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Keywords:

  • leukemia cutis;
  • acute myeloid leukemia;
  • chronic lymphocytic leukemia;
  • chloroma;
  • myeloid sarcoma;
  • granulocytic sarcoma;
  • gingival hyperplasia

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Epidemiology/pathogenesis
  5. Clinical appearances
  6. Histopathology/cytology/ immunochemistry
  7. Molecular pathology
  8. Differential diagnoses
  9. Therapy and prognosis
  10. Conclusion
  11. Conflict of interest
  12. References

Leukemia cutis is an extramedullary manifestation of leukemia. The frequency and age distribution depend on the leukemia subtype. The clinical and morphological findings have a wide range of cutaneous manifestations and may present with nodular lesions and plaques. Rare manifestations include erythematous macules, blisters and ulcers which can each occur alone or in combination. Apart from solitary or grouped lesions, leukemia cutis may also present with an erythematous rash in a polymorphic clinical pattern. Consequently, leukemia cutis has to be distinguished from numerous differential diagnoses, i. e. cutaneous metastases of visceral malignancies, lymphoma, drug eruptions, viral infections, syphilis, ulcers of various origins, and blistering diseases. In the oral mucosa, gingival hyperplasia is the main differential diagnosis.

The knowledge of the clinical morphology is of tremendously importance in cases in which leukemia was not yet known.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Epidemiology/pathogenesis
  5. Clinical appearances
  6. Histopathology/cytology/ immunochemistry
  7. Molecular pathology
  8. Differential diagnoses
  9. Therapy and prognosis
  10. Conclusion
  11. Conflict of interest
  12. References

Leukemia is a malignant neoplasm affecting the hematopoietic system. Following a generalization phase in the bone marrow and subsequent appearance of leukemic cells in the peripheral blood, extramedullary manifestation can occur in various organs of the body, including the skin. The classification of various types of leukemia is based on the biological behavior of disease as well as the morphological, immunophenotypical, and cytogenetic characteristics of neo-plastic cells in acute and chronic, lymphocytic or myeloid forms of disease [1, 2]. Acute leukemia has been divided into sub-types by the French-American-British (FAB) Cooperative Group: acute lymphocytic leukemia (ALL) has been sub-divided into types L1–L3 and acute myeloid leukemia (AML) into types M0–M7[3, 4].

The clinical symptoms of acute leukemia are caused by the often rapidly developing bone marrow insufficiency. The resulting, often serious, clinical picture is characterized by a high fever as well as gastrointestinal and pulmonary symptoms, accompanied by progressively severe anorexia, muscle and joint pain, and hemorrhage. Chronic leukemia, especially chronic lymphocytic leukemia (CLL), is often discovered incidentally after a routine blood test or following identification of splenomegaly on upper abdominal ultrasound [1, 2]. Dermatological symptoms seen in leukemia are divided by clinical and histopathological criteria into unspecific and specific skin changes. Unspecific skin changes are mostly dermatological diseases which have been associated with leukemia and which develop on the basis of abnormal hematopoiesis or as an expression of a cutaneous paraneoplastic disorder. While thrombocytopenia may give rise to hemorrhagic skin diseases, e.g., thrombocytopenic purpura, inadequate granulocytopoiesis can lead to opportunistic, often clinically unusually severe infections such as generalized herpes zoster, furunculosis, and fungal abscess. Cutaneous paraneoplastic disease includes include pyoderma gangrenosum, Sweet syndrome, and insect-sting-like skin changes [5–7]. Specific skin changes include all lesions that are characterized by a leukemic infiltrate and which may be characterized, irrespective of the clinical morphology, as leukemia cutis (LC) [6, 8]. This traditional classification, which differentiates between unspecific and specific skin changes, is based on previously available histopathological examination methods for the detection of cutaneous leukemic infiltration. In practical terms, it is still valid today. Ye t with the availability of modern immuno-histochemical and molecular genetic techniques, leukemic cells can now be identified in unspecific skin changes seen in leukemia and other skin diseases. Leukemic cells have been identified in herpes simplex lesions, psoriasis vulgaris, and in various epidermal neoplasms [9–12]. The diagnosis of LC can therefore no longer be based solely on the appearance of intralesional leukemia cells, but instead improved histopathological, immunohistological, and molecular pathology detection methods should be used. In this sense, LC is a separate disease entity, distinguishable from other dermatological disorders as an ex-tramedullary cutaneous manifestation of leukemia.

