffuse growth
pattern and a monotonous proliferation of centroblasts and immunoblasts
are, irrespective of site, excluded and are classified as
PCFCL has a characteristic clinical presentation
with solitary or grouped plaques and tumors, preferentially
located on the scalp or forehead or on the trunk, and rarely on the
legs. Particularly on the trunk, these tumors may
be surrounded by erythematous papules and slightly indurated
plaques, which may precede the development of tumorous lesions
for months or even many years. In the past, PCFCLs with such a
typical presentation on the back were referred to as “reticulohistiocytoma
of the dorsum” or “Crosti lymphoma"
Presentation with multifocal skin lesions is observed in a small
minority of patients, but is not associated with a more unfavorable prognosis. If left untreated, the skin lesions gradually
increase in size over years, but dissemination to extracutaneous
sites is uncommon.
PCFCLs show nodular to diffuse infiltrates
with almost constant sparing of the epidermis. The histologic
picture is variable, which relates primarily to the age and the
growth rate of the biopsied skin lesion as well as the location.
Clear-cut follicular growth pattern is more commonly observed in
lesions arising on the scalp than those presenting on the trunk.
Small and early lesions contain a mixture of centrocytes, relatively
few centroblasts, and many reactive T cells. Large centrocytes,
often multilobated, are a common feature of PCFCL.
The large neoplastic B cells may have a fibroblast-like appearance.
In small and/or early lesions a clear-cut follicular growth pattern or,
more often, remnants of a follicular growth pattern may be
observed. If present, the abnormal follicles are composed of
malignant bcl-6 follicle center cells enmeshed in a network of
CD21 or CD35 follicular dendritic cells. The follicles are
ill-defined, lack tingible body macrophages, and generally have a
reduced or absent mantle zone.With progression to tumorous
lesions the neoplastic B cells increase both in number and size,
whereas the number of reactive T cells steadily decreases.
Follicular structures, if present before, are no longer visible except
for occasional scattered CD21 or CD35 follicular dendritic cells.
Tumorous skin lesions generally show a monotonous population of
large follicle center cells, generally large centrocytes and multilobated
cells, and in rare cases spindle-shaped cells, with a variable
admixture of centroblasts and immunoblasts. Usually, a
prominent stromal component is present.
The neoplastic cells express the B-cell–associated antigens CD20 and CD79a, and may show monotypic
staining for surface immunoglobulins (sIgs). However, absence of
detectable sIg is common in tumorous lesions showing a diffuse
population of large follicle center cells. PCFCLs consistently
express bcl-6. CD10 expression is particularly observed in
cases with a follicular growth pattern, but is uncommon in PCFCLs
with a diffuse growth pattern. Staining for CD5 and CD43 is
negative. Unlike nodal and secondary cutaneous follicular lymphomas,
PCFCLs do not express bcl-2 protein or show faint bcl-2
staining in a minority of neoplastic B-cells.
Staining for MUM-1/IRF4 is negative.
Clonally rearranged immunoglobulin genes
are present. Somatic hypermutation of variable heavy and light
chain genes has been demonstrated, which further supports the
follicle center cell origin of these lymphomas. In most studies
PCFCLs, including cases with a follicular growth pattern, do notshow the t(14;18), which is characteristically found in systemic
follicular lymphomas and a proportion of systemic diffuse large
B-cell lymphoma.(see “Comment” under “Primary cutaneous
Inactivation of p15 and p16 tumor suppressor genes by promotor
hypermethylation has been reported in about 10% and 30% of
PCFCLs, respectively. Chromosomal imbalances have been
identified by comparative genomic hybridization (CGH) analysis in
a minority of PCFCLs, but a consistent pattern has not yet
emerged.In a recent study using interphase fluorescence in
situ hybridization, no evidence for translocations involving IgH,
myc, or bcl-6 loci were found.45 PCFCLs have the gene expression
profile of germinal center–like large B-cell lymphomas.
Prognosis and predictive factors.
Regardless of the growth
pattern (follicular or diffuse), the number of blast cells, or the
presence of either localized or multifocal skin disease, these
PCFCLs have an excellent prognosis with a 5-year survival of more
than 95%. A recent study suggests that
strong expression of bcl-2 in PCFCLs with a diffuse large-cell
histology is associated with a more unfavorable prognosis.
In patients with localized or few scattered skin
lesions, radiotherapy is the preferred mode of treatment, even in
cases with a predominance of large “cleaved” cells.
Cutaneous relapses, observed in approximately 20% of patients, do
not indicate progressive disease and can be treated with radiotherapy
as well. Anthracycline-based chemotherapy is required
only in patients with very extensive cutaneous disease and patients
developing extracutaneous disease. Recent studies report
beneficial effects of systemic or intralesional administration of
anti-CD20 antibody (rituximab) therapy in small series of PCFCLs,
but the long-term effects of this approach have yet to be
Characteristically, PCFCLs do not express bcl-2
protein, or show faint bcl-2 staining in a minority of tumor cells,
and do not show the t(14;18).However, recent studies report
the presence of t(14;18) and/or bcl-2 expression in a significant
minority of PCFCLs.43,153,165-167 Whether these discrepant results
are the result of differences in patient selection (eg, incomplete
staging) or different definitions for bcl-2 positivity, or represent
regional differences is as yet unknown. Importantly, in PCFCLs
with a follicular growth pattern there are no differences in clinical
presentation and behavior between bcl-2 and/or t(14;18)-positive
and -negative cases.In contrast, recent studies suggest
that expression of bcl-2 protein by more than 50% of the neoplastic
B cells in PCFCLs with a diffuse proliferation of large centrocytes,
observed in approximately 15% of cases, is associated with a more
unfavorable prognosis.158 Further studies are warranted to define
the clinical and biological significance of bcl-2 expression and/or
the presence of t(14;18) observed in some cases of PCFCL.
Notwithstanding, demonstration of bcl-2 expression and/or t(14;
18) should always raise suspicion of a systemic lymphoma
involving the skin secondarily.