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Trastuzumab‐induced toxic epidermal necrolysis in a Her‐2‐positive metastatic breast cancer patient—A rare case report

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Clinical Case Reports
Authors:
  • Independent Researcher
  • Independent Researcher

Abstract and Figures

Key Clinical Message Toxic Epidermal Necrolysis (TEN) is a rare, but potentially fatal mucocutaneous reaction, that may occur due to an immunologic response to certain medications. However, TEN triggered by Trastuzumab is extremely rare. Early diagnosis, recognition, and prompt cessation of the offending drugs and initiation of steroid therapy with supportive management are the most important actions for managing TEN. Although rare, it is important to be vigilant about this potential adverse reactions associated with trastuzumab to ensure patient safety and contribute to better outcomes.
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Clin Case Rep. 2024;12:e9103.
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https://doi.org/10.1002/ccr3.9103
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INTRODUCTION
Overexpression of human epidermal growth factor re-
ceptor 2 (HER- 2) occurs in 25%–30% of breast cancer
patients.1 Trastuzumab is a humanized monoclonal an-
tibody that binds to the human epidermal growth factor
receptor 2 (HER- 2)/neu receptor and has been shown
to increase not only overall survival but also disease-
free survival in patients with HER- 2- positive breast
cancer.2,3
Stevens- Johnson Syndrome (SJS) and Toxic Epidermal
Necrolysis (TEN) exist as a spectrum of mucocutaneous
hypersensitivity reactions with a mortality rate of up to
30%.4 It is characterized by erythema, necrosis, and bul-
lous detachment of the skin and mucosal membranes. If
there is less than 10% epidermal detachment, the diagno-
sis is SJS, if there is between 10% and 30% involvements
of skin, the diagnosis is SJS- TEN overlap syndrome.5 The
more severe TEN designation is used when epidermal de-
tachment is greater than 30%.6
Received: 19 April 2024
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Revised: 28 May 2024
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Accepted: 5 June 2024
DOI: 10.1002/ccr3.9103
CASE REPORT
Trastuzumab- induced toxic epidermal necrolysis in a
Her- 2- positive metastatic breast cancer patient—A rare
casereport
JannatulFerdause1
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Sura JukrupMomtahena1
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RubamaKarim1
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Aditi PaulChowdhury1
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Nowshin TaslimaHossain1
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Md ArifulIslam1
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Maruf BinHabib2
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A. K. M. ShafiulKadir3
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Md ArifulHaque4,5,6
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.
1Ahsania Mission Cancer and General
Hospital, Dhaka, Bangladesh
2Department of Medicine, Ahsania
Mission Medical College, Dhaka,
Bangladesh
3Quest Bangladesh Biomedical
Research Center, Dhaka, Bangladesh
4Department of Public Health, Atish
Dipankar University of Science and
Technology, Dhaka, Bangladesh
5Voice of Doctors Research School,
Dhaka, Bangladesh
6Department of Orthopaedic Surgery,
Yan'an Hospital Affiliated to Kunming
Medical University, Kunming, Yunnan,
China
Correspondence
Jannatul Ferdause, Ahsania Mission
Cancer and General Hospital, Dhaka,
Bangladesh.
Email: taimur.jannatul@gmail.com
Key Clinical Message
Toxic Epidermal Necrolysis (TEN) is a rare, but potentially fatal mucocutaneous
reaction, that may occur due to an immunologic response to certain medications.
However, TEN triggered by Trastuzumab is extremely rare. Early diagnosis, rec-
ognition, and prompt cessation of the offending drugs and initiation of steroid
therapy with supportive management are the most important actions for manag-
ing TEN. Although rare, it is important to be vigilant about this potential adverse
reactions associated with trastuzumab to ensure patient safety and contribute to
better outcomes.
KEYWORDS
anti HER- 2 antibody, HER- 2- positive breast cancer, Steven Johnson syndrome, toxic epidermal
necrolysis, Trastuzumab
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FERDAUSE etal.
