Recent advances in the classification, diagnosis,
and prognosis of the three major entities of
primary cutaneous B-cell lymphoma have
contributed to a better understanding and
management of this disease.
George Van Hook. Rail Yard. Oil on linen, 12˝ × 16˝.
Primary Cutaneous B-Cell Lymphomas:
Recent Advances in Diagnosis and Management
Lubomir Sokol, MD, PhD, Mojdeh Naghashpour, MD, PhD, and L. Frank Glass, MD
Background: Primary cutaneous B-cell lymphoma (PCBCL) is a heterogeneous group of rare clonal B-cell
lymphoproliferative disorders with distinct clinicopathologic features from more common nodal B-cell lymphomas.
Methods: We performed a systematic review of the relevant literature in the MEDLINE database and analyzed
laboratory and clinical data. This review discusses the three most common types of PCBCL: primary cutaneous
marginal zone lymphoma (PCMZL), primary cutaneous follicle-center lymphoma (PCFCL), and primary
cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT).
Results: Skin biopsies with histology, immunohistochemistry, and molecular clonality studies are essential
for a correct diagnosis of cutaneous B-cell lymphoma. Comprehensive lymphoma staging with laboratory and
imaging studies and bone marrow aspiration and biopsy are important for determining the prognosis and
differentiation of PCBCL from secondary skin involvement with systemic B-cell lymphomas. PCMZL and PCFCL
are low-grade PCBCLs, with an estimated 5-year disease-specific survival rate of greater than 95%. Surgical
excision or focal radiation therapy is sufficient to control stages T1 and T2 disease. Rituximab monotherapy
is frequently used for patients with stage T3 disease. PCDLBCL, LT is an intermediate-grade B-cell lymphoma,
with a 5-year disease-specific survival rate of approximately 50%. An anthracycline-based chemotherapy regimen
with rituximab is usually required as initial therapy to improve outcomes.
Conclusions: In less than a decade, significant progress has been made in our understanding of PCBCL.
Novel classification, staging, and prognostic systems have resulted in more accurate diagnosis and prognosis.
Although no randomized prospective studies have been conducted in PCBCL, therapies derived from systemic
B-cell lymphomas have shown promising results.
Introduction
From the Departments of Malignant Hematology (LS), Hematopathology and Laboratory Medicine (MN), and Cutaneous Oncology (LFG) at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
Submitted August 5, 2011; accepted January 5, 2012.
Address correspondence to Lubomir Sokol, MD, PhD, Department
of Malignant Hematology, Moffitt Cancer Center, 12902 Magnolia
Drive, Tampa, FL 33612. E-mail: [email protected]
No significant relationship exists between the authors and the
companies/organizations whose products or services may be referenced in this article.
236 Cancer Control
Primary cutaneous B-cell lymphoma (PCBCL) belongs
to a group of rare B-cell lymphoproliferative disorders
that present in the skin and have no evidence of extracutaneous manifestation at the time of initial diagnosis.1
Clinicopathologic features of PCBCL are distinct from
those of its nodal counterparts. Recently, several advances in the classification, diagnosis, and prognosis of
PCBCL have been made.
In 2005, the World Health Organization (WHO) and
the European Organization for Research and Treatment
of Cancer (EORTC) introduced a new consensus clasJuly 2012, Vol. 19, No. 3
sification for cutaneous lymphoma, which reconciled
previous disagreements between these two classification systems.2-4 The WHO classification of lymphomas
published in 20014 defined PCBCL disease entities based
only on histology and molecular parameters, whereas
the EORTC classification3 included both histology and
skin site.
Three major disease entities of PCBCL have been
recognized in this new joint classification system: primary cutaneous marginal zone lymphoma (PCMZL),
primary cutaneous follicle-center lymphoma (PCFCL),
and primary cutaneous diffuse large B-cell lymphoma,
leg type (PCDLBCL, LT).2
The Ann Arbor staging system used for staging of
systemic non-Hodgkin lymphoma (NHL) has only limited prognostic value in PCBCL as patients are classified in
only two stages: IE and IVE. The International Society
for Cutaneous Lymphoma and the Cutaneous Task Force
of EORTC (ISCL/EORTC) developed a proposal of a new
TNM classification for primary cutaneous lymphomas
other than mycosis fungoides and Sézary syndrome.5
This system is based on the number, size, and area of
distribution of tumor lesions (Table). Although several
retrospective studies investigated a validity of new classification and staging systems on independent cohorts
of patients, no larger prospective study for patients with
PCBCL has been conducted to validate these systems in
clinical practice.
