An atypical presentation of Sweet’s syndrome in a myelofibrosis patient

Abstract

A 46-year-old man with no significant medical history presented to haematology with symptoms of fatigue, dyspnoea on exertion and weight loss. Physical examination revealed a lesion on the right shin and splenomegaly. Labs were significant for leucocytosis with immature components, thrombocytosis and 3% peripheral blasts on smear. A bone marrow biopsy confirmed a diagnosis of myelofibrosis (MF). Dynamic International Prognosis Scoring system was 2. He was started on ruxolitnib, with decitabine added subsequently prior to definitive therapy with an allogenic haematopoietic stem cell transplant. His course with decitabine was complicated with febrile neutropaenia with multiple tender erythematous plaques unresponsive to antibacterial and antifungal coverage. A skin biopsy showed neutrophilic dermatitis, consistent with a diagnosis of Sweet’s syndrome (SS) and empirical treatment with glucocorticoids was initiated resulting in resolution of symptoms. This report reviews the literature for cases of SS in the setting of MF.

Background

Sweet’s syndrome (SS), also known as acute febrile neutrophilic dermatosis, is a rare dermatological condition characterised by tender erythematous skin lesions (papules, nodules and plaques), often associated with fever and leucocytosis. Skin biopsies typically show a diffuse infiltrate consisting predominantly of mature neutrophils that are typically located in the upper dermis and are divided into three subtypes: classical, malignancy-associated and drug-induced. SS has been observed in a broad range of diseases. Malignancy-associated SS is more often associated with haematological rather than solid malignancies. Studies have shown that malignancy-associated SS is more likely to present in association with older age, anaemia, thrombocytopaenia and lack of arthralgias. This case demonstrates an unusual course of SS in the setting of myelofibrosis (MF) with neutropaenia after exposure to decitabine and ruxolitnib. We also reviewed the literature for a handful of cases of SS in MF.

Case presentation

Our patient is previously a healthy 46-year-old man who presented with persistent leucocytosis for 2 months in addition to a right shin lesion. He had been followed by infectious disease and treated with two courses of antibiotics for presumed right lower extremity cellulitis. On presentation to haematology, he reported progressive fatigue, dyspnoea on minimal exertion, feeling constipated and a 25-pound unintentional weight loss in the last 1 year. Family history was notable for a maternal uncle with head and neck cancer, another maternal uncle with GI malignancy and a maternal aunt with myeloid leukaemia. Review of the patient’s blood work 3 years prior to this presentation showed mild thrombocytosis with a platelet count of 510 000. Physical exam elucidated significant splenomegaly extending below the umbilicus and a residual 4 cm fleshy lesion on the right lower shin. The extent of splenomegaly was further quantified with an abdominal ultrasound and measured 31 cm in the longest dimension (figure 1). Laboratory testing with a complete blood count was notable for leucocytosis of 27 000 with immature left-shifted components: 28% metamyelocytes, 5% myelocytes with absolute basophilia, 3% blasts on the differential with platelets of 380 000 and a haemoglobin of 101 g/L. Peripheral smear showed tear drops with a leucoerythroblastic picture (figure 2). Peripheral blood testing with PCR for the BCR-ABL translocation was negative. Accordingly, a bone marrow biopsy was performed and showed extensive MF and 2% blasts with normal cytogenetics, 46 X, Y (figures 3 and 4). Genomic profiling with next-generation sequencing using Genoptix services with a 44-gene myeloid molecular panel uncovered CALR E383fs*48 (type 2 like), ASXL1 A619fs*16, KRAS 416T, CCND2 (Y261*), ETV6, SOCS2 and a subclone of NRAS mutations, JAK2, MPL, BCR-ABL negative. Dynamic International Prognostic Scoring System (DIPSS) score was calculated to be intermediate-2 risk with three points owing to the degree of leucocytosis and circulating blasts.

Figure 1.

Massive splenomegaly measuring 31.6 cm on ultrasound.

Figure 2.

The presence of teardrop red blood cells (RBCs) and a leucoerythroblastic picture with the presence of nucleated RBC precursors and immature myeloid cells (×400).

Figure 3.

Bone marrow biopsy showing hypocellularity and reticulin fibrosis. (A) H&E, 40× and (B) H& E, 100×.

Figure 4.

Bone marrow biopsy showing (A) fibrosis confirmed by trichrome stain, 40× and (B) CD34 antibody identified by immunohistochemistry.

