Aleukemia cutis: Clinicopathological and molecular investigation of two cases

We describe two cases of acute myeloid leukemia (AML) who presented with cutaneous manifestations. Leukemia cutis (LC) is the cutaneous presentation of any type of leukemia and occurs in 10% to 15% of patients with AML, but cutaneous infiltration of AML rarely precedes the involvement of the bone marrow or peripheral blood and is called “aleukemia cutis.” Our first case presented with facial skin thickening, a manifestation which is known as lionization and his initial clinical diagnosis was nonspecific allergic reaction. Our second case presented with urticaria-like lesions with the initial clinical and histomorphologic diagnoses of leukocytoclastic vasculitis. Histopathologic examination of skin biopsy specimens in both patients showed diffuse infiltration of the dermis with a monotonous population of intermediate-sized mononuclear cells by open chromatin and promonocytic features. Bone marrow aspiration leukocyte karyotyping showed normal cytogenetics, and molecular investigation revealed mutations of NPM1 and FLT3 genes. Somatic CEBPA gene mutation was negative in both patients. LC as the first manifestation of leukemia is very rare and could result in delayed diagnosis and affect patient prognosis.     

Leukemia cutis in a patient with acute monocytic leukemia presenting as unique facial erythema

A 67‐year‐old woman was referred to our department with a 1‐month history of facial exanthemas. She had been diagnosed as having acute monocytic leukemia (French–American–British classification, M5b) based on the histological findings of bone marrow. Physical examination revealed diffuse edematous erythema on her cheeks, eyelids and glabella with scattered reddish papules. Histological examination demonstrated dense infiltration of atypical mononuclear cells in the dermis. Specific cutaneous lesions could occur in acute monocytic leukemia more frequently than in other types of leukemia, but rarely show symmetrical edematous erythema limited to the face.     

Leukemia cutis - epidemiology, clinical presentation, and differential diagnoses

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.     

皮肤白血病1例

报告1例以皮肤为首发表现的急性粒单细胞白血病。患者女,63岁。因面部、颈部、胸部斑块6个月,发热3个月就诊,根据临床和实验室检查确诊为急性粒单细胞白血病。本例特点是首先出现白血病的特异性皮肤表现（皮肤白血病）。     

Leukemia cutis in acute lymphocytic leukemia masquerading as viral exanthem.

Leukemia cutis is a specific skin lesion caused by infiltration of leukemic cells into the skin. It is uncommon in acute lymphocytic leukemia (ALL). It typically manifests as red or violaceous papules, nodules, or plaques, mainly on the face. Leukemia cutis presenting with a generalized viral exanthem-like maculopapular eruption appears to be rare in the English literature. We report such a case. A 19 year-old man presented with a generalized purpuric maculopapular eruption of eight day's duration. Hematologic studies showed changes of acute lymphocytic leukemia, T-cell type. A skin biopsy specimen revealed a cuff-like, dense, perivascular infiltration of atypical lymphocytes in the upper and mid-dermis, consistent with leukemia cutis. The rash resolved in two weeks after chemotherapy. Our case illustrates that leukemia cutis should be considered in the differential diagnosis of a generalized morbilliform viral exanthem-like eruptions. Skin biopsy is important in establishing the diagnosis.     

Neonatal osteoma cutis due to a mutation in GNAS

We describe a 4‐week‐old baby boy who presented with white firm cutaneous nodules and failure to thrive. He did not have dysmorphic features, and laboratory tests including serum calcium, phosphorous, thyroid function, and parathyroid hormone level were within normal ranges. Whole exome sequencing revealed an inactivating mutation in GNAS that was previously described as causing pseudohypoparathyroidism.     

Novel nonsense GNAS mutation in a 14‐month‐old boy with plate‐like osteoma cutis and medulloblastoma

Plate‐like osteoma cutis (PLOC) is a dermatological disorder characterized by superficial ossification and rarely occurs without any underlying tissue abnormalities or pre‐existing calcification. The hereditary form of PLOC is mainly due to inactivating mutation in the GNAS gene. Inactivating mutation of the GNAS gene is associated with several diseases, which commonly manifest heterotopic ossification and hormonal resistance; however, the development of malignant neoplasm has never been reported. Herein, we report a case of a patient with a novel nonsense mutation in the GNAS gene, who presented with concurrent PLOC and medulloblastoma.     