Two prognostic systems also have been proposed
for PCBCL.6,7 The National Comprehensive Cancer
Network (NCCN) guidelines for NHL recognized differences in the diagnosis and management of PCBCL
and created separate recommendations for this group
of B-cell malignancies.8 Herein, we discuss the clinical
and pathological characteristics of the most common
entities in the group of PCBCL.
Epidemiology
Primary B-cell lymphoma comprises approximately 20%
of all primary cutaneous lymphomas and less than 1% of
all NHLs.9 This disease ranks second among extranodal
NHLs, after primary gastrointestinal NHLs.
Smith at al7 analyzed data from the Surveillance,
Epidemiology, and End Results (SEER) registry collected
between 1973 and 2001. The age-adjusted incidence rate
of PCBCL was 3.9 per million population. This study
also suggested that the incidence rates steadily increase
with age at diagnosis from 0.09 per million in patients
< 30 years old to 10.8 per million in patients ≥ 80 years
old (120-fold increase; P < .001). The male-to-female
ratio was 1.4:1 for the entire PCBCL group. Low-grade
PCBCLs (PCMZL, PCFCL) usually manifest in middle-age
populations, with a median age of 53 and 58 years, respectively.10 PCDLBCL, LT is a disease of elderly persons,
with a median age > 70 years. The male-to-female ratio
was 1.4 and 2.1 for PCMZL and PCFCL, respectively,
July 2012, Vol. 19, No. 3
and 0.5 for PCDLBCL, LT.10 No significant geographic
or ethnic differences in the occurrence of PCBCL were
reported in the reviewed literature.
Etiology
Although the etiology of PCBCL is not well understood,
several reports from Europe revealed an association
between PCMZL with Borrelia burgdorferi (Bb).11-13
Jelić et al12 reported that 12 of 22 patients (55%) with
PCBCL had a positive serology for Bb. Goodlad et al13
detected Bb-specific DNA sequences in 7 of 20 patients
with PCBCL (5 PCMZL, 5 PCFCL, and 2 PCDLBCL, LT).
A limited number of cases of PCBCL positive for Bb
were treated with antibiotics and showed resolution
of lesions.14,15 However, three studies that included
patients from Europe did not confirm this hypothesis.
Takino et al16 analyzed 60 cases of PCMZL from East
Asia, Germany, and the United States using multiple
clinicopathologic characteristics. All 60 cases were
Table. — ISCL/EORTC Proposal on TNM Classifi cation of Cutaneous
Lymphoma Other Than Mycosis Fungoides and Sézary Syndrome
T
T1 Solitary skin involvement
T1a A solitary lesion < 5-cm diameter
T1b A solitary > 5-cm diameter
T2 Regional skin involvement multiple lesions limited to 1 body
region or 2 contiguous body regions
T2a All-disease-encompassing in a < 15-cm diameter
circular area
T2b All-disease-encompassing in a > 15- and < 30-cm
diameter circular area
T2c All-disease-encompassing in a 30-cm diameter
circular area
T3 Generalized skin involvement
T3a Multiple lesions involving 2 noncontiguous
body regions
T3b Multiple lesions involving ≥ 3 body regions
N
N0 No clinical or pathologic lymph node involvement
N1 Involvement of 1 peripheral lymph node region that drains
an area of current or prior skin involvement
N2 Involvement of 2 or more peripheral lymph node regions or
involvement of any lymph node region that does not drain
an area of current or prior skin involvement
N3 Involvement of central lymph nodes
M
M0 No evidence of extracutaneous non-lymph node disease
M1 Extracutaneous non-lymph node disease present
From Kim YH, Willemze R, Pimpinelli N, et al. TNM classification system for primary cutaneous lymphomas other than mycosis fungoides
and Sézary syndrome: a proposal of the International Society for
Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task
Force of the European Organization of Research and Treatment of
Cancer (EORTC). Blood. 2007;110(2):479-484. Blood by AMERICAN SOCIETY OF HEMATOLOGY Copyright 2012 Reproduced with
permission of AMERICAN SOCIETY OF HEMATOLOGY (ASH) in the
format Journal via Copyright Clearance Center.
