Acute promyelocytic leukaemia presenting as necrotising fasciitis of the perineum (Fournier gangrene)

Abstract

We present a case of an unusual presentation of acute promyelocytic leukaemia (APML), which presented with Fournier gangrene (FG). A 38-year-old man presented with malaise, groin swelling, anal bleeding, fever and was found to have FG. Initial workup revealed pancytopaenia, borderline low fibrinogen, prolonged international normalized ratio (INR), which raised the suspicion for leukaemia. The peripheral blood differential revealed leucopaenia with absolute neutropaenia and a 5% abnormal promyelocytes but no blasts, suspicious for APML. Bone marrow biopsy was performed and fluorescence in situ hydridization (FISH), karyotype and PCR confirmed a t(15;17) translocation, establishing a diagnosis of APML. After 1 month of therapy for intermediate risk APML with All-trans retinoic acid (ATRA) and arsenic trioxide (ATO), repeat chromosomal analysis and repeat bone marrow biopsy revealed no evidence of residual APML. After the consolidation phase was started with ATRA and ATO regimen, the wound healed after 2 months and the patient achieved complete remission.

Background

Acute promyelocytic leukaemia (APML) accounts for 5%–20% of cases of acute myeloid leukaemia (AML).^{1 2} There are approximately 600–800 new cases every year in the USA. We report a rare case of APML presenting as Fournier gangrene (FG) with important and simple learning points.

Case presentation

A 38-year-old previously healthy Cape Verdean man presented to the emergency department (ED) with mild groin pain for 2 days without fever. On examination, he was found to have perineal swelling, tenderness and a small erythematous area in his perineal skin without drainage, suspected to represent an uncomplicated case of folliculitis. Given the small size of the area involved, well-appearance of the patient without systemic symptoms and the absence of risk factors for methicillin-resistant Staphylococcus aureus, no laboratory data were obtained and he was discharged from ED with a 7-day course of cephalexin with instructions to follow with primary care physician.

One week later, he returned to the hospital due to progression of the lesion with increased swelling, anal bleeding, fever and malaise. On repeat examination, there was a small circular perineal lesion measuring 1.5 cm in diameter with extension towards the scrotum with active drainage of feculent material and serosanguinous fluid. There was mild erythema over the scrotal skin and an induration extending from around the wound anteriorly towards the scrotum with a walnut-sized area of induration of the posterior scrotum. Heart rate was 104 bpm and temperature was 102.5°F (39.2°C). This presentation was suspicious of a rectocutaneous fistula, FG or perianal abscess.

Investigations

Initial workup revealed peripheral white blood cells (WBC) of 1×10⁹/L and platelet of 27×10⁹/L, haemoglobin of 8.2 g/L, fibrinogen of 180 mg/dL, INR of 1.41, activated partial thromboplastin time (aPTT) of 27 s, D-dimer of 8510 ng/mL and lactate of 2.1 mmol/L. CT of the abdomen and pelvis with contrast showed an ill-defined region with peripheral hyperattenuation and central relative hypoattenuation in the posterior scrotum with several small foci of gas along the posterior aspect of the scrotum/perineum (figure 1). These findings were consistent with abscess and suspicious for FG, given subcutaneous emphysema.

Figure 1.

CT of the pelvis without contrast showing soft tissue stranding (arrow) within the subcutaneous tissue extending to the rectum. Small pockets of air (arrow head) rendered this lesion suspicious for FG. (A) Axial, (B) sagittal.

The borderline low fibrinogen and prolonged INR with pancytopenia raised the suspicion for a bone marrow disorder with disseminated intravascular coagulation. Differential revealed leucopaenia with absolute neutropenia and 5% abnormal promyelocytes but no blasts, suspicious for APML as well as normocytic normochromic anaemia with occasional tear drop cells, suspicious for myelofibrosis.

Bone marrow biopsy (figure 2) was done and expedited molecular/FISH analysis showed 89% positivity for PML-RARA fusion (figure 3A and B), chromosomal analysis showed t(15;17)(q24;q21). Quantitative PCR for PML/RARA demonstrated the presence of the abnormal transcript. These findings established a diagnosis of APML leading to pancytopaenia and FG. Risk stratification was consistent with intermediate risk APML.

Figure 2.

Bone marrow biopsy. (A) Bone marrow smear showing predominantly promyelocytes. (B) Promyelocyte with convoluted nucleus and Auer Rods (Arrow). (C) Bone marrow core biopsy showing markedly hypercellular bone marrow with overwhelming predominance of promyelocytes. (D) Bone marrow biopsy showing negative CD34 immunohistochemical stain. (E) Positive myeloperoxidase stain.

