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Cutaneous presentation preceding acute myeloid leukemia (AML) is rare, and the prognosis is poor.
We report 4 cases of AML cutis, where skin infiltration precedes any blood or bone marrow evidence of leukemia. We also reviewed 13 cases reported in English and Chinese literature. The 4 cases all presented typical cutaneous lesions without any systemic evidence of leukemia. Histopathological examination found that dense monomorphous cell infiltration involved the dermis. Some cells surrounded blood vessels and skin appendages in a concentric manner or showed single-row arrangement in the collagen fiber bundles. Uninvolved papillary dermis was found to separate normal epidermis from dermal infiltration. Minor cells had a large kidney-shaped or oval nucleus with nucleoli and slightly eosinophilic cytoplasm. Immunohistochemical analysis was positive for CD4, CD56, while CD123 was negative in all cases.
2 patients received chemotherapy ,but others rejected treatment.
Most patients died within 1 year after the onset of skin lesions.
These findings suggest that skin infiltration of AML may precede any systemic evidence, and typical cutaneous lesions in elderly individuals may be indicative for AML.
The clinical manifestation of leukemia cutis (LC) results from an infiltration of leukemic cells into the epidermis, dermis, or subcutaneous tissues. Typically, cutaneous lesions present as multiple substantial reddish or purple red (occasionally dark red or brown), firm papules, plaques, or nodules which are 0.5 to 2.0cm in diameter and involve the trunk and extremities. In some cases, rashes can extend over the whole body. It also can present as a purpuric rash or ecchymosis.
It has been reported that an overall incidence of LC in patients with acute myeloid leukemia (AML) reached 2% to 20%. There are different frequencies of skin involvement in various subtypes of AML. Half of patients with acute monocytic leukemia (AML-M5) may finally develop LC. The presence of LC generally suggests that there are other sites of extramedullary involvement, thereby indicating a poorer prognosis.[2,3] Therefore, early diagnosis and treatment of LC is important for symptomatic relief and improved prognosis.
This Ethics Committee of the Second Hospital of Jilin University has approved this study. All procedures followed were in accordance with the ethical standards of Institutional Review Board of the Second Hospital of Jilin University and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study. General characteristics of 4 patients are shown in Table Table11.
General characteristics of 4 patients.
Four patients were admitted to the Dermatology Department of the Second Hospital of Jilin University and were diagnosed as AML-M5-LC.
Case 1: A 68-year-old woman presented with a 2-year history of papules on the right lower limb, and over the past 2 months lesions had extended over the whole body. The patient did not have fever, pruritus, or weight loss. She was previously diagnosed with lymphomatoid papulosis. On physical examination, there were multiple various sized, skin-colored to erythematous, firm papules over the trunk, extremities, and scalp. Lesions were isolated, and there was no ulceration (Fig. (Fig.1).1). There was no palpable lymph node enlargement. Apart from a low platelet (PLT) count (4.8×109/L), laboratory examination results were normal. She had no evident bleeding trend (including gum bleeding). No special treatment was administered before the pathological examination of the skin lesions.
Clinical features: multiple reddish, substantial papules, and plaques 0.5 to 2.0cm in diameter involving the trunk and extremities.
These findings combined with skin biopsy results suggested that a lymphoreticular tumor was likely. After 20 days, the patient was examined for fever: her leukocyte count was 18.5×109/L. Peripheral blood smearing showed promonocytes accounted for 44% and had large and irregular cell body; these cells were rich in gray-blue cytoplasm; there were vacuoles and small granules in cells; the nuclei were thin and net-like, and there were 1 to 3 clear nucleoli in each nucleus. Following bone marrow examination, she was subsequently diagnosed with AML-M5 and received 2 cycles of chemotherapy (daunorubicin, cytarabine, and neomycin daunorubicin). Following chemotherapy, her lesions were remission but there were no changes in bone marrow and blood tests. The patient died 6 months after diagnosis.
Case 2: A 74-year-old woman presented with a 2-month history of red papules and nodules on the trunk. She was admitted to our department with progressive lesions that increased in number over a 1-week period. Systemic erythrous or cuticolor rashes, substantial papules and nodules of different sizes were found (sorghum sized to broad bean sized), some lesions merged partially, and there was no superficial ulcer. Pain, itching, and no other symptoms were noted (Fig. (Fig.1).1). One week later, the patient was admitted to the hematology department with dizziness, lassitude, and fever. Routine blood test (RBT) showed white blood cells (WBC) count was 16.7×109/L, monocyte count was 6.6×109/L, red blood cells (RBC) count was 1.9×1012/L, hemoglobin (Hb) was 64g/L, and PLTs count was 61×109/L. Peripheral blood smearing showed the WBC increased significantly and granulocytes reduced, naïve granulocytes were observable, mature RBCs displayed different sizes. Among 100 WBCs counted, there were no nucleated cells, lymphocytes accounted for 4%, monocytes increased significantly (86%), and promonocytes and naïve monocytes accounted for 84%. The proportion of cells weakly positive for myeloperoxidase was higher than 3%. She was diagnosed as AML-M5 based on the third bone marrow examination. The patient requested discharge and died 1 month later.