Cancer Control 237
negative for Bb DNA or for API2-MALT1 fusion. Goteri
at al17 tested 73 paraffin-embedded tissue samples from
patients with PCBCL using polymerase chain reaction
(PCR) and showed no evidence of the presence of Bbspecific sequences. Schöllkopf et al18 analyzed 3,055 patients with NHL and 3,187 controls in a Danish-Swedish
case-controlled study. A positive history of a tick bite
or antibodies against Borrelia infection in serum was
found in 1,579 patients and 1,358 controls. Statistical
analysis suggested that the overall risk of NHL was not
associated with a self-reported history of tick bite or the
presence of anti-Borrelia antibodies. Interestingly, in
analyses of NHL subtypes, both parameters were associated with an increased risk of mantle cell lymphoma.
PCBCL (PCFCL = 25, PCMZL = 19, and PCDLBCL, LT
= 7). The authors showed that all but 1 patient with
PCBCL revealed extensive somatic hypermutations. The
mutational pattern suggested a possibility of antigenic
selection with putative common antigen epitopes.
Dijkman et al23 reported that a significant proportion of patients with PCFCL and PCDLBCL, LT demonstrated aberrant somatic hypermutations of BCL-6, MYC,
RhoH/TTF, and PAX5 genes. Interestingly, the higher
expression of activation-induced cytidine deaminase
(AID) was detected in patients with PCDLBCL, LT than
in those with PCFCL. This enzyme creates somatic
mutations responsible not only for antibody diversity
but also for lymphomagenesis.24
Molecular Biology
Primary Cutaneous B-Cell Lymphoma
Recent progress in molecular biology and increased
research interest in the pathobiology of cutaneous lymphoma have resulted in new fi ndings, with potential
clinical implications.
Dijkman et al19 employed array-based comparative
genomic hybridization, fluorescence in situ hybridization, and examination of promoter hypermethylation
in patients with PCFCL (n = 19) and PCDLBCL, LT (n =
12). In patients with PCFCL, the most frequent recurrent
aberrations were DNA amplifications at 2p16.1 (63%) and
deletion of chromosome 14q32.33 (68%). In patients
with PCDLBCL, LT, the most prominent alterations were
a high-level DNA amplification of 18q21.31-q21.33 (67%)
and deletions of a small region within 9p21.3 containing
the CDKN2A and CDKN2B genes. Homozygous deletion
of 9p21.3 was detected in 5 of 12 patients (42%) with
PCDLBCL, LT but in none of 19 patients with PCFCL.
Complete methylation of the promoter region of the CDKN2A gene was demonstrated in 2 patients with PCDLBCL, LT but not in patients with PCFCL. All patients with
PCDLBCL, LT with deletion of 9p21.3 and/or complete
methylation of CDKN2A died as a result of lymphoma.
Bhagavathi et al20 evaluated 10 patients with PCBCL
using immunohistochemistry (IHC) and detected activation of nuclear factor kappa B (NFκB) pathway in 70%
of patients. Only 1 patient showed Epstein-Barr virus
(EBV) positivity using EBV-encoded RNA (EBER) staining, suggesting that a different mechanism(or mechanisms) may be responsible for activation of this pathway.
A study by van Maldegem et al21 reported that the
majority of PCMZLs expressed immunoglobulin G (IgG),
IgA, and IgE and did not show Ig-variable heavy/light
chain (IgV H/IgV L) gene repertoire restriction, as frequently seen in other extranodal MZL. Furthermore,
the isotype-switched PCMZLs lacked a receptor for
interferon gamma-induced chemokines (CXCR3), suggesting that PCMZL evolved in a different inflammatory
environment than did noncutaneous extranodal MZL.
