Abstract
LC is a rare form of extramedullary feature of malignant hemopathy,
seldom associated to CML. Its clinical presentation is pleiotropic and
differential diagnosis is broad. It relies on clinical and typical
histological and biomolecular concordance. Once confirmed, treatment is
based on that of the primary condition. We present a case of a leukemia
cutis revealing a relapse of a CML successfully treated by tyrosine
kinase inhibitor.
Introduction
LC refers to neoplastic leukocytes infiltration within the skin and
encompasses various forms including myeloid sarcomas, chloromas or
monoblastic sarcomas, each differing in their neoplastic precursors (1).
LC is an uncommon condition depending on the subtypes of leukemia that
involve the skin, whether myeloid or lymphoid disorders and is more
commonly described in patients with AML but may also be seen with CML,
acute or chronic lymphocytic leukemia and myelodysplastic syndrome
(1,2). It appears to correlate with the progression of leukemia and is
concomitant in a large majority of with other associated extramedullary
involvement but may occasionally be diagnosed synchronously or months to
year before the hematological disease onset and refers to aleukemic LC
(3,4). Etiopathogenesis behind the skin neoplastic leukocytes migration
remains unclear but mechanisms involving chemotaxis have been suggested;
referring to the concept of skin selective homing (1). LC is generally
asymptomatic and can manifest as either localized or generalized and
encompasses various forms, including papules, plaques, and nodules from
purplish to brownish color. We report herein a case of LC revealing a
relapse of CML in a 62-year-old patient successfully treated by
Dasatinib.
Casehistory/examination
A 62-year-old man presented to our haemato-oncology department for
multiple painful and firm subcutaneous nodes on the forearms, the lefts
buttock and knee. He first described nodes followed by surrounded
hematoma. Past medical history was notable for arterial hypertension
treated by Amlodipine and CML. The latter was diagnosed in 2006 and
initially treated by Imatinib for three years with inadequate
therapeutic response. He then started Dasatinib, which was partially
controlled. He also complained about a worsening dyspnea, sub-pyrexia
and arthralgia. There was no history of trauma, travel, infection, or
new drug initiation. Furthermore, the patient acknowledged recent
irregular medication intake. At physical examination, the patient was
not febrile. Chest auscultation was unremarkable. Rheumatological
examination did not show any joint effusion. Skin examination showed
painful and firm subcutaneous nodes with circumferential purplish
discoloration and peripheral hematoma (Fig. 1).
Methods
At this stage and considering the skin features in context of CML, most
accurate differential diagnosis were the followings: LC, cutaneous
vasculitis, nodular hypodermitis and erythema nodosum.
We initiated our investigations with laboratory tests, revealing :
Hemoglobin 9.5 (13-17 g/dL), White blood cells 199.33 (3.5-11
x10^9/L), Neutrophils 93.05 (1.5 – 6.7 x10^9/L), Lymphocytes 7.18
(1-4 x10^9/L), Monocytes 24.32 (0.2-0.8 x10^9/L) and 5% of
blasts, Platelets 389 (150-400 x10^9/L), C-reactive protein was 18.7
(< 5 mg/L), Haptoglobin < 10 (50-220 mg/dL),
Creatinine 1.32 (0.8-1.3 mg/dL), Lactate dehydrogenase 7.268 (50-150
U/L), Uric acid 12.4 (3.5-7.2 mg/dL). Coagulation tests were consistent
with a disseminate intravascular coagulation (DIVC): D-dimer 23.077
(< 500 ng/mL), fibrinogen 1.07 (1.8-4 g/L), Prothrombin ratio
40% (85-100%). Blood hemocultures were negatives. Serological assays
for HIV, HCV, Rickettsia and syphilis were negative while he presented
immunological scar of contact with CMV, EBV and HBV. The leukocytosis
raised suspicion of a recurrence of CML or even a progression to an AML.
The bone marrow aspiration demonstrated a rich marrow with proliferation
of the granular lineage, without excess blasts (3.9%) and associated
with dysplasia on the erythroid and megakaryocytic lineages (OGATA score
= 2/4). Left knee skin biopsy revealed a moderate interstitial
infiltrate of the derma and hypoderm comprising myeloid-like cells at
various stages of maturation without excess blasts (Fig. 2 and 3).
Immunohistochemistry analysis revealed a strong positive reaction
against Anti-MPO antibody without staining against CD34+ and CD117+. The
epidermis, stratum corneum and basal membrane were unaffected.
Histological appearance was consistent with LC, a dermal and hypodermal
infiltration of CML cells without transformation into AML.
Conclusion and
Results
Final diagnosis was a relapse of CML presented by LC and complicated by
DIVC due to Dasatinib interruption. In the meantime, the patient was
treated with Hydrea before returning to Dasatinib. Hematological
follow-up was marked by biological and clinical remission of the CML
with complete regression of the LC.
Discussion
The patient underwent a relapse of CML simultaneously with the cutaneous
involvement that revealed it. LC is less commonly described in adults
(5), particularly in the case of CML. In our case, there was no additive
cutaneous manifestations of bone marrow insufficiency relative to
cytopenia that can occurs and which may be rigorously interpreted. Other
associated extramedullary involvement may be described in a patient with
LC as the central nervous system that worsens the prognosis (4) but this
was not observed in our evaluation. Osteoarticular pain is another
feature of extramedullary leukemic involvement, typically described by
our patient. Joint swelling has to be distinguished with crystal
arthropathies given the propensity to develop gout in context of active
leukemia. LC may present in various forms, including papules, plaques,
and nodules. Differential diagnosis of those manifestations is broad
such as neoplastic, chemotherapy related, inflammatory conditions
(erythema nodosum, neutrophilic dermatosis, …) or infectious
resulting from immunosuppression, and emphasizes the key role of
histology in the diagnosis work-up (1). Diagnosis of LC relies on
histopathology, and particularly on immunohistochemistry and tissue
immunophenotyping. In our patient, cutaneous involvement was localized
in the dermis and subcutaneous tissue, characterized by a significant
interstitial infiltrate of myeloid-like cells at various and without
excess of blasts. Further investigations confirmed the diagnosis of LC
showing an increased expression of anti-MPO staining, which is
consistent with existing literature (3). It is not possible to
categorize the various forms of leukemia solely through skin biopsy and,
therefore, further investigations such as cytochemical and molecular
genetic analyses are required (1). When LC is suspected, a comprehensive
biological assessment along with bone marrow aspiration and
osteo-medullar biopsy helps to establish diagnosis of systemic leukemia,
which in this case was imputable to the lack of therapeutic observance.
Therapeutic approach of the LC relies on management treatment of the
malignant hemopathy, which varies according to the nature of the
extramedullary involvement. In case of contraindicated chemotherapy,
radiotherapy can solely be used symptomatically on the pain or pruritus
induced by the LC. Combination of radiotherapy and chemotherapy does not
provide additional improvement.
LC is a rare manifestation of malignant hemopathies, and even rarer in
the case of CML. Diagnosis relies on clinical suspicion and should be
confirmed through biological, molecular and histological investigations
in context of a malignant hemopathy; sometimes antedated by the
diagnosis of leukemia cutis.
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