Leukemia Cutis: An Overview
Tuesday, April 07, 2009
Dermatologists may be called upon to diagnose disorders of
extracutaneous organs with skin manifestations such as
paraneoplastic syndromes and/or metastatic cancer. Despite
their importance, these remain poorly described, possibly because
they are at the frontier of both dermatology and
hematology/oncology. Here, we will summarize the features of skin
metastases developing during the course of malignant hemopathies,
also called leukemia cutis.
The name leukemia cutis or "specific localizations of leukemia"
is given for all of the dermatologic disorders that have malignant
hemopoietic cells in the dermis and/or the hypodermis. Leukemia
cutis may derive from the myeloid or the lymphoid lineages.
Myelodysplasia (or myelodysplastic syndromes, MDS) is an
intermediate condition in which the normal differentiation pathways
of one or more myeloid sublineages is altered over a prolonged time
period, leading to cytopenias. However, in most cases, an acute
leukemia will develop. Although a tool for the detection of a low
level of clonal lymphocytic proliferations exists (namely,
polymerase chain reaction (PCR) directed towards B- or T-cell
receptors), there is no such sensitive molecular tool available for
the recognition of clonal myeloid proliferations.
Although the myeloid malignancies are less well known than their
lymphoid counterparts, these are the most frequent
hemopathies implicated in the development of skin-specific
localizations. In the spectrum of these, acute transformation of
myelodysplasia is the most frequent supplier of cutaneous
metastasis - responsible for 39% of these - followed by
acute myeloid leukemias (AMLs), AML 5 in 26% of cases, AML 4 in 8%
and AML 1 in 13%1.
Clinical Presentation May be Atypical
Skin localizations of myeloid malignancies are usually easy to
recognize. These are featured by red or violaceous nodules or
tumors of variable size that develop over a few weeks. There are no
signs of "epidermal" involvement, such as scales, vesicles or
erosions because the infiltrate spares the upper part of the dermis
("Grenz zone") as well as the epidermis.
When facing such a "typical" situation, the diagnosis of
metastatic skin invasion is easily evoked. If the malignancy is not
known, the first step should be to perform a blood cell count and
smear that will allow a quick diagnosis by showing the leukemic
cells. However, since the prognosis - and sometimes the treatment
modalities - of some myeloid leukemias is altered when there
is a demonstrated skin-specific localization, a biopsy should also
More important is the fact that clinicians may be faced with
"atypical" skin presentations of such localizations in some myeloid
hemopathies. Such lesions are frequent in localizations of
myelodysplasias, as well as in those secondary to hypereosinophilic
In MDS, the course of the disease includes the risk of "acute
transformation", the presentations of which are variable. One of
these is the accumulation of leukemic "young" cells in the
skin. However, the clinical features of such invasion appear
to be different from classical tumors in approximately two-thirds
of patients2. These may present as blisters,
necrotic lesions, pruritic papules, purpura and/or cutis verticis
gyrata3. Therefore, a biopsy should be performed of
non-tumoral lesions in patients with MDS. Indeed, in MDS,
specific skin lesions are frequently atypical, and at the
appearance of these lesions, blood smear may still be devoid of
acute transformation in the majority of cases.
This curious phenomenon could be the consequence of the tropism
of some types of malignant myeloblasts for the skin4.
Histopathology should be read carefully by a trained
dermatopathologist. Indeed, evaluation of markers such as CD11c,
CD13, CD33, CD68, cytoplasmic myeloperoxidase, and
chloracetate esterase are often needed because cytology of myeloid
cells on fixed embedded tissues is frequently not specific (in
contrast to blood or marrow smears) and because a molecular
tool for the detection of such infiltrations is not
available5. Determination by the dermatologist (with the
pathologist's support) that skin-invading cells are, in fact,
myeloid is critical in MDS in order to guide appropriate
Dermatologists should also be aware of an entity called
granulocytic sarcoma, chloroma or sometimes aleukemic leukaemia
cutis. This is a rare entity that is characterized by skin nodules
or tumors appearing green in color due to the accumulation of
myeloperoxidase. In nearly one-third of these cases, a myeloid
proliferation is undetectable in peripheral blood or marrow.
Phenotyping of the infiltrate should be done using available
antibodies and histochemical techniques detailed above. Secondary
myeloid leukaemia occurs after a mean delay of up to 5
The pathogenesis of this condition remains unknown, but it has
been speculated that it could correspond to a discrete marrow
myeloid proliferation, undetectable by means of classical
histology, the malignant cells of which display an elective homing
for the dermis. Therefore, cells accumulate in the dermis and are
only able "to be seen" there. The treatment requires
chemotherapy and radiation therapy.