Disseminated De Novo Myeloid Sarcoma in a 17‐year‐old Boy

Myeloid sarcoma (MS) is a rare extramedullary tumor of malignant myeloid cells often associated with acute myeloid leukemia. We report a case of a 17‐year‐old boy presenting with diffuse red‐brown skin nodules ultimately diagnosed with the scarcely described disseminated, de novo MS. It is important for dermatologists to keep MS on their differential when assessing patients with disseminated red‐brown nodules.     

Leukemia cutis in acute myelomonocytic leukemia: infiltration to minor traumas and scars

We describe a patient with acute myelomonocytic leukemia who demonstrated leukemic cell infiltration to scratched wounds and scars from trauma. A 65-year-old Japanese woman developed low grade fever, headache and exanthema. Hematology testing disclosed leukocytosis of 95,600/mm3 with 65% monocytes and 9% blast cells. Infiltrated erythema and nodules were disseminated over most of her body. Moreover, linear scratched wounds and traumatic scars were indurated. Skin biopsy showed dense atypical mononuclear cell infiltration with monocytic characteristics. We discuss the possible reasons for the infiltration of leukemia cells into the wounds and scars from trauma.     

Myeloid sarcoma in a newborn: A rare manifestation of congenital acute myeloid leukemia

Cutaneous myeloid sarcoma is rarely present prior to the diagnosis of congenital acute myeloid leukemia (AML); the former is typically diagnosed with or after the leukemia. We report a 2-day-old male born with multiple cutaneous red to violaceous nodules. Histopathologic and immunohistochemistry findings from a skin nodule were suspicious for myeloid sarcoma. Bone marrow biopsy was initially negative for aberrant blasts; however, at age 4 months, AML with a KMT2A gene rearrangement was identified via bone marrow biopsy.     

Dermoscopic findings in neonatal leukemia cutis

Leukemia cutis is the direct infiltration of cutaneous tissues by leukemic cells and can present as a blueberry muffin baby. We present a case of neonatal leukemia cutis highlighting its dermoscopic features, the presence of fine telangiectatic arborizing vessels distributed within a pink background within all lesions.     

A case of extramedullary hematopoiesis presenting as hemorrhagic panniculitis and evolving in acute myeloid leukemia

Extramedullary hematopoiesis (EMH) in adults is a rare event, usually associated with myeloid disorders, and can be the first sign of chronic myelomonocytic leukemia. We report a case of EMH presenting as a hemorrhagic panniculitis in a patient who did not apparently present any myeloid disorders. The patient received previous chemotherapy for mantle cell lymphoma localized to the large bowel and had been in complete remission for 3 years. The diagnosis of EMH was achieved after a deep incisional biopsy of a nodule from the thigh, and with pathological examination that included immunohistochemical studies. After a follow‐up of 14 months, the patient developed an acute myeloid leukemia, classified as therapy‐related myeloid neoplasm, according to the 2016 World Health Organization (WHO) classification of hematological malignancies. As shown by the rare cases described in literature, the presence of cutaneous EMH should always be a trigger for investigating the patient's hematological system; also, in our experience, a long follow‐up is mandatory.     

Cutaneous presentation preceding acute myeloid leukemia with CD4+/CD56+ expression misdiagnosed as a blastic plasmocytoid dendritic cell neoplasm: A case report

Acute myeloid leukemia (AML) may initially present as cutaneous lesions corresponding to blasts involving the skin as the first clinical manifestation prior to blood and bone marrow (BM) infiltration. Such presentation is known as myeloid leukemia cutis (LC). Blastic plasmocytoid dendritic cell neoplasm (BPDCN) is an aggressive tumor derived from the precursors of plasmocytoid dendritic cells with cutaneous and BM involvement and leukemic dissemination. Myeloid LC and BPDCN may be difficult to distinguish as they share similar clinical and histopathological features, in particular AML with monocytic differentiation. Nevertheless, the correct diagnosis has to be made to determine adequate and effective therapy. Here, we report the case of a 61‐year‐old woman who presented with an AML with MLL rearrangement and CD4+/CD56+ expression presenting as LC and that was misdiagnosed as BPDCN. We emphasize that careful and exhaustive analyses should be performed to make the correct diagnosis.     

