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| CASE REPORT |
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| Year : 2020 | Volume
: 3
| Issue : 2 | Page : 97-99 |
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Retinoic acid syndrome followed by scrotal ulcer during treatment of acute promyelocytic leukemia with all-trans retinoic acid
Sudhir K Atri, Nishil Gowda, Anjali Dhanda, Karthik Ambalavana
Department of Medicine, Pt. B.D. Sharma PGIMS, Rohtak, Haryana, India
| Date of Submission | 29-Apr-2020 |
| Date of Acceptance | 29-Sep-2020 |
| Date of Web Publication | 31-Dec-2020 |
Correspondence Address:
Dr. Nishil Gowda
Department of Medicine, Pt. B.D. Sharma PGIMS, Rohtak 124001, Haryana
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/jco.jco_11_20
All-trans-retinoic acid (ATRA) has shown a significant improvement in the outcome of patients of acute promyelocytic leukemia and is associated with certain unique adverse effects. We report one such case of APL, who developed ATRA syndrome on day 7 of ATRA, which was relieved after ATRA withdrawal and dexamethasone therapy. Subsequently, with the reintroduction of ATRA, patient developed an unexplained fever which was followed by multiple painless ulcers over the scrotum on day 28 of ATRA. ATRA was withdrawn so as not to induce Fournier’s gangrene, and ulcers were closely monitored without the administration of systemic or local corticosteroids. Eventually, ulcers improved and completely healed by 4 weeks. This is a rare case report, wherein the same patient develops ATRA syndrome followed by scrotal ulcers, suggesting that the scrotal ulcer is a rare specific adverse effect of ATRA and its monitoring is required especially in patients having unexplained fever and leucocytosis. Keywords: Acute promyelocytic leukemia, all-trans-retinoic acid, ATRA, ATRA syndrome, scrotal ulcer
How to cite this article:
Atri SK, Gowda N, Dhanda A, Ambalavana K. Retinoic acid syndrome followed by scrotal ulcer during treatment of acute promyelocytic leukemia with all-trans retinoic acid. J Curr Oncol 2020;3:97-9 |
| Introduction | |  |
Acute promyelocytic leukemia (APL) is a unique variety of acute myeloblastic leukemia (AML) characterized by the bone marrow infiltration with abnormal promyelocytes having PML-RARA fusion gene, leading to cytopenias and coagulopathy. A key component of APL management is the all-trans-retinoic acid (ATRA), which promotes maturation of promyelocytes into neutrophils. Among the many adverse effects of ATRA, ATRA syndrome is the most life-threatening adverse effect, occurring in one-quarter of patients on ATRA.[1] ATRA is also associated with scrotal ulcer as a specific cutaneous complication, which has been reported in extremely rare cases.[2],[3],[4],[5],[6]
| Case Presentation | | |
A 33-year-old male presented with a history of epistaxis and fever since 3 days. On examination, he was normotensive with no hepatosplenomegaly. Laboratory studies showed hemoglobin 7.4 g/dL, leucocyte count 1.5 × 109 /L, platelet count <20 × 109 /L, prothrombin time 17.0s (normal 10–12s), activated partial thromboplastin time 29.9s (normal 30–36s), fibrinogen 3.0 g/L (normal 2.2–4.9 g/L), and D-dimer–4352 ng/mL (normal <250 ng/mL). Bone marrow examination and immunophenotyping analysis were consistent with the diagnosis of APL. PML/RARα (bcr1) by RT-PCR was positive. The patient was started on induction therapy with ATRA, 45 mg/m2/day, divided into two doses. Daunorubicin, 60 mg/m2/day for 3 days, was started on day 5 of ATRA (leucocyte count 6 × 109 /L). On day 7 of treatment with ATRA, the patient developed fever and it was followed by dry cough, respiratory distress, oxygen desaturation, and his CT thorax revealed bilateral lung infiltrates with subpleural sparing [Figure 1]. ATRA syndrome was suspected and ATRA was withheld and the patient was started on dexamethasone 10 mg twice a day. Fever subsided in 24h, respiratory distress settled in the next 4 days, dexamethasone was tapered, and ATRA was reintroduced after 6 days (day 17 of ATRA). After 2 days of reintroduction of ATRA, the patient developed a persistent unexplained fever in spite of being treated with appropriate antibiotics and antifungals. On day 28 of ATRA (leucocyte count 6 × 109 /L), the patient noticed painless ulcers over his scrotum. Examination of scrotum revealed four ulcers over the right hemi-scrotum, of which two were coalescing into a single ulcer. Ulcers were having black necrotic base with surrounding erythema and was indurated and nontender [Figure 2]. Bacterial and fungal stains and cultures from ulcer base were negative. ATRA-induced scrotal ulcer was suspected and ATRA was stopped. Subsequently, his fever subsided in 2 days and his scrotal ulcer started to heal and was completely healed by 4 weeks. Meanwhile, the patient achieved hematological recovery on day 33 of induction therapy and bone marrow showed complete remission, and hence ATRA was not restarted. Later, the patient received three courses of consolidation therapy with ATRA and daunorubicin, with no recurrence of differentiation syndrome or scrotal ulcer. He is currently on maintenance therapy and continues to be in remission. | Figure 1: HRCT thorax axial view showing diffuse ground glass opacities noted in bilateral lung fields predominantly in perihilar regions with sub pleural sparing
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| Discussion | | |
ATRA is the standard line of treatment in cases of APL due to its high success rate of remission. Among the many side effects of ATRA, differentiation syndrome stands out as the most dangerous and life-threatening complication, reported in approximately 25% of patients.[1] Meanwhile, unusual and rare scrotal manifestations such as exfoliative dermatitis, ulceration, and Fournier’s gangrene have also been reported. Scrotal ulcers have been described only in few case reports, each having number of cases in a range of one to maximum four.[2],[3],[4],[5],[6] Even though there is a case series from Japan which mentions the incidence being 14% (4 of 29 patients),[6] due to scarcity of case reports, the exact incidence of the ATRA related scrotal ulcers is unknown.