Perez et al22 analyzed the nucleotide sequences
of clonal IgV H gene rearrangement in 51 patients with
Prognostic Scoring Systems
238 Cancer Control
Smith et al7 analyzed 926 patients in the SEER registry
and created a new cutaneous B-cell lymphoma prognostic index (CBCL-PI) based on histology type and skin
site. Four prognostic index groups were identified: (1)
group IA: indolent histology involving any skin site, (2)
group IB: diffuse large B-cell histology involving favorable skin sites (head/neck, arm), (3) group II: diffuse
large B-cell histology involving unfavorable sites (trunk,
legs, disseminated), and (4) group III: immunoblastic
large B-cell histology involving unfavorable sites. The
prognostic groups had 5-year relative survival rates of
94%, 86%, 60%, and 34%, respectively.
The International Extranodal Lymphoma Study
Group (IELSG 11) proposed a new prognostic index
for indolent cutaneous B-cell lymphoma: CLIPI.6 This
prognostic scoring system is based on three prognostic
factors: elevated serum lactate dehydrogenase (LDH)
level (> upper limit of normal), morphology of the lesion
(nodule vs other), and number of lesions (> 2). These
factors were independent predictors for progressionfree survival (PFS). After each prognostic factor was
assigned a value of 1, patients were stratified to the following three risk groups with a score of 0 to 3: low risk
= 0, intermediate risk = 1, and high risk = 2 and 3. The
5-year PFS rates were 91%, 64%, and 48%, respectively
(P < .001).
Diagnosis
Punch (4–6 mm), wedge-incisional, or excisional biopsies are most frequently performed for the diagnosis of
PCBCL. IHC with a panel of antibodies against B-cell
antigens including CD20, CD79a, CD5, CD10, BCL-2,
BCL-6, kappa/lambda, and MUM1/IRF4 is an essential
diagnostic tool. Ig heavy-chain and light chain gene
rearrangement by PCR can be done on paraffin-embedded tissue to confirm a clonal origin of B cells. Flow
cytometry on the fresh tissue can also be useful if the
biopsy specimen contains a sufficient number of malignant cells.
July 2012, Vol. 19, No. 3
Staging
Staging studies for patients with PCBCL are important
not only for the determination of prognosis but also for
the confirmation of diagnosis, as neither histology nor
IHC can differentiate with absolute certainty PCBCL
from cutaneous involvement with systemic B-cell lymphomas. According to ISCL/EORTC recommendations
for staging evaluation (Table) of cutaneous lymphomas
other than mycosis fungoides and Sézary syndrome,5
patients should undergo the following testing: a complete history and physical examination, complete blood
cell count with differential count (CBC/Diff), chemistry
with LDH, flow cytometry on peripheral blood, and
imaging with computed tomography (CT) scan of the
chest, abdomen, and pelvis with contrast or positron
emission-tomography/CT (PET/CT). Although a CT
scan is sufficient for a diagnosis of adenopathy and organomegaly, smaller skin lesions can be missed. Fusion
PET/CT on the other side can visualize metabolically
active disease in relatively small lesions, which might
sometimes be missed on physical examination.
Bone marrow aspiration and biopsy (BMAB) is
recommended for all patients with intermediate-grade
PCBCL. However, there is not a consensus on bone
marrow testing in patients with indolent PCBCL.
Quereux et al25 retrospectively analyzed 62 patients
with PCBCL who underwent staging BMAB. After exclusion of 4 patients with adenopathy and 1 patient with
pancytopenia, a positive bone marrow was found in only
3 of 57 patients (5%), suggesting that a routine BMAB
might not be necessary.
Senff et al26 analyzed results of BMAB in 275 patients
with indolent B-cell lymphomas (82 with MZL and 193
with follicular lymphoma [FCL]) who presented with
skin lesions. In the group with MZL, 2 of the 82 patients (2%) presented with bone marrow involvement,
which was only an extracutaneous manifestation of
lymphoma. In the FCL group, 22 of the 193 patients
(11%) had bone marrow involvement; in 9 of these patients, the bone marrow was the only extracutaneous
disease. Patients with FCL plus skin lesions and bone
marrow involvement had a significantly worse prognosis
than did patients with skin lesions only (5-year diseasespecific survival rate of 63% vs 95%). These results
demonstrated that staging studies with bone marrow
testing are important in patients with FCL but have limited value in patients with MZL manifesting with skin
lesions. The NCCN guidelines for NHL8 consider BMAB
to be optional for patients with PCMZL.