SJS/TEN most commonly presents as an adverse drug
reaction; however, infectious agents, immunotherapy, and
tamoxifen have also been implicated.7 Approximately 25%
of cases are idiopathic.4 Genetic predisposition in carriers
of different human leukocyte antigens (HLA)- B has been
demonstrated.7
We present a 36- year- old female with a history of
HER2- positive left breast cancer with brain metastasis,
FIGURE  Slides
showing histopathology and
immunohistochemistry. (A)
Histopathology slide showing
invasive ductal carcinoma, Grade
3; (B) Immunohistochemistry
showing all estrogen receptors (ER)
negative (magnification 40×); (C)
Immunohistochemistry showing
all progesterone receptors (PR)
negative (magnification 40×); (D)
Immunohistochemistry showing HER2
receptors positive (magnification 40×).
FIGURE  Images showing clinical
feature of TEN. (A) Showing blister
and epidermal detachment of skin on
scalp and ear. (B) Showing epidermal
detachment over back and shoulder. (C)
Showing blister and commencement of
epidermal detachment at the skin over
arm and forearm. (D) Showing blister over
face and commencement of epidermal
detachment at the skin over forehead and
mucositis over lip.
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FERDAUSE etal.
who developed TEN syndrome after her first dose of
trastuzumab.
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CASE HISTORY
This is a confirmed case of carcinoma in the right breast,
with the spread of cancer cells to the lymph nodes in the
right armpit since January 2022. The histology test con-
firmed the diagnosis of Invasive ductal Carcinoma, Grade
III (Figure1A). The receptor status indicated that the es-
trogen receptor (ER) was negative (Figure1B), the pro-
gesterone receptor (PR) was negative (Figure1C), and
the human epidermal growth factor receptor 2 (HER- 2)
was positive (3+) (Figure1D). The patient had received
neoadjuvant chemotherapy, consisting of four cycles of
doxorubicin + cyclophosphamide followed by four cy-
cles of docetaxel at 3- week interval. A right- sided modi-
fied radical mastectomy surgery followed this, and then
loco regional radiotherapy till June 2022. She was ad-
vised to undergo Trastuzumab, an anti- HER- 2 antibody,
but she was unable to afford it. One year later, in June
2023, she presented with brain metastases and underwent
whole- brain radiation, receiving a total dose of 30Gy ad-
ministered in 10 fractions. After finishing radiation, she
was recommended to undergo treatment with either
Trastuzumab or Tucatinib (anti HER- 2 agents) in addition
to oral capecitabine.
Nevertheless, she was unable to get it once again
because of financial limitations. Hence, we started
Lapatinib + capecitabine as palliative therapy. After
1.5 months, the patient consented to receiving Trastuzumab
and was administered her first dosage of the medication.
Three days post- administration of Trastuzumab, she pre-
sented with symptoms including fever, sore throat, odyno-
phagia, and generalized rashes. Based on these grievances,
she was admitted to our hospital.
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METHODS
After being hospitalized, she had a sudden and intense
appearance of painful and itchy blisters on her shoul-
ders, back, abdomen, and scalp. The blisters then spread
to her arms, chest, groin, and thighs, eventually leading
to the outer layer of her skin. There were areas of de-
nuded skin. The result of Nikolsky's sign was positive
(Figure2A,B).
In addition, she had severe mucositis affecting her eyes,
lips, oral cavity, pharynx, and genital area (Figure2C,D).
The estimated extent of body surface area (BSA) affected
was 35%.
TABLE  SCORTEN (score of toxic epidermal necrosis).
Number of parameters Predicted mortality
0 1%
1 4%
2 12%
3 32%
4 62%
5 85%
6 95%
7 99%
Note: Parameters: Age > 40 years, malignancy, heart rate > 120 beats/min,
epidermal detachment>10% of body surface area, serum urea > 10 mmol/L,
serum glucose: 14 mmol/L, serum bicarbonate < 20 mmol/L.