Epidemiology/pathogenesis

  1. Top of page
  2. Summary
  3. Introduction
  4. Epidemiology/pathogenesis
  5. Clinical appearances
  6. Histopathology/cytology/ immunochemistry
  7. Molecular pathology
  8. Differential diagnoses
  9. Therapy and prognosis
  10. Conclusion
  11. Conflict of interest
  12. References

In 2006 about 9 300 people were diagnosed with leukemia in Germany. In 2010 an estimated 9 790 new reports of disease may be expected. The ratio of men to women with leukemia is 1.1 : 1.0 with a slight preponderance of men [13]. For both sexes, the proportion of leukemia patients relative to the total number of cancer patients is about 2.1 %[14]. The average age of disease for men is 68 years and for women 69 years of age [15]. The incidence rates of individual forms of leukemia are age-dependent. Of particular interest to dermatology are CLL and, for AML, acute myelomonocytic leukemia (AMMoL, FAB-M4) and acute monocytic leukemia (AMoL, FAB-M5), because skin changes are most often seen in these forms of disease. In the literature on hematological disease, the overarching terms myeloid sarcoma and granulocytic sarcoma are also used, given that, along with classic LC, other manifestations such as involvement of the pancreas or vertebral bodies are also included [16–19]. The frequency is reported at 2.1–30 % depending on the underlying form of leukemia and can precede apparent leukemia by several months or even years. Thus knowledge of these diseases is of particular importance [20]. In addition to acute forms of leukemia, myeloid sarcoma or LC can also occur in conjunction with chronic leukemia, i.e., CLL and myeloproliferative syndromes, especially chronic myeloid leukemia (CML).

CLL accounts for about 30 % of all types of leukemia, making it the most common type of leukemia in western industrialized nations. The incidence of disease is age-dependent. Up to age 40, CLL is rare. At later ages, the incidence continually increases to a maximum of 30 : 100 000 among 80-year-olds [21]. In 3–10 % of CLL patients, there is transformation into secondary highly malignant non-Hodgkin lymphoma (Richter syndrome). There are also isolated reports of primary cutaneous forms of disease [22].

AML is seldom reported in children and young adults up to age 30. Among 70-year-olds the incidence is 10 : 100 000 [23]. In terms of AML, the frequency of AMMoL is reported at 20 % and AMoL at 10 %[1].

Epidemiological data on the incidence and prevalence of LC are lacking. This rare skin disease is also seen in different forms of leukemia with various frequencies. Statistics on the incidence of LC are based on analyses of various groups of patients with defined forms of leukemia and comparison with one another. Patients with CLL and AML have a greater tendency toward disease [8]. The frequency of LC in CLL is reported at 4–27 %[24–27]. Considering that in terms of numbers, CLL is the most common form of leukemia and usually has course that spans many years, one would expect LC to be most often reported in patients with CLL. When comparing absolute numbers, however, LC is most common in AML. Agis and colleagues performed an analysis of the data from 381 patients with AML [28]. Fourteen patients were found to have LC, corresponding to a prevalence of 3.7 %. Of these 14 patients, 10 had AMMoL or AMoL. At 71.4 %, the rate of these types of leukemia was quite large, a finding that has also been reported by other authors (50.0 % and 72.2 %) [29, 30]. The age and sex distribution of patients with LC do not differ from leukemia patients without cutaneous involvement [28, 29, 31].

The molecular pathogenetic causes for the invasion of leukemic cells into the skin have not been fully elucidated. A recently published review has suggested various hypotheses. One model was proposed in 2008 by Cho-Vega and colleagues and has since been further developed. This hypothesis holds that specific, T-cell-bound antigens (e.g., CD56) and different chemokines or adhesion molecules mediate the migration of leukemic sub-populations to the skin (skin selective homing) [32, 33].

