The recognition of oral manifestations of haematological disease saves lives: a case report – Bulletin of the National Research Centre

A previously healthy 34-year-old female of Asian ethnicity completed a telephone consultation with her GDP following national guidelines during the COVID-19 pandemic. She gave a 5-day history of ‘spontaneous gum bleeding, gum swelling, dental pain from her left upper wisdom tooth and swelling below the lower jaw’. She had recently developed a fever and had limitation of mouth opening to ‘one finger breadth’.

The diagnosis from this telephone consultation was ‘severe periocoronitis or periodontal abscess associated with the upper left wisdom tooth’. She was managed following the Scottish Dental Clinical Effectiveness Programme Advice, Analgesic and Antimicrobial guidance (introduced during the COVID-19 pandemic to optimise triage) with paracetamol and ibuprofen and a prescription for amoxicillin and metronidazole. Thirteen days later she telephoned the same clinician to discuss her on-going symptoms. These included gum swelling, cheek swelling, gum bleeding, a lump in her right throat, unexplained weight loss and constipation. This triggered a two week wait (2WW) referral to the Oral and Maxillofacial Surgery (OMFS) department.

Investigations

The patient was seen on the OMFS 2WW clinic at the Royal Sussex County Hospital (RSCH) 9 days later.

She presented with pain and gingival swelling around the lower right wisdom tooth which had not responded to her oral antimicrobials. Her mouth opening had improved to 25 mm measured intra-incisally.

On clinical examination, the patient had bilateral posterior mandible pain and right mandibular gingival hyperplasia. An Orthopantomogram (OPG) shown in Fig. 1 confirmed the tooth anatomy and did not show any significant dental pathology.

Orthopantomogram taken at RSCH 2WW clinic showing partially over-erupted UR8

Differential diagnosis

A diagnosis of lower right third molar gingival hyperplasia and pericoronitis was made.

She declined excision of the LR8 operculum under local anaesthesia at this appointment and was given a 7-day course of oral co-amoxiclav with a review appointment booked the following week.

At review in the OMFS department the oral signs had not changed. The patient reported new blurred vision and was urgently referred to the Ophthalmology Department, Sussex Eye Hospital, where a diagnosis of sub-inner limiting membrane haemorrhage of the left eye was made. This was managed ‘conservatively’.

The patient had a simple extraction of the over-erupted UR8 and an operculectomy LR8 under local anaesthesia the following week. There were no immediate complications. Further systemic symptoms were identified: lethargy, unanticipated weight loss and she had not opened her bowels for nearly two weeks. She had not been prescribed opiate analgesia and her GP was investigating her symptoms. Her weight loss had been attributed to reduced calorie intake due to oral pain.

Hospital admission

The patient attended the RSCH Emergency Department the following day with continuous bleeding from the extraction site and severe abdominal pain. She was stabilised and had a number of blood tests. Relevant abnormal results are shown in Table 1.

On the basis of this clinical/blood picture and blood film morphology (Fig. 2), a diagnosis of APL was made, and she was reviewed immediately by the Haematology Department and admitted under their care.

Diagnostic Bone Marrow Aspirate (× 50 Power): Hypercellular marrow, abnormal promyelocytes with azurophilic granulation, some containing Auer rods (arrow)

Presentation bloods show a marked pancytopenia with microscopic examination of a blood film highlighting the presence of blasts and hypergranular promyelocytes, with morphological features of those seen in APL. The clotting screen highlights a Disseminated Intravascular Coagulation (DIC) picture with an elevated PT and APTT, a low Fibringen and elevated D-Dimers. Acute phase reactants including serum ferritin and C-reactive protein were elevated, along with the serum LDH – a ubiquitous, non-specific marker of cell turnover.

Bone marrow examination identified the classical Promyelocytic Leukemia Retinoic Acid Receptor Alpha (PML- RARA) fusion sequence chromosomal translocation t(15;17), confirming the diagnosis of APL. Further investigations were undertaken to determine the nature of the abdominal pain and change in bowel habit with an MRI of the ano-rectal region and surgical opinion, confirming a diagnosis of a fistula which was managed conservatively because of the patient’s neutropenia.

Treatment

Immediate treatment focussed on correcting the coagulopathy with platelet transfusion to maintain platelet count > 30–50 × 10⁹/L and fresh frozen plasma and cryoprecipitate to normalise the PT and APTT and to achieve fibrinogen levels > 1.5 g/L (Sanz et al. 2009; Tallman and Altman 2009).

Red Blood Cell transfusions were administered to correct the profound anaemia. Broad spectrum antimicrobials were commenced to cover translocation of gastrointestinal tract organisms along with other prophylactic antiviral and antifungal medications, because of risk in a neutropenic presentation.

AllTrans-Retinoic Acid (ATRA) was commenced upon immediate clinical suspicion of APL, before subsequent confirmation of the diagnosis. This acts to differentiate the abnormal promyelocytes and ultimately the cells undergo apoptosis. It also helps to reduce tissue factor secretion by the abnormal promyelocytes which otherwise drives the DIC picture (Fenaux et al. 1993).

Within 24 h of starting ATRA, the patient became pyrexial, breathless and hypoxic. Transfer to the Intensive Care Unit was necessary and a clinical concern regarding a recognised cardiorespiratory complication of APL, namely differentiation syndrome, was managed with cessation of the ATRA and administration of IV Dexamethasone (Sanz et al. 2009).

Cytoreduction with oral hydroxycarbamide chemotherapy was commenced to control the proliferative WCC. The ATRA was slowly reintroduced at a later date, once the patient had improved from a cardiorespiratory view point.

First line treatment was commenced with Arsenic Trioxide (ATO) induction. The ATO, in combination with ATRA is a non-chemotherapy option for patients with so called ‘low-risk’ disease—in this case due to the presentation WCC of < 10 × 10⁹/L (Overview 2021).

The patient returned back to the haematology ward for the rest of her inpatient care. Regular monitoring was required for ATO complications including QTc prolongation, with judicious electrolyte correction and caution regarding the addition of any QTc prolonging medications including anti-emetics.

Ophthalmological inpatient reviews were obtained to assess the patients visual blurring, noted pre-admission. Examination confirmed a unilateral retinal haemorrhage, managed expectantly but with a higher initial target platelet threshold of 100 × 10⁹/L for two weeks.

The oral biopsy, taken pre-admission from the operculum, was found to have mucosal infiltration by immature myeloid cells.

Bone marrow examination after this first induction cycle of treatment documented a morphological remission with a very low level of the PML-RARA being detected by sensitive molecular techniques.

As an outpatient, blocks of ATRA and ATO consolidation have been delivered over a nine-month period.

Subsequent bone marrow examinations have documented ongoing morphological remission and no evidence of any molecular minimal residual disease.

Outocome and follow up

The oral infiltration and ano-rectal fistula healed conservatively, aided by the restoration of the patient’s own neutrophils.

The patient’s pre-retinal haemorrhage improved spontaneously with almost complete reabsorption of the haemorrhage and normal visual acuity being restored.

At the most recent follow up, ten months post initial diagnosis, the patient was alive and well. Her end of treatment bone marrow assessment confirmed her to be in remission. She has regular follow up in the haematology clinic.