Abstract
Sweet’s syndrome (SS) is a rare condition characterized by the abrupt appearance of painful skin lesions due to neutrophilic dermal infiltration. Hematologic neoplasms, particularly acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs), have been commonly reported in association with SS. Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging entity that is a precursor state to myeloid neoplasms. CHIP has not been previously associated with SS.
We report the case of a 71-year-old man who presented with recurrent, painful edematous and erythematous papules and nodules for 18 months despite treatment with corticosteroids. He had normal blood counts, but a macrocytosis was noted (110 fl). Alternative causes of macrocytosis were ruled out. A skin biopsy confirmed a diagnosis of SS. Bone marrow biopsy specimen yielded a normal karyotype except for loss of the Y chromosome and equivocal morphologic findings. Polymerase chain reaction (PCR) and reverse transcription polymerase chain reaction (RT-PCR) of selected genes from the peripheral blood demonstrated a mixed lineage leukemia (MLL) partial tandem duplication (PTD) and sequence variant in CCAAT/enhancer binding protein alpha (CEBPA). These findings were consistent with a diagnosis of CHIP. The patient was treated with 5-azacitidine and achieved a complete remission of his skin lesions and was able to discontinue corticosteroids.
To our knowledge, this is the first report of a patient with recurrent SS associated with CHIP. In addition to other myeloid neoplasms like AML and MDS, CHIP should be considered as a potential etiology in cases of recurrent SS. Treatment with a hypomethylating agents such as azacitidine could also serve as an alternative to systemic corticosteroid therapy.
Keywords
Introduction
Sweet’s syndrome (SS) is a neutrophilic dermatosis characterized by the abrupt appearance of edematous and erythematous papules, plaques, or nodules on the skin often with fever, leukocytosis, or internal organ involvement [Sweet, 1964]. Approximately 21% of patients newly diagnosed with SS were previously or subsequently diagnosed with either a hematologic (15%) or solid cancer (6%) [Cohen and Kurzrock, 1993; Raza et al. 2013]. Of all cases of malignancy-associated SS, 85% occurs in patients with hematologic neoplasms, particularly myelodysplastic syndromes (MDS) [Kulasekararaj et al. 2015]. Cases of patients who do not meet diagnostic criteria for MDS include those who lack MDS-defining dysplasia, cytopenia, blast increase, or karyotype changes, and who have nonspecific hematologic abnormalities such as persistent eosinophilia or macrocytosis, presenting a diagnostic challenge. Over 30% of patients who fail to meet diagnostic criteria for MDS will carry a somatic mutation indicative of clonal hematopoiesis detected by next-generation sequencing [Kuznia et al. 2013; Kwok et al. 2015; Steensma et al. 2015]. This allows the potential to identify individuals with clonal hematopoiesis of indeterminate potential (CHIP) who are at greater risk of progression to overt myeloid neoplasms even in the absence of morphologic disease [Kwok et al. 2015; Steensma et al. 2015]. The term CHIP is a purposed term, which has not been accepted by WHO. It describes individuals with a hematologic malignancy-associated somatic mutation in blood or marrow, but without other diagnostic criteria for a hematologic malignancy [Steensma et al. 2015]. Since lower-risk and higher-risk MDS cases associated with SS may respond to hypomethylating agents such as 5-azacitidine and decitabine [Garcia-Manero, 2008], the diagnosis of individuals with SS and underlying CHIP may improve treatment and outcomes.