Clinical appearances

  1. Top of page
  2. Summary
  3. Introduction
  4. Epidemiology/pathogenesis
  5. Clinical appearances
  6. Histopathology/cytology/ immunochemistry
  7. Molecular pathology
  8. Differential diagnoses
  9. Therapy and prognosis
  10. Conclusion
  11. Conflict of interest
  12. References

The time between the appearance of LC and the diagnosis of the underlying leukemia varies. In the majority of patients (according to the literature, 55 to 77 %), LC develops in patients who have already been diagnosed with leukemia.

The simultaneous cutaneous and systemic manifestation of leukemia is less frequent at 23–38 %. In the rarely occurring aleukemic LC, which affects up to 7 % of patients, specific cutaneous signs of leukemia may precede hematologic detection of disease in the peripheral blood or bone marrow by several months or years [6, 8].

There are no preferred sites of involvement in LC. The trunk, extremities, and head are equally affected. LC less often appears on palmoplantar surfaces and the oral mucosa [8]. Clinical lesions seen in LC may be solitary or multiple, either affecting circumscribed areas or disseminated in an exanthematous rash. Generalized distribution of cutaneous lesions may be an indication of an acute form of leukemia. Solitary, scattered, or grouped lesions are seen in both acute and chronic leukemia [30]. The different growth dynamics of cutaneous forms may also serve as an indication as to which form of leukemia the patient has. Rapid growth, sometimes in spurts, tends to be characteristic for acute leukemia while in chronic forms gradual, progressive growth is more common [5]. Clinical morphology is not useful for diagnosis of leukemia type in LC given that individual lesions are not pathognomic for the different forms of leukemia, although chloroma and gingival hyperplasia may be exceptions [6, 29]. The most common clinical findings in LC are nodular structures such as papules, nodules, and larger tumors (Table 1). Their frequency has been analyzed in a study by Su and colleagues that included 42 patients with different forms of leukemia [8]. Dome-shaped papules, sometimes as large as a pea, are usually soft rather than firm (Figures 1, 2). Larger nodules or plaques with diameters measuring several centimeters may be flat or raised in calotte-like fashion and may have a rubbery consistency or possibly more firm (Figures 3–5). Harder LC tumors, sometimes as large as a fist, may also be covered with crusts or scale, with or without ulceration [6, 8, 30]. Nodular lesions vary widely in color from yellowish to brown, red, or purple. Some authors have even reported a blue, blue-gray, or hemorrhagic tinge (Figures 6, 7) [34–37]. Less often there may be superficial oozing erosions or craterlike ulcerations [8, 29, 31, 38–41].

Table 1.  Clinical morphology in leukemia cutis.
Common findings
• Papules, nodules, tumors
• Plaques
Rare findings (combined appearance and transitions between individual morphologies are possible)
• Erythema
• Erythroderma
• Ulcer
• Blisters
Colors
• Red, red-brown
• Brown, yellowish
• Bluish, gray
• Hemorrhagic, purpuric
• Deep lesions may have skin-colored surfaces
Distribution
• No predilection sites
• Singular, grouped, or disseminated
• Exanthematous spread
Involvement of oral mucosa
• Gingival hyperplasia
• Nodules, ulcers
Special features
• Chloroma
• Leonine facies
• Affecting scars
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Figure 1. Lichenoid papules on the left forearm; chronic lymphocytic leukemia.

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Figure 2. Red-brown papules on the lower leg; chronic lymphocytic leukemia.

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Figure 3. Infiltrated nodules on the forehead; acute myelomonocytic leukemia (chloroma).

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Figure 4. Nodule on the lower lip; chronic lymphocytic leukemia.

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Figure 5. Erythematous solid nodules on the right hand in a paraungual distribution; chronic lymphocytic leukemia.

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Figure 6. Hemorrhagic nodules on the trunk; acute myelomonocytic leukemia.

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Figure 7. Purple erythema and hair loss in the parietal region; acute monocytic leukemia.

