Sweet's syndrome in the setting of CD34-positive acute myelogenous leukemia treated with granulocyte colony stimulating factor: evidence for a clonal neutrophilic dermatosis

BACKGROUND: Sweet's syndrome in the setting of hematologic dyscrasias can be categorized into paraneoplastic-associated SS, drug-induced SS, and SS with leukemia cutis. Apart from those cases demonstrating concomitant leukemic infiltrates, it has been surmised that SS is a reactive phenomenon induced by a specific cytokine milieu. METHODS: The authors present a patient with CD34+ acute myelogenous leukemia (AAML) who developed SS in the setting granulocyte colony stimulating factor (GCSF) therapy. Routine light microscopy and molecular studies were carried on the patient's skin biopsy specimen and post-treatment marrow. An X inactivation assay for clonality was employed. RESULTS: Routine light microscopic examination revealed differentiated myeloid precursors including myelocytes and metamyelocytes within the subcutis; myeloblasts were not identified. In addition, in the overlying skin, features typical of SS were observed. The neutrophils demonstrated dysplastic features including hypolobation compatible with a Pseudo Pelger-Huet anomaly. X inactivation studies showed clonality both within her post-treatment marrow and skin biopsy specimen. CONCLUSIONS: Sweet's syndrome developing in CD34+ AML patients following GCSF therapy likely reflects therapy induced differentiation of sequestered leukemic cells, hence indicative of a clonal neutrophilic dermatosis.     

De novo myeloid sarcoma in a 4‐month‐old infant: a case report and review of the literature

Myeloid sarcoma is a rare tumor of immature myeloid cells in an extramedullary site. Myeloid sarcoma may present in a variety of locations; skin is one of the common sites. It may precede or occur concurrently with acute myeloid leukemia, chronic myeloid leukemia, other forms of myeloproliferative disorders/myelodysplastic syndrome or de novo. We report a case of a 4‐month‐old female who presented with cutaneous lesions without evidence of leukemia, determined to be de novo myeloid sarcoma. She had erythematous nodules in multiple skin sites. Biopsy revealed a diffuse atypical mononuclear cell infiltrate involving the entire dermis and extending to the subcutis. The infiltrate was diffusely positive for lysozyme, CD43, CD15, CD33, CD68 and CD117 and was negative for CD3, CD20, CD34, CD56, CD79a, CD99, myeloperoxidase, desmin, chromogranin and synaptophysin, supporting a diagnosis of myeloid sarcoma. No leukemic involvement was found on evaluation of peripheral blood or bone marrow aspiration. Chromosomal abnormalities were found at chromosomes 7, 10 and 11. The skin lesions resolved following multiple chemotherapy courses, then recurred requiring additional treatment. De novo myeloid sarcoma involving skin without evidence of leukemia can occur in an infant and may present a diagnostic challenge.     

Chronic recurrent lymphocytic Sweet syndrome as a predictive marker of myelodysplasia: a report of 9 cases

BACKGROUND: Sweet syndrome is an acute neutrophilic dermatosis that occurs with malignant diseases, mainly myeloid hemopathies, in about 20% of cases. When associated with myelodysplasia, Sweet syndrome may be clinically atypical. It can be histologically unusual. Concomitant infiltration of mature neutrophils and immature myeloid cells has been reported, and its significance is still debated. In few patients, lymphocytic infiltrates are the presenting feature of Sweet syndrome with myelodysplasia. OBSERVATIONS: We present 9 male adult patients with chronic Sweet syndrome, all with recurrent eruptions of erythematous and annular plaques that were associated with relapsing polychondritis in 4 of the 9 patients. Results from sequential biopsies showed that infiltrates were initially composed of lymphocytes and that neutrophilic dermal infiltration typical of Sweet syndrome occurred 24 to 96 months later, except in 2 cases. Moreover, atypical mononuclear cells were present on all initial biopsy specimens and strongly reacted to CD68 and myeloperoxidase, indicating a myeloid origin. Myelodysplastic syndrome occurred in all 9 patients, concomitantly with the neutrophilic infiltrate in 4 cases. CONCLUSIONS: Lymphocytic infiltrates with a clinical aspect of Sweet syndrome might represent the initial stage of a cutaneous dysgranulopoiesis syndrome and should lead to the research of atypical myeloid cells in skin infiltrate, blood, and bone marrow for the early detection of an associated myelodysplastic syndrome.     

