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Observation Letter

Oral ulcers and cutaneous rash as manifestations of differentiation syndrome in acute promyelocytic leukaemia

Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Department of Clinical Hematology and Medical Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Corresponding author: Dr. Keshavamurthy Vinay, Department of Dermatology, Venereology, and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Singh S, Mustari AP, Lad D, Parkhi M, Vinay K. Oral ulcers and cutaneous rash as manifestations of differentiation syndrome in acute promyelocytic leukaemia. Indian J Dermatol Venereol Leprol doi: 10.25259/IJDVL_576_2022


Differentiation syndrome is a well-known complication of all-trans retinoic acid (ATRA), seen in up to 27% of acute promyelocytic leukaemia (APL) patients treated with the molecule.1 It is also reported to occur with arsenic trioxide (ATO), which is co-prescribed with all-trans retinoic acid in acute promyelocytic leukaemia patients.2 It usually manifests after 5–20 days of starting treatment and the presence of three of the following criteria should rise the suspicion of differentiation syndrome; unexplained fever, weight gain (more than 5 kgs), pleuro–pericardial effusion, pulmonary infiltrates, hypotension, respiratory distress and renal failure.1 Diagnosis is primarily based on clinical presentation, after ruling out infections. Dermatological manifestations of differentiation syndrome are less known and rarely described in the literature. Herein, we report cutaneous manifestations in a case of differentiation syndrome and review the existing literature on all-trans retinoic acid-induced mucocutaneous lesions.

A 73-year-old male patient presented with progressive breathlessness, recurrent fever and ecchymoses over bilateral upper and lower limbs of 14 days’ duration. Investigation revealed pancytopenia (haemoglobin; 7.3 g/dL; total leucocyte count; 3900/mm3 and platelet count 13000/mm3). Serum lactate dehydrogenase was 3045 IU/L, prothrombin time (PT) was 17 seconds (normal 12–15), and activated partial thromboplastin time (APTT) was 32 seconds (normal 36–35). Serum electrolytes and chest radiograph were within normal limits. Bone marrow examination showed >95% promyelocytes and fluorescence in situ hybridization for t (15:17) and polymerase chain reaction (PCR) for promyelocytic leukaemia gene–retinoic acid receptor-α (PML-RARA) was positive. Diagnosis of intermediate risk acute promyelocytic leukaemia was made3 and the patient was treated with oral all-trans retinoic acid (40 mg twice daily) and intravenous arsenic trioxide (10 mg once a day) with improvement in breathlessness, fever and ecchymoses. After three weeks, patient presented with recurrence of fever and breathlessness, painful oral ulcers and swelling and redness of both upper and lower limbs. Examination revealed multiple round to oval coalescing polycyclic superficial ulcers of size 3–4 mm with yellowish base and surrounding erythematous halo over the hard palate [Figure 1]. Patient also had bilateral pitting pedal oedema extending to lower one-third of the legs with overlying diffuse erythema and scaling including soles [Figure 2]. Patient was admitted for evaluation and all-trans retinoic acid and arsenic trioxide were withheld. At admission, blood pressure was 150/88 mm Hg, pulse rate was 90 beats per minute, respiratory rate was 21 breaths per minute, temperature was 104°F and oxygen saturation was 92–97%. On auscultation, bilateral basal crepitation was present. Investigations showed anaemia (haemoglobin; 7.9 g/dL), leucocytosis (total leucocyte count; 19,900/mm3), neutrophilia (12,500/mm3), eosinophilia (1900/mm), elevated C-reactive protein (60 mg/l), D-dimer (1728 ng/mL) and creatinine (1.4 mg/dL). Arterial blood gas analysis, liver function tests, serum procalcitonin, serum galactomannan, serum fibrinogen, coagulation profile (except D-dimer) and serum electrolytes were within normal limits. Chest radiograph showed bilateral diffuse infiltrates with right pleural effusion. Computed tomography (CT) of the chest showed bilateral ground-glass opacity and mild pleural effusion. Bronchoalveolar lavage examination (gram stain, acid-fast bacteria, periodic acid–Schiff were negative) did not show evidence of an infective aetiology. The patient was started on intravenous cefoperazone-sulbactam empirically. Three blood cultures sent 24 hours apart were sterile. Tzanck smear from the oral ulcers was negative for multinucleate giant cells. Cytomegalovirus, Epstein-Barr virus, herpes simplex virus and COVID-19 PCR were negative. Skin biopsy from the leg showed hyperkeratosis and mild superficial perivascular infiltrate of lymphocytes and occasional eosinophils [Figure 3]. The patient continued to have spikes of fever; breathlessness, oral ulcers and rash persisted despite changing the antibiotics to vancomycin and colistin. all-trans retinoic acid and/or arsenic trioxide-induced differentiation syndrome was suspected based on clinical features, lack of response to antibiotics, and history of recent intake of all-trans retinoic acid and arsenic trioxide. The patient was treated with prednisolone 40 mg per day with remarkable improvement in skin and mucosal lesions. The respiratory complaints also improved and there was a significant improvement in the chest radiograph. Prednisolone tapering was started after 10 days and stopped over one month. The patient was restarted on all-trans retinoic acid and arsenic trioxide after one month without any recurrence. Naranjo adverse drug reaction probability scale score was 3 for both all-trans retinoic acid and arsenic trioxide and 6 for a combination of all-trans retinoic acid and arsenic trioxide.