Three cases of osteoma cutis occurring in infancy. A brief overview of osteoma cutis and its association with pseudo-pseudohypoparathyroidism

We report three cases of primary osteoma cutis in children, two of whom (siblings) were associated with Albright's hereditary osteodystrophy (AHO), manifesting as short stature with autosomal dominant inheritance from the father, but no dysmorphic features and no parathyroid hormone (PTH) resistance. Osteoma cutis can manifest as an isolated skin disease, a secondary condition to other skin diseases (such as acne), or in association with several syndromes, including AHO, which in turn may be associated with PTH resistance. The management and prognosis of patients diagnosed with osteoma cutis is determined by whether the skin manifestation has occurred in isolation, in association with a syndrome, or as a secondary skin disease. These three paediatric cases highlight the importance of understanding the aetiology and associations of osteoma cutis in order to appropriately investigate and manage patients who present with this rare skin disease.     

急性髓细胞性白血病(M4型)

报告1例急性髓细胞性皮肤白血病(M4型).患者女,48岁.全身出现丘疹、红色结节14d,伴剧烈瘙痒.体格检查:全身泛发大小不等的红色丘疹、结节,质韧,无压痛.皮损组织病理检查:真皮内弥漫淋巴样细胞浸润,有明显异形及较多核分裂象.免疫组化组织病理检查:CD68阳性(灶性),MPO阳性(少量).骨髓穿刺:白血病细胞大量增生,免疫标记:CD68、CD11b、MPO及HLA-DR均阳性.诊断:急性髓细胞性白血病(M4型).患者经过2次DA(伊达比星、阿糖胞苷)方案化疗后,再次行骨髓穿刺示缓解,但皮损仍有复发.     

Pernio as the presenting sign of blast crisis in acute lymphoblastic leukemia

A previously healthy 5‐year‐old girl presented with acute onset of blue toes and red spots on the nose and fingers. The striking nature of these lesions, along with the finding of submandibular lymphadenopathy, prompted further evaluation. Laboratory findings were remarkable for anemia, high transaminase levels, and high blast count. Histopathologic findings were consistent with early pernio. Further examination revealed acute B‐cell lymphoblastic leukemia. Treatment of the leukemia led to resolution of the pernio.     

Trisomy 8 in myeloid leukemia cutis confirmed by fluorescence in situ hybridization analysis

We present a case of a 64‐year‐old man with refractory acute myeloid leukemia and trisomy 8 who developed leukemia cutis. Interphase fluorescence in situ hybridization (FISH) was performed on a paraffin‐embedded skin section. FISH confirmed a population of cells with trisomy 8 in the blastic infiltrates involving the skin. This case illustrates a novel application of interphase FISH to confirm the diagnosis of leukemia cutis.     

Panniculitis in a 3‐year‐old child with Fanconi anemia‐associated bone marrow hypoplasia heralds transformation to acute myeloid leukemia

Fanconi anemia is a rare, autosomal recessive genomic instability disorder characterized by congenital limb anomalies, panmyelopathy and a high risk of malignancy, principally acute myeloid leukemia. Hematologic malignancy presenting with acute febrile neutrophilic dermatosis (Sweet syndrome), both deep and superficial forms, is well described in Fanconi anemia patients but is a rare phenomenon in otherwise healthy children. We present a case of panniculitis (presumptive subcutaneous Sweet syndrome) heralding transformation to acute myeloid leukemia in a 3‐year‐old boy with a severe Fanconi anemia phenotype.     

Angioinvasive Fusarium and concomitant Enterococcus infection arising in association with leukemia cutis

Leukemia cutis represents the cutaneous infiltration of neoplastic leukocytes or their precursors that results in clinically identifiable skin lesions. For patients with myelodysplastic syndrome, developing such a lesion may indicate impending leukemic transition. These patients are also often immunocompromised, putting them at risk for infection by opportunistic fungal pathogens such as Fusarium. We describe an 85-year-old man with myelodysplastic syndrome who presented with a reddish-purple nodule with a surrounding erythematous plaque on his shin. Histopathologic examination revealed a dense diffuse infiltrate of large atypical cells in the reticular dermis, with ulceration and necrosis. Immunohistochemical studies showed positive staining with CD15, CD68 and myeloperoxidase of constituent large cells. Concurrently, there were branching and septate hyphae with occasional macroconidia-like structures throughout the infiltrate. Cultures from this lesion grew Fusarium and Enterococcus, supporting the diagnosis: leukemia cutis with superinfection involving both Fusarium and Enterococcus. To our knowledge, this is a novel report of two separate infections occurring in a lesion of leukemia cutis. This case shows that in patients with a hematologic malignancy and skin lesions, a high index of suspicion for infection is necessary when reviewing both the clinical and histopathological data to avoid overlooking an important occult infectious agent.