FIGURE  (A) Showing conjunctivitis after recovery. (B)
Showing dyspigmentation at the skin over the abdomen after
recovery.
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The complete blood count revealed leukocytosis with
a count of 22,000/μL (normal range: 4500- 11,000/μL)
and a hemoglobin level of 8 g/dL (normal range: 12–16 g/
dL). The renal and liver function tests yielded normal re-
sults. The C- reactive protein (CRP) level was measured
to be 35 mg/L, which is over the recommended limit of
<10.0 mg/L. Her heart rate was 100 beats/min. Her serum
glucose level and serum Bi carbonate level were within
normal range. Due to the fact that the detachment of the
outermost layer of her skin was 35% of her body surface
area, she was diagnosed with toxic epidermal necrolysis.
Her SCORTEN scale score was 2 (Table1). The patient
received supportive management, including the admin-
istration of high- dose steroids (methylprednisolone), an-
tihistamines (diphenhydramine), analgesics (Tramadol
hydrochloride), antibiotics (piperacillin + Tazobactum
4.5 gm every 6 h), antifungal medication (Caspofungin),
fluid and electrolyte replacement, nutritional support
through nasogastric feeding, oral care using 1% povidone-
iodine mouthwash or benzydamine mouthwash alterna-
tively, local antifungal treatment with 2% miconazole, skin
care, eye care, physiotherapy, and psychological support.
She saw a steady improvement in her health over a period
of 4 weeks. Despite ongoing complications of entropion
resulting in frequent conjunctivitis, as well as bronchiec-
tasis and depigmentation leading to a chronic cough, she
continues to experience these symptoms (Figure3A,B).
Currently, she is undergoing palliative chemotherapy
with the drugs Capecitabine and Lapatinib.
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CONCLUSION AND RESULTS
TEN is a rare but serious drug reaction that can have a rapid
and fatal course. Early diagnosis, recognition, and stopping
the offending drugs immediately while initiating steroid
therapy and supportive management are the most crucial
actions to take. Patients who experience such side effects
should be closely monitored for any lingering sequelae as-
sociated with TEN, including cutaneous, ocular, and oral
sequelae, all of which can significantly impair the quality
of life of cancer patients. It is important to note that this is
the only reported case of TEN triggered by Trastuzumab
therapy. Oncologists must inform their patients about the
potential risks associated with trastuzumab and maintain
constant vigilance to ensure their safety.
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DISCUSSION
In 1956, Alan Lyell, a Scottish dermatologist, reported
the first case of TEN.8,9 TEN is an extremely rare, acute
hypersensitivity reaction involving the skin and mucous
membranes. Its incidence is approximately 0.4–1.2 cases
per million person/year.10 Medications are responsible for
at least 70% of cases of TEN. Allopurinol, antiepileptics
(carbamazepine, lamotrigine, phenobarbital, and pheny-
toin), nevirapine, oxicam NSAIDs, and antibacterial sul-
fonamides are the most common drugs causing TEN.11
Infectious agents have also been implicated, mainly by
mycoplasma, herpes simplex virus, and cytomegalovirus.7
Few cases have been reported following cancer treat-
ments, including vemurafenib, ipilimumab, tamoxifen,
nivolumab, and pembrolizumab.4
TEN was previously considered to be related to Fas–Fas
ligand or granulysin- mediated apoptosis.
More recent studies suggested the reactive oxygen spe-
cies (ROS) as the initiating factor for keratinocyte dam-
age and that it precedes the activation of the apoptotic
systems.