Figure 3.

(A) Karyotype: 20 metaphases have been analysed and 19 of them showed abnormal karyotype. Right chromosome 15 is longer than normal and the right chromosome 17 is shorter. Hence, the translocation is t(15;17). PML gene is on 15q22 and the RARA gene is on 17q12. (B) FISH. PML (green) and RARA (red) genes are fused together, which represents PML/RARA fusion.

Pathological examination of the perineal skin specimen showed skin with ulceration, fibrinopurulent exudate, inflammation and reactive changes. Culture of the perineal tissue grew Bacteroides thetaiotaomicron, Clostridium clostridioforme, diphtheroids, Enterococcus faecalis, Escherichia coli, Streptococcus agalactiae and gram-positive cocci.

Treatment

He was placed on broad-spectrum antibiotics with intravenous piperacillin-tazobactam and vancomycin. Perineal wound exploration, scrotal exploration and rectal examination were performed under anaesthesia. Immediately on suspicion of APML, he was started on All-trans retinoic acid (ATRA) 45 mg/m² (90 mg total daily dose with 40 mg given in AM and 50 mg PM) and arsenic trioxide (ATO) 0.15 mg/kg (14 mg intravenously once a day) for low-to-intermediate risk APML.³ He was also placed on prednisone 0.5 mg/kg for differentiation syndrome and acyclovir prophylaxis forherpes simplex virus (HSV).

Outcome and follow-up

On the fifth day of ATRA, the patient developed leucocytosis (peak of 26.7×10⁹/L) with no symptoms of differentiation syndrome. To control leucocytosis and prevent differentiation syndrome, he was started on hydroxyurea 500 mg every 6 hours. Later on admission, his antibiotics were transitioned to oral metronidazole/levofloxacin and a wound vacuum dressing was placed. The patient was discharged on admission day 11 with a haemoglobin of 7.6 g/L, WBC of 26.7×10⁹/L and platelets of 79×10⁹/L with daily follow-up at the Haematology/Oncology clinic for ATO infusions.

At the 1 month follow-up visit, bone marrow smear revealed normal erythroid precursors, myeloid precursors and mature neutrophils (figure 4A), whereas repeat bone marrow core biopsy and aspirate revealed hypercellular bone marrow showing trilineage haematopoiesis and changes consistent with therapy and no evidence of residual APML (figure 4B). Chromosomal analysis also revealed a normal chromosome complement (figure 4C), without evidence of the abnormal t(15;17) karyotype detected previously or any other chromosomal rearrangement to suggest an acquired clonal abnormality. After obtaining remission, the consolidation phase was started with the ATRA and ATO regimen, which included ATO in clinic 5 days/week for 4 weeks on, followed by 4 weeks off to complete four courses. ATRA daily for 2 weeks on and 2 weeks off to complete seven courses. The wound healed after 2 months and the patient achieved durable complete remission.

Figure 4.

Post-treatment. (A) Bone marrow smear showing normal erythroid precursors, myeloid precursors and mature neutrophils. (B) Bone marrow core biopsy showing lower cellularity with trilinear haematopoiesis, including megakaryocytes (arrow). (C) Normal karyotype, post-treatment.

Discussion

FG is a necrotising fasciitis type I (polymicrobial) of the perineum which often involves the scrotum. The aetiology consists of mixed aerobic/anaerobic infection including facultative organisms (E. coli, Klebsiella, enterococci) along with anaerobes (Bacteroides, Fusobacterium, Clostridium, anaerobic or microaerophilic streptococci).⁴ It is characterised by severe pain that generally starts on the anterior abdominal wall and migrates into the gluteal muscles, scrotum and penis. Clinical features may include tense oedema outside the involved skin, blisters/bullae, crepitus and subcutaneous gas as well as systemic findings such as fever, tachycardia and hypotension. CT may show air along the fascial planes or deeper tissue involvement. Treatment of necrotising fasciitis consists of early aggressive surgical exploration with debridement of necrotic tissue, broad-spectrum antibiotic therapy and haemodynamic support as needed.^5–7

APML is a haematological emergency with high rates of mortality secondary to bleeding diathesis if treatment is not promptly installed. Nevertheless, cure rates are high if it is timely diagnosed and treated. We underscore that the suspicion of APML suffice for the initiation of ATRA, and suspicion should be raised in the setting of microscopic features, such as Auer rods, pancytopaenia or leucocytosis associated with coagulopathy.⁸

A previous study reported cases of haematological malignancies complicated by FG.⁹ In our literature review, we found multiple cases reporting the development of FG after the initiation of ATRA,^10–15 and only one similar case in which FG was present at the time of diagnosis (table 1). The uniqueness of this case relies on the presence of Fournier at the time of diagnosis, as opposed to after therapy, leading to a complicated and nuanced early management.