Therapy
The choice of therapy for PCBCL is usually based on histology (low grade vs intermediate grade), anatomic location,
size, and number of tumor lesions. As a rule, low-grade
(indolent) PCBCL can be managed with observation or
skin-directed therapies (surgical excision, radiation theraJuly 2012, Vol. 19, No. 3
py), whereas intermediate-grade PCBCL requires systemic
therapy with involved-field radiation therapy (Fig 1).
Rituximab Monotherapy
Systemic: Rituximab monotherapy has been successfully used in systemic low-grade B-cell malignancies.
Because PCBCL expresses CD20 antigen, several small
pilot studies with rituximab monotherapy were conducted in patients with PCBCL. Fenot et al27 reported
the results of a retrospective study with single-agent
rituximab in 8 patients with PCDLBCL, LT. Objective responses were observed in 75% of patients after 4 weekly
courses of rituximab. However, all patients relapsed,
with a median disease-free survival of 5.3 months and
a median follow-up 17.7 months.
Valencak et al28 observed a high complete response
(CR) rate of 87.5% in patients with low-grade PCBCL (11
PCFCL and 5 PCMZL) with 4 to 6 weeks of rituximab
monotherapy. Two patients achieved a partial response
(PR). Of 14 patients, 5 (35%) with a CR relapsed within
6 to 37 months.
Morales et al29 reported on a retrospective study of
15 patients with indolent PCBCL (10 PCFCL, 5 PCMZL)
treated with rituximab induction therapy followed by
variable maintenance therapy in a subset of patients. The
objective response rate was 87%, with 60% CRs and 27%
PRs. All patients with PCFCL showed a response, with
80% being a CR. Of 5 patients with PCMLZ, 3 (60%) had
a response, with a median follow-up of 36 months. The
median duration of response was 24 months.
Intralesional: Treatment with intralesional rituximab was tested in a limited number of patients. Kyrtsonis et al30 reported that 2 patients with multiple lesions of PCMZL treated with intralesional rituximab for
18 consecutive weeks achieved regression of lesions.
Heinzerling et al31 treated 2 patients with PCBCL with
intralesional rituximab, achieving partial regression of
the lesions. Patients in both studies did not experience
any adverse reactions except pain at the injection site.
Kerl et al32 reported on 8 patients with low-grade
PCBCL treated with rituximab. Six patients received
intralesional rituximab, 10 mg to 30 mg per lesion, 3
times weekly for 1 or 2 cycles at 4-week intervals. Two
patients received intravenous (IV) rituximab, 375 mg/
m2 once weekly for 4 consecutive weeks. The overall
response rate was 100%. Two patients treated with IV
rituximab did not relapse during a follow-up period of
18 to 24 months. Four patients treated intralesionally
relapsed, with new lesions within a mean of 6 months
after treatment. The injected lesions did not recur.
Roguedas et al33 treated PCFCL patients with intralesional rituximab and observed regression of both
injected and noninjected lesions. Because only a limited
number of patients have been treated with intralesional
rituximab so far, larger prospective studies are necessary to confirm the safety and efficacy of this approach.
Cancer Control 239
Intralesional Interferon: A small number of patients with PCMZL and PCFCL were treated with intralesional interferon alpha (IFN-α), with doses ranging
from 1 to 6 million IU given 3 times a week.9 Interestingly, all patients achieved a CR, with a local recurrence
rate of approximately 25%.
In a phase II study of intralesional adenovirus IFN-γ,
Dummer et al34 treated patients with cutaneous T-cell
and B-cell lymphomas, with a good tolerance and responses in about 50% of patients. Distant responses in
noninjected lesions were observed in about one-third
of patients. This study suggested that activation of the
immune system with biologic agents could be employed
as a therapy for PCBCL.
Radioimmunotherapy: Radioimmunotherapy
(RIT) has become an important part of the therapeutic
armamentarium of systemic recurrent low-grade B-cell
lymphomas. Maza et al35 conducted a pilot study using
RIT with yttrium-90 (90Y)-ibritumomab tiuxetan in patients with PCBCL. Ten patients with relapsed PCBCL
(PCFCL and PCDLBL, LT) were treated with rituximab
on days 1 and 8 followed by a single dose of 90Y-ibritumomab tiuxetan. The CR rate was 100%, with a median
time to relapse of 12 months. These data suggest that
RIT could be an effective therapeutic option for patients
with PCBCL.
