Cutaneous Lymphoproliferative Disorders
Moderator: Dr. Lorenzo Cerroni
Section 2 -
Spectrum of Cutaneous CD30-Positive Lymphoproliferative Disorders
Rein Willemze & C.J.L.M. Meijer
Primary cutaneous CD30-positive lymphoproliferative disorders (LPD) represent the second most common
group of CTCL, accounting for approximately 25% of CTCL. This group includes primary cutaneous
anaplastic large cell lymphoma (C-ALCL), lymphomatoid papulosis (LyP), and borderline cases
C-ALCL and LyP have overlapping clinical, histological and immunophenotypical features and form a
spectrum of disease . Since histologic criteria alone are often insufficient to differentiate between
these two ends of the spectrum, the clinical appearance and course are used as decisive criteria for
thedefinite diagnosis and choice of treatment. The term "borderline case" refers to cases, in which,
despite careful clinicopathologic correlation, a definite distinction between C-ALCL and LyP cannot be
made. Clinical examination during follow-up will generally disclose if the patient has C-ALCL or LyP
These primary cutaneous CD30-positive LPD should be differentiated from:
- skin localizations of systemic ALCL
- cases of MF with transformation into a
CD30-positive large cell lymphoma
- other well-defined types of CTCL, which may
sometimes express the CD30 antigen.
- reactive skin conditions harbouring large CD30+
activated T-cells, such as several viral infections, arthropod reactions, scabies and so on.
Primary Cutaneous Anaplastic Large Cell Lymphoma
C-ALCL is composed of large cells with an anaplastic, pleomorphic or immunoblastic cytomorphology and
expression of the CD30 antigen by the majority (more than 75%) of tumor cells. There is no clinical
evidence or history of LyP, MF or another type of CTCL.
C-ALCL predominantly affect adults, and are rare in children or adolescents. Most patients present
with solitary or localized nodules or tumors that often develop ulceration. Multifocal lesions are seen
in about 20% of the patients. The skin lesions may show partial or complete spontaneous regression, as
in LyP. These lymphomas frequently relapse in the skin. Extracutaneous dissemination occurs in
approximately 10% of the patients, and mainly involves the regional lymph nodes. The prognosis is
usually favorable with a 10-year disease-related survival exceeding 85%
C-ALCL show diffuse infiltrates with cohesive sheets of large CD30+ tumor cells. In most cases the
tumor cells have the characteristic morphology of anaplastic cells, with round, oval or irregularly
shaped nuclei, prominent (eosinophilic) nucleoli and abundant cytoplasm. Less commonly (20–25%), they
have a pleomorphic or immunoblastic appearance. Reactive lymphocytes are often present at the periphery
of the tumor. Ulcerating lesions may show a LyP-like histology with an abundant inflammatory infiltrate
of reactive T cells, histiocytes, eosinophils, neutrophils, and few CD30+ cells. In such cases epidermal
hyperplasia may be prominent.
The neoplastic cells often express a CD4+ T-cell phenotype with variable loss of CD2, CD5 and/or CD3.
Some cases (<5%) have a CD8+ T-cell phenotype. CD30 must be expressed by the majority of neoplastic
cells. Expression of cytotoxic proteins (granzyme B, TIA-1, perforin) is noted in approximately 70% of
the cases. Unlike systemic ALCL, most C-ALCL express the cutaneous lymphocyte antigen (CLA), but do not
express EMA and ALK (anaplastic lymphoma kinase), indicative of the t(2;5) chromosomal translocation
. Staining for CD15 is generally negative. Coexpression of CD56 is observed in rare cases, but does
not appear to be associated with an unfavorable prognosis .
The t(2;5) translocation, which is predominantly found in systemic ALCL in children, is not or rarely
found in C-ALCL .
Solitary lesions can be treated with local radiotherapy or surgical excision. Patients presenting
with multifocal skin lesions should be treated with radiotherapy (if there are only a few lesions) or
with low-dose methotrexate as in LyP
Patients presenting with or developing extracutaneous
disease or rare patients with rapidly progressive skin disease should be treated with doxorubicin-based
Lymphomatoid papulosis (LyP) is defined as a chronic, recurrent, self-healing papulonecrotic or
papulonodular skin disease with histologic features suggestive of a (CD30-positive) malignant lymphoma.
LyP usually presents in adults, but may occur in children as well. The typical skin lesions in LyP
are red–brown papules and nodules that may develop central hemorrhage, necrosis and crusting, and
subsequently spontaneously disappear within 3 to 12 weeks, and may leave superficial atrophic scars. The
predominant sites of involvement are the trunk and limbs. The duration of the disease may vary from
several months to more than 40 years. In up to 20% of patients LyP may be preceded by, associated with,
or followed by, another type of malignant (cutaneous) lymphoma, generally MF, a C-ALCL or Hodgkin's
disease. However, the prognosis is usually excellent. In a recent study of 118 patients with LyP only
five patients (4%) developed a systemic lymphoma, and only two patients (2%) died of systemic disease
over a median follow-up period of 77 months .
Clonally rearranged T-cell receptor genes have been detected in 60-70% of LyP lesions. Identical
rearrangements have been demonstrated in LyP lesions and associated lymphomas . The t(2;5)(p23;q35)
translocation is not or rarely found in LyP .
The histologic picture of LyP is extremely variable, which in part correlates with the age of the
sampled skin lesion. Characteristically, fully developed lesions show a wedge-shaped, initially
non-epidermotropic, infiltrate with scattered or small clusters of large atypical, sometimes
multinucleated or Reed–Sternberg-like, CD30-positive T cells, interspersed in an extensive inflammatory
infiltrate composed of small lymphocytes, neutrophils and/or eosinophils. These large CD30-positive
cells, which have the morphological and immunophenotypical characteristics of the neoplastic cells in
C-ALCL, are relatively few in early lesions, more numerous in fully developed lesions, but may be
completely absent in resolving lesions. The presence of scattered neutrophils within a moderately
acanthotic and parakeratotic, but otherwise unaffected epidermis is a characteristic finding. In rare cases the skin lesions demonstrate a monotonous population or large
clusters of large CD30-positive T cells with relatively few admixed inflammatory cells, a histologic
appearance typically found in C-ALCL .
Since a curative therapy is not available and none of the available treatment modalities affects the
natural course of the disease, the short-term benefits of active treatment should be balanced carefully
against the potential side effects . In patients with relatively few non-scarring lesions, active
treatment is not necessary. In the case of cosmetically disturbing lesions (e.g. scarring or many
papulonodules), low-dose oral methotrexate (5–20mg/week) is the most effective therapy for reducing the
number of skin lesions . Because of the potential risk for developing a systemic lymphoma, long-term
follow-up is required in all patients with LyP.
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