The patient was started on ruxolitnib 20 mg twice daily for splenomegaly-associated symptoms such as early satiety and abdominal pain and tolerated therapy well with improvement in his fatigue and abdominal discomfort and without any worsening cytopaenias. Ultimately, allogeneic haematopoietic stem cell transplant (Allo-SCT) was recommended for his high-risk disease based on the intermediate-2 risk per DIPSS criteria with an unfavourable molecular profile due to the presence of an ASXL1 mutation. A haplo-identical related donor was identified, and the patient was slated for transplant 3 months after the initiation of ruxolitnib. Unfortunately, plans for transplant were put on hold after a repeat abdominal ultrasound showed persistent splenomegaly of 32 cm. The transplant service was concerned about the increased risk of transplant-related mortality and poor outcomes in patients with splenomegaly. That said, the data is controversial and delaying Allo-SCT to address splenomegaly is not the standard. A repeat bone marrow biopsy showed markedly hypocellular marrow with marked collagen fibrosis and 1% blasts.

Alternative therapies for his high-risk MF were entertained; however, Allo-SCT was thought to offer the patient the best chance for long-term survival. The elevated blast count in addition to the unfavourable molecular profile were concerning for myeloid metaplasia for which decitabine was recommended as an adjunct to ruxolitnib in hopes that this combination could improve his disease status and reduce the spleen size prior to a transplant. This treatment course was favoured by the bone marrow transplant team over upfront Allo-SCT, splenectomy or a trial of a higher dose of ruxolitnib. The first cycle of decitabine was administered over 5 days at a daily dose of 20 mg/m². Progressive cytopaenia with neutropaenia and thrombocytopaenia required dose reduction of ruxolitnib to 20 mg/day. Seven days after completion of decitabine, the patient presented with febrile neutropaenia with a temperature of 38.9°C and multiple tender well-circumscribed erythematous plaques with irregular borders and overlying violaceous nodules located on the left thigh, left groin and umbilical region. The patient was admitted to the hospital for broad-spectrum intravenous antibiotics with vancomycin, piperacillin and tazobactam. The fever persisted for more than 3 days with extension of his skin lesions and without improvement of his symptoms.

Investigations

Infectious workup did not uncover any source on blood cultures, urinalysis, a chest X-ray and a transthoracic echocardiogram. Voriconazole was added for fungal coverage. Dermatology was consulted for a punch biopsy of one of his skin lesions.

Differential diagnosis

• SS: malignancy-associated or drug-induced

• Cutaneous infection or septic emboli

• Urticaria and urticarial vasculitis

• Other neutrophilic dermatoses (pyoderma gangrenosum, Bechet syndrome, cutaneous metastatic Crohn’s disease)

• Progression of his myeloid metaplasia with either extramedullary haematopoiesis or leukaemia cutis

Treatment

Despite broad-spectrum antibiotic and antifungal treatment, the patient continued to spike fever and deterioration in his clinical course. The skin biopsy showed neutrophilic diffuse, nodular dermatitis, consistent with a diagnosis of SS (figure 5).

Figure 5.

Punch biopsy of left anterior thigh showing (A) preserved epidermis and oedematous dermis with predominant neutrophils, (B) intraepidermal vesicle formation filled with neutrophils and (C) nodular and diffuse dermatitis with predominant neutrophils.

Outcome and follow-up

Patient was started on empirical treatment for SS with glucocorticoids, which resulted in rapid resolution of fever, pain and skin lesions, along with an improved sense of well-being. A splenectomy was performed thereafter followed by an Allo-SCT.

Discussion

The pathogenesis of SS is not very well understood. Hypothesised mechanisms include hypersensitivity reactions, cytokine dysregulation and genetic susceptibility. The hypersensitivity reaction theory postulates that an immune reaction to bacterial, viral or tumour antigens lead to a cascade of cytokine release, which ultimately promotes neutrophil activation and infiltration.¹ This hypothesis is further supported by the profound response to treatment with glucocorticoids in addition to addressing the underlying malignancy, which is often haematological.² Another postulated mechanism for altered cytokine and chemokine regulation is thought to be secondary to increased levels of granulocyte colony-stimulating factor (G-CSF), whether drug-induced through exogenous G-CSF or through increased production by tumour cells.³ Two published cases demonstrate another possible association between myelodysplastic syndrome and SS in the presence of mutations in the MEFV gene, a gene associated with familial Mediterranean fever.⁴

We present a case of SS in a patient with MF undergoing treatment. A literature review in PubMed of similar cases including patients with MF and SS resulted in seven similar cases published from 1993 to the present (table 1), which highlights the rarity of this presentation.

Table 1.