Hypereosinophilic syndromes (HES) are also important for
dermatologists. These are defined by prolonged persistence of
eosinophilia for 6 months duration, reaching more than 1.5 cells x
109/ml, with at least one organ affected. Such situations may be
either secondary to the polyclonal "reactive" proliferation of
marrow eosinophils, such as what happens in diseases such as Sezary
syndrome, bullous pemphigoid, or parasitic infections. HES may also
occur as a primary myeloproliferation of eosinophil marrow
precursors. A peculiar genome juxtaposition called FLIP1/PDGFR was
found in 50% of primary HES7. After the gut, the skin is
the second target organ of HES, involved in 40% of
cases8. If classical cutaneous signs such as exfoliative
dermatitis and pruritic erythematous eruptions evoke HES, there are
also a variety of misleading signs. These may present as blisters,
vasculitis, mucosal erosions looking like erythema multiforme,
angioedema or even necrotic monomorphic
The reason for this diversity appears to be the consequence of
the pleomorphic pathways that tissue eosinophils may activate.
Indeed, these cells may drive a cytotoxic reaction against
keratinocytes with erosions and blisters through the secretion of
proteins such as major basic protein (MBP)9. The
eosinophils may also activate coagulation and platelet adhesion and
lead to dermal thrombosis with secondary necrosis10.
Finally, such eosinophils may also, in a more benign
"idiopathic" form, induce recurrent episodes of angioedema. These
are due to the deposition of the MBP along the collagen dermal
fibrils that induce mast cell activation and secondary
vasodilatation11. Sometimes, the deposition concerns
other proteins such as eosinophil cationic protein (ECP) or
endotoxin (EDN), and the vasodilatation is therefore mast cell
independent. These various clinical signs illustrate the diversity
with which a single cell type can affect the skin.
Early diagnosis of HES is extremely important in order to treat
the patients before cardiac or neurologic definitive lesions
develop. Eosinophils may be sparse and poorly seen. Therefore,
dermatologists should do repeat biopsies if needed. The use of
immunostaining (specific eosinophil markers) may be helpful in
depicting eosinophilic infiltrate.
Myeloid proliferations might be responsible for the "aseptic"
accumulation of mature neutrophils in the dermis. Diseases such as
Sweet's syndrome (SS), pyoderma gangrenosum (PG) and, more rarely,
neutrophilic eccrine hidradenitis (NEH) or erythema elevatum
diutinum (EED), are grouped together under the term neutrophilic
These diseases show an unexplained migration of mature
neutrophils to the dermis that results in the various clinical
pictures. Distinguishing SS from leukemia cutis may be difficult
because both can present with red indurated plaques. Histopathology
will usually allow for the two to be distinguished from one
another. Of note, the presence of immature cells has been reported
to be detectable in some SS associated with AML, making histology
confusing to interpret12.
Patients with underlying leukemia are susceptible to cutaneous
infections. These are very diverse in their clinical presentation.
The rule is therefore to cultivate biopsy specimens, as well as to
perform special staining for the detection of opportunistic
Regardless of the type of myelogenous leukemia, onset of
specific skin manifestations correlates with an aggressive course
and short survival. In the same way, development of specific
cutaneous localization in the course of MDS implies an acute
transformation, with a usual median survival of only a few
Primary lymphoid proliferations, including T- (mycosis
fungoides) and B-cell lymphomas of the skin (immunocytoma,
follicular lymphoma, high-grade BCLL), as well as subcutaneous
lymphoma (cytophagic panniculitis), will not be included in this
commentary. Instead, this commentary focuses on cutaneous
proliferations secondary to systemic lymphoid malignancy.
What Lymphoid Proliferations Cause Such
A wide number of lymphomas and/or lymphocytic leukemia may induce
secondary cutaneous localizations. Some are more important for
the dermatologist to keep in mind. The HTLV- induced adult T-cell
leukemia (ATL) has cutaneous specific lesions in nearly 80% of
cases. In the same way, angioimmunoblastic lymphadenopathy (AILD)
is responsible for the development of lesions present at diagnosis
in more than half of the cases. Angiocentric and angiotropic
lymphomas are also difficult diseases with an important
dermatologic presentation. In contrast, other lymphoid
malignancies such as BCLL, Waldenström's disease, myeloma, large T-
or B-cell lymphoma display rarer occurrence of skin
The lesions are partly similar to those in AML. Indeed, the
classical signs are unique or multiple nodules or tumors. The
surface is smooth, erythematous or flesh colored. In contrast with
AML, ulceration may develop. This may be found in angiocentric
lymphoma where the lymphocytic infiltration is angiocentric and
angiodestructive. Ulceration may also develop in some large
T-cell lymphomas with epidermotropism.