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A separate entity as a nodular manifestation of LC is chloroma (syn.: myelosar-coma). Originally reported in the orbital periosteum, this tumor usually affects the dermis, the lymph nodes, or the gastrointestinal tract. The lesions often measure several centimeters in diameter, and are dome-shaped and erythematous. Chloromas (χλωρóς= green-yellow) have a green color when cut which is presumably due to the peroxidase content of the myeloid cells (Figure 3). Chloromas are considered a specific form of AML, although they have also been reported in other myeloproliferative diseases [35, 42, 43]. In terms of size, the lesions may be coin-sized or as large as the palm of the hand, or they may coalesce to form even larger lesions. They are usually red or brown-red in color and have a firm consistency. In men, the appearance of plaque-like infiltration affecting both mammillae is considered a specific finding of LC [5]. There is an increased incidence of chloromas in children with AML [44–46]. Usually they are the initial manifestation of disease or are an indication of recurrence. A large study with 92 adult patients with myelosar-coma (chloroma) found that up to 27 % had de novo tumors [47].

Excluding nodular and plaque-like forms, all other clinical forms of LC are rare. Macular rashes have only occasionally been reported; lesions are coin-sized to as large as the palm of the hand with a poorly-defined border and usually with an already palpable infiltrate (Figure 8) [48–51]. With increasing infiltration of the erythematous areas, there may be polymorphism with maculae, plaques, papules, and nodules, developing into a maculopapular exanthem [27–29, 34, 37, 38, 42, 48, 52]. On the face, the transition from erythema to nodular or plaque-like infiltration can lead to a grotesque appearance known as leonine facies [5, 8]. Another clinical feature of LC is the development of nodules and infiltration of scars [29, 32, 39, 53, 54]. If the erythema spreads, erythroderma may occur, accompanied by marked se-bostasis and pityriasiform or exfoliative scaling [5, 8, 55].

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Figure 8. Maculopapular rash on the lateral hemithorax; chronic lymphocytic leukemia.

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Erythroderma is considered an unspecific cutaneous manifestation of leukemia.

In the previously mentioned article by Su and colleagues, of the 42 patients with LC, only 2 had erythroderma [8]. Both of these patients had CLL. In another case report on a patient with exfoliative erythroderma, there was underlying prelymphocytic T-cell leukemia [56].

LC ulcers, which usually appear as solitary lesions and only occasionally as multiple lesions, often measure only a few centimeters in diameter. The ulcer base contains a firmly adherent purulent or hemorrhagic coating, and the ulcer margin is soft and raised. Ulcers may also affect unusual sites such as the groin, scrotum, or face [31, 52, 57, 58]. Leukemic ulcers are resistant to the usual treatment measures for ulcers which, in some cases may help lead to diagnosis. Blisters are a clinical-morphological rarity of LC. They have been reported on the fingers, hands, and arms in symmetrical arrangement, on the trunk in irregular distribution, and may be the size of a fingernail or coin-sized, or occasionally even larger, on a red background and containing clear, purulent, or hemorrhagic material [8, 59, 60].

The most common change affecting the oral mucosa in LC is gingival hyperplasia. The clinical appearance consists of light pink or bright red, circumscribed tumor-like or flat-elevated gingival swelling, sometimes nearly engulfing the teeth. The mucosal surface may be smooth or covered with small bumps. The vulnerable gingiva has a tendency to blood and become necrotic [34, 61].

Gingival hyperplasia is often observed in combination with AML, especially AMMoL and AMoL. In a study by Kaddu and colleagues, gingival hyperplasia was found in 7 out of 17 patients with AML, of whom 6 had either AMMoL or AMoL [29]. In a study by Su and colleagues, gingival hyperplasia was reported in 2 patients with AMMoL and AMoL [8]. The literature contains very rare reports of gingival hyperplasia in CML [35]. Unlike gingival hyperplasia, papules or nodules, as well as ulcers of the oral mucosa may also occur in other forms of leukemia such as CLL [5, 52, 62].

Histopathology/cytology/ immunochemistry

  1. Top of page
  2. Summary
  3. Introduction
  4. Epidemiology/pathogenesis
  5. Clinical appearances
  6. Histopathology/cytology/ immunochemistry
  7. Molecular pathology
  8. Differential diagnoses
  9. Therapy and prognosis
  10. Conclusion
  11. Conflict of interest
  12. References

The histopathological diagnosis of LC is based on an evaluation of the pattern of distribution, cytologic findings, and immunohistochemical characteristics of the tumor cells. The histological appearance generally varies, also over the course of disease, and does not necessarily correlate with clinical appearances [6, 63]. In making the conclusive diagnosis, hematologic results from the peripheral blood and bone marrow as well as the clinical course should be taken into account.