Summary of the case reports of published cases of MF and SS

Year published, Reference	Age/ sex	Diagnosis	Splenomegaly	Treatment	Presentation	Mutations	Outcome
Case report	45/M	MF	Y	Ruxolitnib Decitabine	Fever, erythematous skin lesions	CALR ASXL1 CCND2	Improvement with steroids.
2017, Sakoda et al 14	59/M	Post-ET MF	Y	Ruxolitnib	Erythematous plaques, fever	CALR	Improved with steroids. Proceeded with allogeneic HCST.
2015, Chatterjee et al 15	77/F	Post-ET MF	Y	Ruxolitnib	Pustular lesions, hand swelling	Not known	No improvement with steroids and dapsone. Died soon after.
2014, Liu et al 16	54/M	PMF	Y	5-Azacitidine	Violaceous papules/plaques on torso and extremities	JAK2V617F ASXL1	Eruptions after each 5-A cycle were uncontrolled with high-dose steroids, resolved after a change to low-dose SC decitabine.
2008, Che et al 17	70/M	Refractory MF	Y	Splenic irradiation	Fever, erythema with painful nodules, worse after G-CSF	Not known	Worse with G-CSF. Resolution of fever, pain and lesions 3 weeks after initiation of steroids.
1995, Shiga et al 18	61/M	Post-ET MF	Y	Busulfan, splenic irradiation,	Fever, with eruptions on face and upper extremities	Not known	Worse with G-CSF. Rapid resolution of symptoms with oral prednisone 30 mg.
1995, Brodkin and Schwartz19	68/M	Myeloproliferative disorder with MF	N	Hydroxyurea, folate	Solitary, enlarging lesions on dorsum of hand and face	Not known	Initial improvement with steroid. Recurrences treated with triamcinolone, then SC INF-alpha. Despite improvement after treatment, patient had progressive deterioration and eventual death.
1993, Delgado et al 20	69/M	Grade II MF, idiopathic	Y	N/A	Fever, erythematous painful lesions on the scalp, brow, thigh	Not known	Initial resolution with prednisone. Patient later presented with worsening symptoms, given antibiotics and steroids, diagnosed with pyoderma gangrenosum and died soon after.

G-CSF, granulocyte colony-stimulating factor; HCST, hematopoietic stem cell transplant; MF, myelofibrosis; SC, subcutaneous; SS, Sweet’s syndrome

Two of the patients in these cases developed sequelae of SS after treatment with ruxolitnib, a Janus kinase inhibitor approved for the treatment of high-risk MF. Our patient had MF treated with ruxolitnib for over 3 months prior to the development of SS which developed after initiation of decitabine, a hypomethylating agent, and during an episode of neutropaenia. In addition, the patient’s initial presentation with MF was coupled with one similar lesion that was thought to be cellulitis. The lesion was not biopsied and over weeks resulted in an asymptomatic fleshy lesion which in retrospect could have been the initial manifestation of SS in our patient. This first lesion, and the multiple subsequent lesions that developed more than 3 months later on ruxolitnib argue that the pathogenesis of SS in this patient is possibly independent from this therapy. More so, the detection of several somatic mutations such as ASXL1 in this case warrant an investigation into the possibility of an association between these genetic aberrancies and the development of SS in patients with MF. Of note, these myeloid mutations are commonly reported in patients with myelodysplastic syndrome, which has been associated with SS. Our case and other published reports in patients with MF suggest several possible associations including the use of ruxolitnib, hypomethylating agents, neutropaenia and inflammatory milieu, and possibly the genetic makeup; however, these findings need to be further explored before any definitive conclusion.

With the absence of large clinical trials for the treatment of SS recommendations for therapy are primarily based on expert opinion and published cases and series.⁵ The first-line treatment of SS, regardless of subtype, is administration of glucocorticoids. Typically, oral prednisone 0.5–1 mg/kg/day is the starting dose in adults resulting in a near instant resolution of fever and a rapid improvement in skin lesions within 1–2 weeks.⁶ For patients who have a small number of localised lesions, topical or intralesional corticosteroids have also been used successfully, either as monotherapy or concurrently with other therapies.^{7 8}

The prognosis in SS is variable, and some patients achieve complete resolution of symptoms and skin lesions without any treatment (such as in drug-related SS after removal of the offending agent) while other patients’ symptoms persist for weeks to months, few ending in death.^{9 10} The skin lesions in malignancy-associated SS can occur at any time before, during or after the diagnosis of cancer. In malignancy-associated SS, recurrence is more likely to occur, which several studies have proposed may signal a relapse of the malignancy.^{11 12} Likewise, as the lesions can precede a diagnosis of malignancy, SS can be the cutaneous harbinger of a yet to be determined malignancy.¹³

In conclusion, we herein present a case of MF-associated SS. Although rare, the concurrence of SS and MF has been documented in several case reports. Few reports describe SS in the setting of ruxolitnib use while our case introduces other possible suspects including association with somatic mutations or in conjunction with neutropaenia secondary to the use of hypomethylating agents. Observation of cutaneous lesions in MF should raise suspicion for the diagnosis of SS, and prompt treatment should begin to provide remedy and for the amelioration of symptoms. Nevertheless, further studies are needed to better characterise the pathogenesis and prognosis of malignancy-associated SS.

Learning points.

• There should be a high level of suspicion for Sweet ’s syndrome (SS) in presence of haematological malignancies or myelofibrosis (MF).

• The lesions in SS can occur at any time before, during or after an associated diagnosis (MF vs malignancy, etc).

• Several cases have documented the association between ruxolitnib treatment and the development of SS.