Report of a case
A 71-year-old man presented with an 18-month history of recurrent, painful, erythematous papules, plaques, and nodules that started after recent hip surgery. The lesions initially appeared on his trunk, then spread to his face and extremities (Figure 1). His medical history was otherwise unremarkable, and he was not taking any antibiotics, nonsteroidal anti-inflammatory or other medications that could be the cause for his rash. There was no fever, leukocytosis, or lymphadenopathy. There was a concern for allergic reaction to metal implants since the rash followed bilateral hip replacement, so he underwent replacement with ceramic implants. The rash persisted despite the second surgery. The rash responded to systemic glucocorticoids but relapsed shortly after the discontinuation of each prednisone burst. Skin biopsies from the left upper back and left flank revealed a dense dermal infiltration of neutrophils with rare eosinophils on hematoxylin–eosin staining consistent with SS. The gram stain, bacterial, and fungal cultures on skin biopsies were all negative, and no molecular or cytogenetic studies were conducted on the biopsy. Because SS is associated with malignancy, further diagnostic workup was performed. His complete blood count revealed macrocytosis with a mean corpuscular volume (MCV) of 110 fl (reference range, 80–97 fl), mild hypereosinophilia with peripheral absolute cell count of 1180/μl (reference range, 50–700/μl), but no cytopenias (hemoglobin 15.1 g/dl, ANC 2200/μl, platelets 152,000/μl). Thyroid, serum B12, copper, red blood cell folate, and serum tryptase were normal. An autoimmune workup was unremarkable, as well as the extensive infection workup including fungal, bacterial blood cultures, and serologic testing for human immunodeficiency virus (HIV) and hepatitis A, B, and C, which were all negative. Serum viral PCR for cytomegalovirus and Epstein–Barr virus was also unremarkable. The patient had no respiratory or gastroenterology infection symptoms or risk factors for parasitic infection that could cause the rash and the hypereosinophilia. Flow cytometry showed no evidence of paroxysmal nocturnal hemoglobinuria. Computed tomography of the chest, abdomen, and pelvis showed no pathologic findings. Bone marrow biopsy analysis revealed mild hypercellular marrow with 50% cellularity and trilineage hematopoiesis, no increase in blasts, and mild dyserythropoiesis. Cytogenetic tests showed loss of chromosome Y in 18 out of 20 cells, a known finding in elderly males and without clinical significance [Stone and Sandberg, 1995]. Fluorescence in situ hybridization (FISH) analysis utilizing probes specific for aberrations commonly associated with MDS/eosinophilia (5q15.31, 7q22, +8cen, 9q34, 20q12, [PDGFR-alpha (4q12) and PDGFR-Beta (5q32)], t(9;22)) were normal. JAK2 V617F, calreticulin mutation analysis, and T-cell receptor rearrangement assays were negative. A second bone marrow biopsy and opinion were obtained at Washington University in St Louis with the same results.
Rash before treatment with Vidaza.
Since the patient’s rash was initially responsive to bursts of steroid treatment, but later recurred and became refractory to the steroid treatment, the patient was started on methotrexate therapy. He was treated with weekly methotrexate (10 mg/m2) but again showed no improvement. Since targeted gene sequencing can identify somatic events in the majority of MDS patients, including many with normal karyotypes, PCR sequencing of exonic hotspots in 11 genes (NPM1, IDH1, IDH2, ASXL1, PHF6, TET2, DNMT3A, KIT, FLT3 TKD, FLT-3 ITD, CEBPA) and RT-PCR for mixed lineage leukemia partial tandem duplication (MLL-PTD) transcript from peripheral blood were performed (Genoptix, Carlsbad, CA, USA). A synonymous variant and polymorphism in CCAAT/enhancer binding protein alpha (CEBPA) was detected (c.690G > T, p.T230T) which is a benign and nonsignificant polymorphism. However, an MLL-PTD was detected, providing a diagnosis of CHIP-associated SS. Given this new diagnosis of CHIP and the prior lack of response to methotrexate, he was started on treatment with 5-azacytidine (75 mg/m2 for 7 days of a 28-day cycle) for six cycles [Garcia-Manero, 2008; Martinelli et al. 2014]. Within 6 weeks of his first cycle, all lesions resolved (Figure 2), and his steroid requirement decreased from 590 mg/month for the past 6 months, to none. His eosinophilia improved to 700/μl, and his macrocytosis also normalized (MCV 97 fl). However, the MLL-PTD clonal abnormalities test and FISH studies for –Y could not be repeated after his improvement due to insurance coverage issues. As he achieved a complete remission, 5-azacytidine was discontinued after completion of six cycles, and he remains in remission for 8 months on last follow up, 2 months ago, off treatment. His complete blood count, MCV, and peripheral blood manual differential has remained within normal limits, which implied no progression to MDS. However, the patient refused to have repeated bone marrow biopsy with molecular studies as a follow up for disease progression, and repeated peripheral blood molecular studies could not be conducted.
After treatment with Vidaza.
Discussion
SS (acute febrile neutrophilic dermatosis) is a rare condition characterized by painful skin lesions due to neutrophilic dermal infiltration [Sweet, 1964]. It has been observed in association with a broad range of disorders. In 2007, Cohen divided SS into three types: classical (or idiopathic), malignancy associated, and drug induced [Cohen, 2007]. Malignancy-associated Sweet’s syndrome (MASS) occurs as a paraneoplastic syndrome in patients with cancer and may be the presenting symptom of an undiscovered visceral or hematologic neoplasm [Cohen, 2007]. MASS accounts for 21% of SS cases [Cohen and Kurzrock, 1993; Raza et al. 2013] and is more likely to occur in association with hematologic malignancies than solid tumors [Raza et al. 2013], [i.e. acute myeloid leukemia (AML) and MDS]. While MASS may respond to treatment of the underlying cancer, the frequency of occurrence is unknown.