In a study by Klco and colleagues, about one-third of patients with LC had a diffuse pattern of infiltration with involvement of the superficial and deep dermis [47]. Focal, perivascular, or adnexal patterns of growth have also been reported [64].

In LC with underlying CLL, about half of patients have epidermal infiltration, which is usually focal [65]. The leukemic infiltrate may be diffuse or nodular, with perivascular or periadnexal involvement and generally has a well-defined boundary (Figure 9a) [6]. The cytologic appearance of ALL is characterized by a monomorphic infiltrate of moderately-sized or large lymphoid cells with pleo-morphic nuclei and a thin basophilic cytoplasm. In CLL, small or medium-sized lymphocytes with hyperchromatic nuclei and sparse cytoplasm predominate [29, 65, 66]. Immunohistochemistry shows a heterogeneous appearance. The B lymphoblasts in ALL are positive for CD79a and TdT, while T lymphoblasts are positive for CD1a, CD3, CD43 and TdT. In CLL the tumor cells may express CD5, CD19, CD20, CD43 and occasionally CD5 (Figure 9b) [29, 32, 66, 67]. The cytologic appearance of individual AML forms is characterized by various monomorphic cell lines, which in myeloblastic leukemia (FAB-M1 and -M2) are characterized by medium-sized to large mononuclear cells with a light cytoplasm and large, basophilic cell nuclei. AMMoL and AMoL are generally dominated by medium-sized, round or oval-shaped mononuclear cells which may have an eosinophilic cytoplasm and segmented or kidney-shaped basophilic nuclei (Figure 10a). A working group led by Bénet and colleagues recently reported various indications of a possible association between individual histological patterns and different forms of leukemia. In LC lesions with underlying AMMoL/AMoL the authors reported that a granuloma-annulare-like pattern was frequently seen [64].

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Figure 9. (a) Histology of B-CLL. Skin biopsy with regular epidermis und with cuff-like, quite monotonous infiltration of lymphoid cells around the superficial and deep dermal capillaries; no infiltration of lymphocytes in the epidermis (Giemsa X 10). (b) CD5 positive B-lymphocytes (CD5, X 10).

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Figure 10. Histology of AMoL. Perivascular and perifollicular infiltrates of relatively small round cells with poor cytoplasm and grooved (monocyte-like) nuclei. (a) Between the blast infiltrates some nuclear debris (Giemsa, X 10). (b) Some spotted positivity of the cytoplasm of these cells for ASD-chloroacetate-esterase, typical for monocytoid myeloid blasts (ASD-chloracetate-esterase, X 40).

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In CML, the pleomorphic infiltrate is composed of myelocytes, metamyelocytes, eosinophilic metamyelocytes, and segmented neutrophilic granulocytes [29] (Figure 10a). Immunohistochemistry studies show that in 50–65 % of patients with AML and 70–80 % with CML, NASD is positive [29, 66]. Lysozyme, MPO, CD74, CD43 and other antibodies are also among the most frequently used markers for myeloid leukemia (Figure 10b). It is not possible to classify the different forms of leukemia by skin biopsy alone; additional cytochemical and molecular genetic studies (e.g., bone marrow biopsy) are needed [32, 66]. A diagnosis of LC was confirmed, however, in 173 skin biopsies using an antibody panel (CD33, CD68, and MPO) [64, 33].

Molecular pathology

  1. Top of page
  2. Summary
  3. Introduction
  4. Epidemiology/pathogenesis
  5. Clinical appearances
  6. Histopathology/cytology/ immunochemistry
  7. Molecular pathology
  8. Differential diagnoses
  9. Therapy and prognosis
  10. Conclusion
  11. Conflict of interest
  12. References

The complex migration of leukemic cells to the skin (skin selective homing, see Epidemiology/Pathogenesis) is the subject of intense study, especially on molecular pathological features. Numerous chromosomal mutations have already been described for AML [33]. In regard to LC, there have also been a number of reports of various chromosomal anomalies (especially affecting chromosomes 8 and 21) [68, 69].