Case 3: An 82-year-old man was admitted to our department with a 2-month history of extensive kermesinus papules on the prothorax and lesions extending over the trunk, limbs, face, and scalp. Systemic dark red or cuticolor rashes and nodules of different sizes were observed (sorghum sized to broad bean sized), lesions were not merged, and there was no superficial ulcer (Fig. (Fig.1).1). Laboratory examination was almost normal. RBT showed that WBC count was 4.89×109/L, monocytes count was 0.7×109/L, RBC count was 4.0×1012/L, Hb was 130g/L, and PLT count was 174×109/L. At disease onset, the WBC count was 14.5×109/L and Hb was 109g/L. He was previously diagnosed with drug eruption. Six months later, the patient was diagnosed with AML-M5 based on bone marrow examination. Peripheral blood smearing showed promonocytes accounted for 10%, immature monocytes for 11%, lymphocytes for 17%, metagranulocytes for 4%, rod-shaped nuclear cells for 8%, and segmented cells for 35%. This patient received 1 course of chemotherapy (cytarabine, daunorubicin, and homoharringtonine). Following chemotherapy, remission of the lesions were observed, but the patient died in 8 months after therapy.
Case 4: A 70-year-old man presented to our department with a 40-day history of extensive claret papules on the anterior chest. On admission, physical examination showed no palpable superficial lymph nodes enlargement, dark purple papules were diffusely distributed at the cheeks, trunk, and limbs. Pain, itching, and other symptoms were not observed (Fig. (Fig.1).1). The weight loss was 10kg in the past month. Laboratory examinations showed normal. He was diagnosed with granuloma fungoides. Ten days later, RBT showed WBC count was 14.7×109/L, monocytes count was 7.4×109/L, PLT count was 51.0×109/L, RBC count was 3.9×1012/L, and lymphocytes count was 4.4×109/L. Blood smearing showed WBCs increased significantly, granulocytes reduced, and mature RBCs showed different sizes. Among 100 WBCs counted, there were 1 proerythroblast and 3 orthochromatic erythroblasts, lymphocytes reduced significantly, monocytic cells increased markedly, but they were mature monocytes. Platelets were observable. Based on skin biopsy results, immunohistochemistry, and bone marrow examination, he was diagnosed with AML-M5. This patient rejected chemotherapy and died in the first year following diagnosis.
Pathohistologic changes for the 4 cases were similar. Epidermis had no significant changes. A dense monomorphous cellular infiltration involved the dermis. Some cells surrounded blood vessels and skin appendages in a concentric manner or showed single-row arrangement in the collagen fiber bundles. Uninvolved papillary dermis was found to separate normal epidermis from underlying dermal infiltration (Fig. (Fig.2A).2A). Minor cells had a large kidney-shaped or oval nucleus with 1 or more conspicuous nucleoli, and abundant pale, slightly eosinophilic cytoplasm. Sometimes atypical mitotic figures were present (Fig. (Fig.2B).2B). It is in accordance with literature (Tables (Tables22 and and33 ).
(A) Magnification of hematoxylin-eosin staining (HE) ×100. (B) Magnification of HE ×400. (C–E) The marker CD4, CD56 were positive, and CD123 was negative.
Summary of cases reported in the literature since 1986.
Summary of cases reported in the literature since 1986.
Immunohistochemical results were lack of specificity. Immunohistochemical analyses for the 4 cases were similar (Fig. (Fig.2C–E).2C–E). Markers for CD4, CD56, and leukocyte common antigen were positive and markers for CD20, CD34, and CD123 were negative in all cases. Marker CD68 was positive in cases 2 and 4 and CD45RO was positive in cases 1 and 2. CD3 and CD30 were negative in case 1 and CD117 was negative in cases 2, 3, and 4 (Table (Table4).4). The marker CD68 (7/9, 9 cases received immunohistochemical examination and 7 cases were positive) was positive and the markers including CD45RO(4), CD56(2), and CD4(4) were positive in all cases. The markers CD3(4), CD20(3), CD30(2), CD34(3), and CD117(2) were negative in all cases. Above all, the marker CD4 and CD56 were strongly positive; CD123 and CD20 were negative.
Treatments and the outcomes of these cases in the literature since 1986.
Findings from immunohistochemistry of the skin in 4 patients.
Skin infiltration preceding any blood or bone marrow evidence of leukemia is classified as aleukemic leukemia cutis (ALC) and is very rare. All 4 of our cases are AML-M5-ALC. In the present report, the 4 patients were older than 68 years (median: 73.5 years). In previously reported 14 cases, only 2 patients were diagnosed at about 40 years old, and the median age was 64.4 years. AML-M5-LC occurs most frequently in elderly people. The patients in our cases reports showed a similar clinical presentation to cases documented in the literature.[2,16–19] Gingival hypertrophy is also striking and unique finding of the M4/M5 variants,[1,20] although this feature was not reported in our patients.
