Bullous Sweet syndrome as a presentation of chronic myelogenous leukaemia

Abstract

A woman in her 40s presented with a 3-month-long history of fever and tender erythematous bullous skin lesions not responsive to antibiotics. There had been no previous gastrointestinal, respiratory or urinary infection, nor did she have any history of autoimmune disease, drug reaction or vasculitis.

Histological evaluation of skin biopsy showed diffuse dense neutrophilic infiltrates located in dermis diagnostic of Sweet syndrome. Haematological investigations showed leucocytosis with circulating immature cells, which on further investigations with bone marrow biopsy, were evident of chronic myelogenous leukaemia in the accelerated phase. Sweet syndrome was the presenting characteristic of chronic myelogenous leukaemia in this case, which is a rare association. Investigating unusual skin lesions can aid in the suspicion of underlying cancer, allowing for prompt action.

Background

A variety of cutaneous lesions are frequently encountered in clinical practice, which could be secondary to allergic reactions, infections or an underlying systemic illness including malignancy. Some of the most commonly observed paraneoplastic dermatological manifestations include acanthosis nigricans, necrolytic migratory erythema, acrodermatitis paraneoplastica, exfoliative erythroderma, paraneoplastic pemphigus, pyoderma gangrenosum and Sweet syndrome.¹

Sweet syndrome is a neutrophilic dermatosis characterised by a particular constellation of clinical symptoms, signs and histopathological findings: fever, peripheral leucocytosis, painful erythematous skin lesions (papules, plaques and nodules) that typically reveal a dense dermal neutrophilic infiltrate, and dramatic recovery of both symptoms and physical findings following treatment with systemic corticosteroids.² Sweet syndrome is frequently related to malignancies and chronic inflammatory disorders, and it can be caused by drugs as well. It can also be triggered by past infections or during pregnancy.³

We present a case of bullous variant of Sweet syndrome associated with chronic myelogenous leukaemia (CML) where the patient presented with crusted bullae and tender erythematous crusted plaques on all four limbs and face. Investigations revealed leucocytosis with peripherally circulating blasts, myelocytes and metamyelocytes. Skin biopsy revealed Sweet syndrome and bone marrow biopsy-confirmed evidence of CML in the accelerated phase. The skin lesions, which had previously been resistant to therapy, surprisingly disappeared after 3 days of initiating systemic corticosteroids.

In this case, the skin lesions were a crucial clinical finding in detecting and treating the underlying CML. Because of the early intervention, our patient had a good outcome.

Case presentation

A woman in her 40s with no known comorbidities presented with a history of fever on and off and painful skin lesions for 3 months that were unresponsive to antimicrobials and anti-allergic medication. She had no addictions and her family history was insignificant for any autoimmune disease or malignancies. She denied any history of trauma, insect or animal bite, and had neither travelled anywhere recently nor had exposure to sick contacts. She did not have any joint pain, oral ulcers or visual problems.

On physical examination, the cutaneous lesions were tender to palpation. The skin of both of her hands was covered with crusted bullae, a few of them with whitish xanthochromic fluid. On both upper and lower limb extensor surfaces, there were multiple, widespread, tender erythematous crusted plaques with sharp and distinct margins (figure 1A–D). There was swelling of all four limbs. Similar lesions were reported by the patient on the face, which had resolved spontaneously. No ulcerations or blisters were found on the mucous membranes, and there was no lymphadenopathy appreciated. Abdominal examination revealed massive splenomegaly. Respiratory, neurological and cardiovascular examinations were unremarkable.

Figure 1.

(A–D) Multiple tender erythematous bullous skin lesions on arms, legs and hands at initial presentation.

Investigations

Routine investigations were done that revealed haemoglobin 840 g/L, leucocytosis of 75 x10⁹/L and platelet count of 659 x10⁹/L. The absolute neutrophil count was 33 x 10E9/L. The patient’s complete blood count is presented in table 1. Peripheral blood film showed 4% myeloblasts, 24% myelocytes and 25% metamyelocytes raising concern for haematological malignancy (figure 2A, B), for which she was admitted to our inpatient haematology service.