Fas is a membrane- bound protein responsible for the
initiation of programmed cell death through a series of in-
tracellular events. Fas ligand (FasL), which is usually pro-
duced by cytotoxic T (CTL) cells and natural killer (NK)
cells, tends to bind to Fas on target cells, initiating apop-
tosis. The fact that the number of these cells is low in skin
biopsies taken from TEN patients indicates that they are
not the source of FasL.12 Virad etal.'s study in 1998 found
a high level of keratinocyte localization of FasL. This sug-
gests that keratinocytes may be responsible for their own
death.13 Granulysin is a pro- apoptotic protein that was
also detected in TEN blisters. It is one of many cytotoxic
molecules secreted by CTL and NK cells that lead to cell-
mediated cytotoxicity.14
Oxidative stress is one of the proposed theories of
TEN. Glutathione S- transferase- p (GST- p) is a biomarker
of oxidative stress in keratinocytes. A higher level of this
marker has been detected in TEN patients compared to
other cutaneous drug reactions.15 The culprit drug may
interfere with the detoxification pathways resulting in the
accumulation of reactive oxygen species (ROS), triggering
programmed cell death.16
TEN usually presents with a prodrome of fever, mal-
aise, and upper respiratory tract symptoms 7–21 days after
the initiation of the causative drug. Features more sugges-
tive of TEN are acute onset and rapid worsening of pain-
ful lesions of the skin and mucous membranes, including
eyes, mouth, nose, and genitalia. Skin lesions manifest as
blisters and ulcerations arising on generalized macules
with purpuric centers. The large denuded areas lead to
massive loss of fluid and protein, bleeding, hypothermia,
and infection. Necrolysis of respiratory and gastrointesti-
nal epithelium can occur and lead to bronchial obstruc-
tion and profuse diarrhea. The Nikolsky's sign, which
describes the detachment of the epidermis by minimal
tangential pressure, is a helpful clinical indicator.10,17,18
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FERDAUSE etal.
The prognosis of TEN is assessed based on the
SCORTEN scale,8,10 showing in Table1.
It is based on seven variables that need to be evaluated
within the first 24 h of hospital admission. These variables
include age, affected body surface area, heart rate, and pres-
ence of malignancy, serum urea, glucose, and bicarbonate.19
The mainstay treatment of TEN is supportive care until
re- epithelialization of the affected skin. Supportive mea-
sures include fluid resuscitation, pain management, wound
care, and nutritional support. Early management of these
cases in the emergency department should focus mainly on
two measures: discontinuation of the offending drug and
early referral to a burn unit or intensive care unit with ex-
perience in dealing with such cases. When taken in the first
24 h of blister formation, these two measures decrease infec-
tion rate and hospital stays and improve overall survival.20
The airway should be observed frequently, along with
the provision of supplemental oxygen via a face mask if
needed. In case of respiratory distress, endotracheal in-
tubation should be done by an expert. Fluid resuscitation
using crystalloids should be guided by one of the standard
burn resuscitation Performa (e.g., Parkland formula). The
target of resuscitation should be to maintain adequate
tissue perfusion by achieving an adequate mean arte-
rial blood pressure (ABP > 65 mm Hg), a central venous
pressure between 8 and 12 mmHg, and a urine output of
0.5–1 mL/kg/h.21,22 Pain management is extremely im-
portant to decrease a patient's distress. Opiates or patient-
controlled analgesia (PCA) can be used. The non- adhesive
sterile dressing should be used to dress areas of skin ero-
sions, and care should be taken to prevent hypothermia,
especially in the prehospital setting.20
Nutritional support is crucial in TEN patients due to
the hypercatabolic nature of this disease. Enteral feeding
is superior to parenteral feeding as it decreases the risk
of bacterial translocation. If oral mucosa is significantly
affected, a nasogastric tube may be used. Energy require-
ments and nutritional support must be carefully calcu-
lated (aim to 20–25 kcal/kg/day).23,24
Several complications can occur in TEN patients be-
cause of the extensive cutaneous and mucosal membrane
involvement. In the early stage, the presence of painful
stomatitis may interfere with oral intake with an increased
risk of dehydration. Loss of the epithelial barrier increases
the risk of infection and septicemia. This may evolve
into septic shock and multi- organ failures.25 In the long
term, the involved skin may show signs of hypo or hyper-
pigmentation, while the affected mucosal surfaces may
heal by stenosis and strictures. In females, vulvovaginal
involvement is common and can lead to stenosis, vulvar