External-Beam Radiation Therapy: Senff et al36
reported on the results of radiotherapy with curative
intent in 153 patients with PCBCL classified according
to the WHO-EORTC classification in a multicenter, retrospective study. This large cohort of PCBCL patients
included 25 cases with PCMZL, 101 with PCFCL, and
27 with PCDLBCL, LT. The median radiation dose was
40 Gy (range, 20 Gy to 46 Gy). Complete remission was
achieved in 151 of 153 patients (99%). Relapse rates for
patients with PCMZL, PCFCL, and PCDLBCL, LT were
60%, 29%, and 64%, respectively, and the overall 5-year
disease-specific survival rates were 95%, 97%, and 59%.
Patients manifesting PCFCL on their legs had a higher
relapse rate (63%) and a worse disease-specific survival
rate (44%) than did patients with PCFCL on other sites
(relapse rate 25%; disease-specific survival rate 99%).
This study suggested that radiation therapy is an effective treatment for patients with PCBCL; however,
patients with PCDLBCL, LT and PCFCL manifesting on
the legs require more aggressive systemic therapy.
Neelis et al37 reported on the results of low-dose
palliative radiotherapy (4 Gy in 2 fractions) in patients
PCMZL/ PCFCL
PCDLBCL, LT
T1, T2
Solitary/regional
T3
Generalized
Extracutaneous
disease
T1, T2
Solitary/regional
T3
Generalized
Watch and wait
Surgical excision
Radiation therapy
Intralesional therapy
Watch and wait
Rituximab
Radiation therapy
Chemotherapy
Treat as systemic lowor intermediate-grade
lymphomas
R-CHOP +
radiation therapy
Clinical study
R-CHOP ±
radiation therapy
Clinical study
Relapsed1/refractory2
Relapsed/refractory
Treat with one of initial options1
Treat as systemic MZL or FL2
Clinical study
Treat as systemic DLBCL
Clinical study
Fig 1. — Primary cutaneous B-cell lymphoma treatment algorithm. PCMZL = primary cutaneous marginal zone lymphoma, PCFCL = primary cutaneous follicle-center lymphoma, PCDLBCL, LT = primary cutaneous diffuse large B-cell lymphoma, leg type, R-CHOP = rituximab, cyclophosphamide,
doxorubicin, vincristine, prednisone, MZL = marginal zone lymphoma, FL = follicular lymphoma, DLBCL = diffuse large B-cell lymphoma.
240 Cancer Control
July 2012, Vol. 19, No. 3
with PCBCL, which included 18 patients with low-grade
disease (10 PCMZL and 8 PCFCL) with 44 symptomatic
plaques and tumors. A CR was observed in 33 lesions
(75%) at the first follow-up visit (4 to 6 weeks following
radiation therapy). A PR was seen in 5 lesions (11%), and
stable disease was seen in 6 patients (13%). The overall
response rate (CR and PR) was 86%. After a median
of 6.3 months, 13 of 44 lesions were re-treated at the
same site due to persistent (n = 8) or recurrent (n = 5)
symptomatic disease, using a conventional-dose fractionation regimen with 20 Gy in 8 fractions. These results
demonstrated that a short radiotherapy regimen with a
low total dose was efficacious, with acceptable toxicity.
Combined Chemotherapy: Senff et al9 reported
cumulative data from 8 publications on 104 PCFCL patients with disseminated cutaneous lesions using systemic chemotherapy. The CR rate was 85%, with a relapse
rate of 48%. A majority of patients received a regimen
of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or CHOP-like chemotherapy. A review
of the literature suggested that patients with PCDLBCL,
LT treated with CHOP (n = 29) or cyclophosphamide,
vincristine, and prednisone (n = 3) had a CR rate of 81%.
Of 26 patients, 14 (54%) relapsed.9
Grange et al38 compared the outcomes of patients
treated with different anthracycline-containing chemotherapy regimens and rituximab (12 patients) with those
of patients treated with other therapies (48 patients).
The 2-year survival rates were 81% and 59%, respectively.