Table 1.

Result of complete blood count and peripheral smear findings

Haemoglobin	840 g/L
Leucocyte count	75 x 10E9/L
Absolute neutrophil count	33 x 10E9/L
Myeloblasts	4%
Myelocytes	24%
Metamyelocytes	25%
Blasts	4%
Platelets	694 x 10E9/L

Figure 2.

(A) Peripheral film showing myeloblasts; (B) peripheral film showing myelocytes and metamyelocytes.

Disseminated intravascular coagulation was ruled out and other laboratory tests including serum electrolytes, creatinine, blood urea nitrogen and liver function tests were unremarkable. Blood culture revealed no growth and the autoimmune profile was negative.

Bone marrow analysis showed hypercellularity of 85%, dysmyelopoiesis with increased immature myeloid precursors such as promyelocytes, myelocytes and metamyelocytes, 11% blast cells and fibrosis, favouring the diagnosis of CML in accelerated phase as per WHO classification (figures 3 and 4A, B). Bone marrow cytogenetic revealed all cells to be showing 9;22 translocations resulting in Philadelphia chromosome. BCR-ABL1 translocation was detected in 95% of the 200 nuclei scored through fluorescence in situ hybridisation.

Figure 3.

Bone marrow aspirate showing immature myeloid precursors such as blast cells.

Figure 4.

(A) Bone marrow trephine showing granulocytic infiltration; (B) bone marrow trephine showing fibrosis.

A biopsy of the skin lesions along with a bone marrow biopsy was then sought. The skin punch biopsy revealed skin tissue showing spongiotic epidermal vesicles with diffuse neutrophilic infiltrates in the dermis (figure 5A, B). Given the morphological features and clinical history, a diagnosis of Sweet syndrome was reported. Special stain periodic acid-Schiff diastase did not highlight any fungal organisms.

Figure 5.

(A, B) Histopathology slides of the skin biopsy. (A) Ulcerated epidermis with basket-weave keratosis, along with intraepidermal vesicles with marked spongiosis. (B) The underlying dermis exhibits diffuse neutrophilic infiltrate which is extending throughout the whole thickness of the tissue with nuclear debris.

Treatment

For the skin lesions of Sweet syndrome, the patient was started on systemic steroids (500 mg methylprednisolone intravenously) for 3 days along with a concoction of clobetasol propionate, Polyfax, liquid paraffin and white soft paraffin to be applied topically. Within 3 days of the initiation of treatment, the patient’s skin lesions started to resolve. For the accelerated phase of CML, she was started on nilotinib and discharged to follow-up as an outpatient.

Outcome and follow-up

On her follow-up visit 1 month later, she was clinically and vitally stable with no active symptoms and no new skin lesions.

Discussion

The case mentioned above is elaborating on the unique and unusual presentation of Sweet syndrome with bullous lesions as well as lesions in other stages of eruption, such as erythematous and tender flat lesions with well-defined sharp borders, fluid-filled blistering lesions and nodular ulcerated lesions, as presenting symptoms of CML.

CML is a type of myeloproliferative disorder that usually presents with quite vague symptoms such as fever, fatigue, bone pain, and may or may not have weight loss, while splenomegaly can be found in more than 50% of patients, making it the most common physical finding.⁴ We have described here a patient with CML who presented with bullous Sweet syndrome, an association that has not been previously reported.

Sweet syndrome or acute neutrophilic dermatosis has been commonly seen in three different clinical backgrounds which could be classic (or idiopathic), malignancy associated and drug induced.⁵ Since many of the cases of Sweet syndrome are cancer related, several published studies have decided to separate the two forms. The onset of Sweet syndrome can precede, follow or appear concurrently with the patient’s cancer diagnosis. It was also reported that it occurred most commonly with acute myeloid leukaemia among haematological disorders and could either be found as a paraneoplastic syndrome or be drug induced (chemotherapy) or occur concurrently with leukaemia cutis. Other patients with Sweet syndrome and solid tumours were most commonly associated with gastrointestinal, genitourinary and breast tumours.⁶

Another study reviewed and combined the data from 15 studies of patients with Sweet syndrome in order to precisely determine the incidence of malignancy-associated Sweet syndrome in which there were 21% of patients who had either a solid tumour or haematological malignancy.⁷ The percentage of CML’s association with Sweet syndrome has yet to be defined but to the best of our knowledge, only eight such cases have been published.

