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Clinical Updates

Sélim Aractingi, MD, PhD

Leukemia Cutis: An Overview

Selim Aractingi

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.

Myeloid Hemopathies

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 be performed.

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 syndromes (HES).

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 treatment.

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 months6.

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 papules9.

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. 

Differential Diagnosis

Neutrophilic Disorders
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 dermatoses (ND).

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.

Infections

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 infections.

Prognosis

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 months.

Lymphoid Malignancies

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 Lesions?
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 localizations. 

Clinical Presentation

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 eventually repeated.

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 repeated.

Diagnosis

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.

Conclusion

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.

References

  1. Su WP, Buechner SA, Li CY. Clinicopathologic correlations in leukemia cutis. J Am Acad Dermatol 1984;11:121-128.
  2. Aractingi S, Bachmeyer C, Miclea JM, et al. Unusual specific cutaneous lesions in myelodysplasic syndromes. J Am Acad Dermatol 1995;33:187-191.
  3. Cheson BD, Christiansen RM. Cutis verticis gyrata: unusual chloromatous disease in acute myelogenous leukemia. Am J Hematol 1980;8:415-418.
  4. Vignon-Pennamen MD, Aractingi S. Sweet's syndrome and leukemia cutis: a common skin homing mechanism? Dermatology 2003;206:81-84.
  5. 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.
  6. Bachmeyer C, Turc Y, Fraitag S, Delmer A, Aractingi S. [Aleukemic monoblastic leukemia cutis] Article in French. Ann Dermatol Venereol 2003;130:773-775.
  7. 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 2003;348:1201-1214.
  8. Fauci AS, Harley JB, Roberts WC, et al. NIH conference. The idiopathic hypereosinophilic syndrome. Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med 1982;97:78-92.
  9. Aractingi S, Janin  A, Zini JM, et al. Specific mucosal erosions in hypereosinophilic syndrome. Evidence for eosinophilic protein deposition. Arch Dermatol 1996;132:535-541.
  10. 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 2002;46:S133-136.
  11. Gleich GJ, Schroeter AL, Marcoux JP, et al. Episodic angioedema associated with eosinophilia. N Engl J Med 1984;310:1621-1626.
  12. Tomasini C, Aloi F, Osella-Abate S, Dapavo P, Pippione M. Immature myeloid precursors in chronic neutrophilic dermatosis associated with myelodysplastic syndrome. Am J Dermatopathol 2000;22:429-433.
  13. 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.

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