MDSs are clonal stem cell disorders that manifest with cytopenias, dysplastic morphology of blood and marrow cells, and clonal hematopoiesis [Swerdlow et al. 2008]. The emerging developments in MDS molecular biology warranted reconsideration of the MDS definition. It has come into question whether patients with hematologic abnormalities that do not meet MDS criteria (i.e. unexplained persistent eosinophilia or macrocytosis), but who present with MDS-associated somatic mutations, like our patient, should be diagnosed with MDS [Kuznia et al. 2013; Cargo et al. 2015; Steensma et al. 2015]. It has been reported that more than one mutation typical for MDS could be found in ~50% of patients with suspected MDS who did not meet morphologic diagnostic criteria [Kuznia et al. 2013; Cargo et al. 2015; Kwok et al. 2015]. Moreover, targeted gene sequencing can identify somatic events in over 80% of MDS patients, including many with normal karyotypes or more indolent disease, and can conclusively establish the presence of clonal hematopoiesis [Kwok et al. 2015]. Cargo and colleagues identified distinguishing features between those with early MDS and reported healthy individuals [Cargo et al. 2015]. The mutations detected had significantly greater median variant allele fraction and occurred more commonly with two or more mutations. Therefore, acquisition of somatic mutations that drive clonal expansion in the absence of cytopenias and dysplastic hematopoiesis has been described as a CHIP. Steensma and colleagues distinguished CHIP from MDS with the presence of a somatic mutation associated with hematological neoplasia at a variant allele frequency of at least 2%, in the absence of definitive morphological evidence of a hematological neoplasm [Steensma et al. 2015]. Mutational analysis can potentially predict those patients at high risk of disease progression and who may suffer from a paraneoplastic phenomenon, such as SS. Jo and colleagues reported the finding of MEFV mutations in two Japanese patients with high-risk MDS and SS [Jo et al. 2015]. As mentioned, CHIP is a premalignant disease that is diagnosed by detecting the somatic mutation in blood or marrow, but without other diagnostic criteria for a hematologic malignancy, so following up on morphologic, cytogenetic and molecular changes on repeated bone marrow, and blood is warranted to monitor the progression to MDS [Garcia-Manero, 2008; Kuznia et al. 2013; Cargo et al. 2015]. However, the interval and the frequency of the monitoring studies need to be established. In our case, the patient had associated clinical manifestation, in addition to the nonspecific hematologic abnormality such as macrocytosis and eosinophilia that were useful for monitoring remission and progression of the disease. However, repeated bone marrow and blood molecular studies should have been considered, but were challenging in this case.
We describe for the first time a patient with recurrent SS associated with CHIP. While CHIP-associated SS presents a diagnostic challenge, it may respond to treatment with hypomethylating agents as our patient did [Garcia-Manero, 2008]. The use of hypomethylating agents, azacitidine and decitabine, has been the standard of care for treating MDS [Fenaux et al. 2009]. Azacitidine is a pyrimidine analogue of cytidine. Overall, it is a well tolerated drug in patients with MDS; cytopenias, nausea, vomiting, and diarrhea are the most common adverse effects [Keating, 2012]. There is clear precedence for SS associated with MDS responding to hypomethylating agents in the literature. Martinelli and colleagues describe the first case of clinical remission of refractory SS following hypomethylating therapy with azacitidine in a patient with MDS who concurrently obtained a complete hematologic response [Martinelli et al. 2014]. In both cases reported by Jo and colleagues, the SS also responded to hypomethylating agents [Jo et al. 2015]. It is also noteworthy that cases of drug-induced SS have been reported in the literature that occurred in response to the use of azacitidine for the treatment of MDS and leukemia [Tintle et al. 2011; Trickett et al. 2012; Bonazza et al. 2015]. It has been reported that MLL-PTD is associated with increased global DNA methylation, which might explain the patient response to a hypomethylating agent [Whitman et al. 2008; Kao et al. 2015]. However, in our case, we did not test the methylation status of bone marrow cells before and after therapy, and it may not be universal for all CHIP cases.
Conclusion
Chronic, recurrent SS can be associated with myeloid disorders, potentially including CHIP. Patients with unexplained SS should be further screened for underlying myeloid neoplasia through extensive genomic interrogation. Though this represents a single case, CHIP-associated SS may be responsive to hypomethylating agents. Hypomethylating agents could be considered an appropriate therapy for SS cases associated with CHIP in patients with symptoms that are refractory to standard therapy.
Clinical Practice Points
SS is a rare condition and it has been commonly reported in association with hematologic neoplasms, particularly AML and MDS. However, CHIP is an emerging entity that is a precursor state to myeloid neoplasms and has not been previously reported in association with SS.
We describe, to our knowledge, the first reported case of a patient with recurrent SS associated with CHIP who was treated with 5-azacitidine and achieved a complete remission of his skin lesions and was able to discontinue corticosteroids.
In addition to other myeloid neoplasms like AML and MDS, CHIP should be considered a potential etiology in cases of recurrent SS and treatment with a hypomethylating agent such as azacitidine could also serve as an alternative to systemic corticosteroid therapy.
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors declare that there is no conflict of interest.