Differential diagnoses

  1. Top of page
  2. Summary
  3. Introduction
  4. Epidemiology/pathogenesis
  5. Clinical appearances
  6. Histopathology/cytology/ immunochemistry
  7. Molecular pathology
  8. Differential diagnoses
  9. Therapy and prognosis
  10. Conclusion
  11. Conflict of interest
  12. References

LC lesions, and their number and distribution, can provide important clues for differential diagnosis (Table 2). If there are solitary lesions or only a few papules and nodules, in addition to CL, metastasis of visceral malignancy should also be considered, although then the lesions are usually are very firm or even rock-hard (e.g., breast cancer) [70]. Hemorrhagic or purpuric nodules and plaques on the trunk, and especially on the lower legs, should be distinguished from vasculitis allergica and Kaposi sarcoma [31, 36–38, 48]. Flat nodules and infiltrated erythema, which also occur on the lower legs, should raise suspicion of possible erythema nodosum [8, 51, 71]. Depending on the severity of infiltration, the erythematous bright red, or red-brown plaques in LC may imitate erythema ex-udativum multiforme, panniculitis, or the clinical appearance of mycosis fun-goides [32, 40, 49, 51]. Unlike bacterial paronychia, paraungual manifestation of leukemic infiltrates appears on several fingers simultaneously and is characterized by more severe elevation of the nail wall region [72].

Table 2.  Differential diagnosis of leukemia cutis (localization/clinical morphology).
Trunk and extremities
• Metastasis of visceral malignancy, lymphoma, Kaposi sarcoma, basal cell carcinoma, squamous cell carcinoma
• Drug eruption, viral exanthem, syphilitic exanthem, pityriasis rosea, vasculitis allergica, bullous autoimmune skin disease, erythroderma of various origins
• Ulcers of various origins
Extremities
• Dyshidrotic eczema, pompholyx
• Paronychia of various origins
Face
• Seborrheic dermatitis
• Lupus erythematosus
• Morbihan disease
Oral mucosa
• Idiopathic gingival fibromatosis
• Drug-induced gingival hyperplasia
• Plaut-Vincent angina
• Primary syphilis, gummata

If there is exanthematous spread of nodular lesions, papular drug eruptions, sarcoidosis, a syphilitic exanthem, and lymphoma are among the most important differential diagnoses in LC [5, 32, 35, 48]. Circumscribed facial erythema may raise suspicion of seborrheic dermatitis or lupus erythematosus. An increased infiltrate may cause the clinical appearance of Morbihan disease before development of leonine facies [31, 50]. Unlike LC of the face, Morbihan disease has a much longer history which initially involves fluctuating severity of the puffy areas of swelling and which is characterized by edematous findings on palpation [73]. Macular or maculopapular exanthems related to LC may be mistaken for viral exanthems, drug eruptions, syphilis, or pityriasis rosea [5, 35, 74]. The paraclinical features of acute forms of leukemia make it more difficult to distinguish the disease from viral infections or drug-induced hypersensitivity syndromes [75]. The maximum variant of an erythematous manifestation of LC is erythroderma, which should be differentiated from similarly severe skin diseases of another origin [55]. Blisters on the fingers, may resemble findings in dyshidrotic eczema or pompholyx [59]. Large blisters on the trunk should be distinguished from bullous autoimmune diseases [55]. Ulcers in unusual locations such as on the face, trunk, thighs, or genital area, as have been reported in LC, should be distinguished from pyoderma gangrenosum and ulcus molle [52, 57]. Leukemic ulcers on the lower legs do not differ clinically/morphologically from leg ulcers due to other causes, but may occur at unusual sites and may have an undermined or raised margin [52, 58]. In the differential diagnosis of leukemic gingival hyperplasia, idiopathic gingival fibromatosis and gingival hyperplasia due to medication use, should be taken into consideration. Idiopathic gingival fibromatosis is an autosomal dominant inherited disease that manifests in early childhood [76]. Typical drugs that can cause gingival hyperplasia include cy-closporine A, phenytoin, and nifedipine [77]. Nodules and ulcers appearing on the oral mucosa in LC should be differentiated from Plaut-Vincent angina, from lesions seen in influenza infections, and from primary syphilis or gummata [35, 61].