Figure 1:: Multiple oral ulcers with yellowish base and surrounding erythematous halo over the hard palate
Figure 2:: Bilateral pedal oedema with overlying diffuse erythema and scaling
Figure 3:: The skin biopsy shows hyperkeratosis and superficial dermal mild perivascular infiltrate of lymphocytes and occasional eosinophils (Haematoxylin and eosin, ×;400)

Acute promyelocytic leukaemia is a type of acute myeloid leukaemia that affects both children and adults. The first line of therapy for acute promyelocytic leukaemia is a combination of all-trans retinoic acid and arsenic trioxide. all-trans retinoic acid is a vitamin A derivative used in the treatment of acute promyelocytic leukaemia which acts via a retinoic acid receptor (RAR α, β and γ) that helps in the differentiation and apoptosis of malignant cells.4 Arsenic trioxide also helps in the differentiation of malignant cells by degrading promyelocytic leukemia gene–retinoic acid receptor-α (PML-RARA).

Differentiation syndrome is a serious, life-threatening, unpredictable clinical syndrome due to the differentiation of blast cells in acute promyelocytic leukaemia patients after induction therapy with all-trans retinoic acid and/or arsenic trioxide. It has also been reported in patients of pustular psoriasis and psoriasis vulgaris treated with acitretin.5 The precise mechanism of differentiation syndrome is unknown, but the differentiating acute promyelocytic leukaemia cells are primary mediators of inflammation. These cells have an increase in adhesive property and interleukin production that helps in transmigration through vessels, infiltration into various organs and subsequent immune-mediated organ damage. This leads to capillary leak, oedema, haemorrhage, leucocyte infiltration and release of inflammatory mediators and subsequent organ failure, commonly respiratory failure.6

The risk factors for differentiation syndrome include baseline high total leucocyte count (TLC), rapidly improving TLC and CD13 expression of leukaemic cells.7 The occurrence of differentiation syndrome is associated with an increased risk of extramedullary relapse.8 Differentiation syndrome has a spectrum of cutaneous manifestations including labial and lingual ulcers, scrotal ulcers and Sweet’s syndrome. Other all-trans retinoic acid-induced cutaneous manifestations reported are exfoliative dermatitis, xerosis, xerostomia, cheilitis and ulcers over the vulva, pubis, perianal area and lower abdomen [Table 1].9-18 Riganti et al.9 reported a painful lingual ulcer as part of differentiation syndrome and there was complete resolution after three days of starting dexamethasone (8 mg/day). In contrast, our patient had multiple smaller ulcers.

