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| DRUG WATCH |
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| Year : 2023 | Volume
: 55
| Issue : 2 | Page : 138-140 |
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Genital ulcers following all-trans-retinoic acid therapy: A case series with review of literature
Neerja Saraswat1, Sushil Kumar1, Rahul Prem2, Durga Madhab Tripathi1
1 Department of Dermatology, Military Hospital Agra, Agra, Uttar Pradesh, India
2 Department of Internal Medicine, Military Hospital Agra, Agra, Uttar Pradesh, India
| Date of Submission | 19-Oct-2021 |
| Date of Decision | 14-Apr-2023 |
| Date of Acceptance | 28-Apr-2023 |
| Date of Web Publication | 03-Jun-2023 |
Correspondence Address:
Sushil Kumar
MLN Medical College, Prayagraj, Uttar Pradesh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijp.ijp_811_21
All-trans-retinoic acid (ATRA) has transformed the treatment of acute promyelocytic leukemia. Most of the adverse effects associated with this drug are minor barring differentiation syndromes. Genital ulcers feature among the underreported adverse effects of ATRA which needs to be kept in mind to avoid life-threatening complications. We describe two cases who developed genital ulcers while treated with ATRA.
Keywords: Acute promyelocytic leukemia, all-trans-retinoic acid, genital ulcers
How to cite this article:
Saraswat N, Kumar S, Prem R, Tripathi DM. Genital ulcers following all-trans-retinoic acid therapy: A case series with review of literature. Indian J Pharmacol 2023;55:138-40 |
How to cite this URL:
Saraswat N, Kumar S, Prem R, Tripathi DM. Genital ulcers following all-trans-retinoic acid therapy: A case series with review of literature. Indian J Pharmacol [serial online] 2023 [cited 2023 Sep 22];55:138-40. Available from: https://www.ijp-online.com/text.asp?2023/55/2/138/378035 |
| » Introduction | |  |
All-trans-retinoic acid (ATRA) has become a landmark drug in the management of acute promyelocytic leukemia (APML). Its combination with other systemic therapy leads to the induction of complete remission in 90% cases of APML. Although differentiation syndrome (DS) is the most dreaded and life-threatening adverse effects of ATRA, a variety of other side effects such as xerosis, xerostomia, and cheilitis are also reported. Genital ulceration is one of the rare adverse effects of ATRA. Herein, we report two cases, one male and a female between the age of 36–40 years who presented to us with ATRA-induced genital ulceration.
| » Case Reports | | |
Case 1
Our first case was a 36-year-old female who was diagnosed to have APML (t[15;17] translocation on cytogenetic analysis). She presented with fever, sore throat, weakness, and two episodes of hemoptysis. She was started on ATRA at the dose of 45 mg/m2 and idarubicin. Two weeks later, she developed fever and multiple painless ulcers in the vulval mucosae, for which she was reviewed by the gynecologist and referred to the dermatologist. Her repeated blood culture and pus swab did not show any growth and she did not respond to broad-spectrum antibiotics. Her dermatological examination revealed six superficial ulcers, two at 3 o' clock and one each at 7, 9, and 12 o' clock positions [Figure 1]. There was no induration and discharge, the surrounding skin was normal, and the base was clean. She was suspected to have ATRA-related vulval ulcers. ATRA was suspended in consultation with oncologist. Her fever subsided in 24 h and ulcer healed completely in 3 weeks of stopping ATRA. ATRA was restarted and the patient tolerated treatment without any adverse events. | Figure 1: Dermatological examination revealed six superficial ulcers, two at 3 o' clock and one each at 7, 9, and 12 o' clock position
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Case 2
Our second case was a 40-year-old male reported with complaints of fever, cough, malaise, bleeding from the gums, and hematuria of 6 weeks duration. The patient reported to urologist with these complaints, his investigation revealed pancytopenia, increased prothrombin, and activated partial thromboplastin time. His peripheral blood smear revealed atypical cells. The diagnosis of APML was subsequently confirmed by maturation arrest and hypercellular bone marrow aspirate at the promyelocytic stage and cytogenetic analysis revealing the presence of t (15;17) translocation. The patient was put on the induction regimen of ATRA 45 mg/m2/day and idarubicin 12 mg/m2/day on day 2, 4, 6, and 8. On the 11th day of the therapy, the patient developed high-grade intermittent fever, and on day 13th, he noticed a solitary painless ulcer on the base of the penis. He denied any history of oral ulcers, redness of eyes, and sexual exposure for the past 2 months. He was referred to the dermatology department for further management. Examination of the ulcer revealed a solitary, superficial ulcer with a clean base [Figure 2]. Bacterial and fungal stains from the ulcer base were negative. He was suspected to have ATRA-induced genital ulcer and his ATRA was stopped. The fever subsided in 48 h and his ulcer healed completely in the next 4 weeks of suspending ATRA. ATRA was restarted without any similar complaints later. | Figure 2: Examination of the ulcer revealed solitary, superficial ulcer with clean base
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| » Discussion | | |
ATRA is the most widely used treatment modality for APML patients. ATRA alone causes complete but brief remission in APML cases by enhancing maturation of promyelocytes into neutrophils and increasing apoptosis of APML cells. However, to sustain remission further induction, consolidation, and maintenance chemotherapy is required.