Therapy and prognosis

  1. Top of page
  2. Summary
  3. Introduction
  4. Epidemiology/pathogenesis
  5. Clinical appearances
  6. Histopathology/cytology/ immunochemistry
  7. Molecular pathology
  8. Differential diagnoses
  9. Therapy and prognosis
  10. Conclusion
  11. Conflict of interest
  12. References

Rubin and colleagues proposed the hypothesis in 1985 that LC may develop independently of AMoL. They reported on a 13-month old girl with AMoL and LC. After the disease had been in remission for five months (with continued systemic chemotherapy), the infant experienced an isolated recurrence of LC. Except for the head region, there were disseminated multiple cutaneous nodules. Upon initial diagnosis of AMoL, the infant had undergone whole-brain radiotherapy. The recurrence of LC resolved completely after whole body surface electron irradiation. The girl was still in remission after 12 months.

The authors concluded that the leukemic cells in the skin may have survived the multiple chemotherapy regime due to an unspecified escape mechanism, but that they had been destroyed in the head region by the whole-brain radiotherapy performed at that time [78]. This hypothesis is still current. For instance, recurrent chloroma reportedly occurs more frequently in organ systems that are less accessible to systemic chemotherapy or radiation therapy (e.g., CNS, ovaries, uterus) [33]. Given the high sensitivity of LC to radiation, even today under certain conditions exanthematous spread or isolated LC lesions may be treated with radiation therapy [29, 33].

In LC the treatment of the underlying leukemia is a primary goal [1, 2]. Parallel to remission of hematological findings, there is generally also complete or partial resolution of cutaneous manifestation [28–30]. Studies by Kaddu and colleagues [29] have shown the influence of chemotherapy on the course of LC in 15 patients with AML. The authors reported that remission occurred in all patients, and in 10 patients, there were no recurrences of LC over the course of disease. Yet 9 of the 10 patients died within 12 months of causes related to leukemia. Thus the resolution of LC in response to chemotherapy cannot be assumed to be a prognostic indicator for the course of disease.

LC has been interpreted by a few authors as a systemic manifestation and is thus considered an unfavorable factor in prognosis [6, 29–32]. Thirty-seven (88 %) out of 42 patients with various forms of leukemia died, most within one year of diagnosis with LC. With an average survival time of only 1.3 and 3.6 months after diagnosis of LC, the prognosis for AMMoL and AMoL was especially poor [8].

The prognostic significance of LC is undisputed. Agis and colleagues compared the results of chemotherapy in AML between patients with and without LC. They found no difference in the number of patients with complete remission or the number of premature fatalities. Nor were there significant differences in the recurrence-free survival and average duration of complete remission [28]. Other working groups have shown that there is no direct relationship between the extent of infiltration of the skin in LC or a specific histological infiltration pattern and prognostic significance [27, 67].

In the future, the molecular pathological diagnosis of various gene mutations (e.g., NPM1, FLT3) will be very important for the pathogenetic interpretation and prognosis of LC and underlying forms of leukemia [33].

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Epidemiology/pathogenesis
  5. Clinical appearances
  6. Histopathology/cytology/ immunochemistry
  7. Molecular pathology
  8. Differential diagnoses
  9. Therapy and prognosis
  10. Conclusion
  11. Conflict of interest
  12. References

The clinical appearances of LC are highly variable and include mainly papules, maculae, nodules, and plaques. Conclusions about the histopathological type of underlying leukemia are only possible with immunohistochemical and molecular genetic methods.

In more than half of patients, LC develops only after diagnosis of the underlying leukemia. In up to 7 % of patients it may occur as the initial manifestation. A skin biopsy is the method of choice for early confirmation of the presumptive diagnosis.

Interdisciplinary hematologic/dermatologic follow-up is essential, even for patients in remission with underlying leukemic disease for prompt identification of cutaneous recurrences.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Epidemiology/pathogenesis
  5. Clinical appearances
  6. Histopathology/cytology/ immunochemistry
  7. Molecular pathology
  8. Differential diagnoses
  9. Therapy and prognosis
  10. Conclusion
  11. Conflict of interest
  12. References
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