Table 1.

Literature review of the association between Fournier gangrene and APML

Author	Time of ATRA	Age/Sex	Notes	Outcome
Fukuno et al (2009)11	FG after ATRA; on day 22.	43/M	Treated with antibiotics and surgical debridement including left testectomy	Remission, relapse, death from cerebral haemorrhage from extramedullary tumour
Lévy et al (1997)12	FG after ATRA; on day 13.	44/M	Strep. faecalis and Staph. coag negative; treated w/antibiotics and debridement	Remission
Naithani et al (2008)14	FG after ATRA	17/M	Staph. aureus and E. coli, treated with antibiotics	Remission, relapse, remission
Faber et al (1998)17	FG before ATRA	50/M	E. coli, treated with antibiotics and debridement	Death from septic shock within 24 hours
Patrizi et al 20 20	FG after ATRA	21/M		Remission
Goto et al (1998)21	FG after ATRA	43/M		Remission
Valizadeh (2011)22	FG after ATRA; after 2 weeks	36/M	Treated with antibiotics and debridement	Unknown
Furtado et al (2018)	FG before ATRA	38/M	Polymicrobial, treated w/antibiotics and debridement	Remission

APML presenting with necrotising fasciitis of the perineum was reported before in a 4-month-old patient¹⁶ and in an adult patient.¹⁷ To the best of our knowledge, this is the second case in an adult patient in which FG had developed prior ATRA therapy.

Mechanistically, in our case, it is reasonable to suspect the immunocompromised state from APML predisposed the patient to necrotising fasciitis of the genitalia rather than a complication of antileukaemic therapy solely, the timing of events in this case also supports this hypothesis. However, it is unclear whether FG was caused by APML or a mere coincidence. Unfortunately, our patient initially presented with fairly nonspecific symptoms on his first visit to the ED, with symptoms and signs that could represent folliculitis or other common skin infections. In this particular case, a simple laboratory testing, such as a complete blood count, would probably have resulted in an earlier diagnosis, which could have prevented a surgical debridement. The discussion of whether every patient presenting to the ED should have basic laboratory is out of the scope of this case report and should derive from research designed with this goal. Nonetheless, we encourage clinicians to have a low threshold for performing inexpensive testing when facing unusual presentations.

In the treatment of APML, ATRA-ATO therapy is currently standard for low-to-intermediate risk disease (WBC <10 × 10⁹/L).³ Monitoring for differential syndrome is paramount and prompt treatment with dexamethasone is recommended if there is development of fever, peripheral oedema, hypotension, serositis or respiratory, renal and/or hepatic dysfunction. The differential with sepsis can be challenging. Some patients require addition of chemotherapy if WBC rises too rapidly. Induction therapy aims to reduce the total body leukaemia cell population from approximately 10¹² to below the cytologically detectable level of about 10⁹ cells. Although ~90% of patients with newly diagnosed APML will achieve complete remission with induction therapy, virtually all of them will relapse without additional therapy. Consolidation therapy is directed at leukaemia cells that survived induction therapy but are not detectable by conventional tests thereby converting patients with morphological and cytogenetic remission into a more durable molecular remission and, eventually, cure.¹⁸ A study showed that a combination of ATRA and ATO given for induction and consolidation therapy is at least not inferior and is possibly superior to standard ATRA and anthracycline-based chemotherapy for adults with low-to-intermediate-risk APML.³ Another trial in all risk groups of APML demonstrated that ATRA and ATO has a high cure rate and less relapse than ATRA and idarubicin, with a low incidence of liver toxicity.¹⁹

Learning points.

• Acute promyelocytic leukaemia (APML) can present with Fournier gangrene. Recognition of this presentation is critical to institution of appropriate therapy as early as possible.

• Identify the features in the workup for leukaemia that prompt suspicion of APML: specifically, coagulopathy and pancytopaenia or circulating promyelocytes. The presence of Auer rods in blasts, HLA-DR negative and CD34 negative blasts further suggests this diagnosis.

• Recognise that the treatment of leukaemia-associated coagulopathy with ATRA is a haematological emergency and should start immediately while genetic testing for a definitive diagnosis of APML is performed.

• In the treatment of APML, ATRA-ATO therapy is currently standard for low-to-intermediate risk disease (WBC<10 × 10⁹/L).

• Consolidation therapy is directed at leukaemia cells that survived induction therapy but are not detectable by conventional tests thereby converting patients with morphological and cytogenetic remission into a more durable molecular remission and, eventually, cure.