Incidentally, we found that all 4 cases showed strong positive CD56 staining. Di Bona et al found that AML-M5 accounted for 37% in 37 AML cases of CD56 positivity. It was the highest proportion across the AML subtypes. Through literature review, it was thought that CD56 positivity is correlated with AML-M5-LC. Generally, CD56 may be also expressed in the normal NK cells, CD3+ cytotoxic T cells, some CD4+T cells, and monocytes. In addition, cells of neuroectodermal origin (such as nerve cells and neuroendocrine cells) may also express CD56. Tumor cells of lymphoma, pseudolymphoma, blastic plasmacytoid dendritic cell neoplasm (BPDCN), Merkel cell carcinoma, and small cell lung cancer with skin metastasis are also positive for CD56. When the pathological examination shows changes similar to those in skin infiltration of AML and tumor cells are negative for markers of T cells and B cells, being positive for CD56 is indicative of leukemia or BPDCN. Although immunohistochemical changes lack specificities, CD4, CD56 in all 4 patients were strongly positive, and the marker CD123 was negative. Expression of CD4, CD56, and lack of CD123 may be the immunological markers for AML-M5-LC.
This disease should be differentiated from metastatic skin tumors, lymphomas, and neuroendocrine tumors according to the clinical and pathological features. Metastatic skin tumors may also manifest multiple nodules and papules clinically and the infiltration of private-like tumor cells with evident atypia in dermal collagen fibers pathologically. However, the primary cancer may be identified by systemic examination in patients with metastatic skin tumors. In addition, immunohistochemistry may display features identical to those of primary cancer, and bone and blood examination may fail to show abnormalities. Plaques or nodules and evident itching are the predominant clinical characteristics of cutaneous T-cell lymphoma; pathologically, tumor cells are proepidermal, spinal lamina lymphocytes form typical Pautrier microabscess, and immunohistochemistry shows that tumor cells are positive for markers of clonal T lymphocytes (CD3 and CD4). However, tumor cells of AML have no CD3 expression. Merkel cell carcinoma is one of neuroendocrine tumors, and tumor cells are smaller than spine cells and have little cytoplasm; pathologically, Merkel cell carcinoma is similar to AML and also positive for CD56; tumor cells of Merkel cell carcinoma are also positive for other markers of neuroendocrine tumors (TTF-1, CgA, Syn, NSE, and CK20), but negative for CD4. In addition, bone marrow examination and flow cytometry does not show changes as in AML. In case 4 of present report, the disease should be differentiated from CD4+CD56+ BPDCN according to the clinical and pathological features. However, this disease was positive for CD123, and flow cytometry did not show the changes as in AML. In the present report, the case was negative for CD123, and thus CD4+CD56+ BPDCN may be excluded.
The present treatments mainly include chemotherapy in which Daunorubicin (ZHEJIANG HISUN PHARMACEUTICAL CO. LTD, Taizhou City, Zhejiang province, China), neomycin daunorubicin, cytarabine, retinoic acid, gituximab, etoposide, and methotrexate are used. Radiotherapy may also be employed if necessary. Our findings and those reported in previous studies[3–9,11,12] showed that there is no effective treatment for this disease. Lee et al employed sorafeni in the treatment of skin infiltration of AML with internal tandem duplication, and complete remission was observed.
Skin infiltration of AML-M5 has a poor prognosis, and most patients died within 1 year after diagnosis.[3–9,11,12] This may be explained as that tumor cells in the skin escape from the killing of chemotherapeutics because most chemotherapeutics mainly kill tumor cells in the bone marrow, tumor cells in the skin are hard to be killed, and these tumor cells may be a major cause of recurrence.[1,20] Thus, some clinicians proposed that total skin electron beam radiation therapy may be employed simultaneously with chemotherapy in leukemia patients with skin involvement.[1,20] There is evidence showing that increased lactate dehydrogenase in patients with skin infiltration of AML predicts a poor prognosis.
Taken together, the progression of molecular biology and the application of genetic diagnosis in skin infiltration of AML-M5 may help the development of effective treatments such as target therapy and biotherapy.
In conclusion, clinicians should pay special attention to the differential diagnosis of this disease in elderly patients. It has a higher skin infiltration rate compared with other subtypes and a poor prognosis. Skin biopsy and immunohistochemical examination, combined with routine blood analysis and bone marrow examination, are required to ensure early diagnosis and proper treatment to delay the progress of this disease. Improvements in present treatment for AML-M5-LC require further discussion.
Abbreviations: ALC = aleukemic leukemia cutis, AML = acute myeloid leukemia, AML-M5 = acute monocytic leukemia, BPDCN = blastic plasmacytoid dendritic cell neoplasm, Hb = hemoglobin, HE = hematoxylin-eosin staining, HLA-DR = human leucocyte antigen DR, LC = leukemia cutis, LCA = leukocyte common antigen, PLT = platelet, POX = myeloperoxidase, RBT = routine blood test, WBC = white blood cell.
The authors have no funding and conflicts of interest to disclose.