Sweet's syndrome in acute myelogenous leukemia presenting as periorbital cellulitis with an infiltrate of leukemic cells

Sweet's syndrome is characterized by the abrupt onset of fever, neutrophilic leukocytosis, and erythematous, tender pseudovesiculated plaques or nodules that respond readily to corticosteroid therapy. It is usually distinguished by the presence of mature neutrophils on histopathologic examination. We describe a 38-year-old man with acute myelogenous leukemia who had an erythematous vesicular eruption of the left eye develop that resembled cellulitis. A biopsy specimen revealed a dermal infiltrate of mature neutrophils and immature myeloblastic precursors. He later had hemorrhagic pseudovesiculated plaques develop bilaterally on his hands. A biopsy specimen again revealed abundant neutrophils with immature forms. A similar eruption developed at the site of a Hickman catheter placement 4 months later. His skin lesions responded rapidly to oral corticosteroids. This case is unique in that his initial presentation of Sweet's syndrome resembled orbital cellulitis that was characterized by immature myeloid precursors on histopathology.     

Subcutaneous histiocytoid Sweet's syndrome in a patient with myelodysplastic syndrome and acute myeloblastic leukemia

Subcutaneous histiocytoid Sweet's syndrome is a rare variant of histiocytoid Sweet's syndrome (SS). We present a 68‐year‐old woman with subcutaneous histiocytoid SS in association with refractory myelodysplastic syndrome transformed to acute myeloblastic leukemia (AML), status post induction chemotherapy and with persistent blasts (50%) in the bone marrow and blood, accompanied with neutropenia. The patient presented to the emergency room with fever and altered mental status. Clinical examination revealed approximately 20 scattered 0.5–2 cm, pink to pink‐purple non‐tender firm nodules on the legs and left arm. The differential diagnosis included Sweet's syndrome (deep), leukemia cutis, infection, polyarteritis nodosa and erythema nodosum. Histopathologic examination of a biopsy from the left arm revealed a nodular infiltrate of neutrophils and histiocytoid mononuclear cells solely in the lobular compartment of the subcutaneous fat with focal areas of necrosis. Most cells in the infiltrate labeled with myeloperoxidase (MPO) including the histiocytoid cells. The cells were negative for CD34 and CD117. All special stains for microorganisms were negative. A diagnosis of subcutaneous histiocytoid SS was made. A subcutaneous histiocytoid SS should be suspected when a neutrophilic/histiocytoid panniculitis, occurring in the setting of myeloid disorders, is encountered and after exclusion of an infectious process and leukemia cutis.     

An interesting case of pyoderma gangrenosum with immature hystiocytoid neutrophils

We present a unique case of a 36‐year‐old male who developed more than 20 pyoderma gangrenosum (PG) ulcers showing on histopathology a dense inflammatory infiltrate composed of histiocytoid mononuclear immature cells with a strong positivity for myeloperoxidase and Leder stain, suggesting a myeloid lineage in the absence of a concomitant myeloproliferative disorder. Histiocytoid Sweet syndrome (SS) is now recognized as a histological subtype of SS. Although PG and SS belong to the spectrum of neutrophilic diseases, to the best of our knowledge, this is the first case of a “Histiocytoid pyoderma gangrenosum” encompassing immature granulocytes in the absence of leukemia cutis.     

Leukemic cells within skin lesions of psoriasis in a patient with acute myelogenous leukemia

We report on an 81-year-old man with acute myelo-monocytic leukemia (FAB M4) and a long-standing history of psoriasis. Biopsy of psoriatic plaques revealed the coexistence of characteristic histopathologic aspects of psoriasis together with an infiltrate of blasts with features of myelo-monocytes, suggestive of a specific leukemic infiltrate within plaques of psoriasis. Immunohistologic stainings showed positivity of blasts for LN2 (CD74), MT1 (CD43), and lysozyme, consistent with a myeloid lineage of these cells. To the best of our knowledge, this is the first report on the association of psoriasis with myelogenous leukemia. The presence of leukemic cells within psoriatic skin plaques may be explained by non-specific recruitment of recirculating malignant cells to the skin. Alternatively, as psoriasis is an inflammatory disease involving granulocytes among other cell types, it may be hypothesized that leukemic cells retain to some extent their capability to respond to physiologic stimuli and enter the skin in response to specific chemotactic factors.     