Among the above-mentioned cases of CML and Sweet syndrome, two showed the causative factor to be drugs. The rare case of the bullous type of Sweet syndrome was illustrated in a case report in which initially, after being exposed to a radiocontrast agent, the patient had a hypersensitive reaction and blistering rashes which were established to be from bullous Sweet syndrome.⁸ Another rare case of subcutaneous Sweet syndrome in a patient with CML published in 2014 described a patient who had been under treatment with imatinib for diagnosed CML since 2009 and developed characteristic skin lesions while on supportive treatment in the hospital. It is intriguing to know that her nodules responded to chemotherapy rather than with steroids.⁹ A case report showed the association of Sweet syndrome with drugs like hydralazine and mentioned previous associations with oral contraceptives, minocycline and trimethoprim/sulfamethoxazole as well,¹⁰ all of which were ruled out in our patient’s case. Drug-induced Sweet syndrome has also shown associations with granulocyte-colony-stimulating factor such as stated in another case report that showed an association between the formation of bullous Sweet syndrome after administration of pegfilgrastim, azathioprine, all-trans retinoic acid and, with less evidence, vaccination, anticancer agents, non-steroidal anti-inflammatory medicines and hydroxychloroquine,¹¹ none of which had been in short-term or long-term use by our patient.

Another study reviewed different works of literature to relate a patient of CML in accelerated phase with Sweet syndrome who had been on treatment with imatinib. The patient had developed the skin lesions in question during hospital admission while being on supportive care.¹² Our patient similarly was found to be in the accelerated phase of CML and was started on imatinib upon diagnosis as well, but the difference here is the presentation of bullous Sweet syndrome before her admission and work-up and the presence of hyperleucocytosis, which pointed towards a haematological cause. An article published in 2005 portrayed an instance of Sweet syndrome caused by the use of imatinib to treat CML. A 53-year-old African American woman with CML developed neutrophilic dermatosis consistent with Sweet syndrome after receiving imatinib treatment on two consecutive occasions.¹³

On presentation, our patient’s lesions also raised suspicion of autoimmune disease as the cause, and as previously mentioned, she was investigated for autoimmune association with the anti-nuclear acid test and extractable nuclear acid profile. The importance of ruling out autoimmune causes such as systemic lupus erythematosus (SLE) is crucial because there is a staggering resemblance between bullous SLE and bullous Sweet syndrome lesions where the histopathological examination of skin biopsy of all cases of SLE showed an interstitial neutrophilic infiltrate with leucocytoclasia where in five of them, the density was sparse, whereas in the other nine cases, it was moderately thick which, although is an uncommon finding, points to a link between the two.¹⁴

Bullous Sweet syndrome is a rare entity related to CML. It is crucial to investigate any unusual or treatment-resistant skin lesions with a skin biopsy. Physicians should keep in mind that skin lesions may be a warning sign of the advancement of an underlying malignancy that requires prompt identification and management. Therefore, such patients should undergo rapid screening for age-related, gender-specific and risk factor-associated malignancies.

Learning points.

• The case highlights that in patients with Sweet syndrome, a high index of suspicion should be maintained for underlying haematological malignancies such as chronic myelogenous leukaemia.

• Skin lesions that are resistant to common treatment must be thoroughly investigated with skin biopsy and blood tests especially for age and gender-specific malignancies.

• Corticosteroids have a substantial effect in improving Sweet syndrome.

Ethics statements

Patient consent for publication

Next of kin consent obtained.