Although ATRA is well-tolerated drug and minor adverse effects such as fever, headache, xerosis, xerostomia, hyperlipidemia, and arthralgia are reported commonly. DS, previously known as retinoic acid syndrome, is undoubtedly the most serious complication of differentiating agents such as ATRA and arsenic trioxide therapy. DS is seen in approximately 25% of patients during induction therapy on ATRA.
Genital ulcers due to ATRA are unique and rarely described cutaneous adverse effects. Even though both the adverse effects, DS and genital ulcers are the result of cytokines released from maturing neutrophils, it is still debatable, whether genital ulcers are a part of the systemic inflammation producing DS or a specific adverse effect of ATRA.[1]
ATRA-induced scrotal ulcerations were first described by Sun et al.[2] in 1993 in a Chinese patient who developed scrotal ulcers and exfoliative dermatitis. Further studies revealed that these genital ulcerations due to ATRA are generally seen between the 19th and 22nd day of the therapy and resolve within 3 weeks to 3 months with or without local or systemic corticosteroid application. Although the exact mechanism is elusive till date, it has been proposed that genital ulceration due to ATRA therapy occurs due to the release of various cytokines such as tumor necrosis factors, interleukin (IL) 1, IL6, and IL8 which stimulate peripheral leukocytes eventually resulting in ulcerations. Another mechanism proposed is the production of oxygen radicles such as superoxide-induced activation of leukocytes and subsequent tissue damage. [Table 1] depicts studies reporting genital ulcers due to ATRA in the literature. We feel that ATRA-related genital ulcers are grossly underreported due to the anatomical site and painless nature of these ulcers.[3],[4],[5]
The approach to the management of ATRA-related genital ulcers is still debatable. While suspending ATRA has been advised by some authors due to the progression of genital ulcers into Fournier's gangrene which is a life-threatening condition, some authors have reported that genital ulcers do not worsen, even if ATRA is continued. A similar dilemma exists regarding the use of oral or topical corticosteroids.
We recommend that the decision to continue or to suspend ATRA has to be tailor-made depending upon the clinical condition of the patients. Considering, the major benefit of ATRA in the management of APML, the use of topical antibiotics and corticosteroids to prevent secondary infection may be beneficial. We also recommend that since these genital ulcers are painless in nature and are less likely to be reported by the patients, it is prudent to be proactive in cases managed with ATRA so as to avoid life-threatening conditions like Fournier's gangrene to develop. We report two cases of genital ulcers due to ATRA to highlight its rarity. As per the World Health Organization-Uppsala Monitoring Center causality criteria, our case qualifies for “probable” category.[6]
We chose to stop ATRA in both the cases due to the fever associated and keeping the possibility of the penile ulcer progressing to Fournier's gangrene. However, both our cases were restarted on ATRA without any similar complaints which have been observed in past studies too.
| » Conclusion | | |
Genital ulcers due to ATRA therapy are an uncommon and poorly understood cutaneous adverse effect and need to be kept as a possibility. To avoid life-threatening complications in these cases, it may be prudent to counsel the patients before the initiation of the therapy.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for 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.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| » References | | |
| 1. | Degos L, Dombret H, Chomienne C, Daniel MT, Micléa JM, Chastang C, et al. All-trans-retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia. Blood 1995;85:2643-53.  |
| 2. | Sun GL. treatment of acute promyelocytic luekemia(APL) with all trans retinoic acid (ATRA): a report of five year experience. Zhonghua Zhong Liu Za Zhi 1993;15:125-9 |
| 3. | 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. [Full text] |
| 4. | Valizadeh N. Fournier's gangrene in a case of acute promyelocytic leukemia during ATRA therapy. Int J Hematol Oncol Stem Cell Res 2011;39-40. |
| 5. | Al Huneini M, Wasim F, Al Farsi K, Al-Khabori M, Al Kindi S. Genital ulcer development in patients with acute promyelocytic leukaemia treated with all-trans retinoic acid: A case series. Oman Med J 2013;28:207-9. |
| 6. | Yavasoglu I, Unubol M, Sargin G, Kadikoylu G, Bolaman Z. Penile ulcer atra related in patient with acute promyelocytic leukemia. Mediterr J Hematol Infect Dis 2012;4:e2012054. |
[Figure 1], [Figure 2]
[Table 1]
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