Histiocytoid neutrophilic dermatoses and panniculitides: variations on a theme

Requena et al, in their article titled "Histiocytoid Sweet syndrome," in 2005, established that the dermal infiltrate in some patients with Sweet's syndrome is composed of histiocyte-like immature myeloid cells, not polymorphonuclear leukocytes as is the norm. With this premise in mind, we report on 6 cases of inflammatory skin disease in which the common denominator was a dermal and/or subcutaneous infiltrate of histiocytoid myeloid cells in patients with new-onset cutaneous eruptions and systemic symptoms. The cases were diverse clinically and microscopically, fell short of the criteria necessary for a diagnosis of classical Sweet's syndrome, and were difficult to categorize at the outset. The systemic manifestations ranged from malaise alone to a combination of fever, chills, night sweats, and polyarthralgia. The clinical morphology of the cutaneous eruptions varied from being papulovesicular in 1 patient to mainly consisting of erythematous plaques and nodules in the remainder. The dermatologists' differential diagnoses included Sweet's syndrome in 3 cases, a drug eruption in 2, and other entities such as erythema nodosum and Well's syndrome. Biopsies in all cases revealed a dermal and/or subcutaneous infiltrate composed predominantly of mononuclear histiocytoid cells of myeloid origin. With the benefit of detailed clinicopathologic correlation, the cases were classified for the purpose of this report as follows: Sweet's-like neutrophilic dermatosis, histiocytoid (3 cases); subcutaneous Sweet's syndrome, histiocytoid (2 cases); histiocytoid neutrophilic dermatosis, unspecified (1 case). In addition, we describe a further instructive case that exhibited overlap with those in the series but proved ultimately to represent leukemia cutis. The spectrum of observations in this report supports and expands the original concept of histiocytoid Sweet's syndrome.     

Tumor‐forming plasmacytoid dendritic cells associated with myeloid neoplasms. Report of a peculiar case with histopathologic features masquerading as lupus erythematosus

Plasmacytoid dendritic cells (PDC) belong to a subtype of dendritic cells that are normally absent in healthy skin. In some inflammatory diseases of the skin, especially lupus erythematosus (LE), these cells are occasionally recruited in great amounts, which can be used as a helpful clue for diagnosis. Rarely, PDC may also accumulate in the skin of patients with myeloid leukemia, a yet poorly known condition currently called ‘tumor‐forming PDC associated with myeloid neoplasms’. In this study, we describe a patient with unsuspected chronic myelomonocytic leukemia who developed cutaneous lesions characterized by a dermal infiltrate rich in PDC. Similarly to LE, such neoplastic PDC were accompanied by interface dermatitis‐like changes, but displayed an aberrant phenotype and shared the same chromosomal abnormality with the leukemic cells identified in the bone marrow, thus revealing the neoplastic nature of the process. This observation illustrates that tumor‐forming PDC associated with myeloid neoplasms may microscopically mimic LE in some patients. Accordingly, a hematologic workup is recommended in any skin lesion featuring excessive numbers of PDC, even if morphological alterations suggestive of interface dermatitis are found.     

Differentiation syndrome during ivosidenib treatment with immunohistochemistry showing isocitrate dehydrogenase R132H mutation

We report a case of differentiation syndrome in a patient receiving the IDH1 inhibitor ivosidenib, with skin biopsy showing isocitrate dehydrogenase (IDH) R132H-mutated leukemia cutis. A 72-year-old man with IDH1-mutated acute myeloid leukemia (AML), status-post allogeneic cell transplantation, on ivosidenib for 6 months, was admitted for culture-negative neutropenic fever, pink and purpuric plaques and patches on the legs, abdomen and back, edema, hypotension, and shortness of breath. Skin biopsy revealed an infiltrate of atypical, immature, myeloperoxidase-positive mononuclear cells compatible with leukemia cutis or Sweet syndrome. Although dermal edema and interstitial neutrophilic infiltrate with karyorrhexis characteristic of Sweet syndrome were not seen, the atypical cells lacked expression of CD117 and CD34, which were expressed in the original leukemia. Additional immunohistochemical staining of suspected blasts was strongly positive for IDH1 R132H, suggesting a diagnosis of leukemia cutis. As the immunophenotype of blasts in skin infiltrates can significantly differ from the immunophenotype seen in blood and bone marrow, this case shows that mutation-specific antibodies such as anti-IDH1 R132H may be useful to help distinguish malignant from non-malignant infiltrates in the skin. Furthermore, differentiation syndrome may show histopathologic features of leukemia cutis on skin biopsy.     