Eleven of 12 patients (92%) achieved a CR vs 62% of the
group treated with other therapies. Although limited
published data are available on the use of CHOP with
rituximab in PCDLBCL, LT, this regimen is frequently
used in clinical practice based on data extrapolated
from clinical studies conducted in systemic diffuse large
B-cell lymphoma.
and BCL-2. The IgV H is rearranged in a majority of patients. Chromosomal abnormalities, including t(14;18)
(q32;q21) involving the IgH and MLT genes and t(3;14)
(p14;q32) involving the IgH and FOXP1 genes,1,2 were
detected only in a small proportion of patients.
A
B
Primary Cutaneous Marginal Zone Lymphoma
PCMZL is included in the group of extranodal marginal
zone lymphomas of the mucosa-associated lymphoid tissue type in the 2008 WHO classification and accounts
for approximately 25% of all PCBCLs.2 Patients usually
present with red or violaceous papular or nodular lesions
on the trunk or arms. A majority of patients present
with multiple lesions.2,39
Histopathology
The morphology of cutaneous lesions (Fig 2) shows
a nodular or diffuse infi ltrate of mixed population of
small- to medium-sized lymphocytes, marginal zone B
cells, lymphoplasmacytoid cells, and plasma cells with a
few centroblast or immunoblast-like cells. PCMZLs infiltrate the dermis, with no propensity for the epidermis.1,2
Immunophenotype and Genetics
Malignant cells coexpress CD19, CD20, CD22, CD79a,
July 2012, Vol. 19, No. 3
C
Fig 2. — Primary cutaneous marginal zone lymphoma. (A) Dense nodular infiltrate with follicles containing reactive germinal centers within
the dermis with unremarkable overlying epidermis (hematoxylin-eosin,
original magnification ×20). (B) Note characteristic arrangements of
the pale-staining neoplastic marginal zone cells (MZ) surrounding reactive follicle with central germinal centers (GC). (C) Marginal zone cells
(“centrocyte-like”) with abundant pale cytoplasm are shown.
Cancer Control 241
Prognosis
The prognosis of patients with PCMZL is excellent, with
a 5-year disease-free survival rate of 98% to 100%10,40
despite multiple relapses (46%).9 This lymphoma rarely
transforms into large B-cell lymphoma or shows systemic dissemination.41
with lesions manifesting at sites other than the legs (5year overall survival rate = 22% vs 92%). In a multivariate analysis, only location on the legs and expression of
FOXP1 were significant prognostic factors associated
with a poor prognosis.10
Therapy
Asymptomatic patients with stable solitary or multiple
lesions can be observed (Fig 1). The most common
initial therapy for a solitary lesion or a small number of
lesions (T1, T2) includes complete surgical excision or
radiation therapy. Patients with multifocal lesions may
respond to rituximab, RIT, or spot external-beam radiation therapy. A small number of patients have been
treated with intralesional rituximab or interferon-α or
corticosteroids. Patients with PCMZL usually do not
require treatment with systemic chemotherapy except
in rare cases with extracutaneous extension or refractory disease to radiation therapy or immunotherapy.
Chemotherapy or chemoimmunotherapy indicated for
treatment of systemic MZL is usually used in these
circumstances.8
A
Primary Cutaneous Follicle-Center
Lymphoma
PCFCL is the most common subtype of cutaneous B-cell
lymphoma, comprising about 55% of all PCBCLs. Patients
usually present with red-brown papules or nodules localized on the scalp, forehead, or trunk.1,10
Histopathology and Immunophenotype
PCFCL lesions can show a nodal, nodal and diffuse,
or diffuse pattern consisting of medium to large
centrocytes with a variable number of centroblasts
(Fig 3) and an absence of epidermotropism.