adenosis, and dyspareunia. In men, phimosis is the most
common complication.26
Ocular complications are one of the most common and
serious sequelae of TEN. Therefore, early ophthalmologi-
cal consultation is advisable in such cases. Corneal ulcers,
xerophthalmia, meibomian gland dysfunction, panophth-
amitis, or even blindness are some of the reported compli-
cations.27 Respiratory complications include pulmonary
embolism, adult respiratory distress syndrome (ARDS),
and pneumonia.28 Gastrointestinal complications are in
the form of extensive bleeding from the affected mucosa,
gingival synechia, and xerostomia due to affection of the
salivary glands.29
AUTHOR CONTRIBUTIONS
Jannatul Ferdause: Conceptualization; data curation;
formal analysis; investigation; methodology; supervision;
writing – original draft; writing – review and editing. Sura
Jukrup Momtahena: Data curation; formal analysis; in-
vestigation; methodology; resources; validation; writing
– original draft; writing – review and editing. Rubama
Karim: Data curation; formal analysis; investigation;
methodology; software; validation; visualization; writ-
ing – review and editing. Aditi Paul Chowdhury: Data
curation; formal analysis; investigation; methodology; re-
sources; software; validation; writing – review and editing.
Nowshin Taslima Hossain: Data curation; formal anal-
ysis; investigation; methodology; resources; software; vali-
dation; writing – review and editing. Md Ariful Islam:
Data curation; formal analysis; investigation; methodol-
ogy; resources; software; visualization; writing – review
and editing. Maruf Bin Habib: Data curation; formal
analysis; investigation; methodology; resources; valida-
tion; visualization; writing – review and editing. A. K.
M. Shafiul Kadir: Data curation; formal analysis; inves-
tigation; methodology; resources; software; visualization;
writing – review and editing. Md Ariful Haque: Formal
analysis; investigation; methodology; resources; software;
visualization; writing – original draft; writing – review and
editing.
ACKNOWLEDGMENTS
The authors have nothing to report.
FUNDING INFORMATION
Authors have not received any funds.
CONFLICT OF INTEREST STATEMENT
The authors declare that they have no financial conflict of
interest with regard to the content of this report.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data
were created or analyzed in this study.
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FERDAUSE etal.
ETHICS STATEMENT
None.
CONSENT
Written informed consent was obtained from the patient
to publish this report in accordance with the journal's pa-
tient consent policy.
ORCID
Md Ariful Haque https://orcid.
org/0000-0003-4632-5153
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How to cite this article: Ferdause J, Momtahena
SJ, Karim R, et al. Trastuzumab- induced toxic
epidermal necrolysis in a Her- 2- positive metastatic
breast cancer patient—A rare case report. Clin Case
Rep. 2024;12:e9103. doi:10.1002/ccr3.9103
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Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases characterized by detachment of the epidermis and mucous membrane. SJS/TEN are considered to be on the same spectrum of diseases with different severities. They are classified by the percentage of skin detachment area. SJS/TEN can also cause several complications in the liver, kidneys, and respiratory tract. The pathogenesis of SJS/TEN is still unclear. Although it is difficult to diagnose early stage SJS/TEN, biomarkers for diagnosis or severity prediction have not been well established. Furthermore, optimal therapeutic options for SJS/TEN are still controversial. Several drugs, such as carbamazepine and allopurinol, are reported to have a strong relationship with a specific human leukocyte antigen (HLA) type. This relationship differs between different ethnicities. Recently, the usefulness of HLA screening before administering specific drugs to decrease the incidence of SJS/TEN has been investigated. Skin detachment in SJS/TEN skin lesions is caused by extensive epidermal cell death, which has been considered to be apoptosis via the Fas-FasL pathway or perforin/granzyme pathway. We reported that necroptosis, i.e. programmed necrosis, also contributes to epidermal cell death. Annexin A1, released from monocytes, and its interaction with the formyl peptide receptor 1 induce necroptosis. Several diagnostic or prognostic biomarkers for SJS/TEN have been reported, such as CCL-27, IL-15, galectin-7, and RIP3. Supportive care is recommended for the treatment of SJS/TEN. However, optimal therapeutic options such as systemic corticosteroids, intravenous immunoglobulin, cyclosporine, and TNF-α antagonists are still controversial. Recently, the beneficial effects of cyclosporine and TNF-α antagonists have been explored. In this review, we discuss recent advances in the pathophysiology and management of SJS/TEN.