Myeloid leukemia cutis in the setting of myelodysplastic syndrome: a crucial dermatological diagnosis

Cutaneous involvement by myeloid leukemic cells is an unusual phenomenon. Clinical manifestations vary from erythematous papules to plum-colored plaques and nodules that may become purpuric and ulcerate. The definitive diagnosis of myeloid leukemia cutis requires the analysis of biopsy specimens using immunohistochemical staining to determine the expression of selective cell surface markers. We will review myeloid leukemia when first evident in the skin, particularly in the setting of myelodysplastic syndrome. The diagnosis of leukemia cutis in patients with myelodysplastic syndrome is indicative of concomitant or impending acute leukemic transformation. The early recognition and accurate identification of leukemic skin infiltrates in myelodysplastic patients is crucial, as this finding can have significant therapeutic and prognostic implications.     

Sweet's syndrome without granulocytosis

Background Sweet's syndrome (SS), acute febrile neutrophilic dermatosis, has been linked to hematologic malignancies and presents with characteristic edematous dermal plaques. Peripheral blood neutrophilia is frequently seen in association with SS and is one of the diagnostic criteria.
Objective To report the clinical, laboratory, and hematologic data of four patients with myeloid leukemia who developed SS after chemotherapy. Three of these patients were neutropenic.
Methods A retrospective study of four patients with SS and hematologic malignancies was undertaken. Three patients had de novo acute myelogenous leukemia and one was in the acute blast crisis of chronic myelogenous leukemia.
Results Sweet's syndrome was not originally suspected in these patients because of the low peripheral white blood cell counts caused by chemotherapy. All of the patients presented with fevers, arthralgias, and an eruption. They had been treated with antibiotics because of a presumed infection. Once the correct diagnosis was made and oral prednisolone was started, a rapid response followed.
Conclusions Sweet's syndrome should be considered in the differential diagnosis when acute myeloid leukemic patients develop skin lesions and unexplained fevers regardless of the peripheral blood counts.     

Primary cutaneous T cell lymphomas: photochemotherapy immunomodulation with analysis of the inflammatory‐expansive cellular dynamic

Primary cutaneous T cell lymphomas (CTCLs) are characterized by hyperproliferation of malignant CD4+ T cells with primary localization on the skin. The common characteristics are the migration of the malignant mature T‐lymphocytes into the epidermis, with hyperproliferation of malignant CD4+ T cells and epidermotropism. Sézary syndrome (SS) is the leukemic variant. It was established that CTCLs arise from a clonal expansion of CD4+ T cells with an identical rearrangement of the T cell receptor. The purpose of this study was to evaluate the immunomodulation effect of photochemotherapy‐A (psoralen plus ultraviolet A (PUVA)). Pre‐ and post‐PUVA punch skin biopsies of nine patients were stained immunohistochemically for CD34+, CD8+, CD7+, CD16+, CD56+, CD1a+, Bcl2+, p53+, CD45RA+, and CD45RO+ cells. The results showed a pre‐PUVA cells/mm² without significant difference among expansive or reactive cells. Post‐PUVA analysis showed a significant decrease in the mean of expansive‐reactive cells. PUVA immunomodulated decreasing cellular infiltrate. These findings could contribute to the comprehension of how PUVA acts. We achieved ectoscopic clearance of the lesions, although post‐PUVA, there still was a mononuclear pathological infiltrate. This result demonstrates that the PUVA treatment should only be withheld when the histological analysis is normal.     

Bullous pyoderma gangrenosum as a manifestation of leukemia cutis

The authors present the case of a 67-year-old patient in whom bullous pyoderma gangrenosum was the first symptom of acute myeloid leukemia. Histologically leukemic cells were found in the skin infiltrate, on the basis of which this lesion satisfied the criteria of leukemia cutis. It was underlined that in the background of such atypical bullous cases there are often hemoblastoses or their malignant transformation. Finally the connection between bullous pyoderma gangrenosum and atypical vesiculous Sweet syndrome is discussed.     

Atypical cutaneous myeloid infiltrate in myelodysplastic syndrome: a case report

We report the case of a 31-year-old man with an atypical myeloid dermal infiltrate manifested by a 1.5-year history of recurrent erythematous plaques over his body that previously were shown to be culture positive for Staphylococcus aureus and had responded well to oral antibiotic treatment. The ultimate diagnosis was refractory anemia with excess blasts-2 (RAEB-2), a myelodysplastic syndrome (MDS). Whether it is a specific or nonspecific lesion, cutaneous involvement in MDS is a poor prognostic factor. Leukemia cutis (LC), a specific dermal infiltrate of malignant hematopoietic cells, particularly is associated with progression to acute leukemia. However, the pathology of our patient's lesions revealed a more sparse sprinkling of atypical mononuclear cells indicative of an inflammatory recruitment of leukemic cells to the dermis. Nonetheless, the guarded prognosis of this high-risk subtype of MDS mandates continued monitoring for development of LC and progression to leukemia.     