Malignant cells coexpress CD19, CD20, CD22,
CD79, and BCL-6. CD10 is usually positive in lesions
with a follicular growth pattern but negative in lesions
with a diffuse growth pattern.1 BCL-2 and MUM1/
IRF4 expression by IHC is detected in about 10% of
patients.10 In contrast to nodal follicular lymphoma,
t(14;18) is usually negative. However, several studies
demonstrated the presence of BCL-2 rearrangements
in a minority of patients using fluorescence in situ hybridization or PCR.1
B
Prognosis
Patients with PCFCL have an excellent prognosis, with
a 5-year disease-specific survival rate of 95% to 98%.10,40
The cutaneous relapse rate is approximately 30%, and
a number of relapses do not correlate with prognosis.9
The histologic pattern does not have any impact on
long-term outcome.1,2 Interestingly, patients presenting
with cutaneous lesions on one or both legs showed a
significantly worse prognosis compared with patients
242 Cancer Control
C
Fig 3. — Primary cutaneous follicle-center lymphoma, with a follicular
growth pattern. (A) Note the closely packed follicles without mantle
zones and an unremarkable overlying epidermis (hematoxylin-eosin,
original magnification ×20). (B) Neoplastic follicles are devoid of tingible
body macrophages and lack polarity (hematoxylin-eosin, original magnification ×400). (C) Centrocytes predominate, along with few centroblasts and histiocytes (hematoxylin-eosin, original magnification ×600).
July 2012, Vol. 19, No. 3
Therapy
Treatment of patients with PCFCL follows recommendations for treatment of patients with PCMZL (Fig 1) and
includes observation, complete surgical excision, or
radiation therapy for a single lesion or small numbers
of lesions (stage T1 or T2). Asymptomatic patients with
more advanced skin disease can be observed or treated
with immunotherapy or RIT. Systemic therapy can be
considered in patients manifesting with multiple lesions
on the lower extremities, although this recommendation is based only on a retrospective analysis of a small
number of patients.9
the NCCN guidelines.8 Patients who are not eligible for
systemic chemotherapy may benefit from external-beam
radiation therapy or RIT.
Conclusions
The novel WHO-EORTC classification, the TNM staging
system, and the prognostic scoring system in PCBCL
Primary Cutaneous Diffuse Large
B-Cell Lymphoma, Leg Type
PCDLBCL, LT is an intermediate-grade B-cell lymphoma
that comprises only 1% to 3% of all cutaneous lymphomas and approximately 10% to 20% of PCBCLs. Skin
lesions most frequently resembling tumor nodules can
be solitary or multiple, with a predilection to the lower
extremities and/or trunk.
A
Histopathology and Immunophenotype
Morphologically, lesions usually show a diffuse infiltrate
of large B cells, centroblasts, or immunoblasts, with
frequent invasion into the subcutis (Fig 4). Malignant
cells coexpress CD20, CD79a, BCL-2, MUM1/IRF4m, and
intracytoplasmic IgM in a majority of cases.1,8,42
Genetics
Clonality studies are usually positive for a clonal IgH
gene rearrangement by PCR. A characteristic chromosomal abnormality for nodal low-grade follicular
lymphoma with t(14;18)(q32;q21) is not present. The
inactivation of CDKN2A by either deletion of 9p21.3 or
promoter hypermethylation was found in 67% of patients.43 This molecular abnormality was associated
with a worse prognosis. A majority of patients show
chromosomal aberrancies, among which gains of 18q
and 7p and losses of 6q were most frequent.2
B
Prognosis
The course of disease is characterized with frequent
relapses and dissemination into extracutaneous regions.
The 5-year disease-specific survival rates ranged from
43% to 63% in three larger studies.10,38,40 In a multivariate
analysis, no independent prognostic factor was found.10
In a retrospective study, patients treated with combined
anthracycline and rituximab-based therapies had a more
favorable short-term outcome compared to patients treated with chemotherapy regimens without rituximab.38
C
Therapy
Multiagent chemotherapy with rituximab (R-CHOP)
followed by involved-field radiation therapy is a recommended frontline therapeutic approach, according to
July 2012, Vol. 19, No. 3
Fig 4. — Primary cutaneous diffuse large B-cell lymphoma, leg type. (A)
Diffuse infiltrate involves the entire dermis and extends into the subcutaneous fat (hematoxylin-eosin, original magnification ×20). (B–C) Note
the predominance of large transformed cells with vesicular chromatin
and prominent nucleoli (immunoblasts).
Cancer Control 243
have contributed to a better understanding and management of these rare lymphomas. Although conducting
large prospective clinical trials in patients with PCBCL
will be difficult due to the rarity of this disease, it is possible that novel targeted therapies developed for more
common systemic B-cell lymphomas will also demonstrate efficacy in patients with PCBCL.
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