In ATL, the common types of specific skin lesions are
papules, usually with a generalized distribution. In addition,
plaques, ichthyosis-like skin lesions, nodules, tumors, and/or
erythroderma may be seen13.
AILD is characterized by cutaneous initial lesions in more than
50% of the cases. In contrast with previous lymphocytic
hemopathies, the main features are a diffuse, progressively
worsening, macular-papular eruption with fever and lymph node
enlargement. The picture is considered to be strongly misleading,
evoking adverse drug reactions. However, if any drug could
have been suspected in the affected recipients, its withdrawal will
allow improvement of the eruption. Skin pathology displays the
diagnosis but should be carefully read by a trained pathologist and
Angiocentric lymphoma, whether induced by Epstein-Barr Virus or
not, is also important to consider. This relies on the fact that
the features are also atypical, characterized by necrotic and/or
ulcerated lesions that heal spontaneously, and waxes and wanes.
Histology is frequently difficult to interpret and needs to be
The diagnosis of cutaneous localizations of lymphocytic
malignancies is the kingdom of pathologists. Indeed, cellular
infiltrates can be - including now on paraffin-embedded skin
sections - stained with a great variety of antibodies that allow
the precise identification of expressed antigens. In addition to
this, PCR can be used to identify the presence of a low-level
predominant TCR or BCR gene in the skin. Therefore, these tools
enable the clinician to diagnose the type of localization.
Specific localizations in myelogenous leukemias may reveal the
hemopathy or implicate a poor prognosis requiring a modification in
therapy. Several types of lymphomas frequently affect the skin with
(sometimes) atypical, disseminated exanthema or necrotic misleading
lesions. Sensible and modern tools are now available for the
detection of such lymphocytic proliferations.
- Su WP, Buechner SA, Li CY. Clinicopathologic correlations in
leukemia cutis. J Am Acad Dermatol
- Aractingi S, Bachmeyer C, Miclea JM, et al. Unusual
specific cutaneous lesions in myelodysplasic syndromes. J Am
Acad Dermatol 1995;33:187-191.
- Cheson BD, Christiansen RM. Cutis verticis gyrata: unusual
chloromatous disease in acute myelogenous leukemia. Am J
- Vignon-Pennamen MD, Aractingi S. Sweet's syndrome and
leukemia cutis: a common skin homing mechanism?
- Sepp N, Radaszkiewicz T, Meijer CJ, et al. Specific
skin manifestations in acute leukemia with monocytic
differentiation. A morphologic and immunohistochemical study of 11
cases. Cancer 1993;71:124-132.
- Bachmeyer C, Turc Y, Fraitag S, Delmer A, Aractingi S.
[Aleukemic monoblastic leukemia cutis] Article in French. Ann
Dermatol Venereol 2003;130:773-775.
- Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine
kinase created by fusion of the PDGFRA and FIP1L1 genes as a
therapeutic target of imatinib in idiopathic hypereosinophilic
syndrome. N Engl J Med
- Fauci AS, Harley JB, Roberts WC, et al. NIH
conference. The idiopathic hypereosinophilic syndrome. Clinical,
pathophysiologic, and therapeutic considerations. Ann Intern
- Aractingi S, Janin A, Zini JM, et al. Specific
mucosal erosions in hypereosinophilic syndrome. Evidence for
eosinophilic protein deposition. Arch Dermatol
- Aractingi S, Bachmeyer C, Pautier P, et al. Necrotic
cutaneous lesions induced by hypereosinophilic syndrome secondary
to a T-cell lymphoma. J Am Acad Dermatol
- Gleich GJ, Schroeter AL, Marcoux JP, et al. Episodic
angioedema associated with eosinophilia. N Engl J Med
- Tomasini C, Aloi F, Osella-Abate S, Dapavo P, Pippione M.
Immature myeloid precursors in chronic neutrophilic dermatosis
associated with myelodysplastic syndrome. Am J
- Bittencourt AL, Barbosa HS, Vieira MD, Farre L. Adult T-cell
leukemia/lymphoma (ATL) presenting in the skin: Clinical,
histological and immunohistochemical features of 52 cases. Acta
Oncol 2009 Jan 22:1-7 [Epub ahead of print].
. Of note, chronic BCLL presents as nodules or plaques,
frequently involving the nose or the ears.