ATRA syndrome is characterized by endothelial damage, capillary leakage, and systemic inflammation and infiltration involving internal organs by maturing neutrophils due to cytokine release,[1],[7] whereas the genital ulcers show neutrophilic infiltration and focal necrosis involving exclusively the skin of genital region.[5],[6] Even though both these adverse effects are thought to be due to the cytokine response of maturing neutrophils, it is still unclear whether genital ulcer is a part of the systemic inflammation producing ATRA syndrome or it is a specific adverse effect of ATRA. In our patient, after the reintroduction of ATRA, development of genital ulcer was not associated with recurrence of ATRA syndrome. This might suggest that genital ulcer is a specific adverse effect of ATRA rather than a part of ATRA syndrome.
ATRA-related genital ulcers are reported to appear only in the induction therapy, from as early as day 7 of induction to day 32, with a time lag between fever and genital ulcer development.[3],[4],[5],[6] Similarly in our patient, scrotal ulceration developed after 9 days of fever on day 28 of ATRA. Hence, APL patients with fever and increasing neutrophil count are to be monitored for genital ulcer development.
There are different approaches mentioned in the management of ATRA-related scrotal ulcer. Due to the possibility of progression of the genital ulcer into life-threatening Fournier’s gangrene, discontinuation of ATRA is advised by many,[6],[8],[9] although continuation of ATRA has not always shown worsening of genital ulcer.[3],[4],[5],[6],[10] Similar dilemma exists for the administration of systemic and local steroids in genital ulcer. In our case we took the former approach and ATRA was withheld and steroids were not administered. Eventually, the ulcer healed in 4 weeks with no evidence of further worsening. As our patient went into complete remission after 5 days of ATRA withdrawal, there was no major change in the APL management. Due to the lack of prospective trails for the management of ATRA related genital ulcer, it is better to tailor the approach according to the patient’s condition and watch for worsening of the ulcer.
Clinicians managing APL with ATRA are usually aware and hence patients are monitored for the ATRA syndrome due to its higher incidence and its association with high mortality if not intervened early. Similarly, rarely developing genital ulcers can also progress to life-threatening Fournier’s gangrene if it is not recognized early and intervened. However, genital ulcers are usually reported late or underreported due to the painless nature and its location. Hence, we feel that the clinicians must also be aware of this distressing rare cutaneous complication of ATRA, monitor and intervene early in the course of the disease.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
| References | | |
| 1. | Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell RP Jr. The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann Intern Med 1992;117:292-6.  |
| 2. | Sun GL [Treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA): A report of five-year experience]. Zhonghua Zhong Liu Za Zhi 1993;15:125-9. |
| 3. | Tajima K, Sagae M, Yahagi A, Akiba J, Suzuki K, Hayashi T et al. Scrotum exfoliative dermatitis with ulcers associated with treatment of acute promyelocytic leukemia with all-trans retinoic acid. Rinsho Ketuseki 1998;39:48-52. |
| 4. | Mori A, Tamura S, Katsuno T, Nishimura Y, Itoh T, Saheki K, et al. Scrotal ulcer occurring in patients with acute promyelocytic leukemia during treatment with all-trans retinoic acid. Oncol Rep 1999;6:55-8. |
| 5. | Esser AC, Nossa R, Shoji T, Sapadin AN All-trans-retinoic acid-induced scrotal ulcerations in a patient with acute promyelocytic leukemia. J Am Acad Dermatol 2000;43:316-7. |
| 6. | Fukuno K, Tsurumi H, Goto H, Oyama M, Tanabashi S, Moriwaki H Genital ulcers during treatment with ALL-trans retinoic acid for acute promyelocytic leukemia. Leuk Lymphoma 2003;44:2009-13. |
| 7. | Koga H, Fujita I, Miyazaki S Effects of all-trans-retinoic acid on superoxide generation in intact neutrophils and a cell-free system. Br J Haematol 1997;97:300-5. |
| 8. | Shimizu D, Nomura K, Matsuyama R, Matsumoto Y, Ueda K, Masuda K, et al. Scrotal ulcers arising during treatment with all-trans retinoic acid for acute promyelocytic leukemia. Intern Med 2005;44:480-3. |
| 9. | Charles KS, Kanaa M, Winfield DA, Reilly JT Scrotal ulceration during all-trans retinoic (ATRA) therapy for acute promyelocytic leukaemia. Clin Lab Haematol 2000;22:171-4. |
| 10. | Pavithran K, Arjun R, Aruna R, Thomas M Scrotal ulceration during induction therapy of acute promyelocytic leukemia with ATRA. Am J Hematol 2004;75:260-1. |
[Figure 1], [Figure 2]
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