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Stevens-Johnson syndrome (SJS) is characterized by mucocutaneous tenderness and typical hemorrhagic erosions, erythema and epidermal detachment presenting as blisters and areas of denuded skin. SJS is often observed after drug use as well as after bacterial or viral infections. Several drugs are at high risk of inducing SJS, but there are no cases in the English literature regarding anabolic steroid use triggering SJS. In our paper, we describe a case in which use of anabolic androgenic steroids (AAS) was associated with SJS. The patient participated in competitive body-building and regularly took variable doses of AAS. Initial symptoms (headache, weakness, pharyngodynia, and fever) were ignored. After a week he presented to the Emergency Department with a burning sensation on the mouth, lips, and eyes. Painful, erythematous, maculopapular, and vesicular lesions appeared all over the body, including on the genitals. During hospitalization, he also developed a cardiac complication. The patient had not taken any drugs except AAS.
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Stevens-Johnson syndrome and toxic epidermal necrolysis represent a spectrum of severe cutaneous adverse reactions that carry the potential for severe, long-Term adverse effects, including death. Although medications are most commonly implicated in the development of these diseases, other factors, including infection and genetics, play a role. Management is generally supportive in nature and includes maintenance of the patient's airway, breathing, and circulation. Special disease considerations include the use of skin barrier management, unique infection prevention measures, and systemic immunomodulatory therapies. Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
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Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse reactions to drugs which cause a life-threatening eruption of mucocutaneous blistering and epithelial sloughing. The two terms describe phenotypes occurring at either end of a severity spectrum: SJS is the less extensive form (<10% body surface area (BSA) detachment), while TEN is the more extensive (>30% BSA detachment). Cases in which there is 10-30% epidermal detachment are referred to as SJS-TEN overlap. This article is protected by copyright. All rights reserved.
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The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the diagnosis and management of the full spectrum of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and SJS-TEN overlap in adults during the acute phase of the disease. The document aims to: Offer an appraisal of all relevant literature up to February 2016, focusing on any key developments. Address important, practical clinical questions relating to the primary guideline objective, i.e. accurate diagnosis and identification of cases and suitable treatment. Provide guideline recommendations. Discuss areas of uncertainty, potential developments and future directions.
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Introduction: Afatinib is a tyrosine kinase inhibitor (TKI), that has been approved for treating patients with epidermal growth factor receptor (EGFR) mutated advanced non-small-cell lung cancer (NSCLC). Stevens-Johnson syndrome (SJS) related to EGFR directed TKIs is a rare adverse event. Case presentation: We report a case of a 79-year-old white female with EGFR-mutated, metastatic non-small-cell lung cancer treated with afatinib as first-line palliative treatment, who developed a SJS after two months of treatment. Discontinuation of the TKI and systemic glucocorticoid treatment led to improvement of symptoms and recovery. Conclusion: Severe adverse cutaneous drug reactions that predominantly involve the skin and mucous membranes during treatment with afatinib should alert clinicians to suspect SJS and react appropriately.