Neutrophilic dermatoses as systemic diseases

Neutrophilic dermatoses (ND) are inflammatory skin conditions characterized by a sterile infiltrate of normal polymorphonuclear leukocytes. The main clinical forms of ND include Sweet syndrome, pyoderma gangrenosum, erythema elevatum diutinum, subcorneal pustular dermatosis, and their atypical or transitional forms. ND are often idiopathic, but they may be associated with myeloid hematologic malignancies (Sweet syndrome), inflammatory bowel disease or rheumatoid arthritis (pyoderma gangrenosum), and monoclonal gammopathies (erythema elevatum diutinum, subcorneal pustular dermatosis). The possible infiltration of internal organs with neutrophils during the setting of ND underlies the concept of a neutrophilic systemic disease. ND may be seen as a polygenic autoinflammatory syndrome due to their frequent association with other autoinflammatory disorders (monogenic or polygenic) and the recent published efficacy of interleukin-1 blocking therapies in their management.     

Subacute myelomonocytic leukemia--an unusual skin manifestation

This case report concerns a 44-year-old woman with subacute myelomonocytic leukemia who developed an unusual bullous lesion on her leg. Initially treated as a bacterial ecthyma, this lesion proved to be a specific leukemic infiltrate. We will briefly review myelomonocytic leukemia and the skin findings of the myeloid leukemias.     

Cutaneous pustular leukemoid reactions in trisomy 21

We report two neonates with Down syndrome and postnatal leukemoid reactions who developed acute widespread pustular eruptions. The white blood cell (WBC) counts on the first day of life were markedly elevated, with blasts seen on examination of the peripheral blood smear. The skin eruptions progressed and became pustular. Viral and bacterial cultures were negative. Skin examination revealed pustules on an erythematous base on the cheeks, shoulders, trunk, and proximal extremities. Skin biopsy specimens showed an intraepidermal pustule with an inflammatory infiltrate including neutrophils, eosinophils, and mononuclear cells. The mononuclear cells had atypical, immature-appearing nuclei. In patient 1, these cells were strongly myeloperoxidase positive on immunohistochemistry, indicating myeloid lineage. In patient 2, these cells were CD3-positive T cells. Patient 1 received a 5-day infusion of continuous cytarabine (ara-C) secondary to high WBC counts and symptomatic hyperviscosity. During therapy, the high WBC count and the pustules resolved. The lesions of patient 2 improved with topical mometasone furoate and resolved as her WBC count decreased. Recently, similar cases have been reported. Transient myeloproliferative disorders, or leukemoid reactions, should always be considered when newborns with Down syndrome or trisomy 21 mosaicism develop a pustular eruption.     

Histiocytoid Sweet syndrome: a dermal infiltration of immature neutrophilic granulocytes

OBJECTIVE: To describe a series of 41 patients with fresh lesions of Sweet syndrome in which the histopathologic study demonstrated an inflammatory infiltrate mostly composed of histiocytoid mononuclear cells. DESIGN: Histopathologic, immunohistochemical, and cytogenetic studies of the inflammatory infiltrate in a case series of histiocytoid Sweet syndrome. SETTING: University departments of dermatology and a private laboratory of dermatopathology. METHODS: Conventional histopathologic study as well as immunohistochemical investigations were performed using the alkaline phosphatase antialkaline phosphatase technique with a large panel of antibodies. In some cases, fluorescent in situ hybridization studies were performed to investigate the presence of the bcr/abl gene fusion. RESULTS: Immunohistochemical studies demonstrated that most cells of the infiltrate showed immunoreactivity for CD15, CD43, CD45, CD68, MAC-386, HAM56, and lysozyme, which is consistent with a monocytic-histiocytic immunoprofile. However, intense myeloperoxidase reactivity was detected in most of the cells with histiocytic appearance, which raised the possibility of specific cutaneous involvement by myelogenous leukemia. Nevertheless, cytologic peripheral blood examinations, fluorescent in situ hybridization studies to investigate the bcr/abl gene fusion, and follow-up of the patients, taken all together, ruled out this possibility. CONCLUSIONS: This case series demonstrates that some fresh cutaneous lesions of Sweet syndrome are histopathologically characterized by an infiltrate mostly composed of cells that may be misinterpreted as histiocytes, when in fact they are immature myeloid cells. We named this histopathologic variant histiocytoid Sweet syndrome, which should not be mistaken with leukemia cutis or other inflammatory dermatoses that are histopathologically characterized by histiocytes interstitially arranged between collagen bundles of the dermis.