Table 1::
Summary of ATRA-induced cutaneous manifestations
Year Disease Treatment received for primary disease Clinical presentation Cutaneous manifestation Number of features fulfilling diagnostic criteria of DS Treatment of cutaneous manifestations Treatment response
1994 APL ATRA, 80 mg per day Fever and leucocytosis Skin nodules over arms (Sweet’s syndrome) 1 Intravenous methylprednisolone 1 gram for three days Improvement of skin lesions
2000 APL ATRA, 45 mg/m2 and ADE regimen Fever, fluid overload Multiple scrotal ulcers 2 Prednisolone 40 mg Healed after three weeks
2000 APL ATRA 40 mg BD Fever Multiple scrotal ulcer 1 ATRA continued No mention of steroids Ulcer healed after completion of treatment
2002 APL ATRA, 45 mg/m2, daunorubicin 60 mg/m2/day and cytarabine 200 mg/m2/day Fever and weight gain Violaceous and erythematous papulo-vesicles on the limbs and upper trunk (Sweet’s syndrome) 2 ATRA was stopped Dexamethasone 20 mg per day Improvement after two weeks
2005 APL ATRA, 40 mg BD and chemotherapy Fever, lower extremity oedema, and mild pulmonary infiltrates Solitary scrotal ulcer 3 ATRA was stopped No mention of steroids Ulcer healed shortly after stopping ATRA
2011 APL ATRA, 45 mg/m2, daunorubicin and cytarabine Fever, breathlessness, fatigue, pallor, tachypnoea and pancytopenia Solitary superficial scrotal ulcer 2 ATRA was stopped No mention of steroids Ulcer healed in three weeks
2012 APL ATRA, 40 mg BD and idarubicin Fever, weight gain, mild pleural, pericardial, and peritoneal effusion Solitary lingual ulcer 3 ATRA was stopped Dexamethasone 8 mg per day Ulcer healed after seven days
2018 APL ATRA, 40 mg BD, cytarabine and daunorubicin Fever and breathlessness Painful labial ulcer with scrotal ulcer 2 ATRA was stopped Started on Dexamethasone (dose not mentioned) Ulcers healed after 20 days
2020 GPP Acitretin, 25 mg per day Fever, facial puffiness, breathlessness and dry cough, tachycardia, dyspnoea, hypotension, oedema, bilateral basal crepitations Generalised erythema and scaling with relative sparing of the palms and soles and periorbital oedema 3 ATRA was stopped Intravenous betamethasone Improvement after 2 days
2020 APL ATRA, 45 mg/m2 and Daunorubicin 60 mg/m2/day Fever, breathlessness, pulmonary infiltrates and pancytopenia Multiple coalescing scrotal ulcers 3 ATRA was stopped Dexamethasone 10 mg BD Healed in four weeks
APL ATRA, 40 mg BD Fever, breathlessness, leucocytosis, pulmonary infiltrates, pleuro-pericardial effusion and elevated creatinine Oral ulcers, pedal oedema with diffuse erythema and scaling including soles 4 ATRA was stopped Prednisolone 40 mg per day Improvement after three days

BD: twice a day, ATRA: All-trans retinoic acid, APL: acute promyelocytic leukaemia, GPP: generalised pustular psoriasis, ADE: daunorubicin, etoposide and cytarabine, DS: differentiation syndrome

Even though all-trans retinoic acid or arsenic trioxide can induce differentiation syndrome, cutaneous manifestations are exclusively reported with all-trans retinoic acid-induced differentiation syndrome. These manifestations respond well after stopping all-trans retinoic acid and starting systemic steroids. The decision to stop drugs should be tailored to individual patients and depends on the severity of differentiation syndrome. The treatment of differentiation syndrome includes dexamethasone 10 mg twice a day till resolution or for a minimum of three days.19 Prednisolone 40 mg per day has also been used to treat differentiation syndrome and same was used in index because of the lack of severe systemic symptoms.10

In our patient, the oral ulcers, pedal oedema, erythema and scaling were attributed to differentiation syndrome as these started after two weeks of starting all-trans retinoic acid and arsenic trioxide and responded dramatically to systemic steroids. Dermatologists should be aware of these cutaneous manifestations that help in the early diagnosis and better management of the patient.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship


Conflict of interest

There are no conflicts of interest.


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