10.5826/dpc.1302a130
text/xml
2160-9381
2847
en
Riccardo G. Borroni
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
tyrosin-kinase inhibitors
Sorafenib-Induced Acute Generalized Exanthematous Pustulosis
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Research Letter
2023-04-29
2022-09-14
2023-04-29
2023-06-05
e2023130
Dermatol Pract Concept
Riccardo G. Borroni
2023/04/29
10.5826/dpc.1302a130
e2023130
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy
2160-9381
tyrosin-kinase inhibitors
en
e2023130
Alegre-Sánchez A, de Perosanz-Lobo D, Pinilla-Pagnon I, Muñoz-Zato E. Sorafenib-induced Acute Generalized Exanthematous Pustulosis: An Increasing Association? Actas Dermosifiliogr. 2017;108(6):599-601. DOI: 10.1016/j.ad.2016.11.018. PMID: 28262110.
Sorafenib-Induced Acute Generalized Exanthematous Pustulosis
https://dpcj.org/index.php/dpc/article/download/2847/2083
                    Sorafenib-Induced Acute Generalized
                         Exanthematous Pustulosis
              Andrea Cortese1,2, Saverio Pancetti3, Tiziana Pressiani4, Francesco Toso1,2,
               Giovanni Fiorillo1,2, Antonio Costanzo1,2, Riccardo Giovanni Borroni1,2


1 Dermatology, Humanitas Research Hospital – IRCCS, Rozzano (MI), Italy
2 Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy
3 Pathology, Humanitas Research Hospital - IRCCS, Rozzano (MI), Italy
4 Oncology, Humanitas Research Hospital - IRCCS, Rozzano (MI), Italy



Key words: sorafenib, acute generalized exanthematous pustulosis, severe cutaneous adverse reaction; tyrosin-kinase inhibitors
Citation: Cortese A, Pancetti S, Pressiani T, et al. Sorafenib-Induced Acute Generalized Exanthematous Pustulosis. Dermatol Pract Concept.
2023;13(2):e2023130. DOI: https://doi.org/10.5826/dpc.1302a130
Accepted: November 17, 2022; Published: April 2023
Copyright: ©2023 Cortese et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Andrea Cortese, MD, Dermatology, Humanitas Research Hospital – IRCCS, Via A. Manzoni 56, 20089 Rozzano
(MI), Italy. E-mail: andreacortese08@gmail.com




Introduction                                                             Past medical history was negative for psoriasis. On physi-
                                                                         cal examination, numerous disseminated tiny non-follicular
Acute generalized exanthematous pustulosis (AGEP) is a se-               pustules were observed overlying confluent erythematous
vere cutaneous adverse reaction (SCAR), with an incidence                macules on his trunk and limbs, involving about 75% of
rate between 1 and 5 cases per million per year. Clinically,             the body surface area (Figure 1). Furred tongue and desqua-
AGEP is characterized by the abrupt onset of edematous                   mation of the lips were also present. Body temperature was
erythema and widespread small sterile pustules. Fever with               38.5 °C. No enlarged lymph nodes or hepatosplenomegaly
leukocytosis generally accompany cutaneous findings and                  were noticed. Complete blood count showed leukocytosis
mucous membrane may also be affected; the mortality rate of              with relative neutrophilia (80%, normal range 50%-75%);
AGEP is up to 5%. The main differential diagnosis of AGEP                ­serum bilirubin level was increased (3.0 mg/dL, normal range
with generalized pustular psoriasis is often challenging [1].            0.3-1.2 mg/dL). Blood and skin cultures resulted negative.
                                                                         ­Histological examination of a skin biopsy showed multifo-

Case Presentation                                                        cal spongiosis in the epidermis, with intraepidermal pustules
                                                                         containing fibrin and neutrophils. In the superficial dermis, a
A 62-year-old man with HBV-related chronic hepatitis was                 mixed inflammatory infiltrate composed of scattered neutro-
referred to our Dermatology Unit for the acute onset of                  phils and lymphocytes was present (Figure 2).
skin and mucosal lesions associated with fever, 7 days since                  According to the validation score of the EuroSCAR study
the start of oral sorafenib 400 mg twice daily. for radia-               group [2], a diagnosis of acute generalized exanthematous
tion therapy-refractory stage IV hepatocellular carcinoma.               pustulosis (AGEP) was made; using the Naranjo scale [3] the



Research Letter | Dermatol Pract Concept. 2023;13(2):e2023130                                                                           1
    Figure 1. Confluent erythematous macules on his trunk and limbs, involving about 75% of the body surface area, d with overlying
    disseminated tiny non-follicular pustules.



                                                                      skin reaction collected six points and was considered proba-
                                                                      bly relate” to sorafenib (Figure 3), so the drug was discontin-
                                                                      ued with steady improvement in the following days.



                                                                      Conclusions
                                                                      Sorafenib is an oral multi-kinase inhibitor that mainly tar-
                                                                      gets C-RAF, B-RAF, vascular endothelial growth factor
                                                                      (VEGF) receptors, and platelet-derived growth factor recep-
                                                                      tor (PDGFR). The drug is approved for the treatment of both
                                                                      unresectable hepatocellular carcinoma and advanced renal
                                                                      cell carcinoma. Up to 60% patients treated with sorafenib
                                                                      experience cutaneous adverse events, including hand-foot
                                                                      skin reactions, maculo-papular exanthem, pruritus, alopecia,
                                                                      subungual splinter hemorrhages, seborrheic dermatitis-like
                                                                      eruption and erythema multiforme [4]. AGEP has been Most

Figure 2. Intraepidermal pustule containing fibrin and neutrophils;
                                                                      commonly associated with aminopenicillins, quinolones,
in the superficial dermis, a mixed inflammatory infiltrate composed   chloroquine and sulphonamides, and to our knowledge only
scattered neutrophils and lymphocytes was present.                    three cases of sorafenib-induced pustular reactions were




2                                                                         Research Letter | Dermatol Pract Concept. 2023;13(2):e2023130
                                                                                                                                  Do not
  #                                              Naranjo Questions                                               Yes     No       know
  1.    Are there previous conclusive reports on this reaction?                                                   1        0         0
  2.    Did the adverse event occur after the suspected drug was administered?                                    2       -1         0
  3.    Did the adverse reaction improve when the drug was discontinued or a specific                             1        0         0
        antagonist was administered?
  4.    Did the adverse reaction reappear when the drug was readministered?                                       2       -1         0
  5.    Are there alternative causes (other than the drug) that could have on their own cause the                 -1       2         0
        reaction?
  6.    Did the reaction reappear when a placebo was given?                                                       -1       1         0
  7.    Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?                 1        0         0
  8.    Was the reaction more severe when the does was increased or less severe when the dose                     1        0         0
        was decreased?
  9.    Did the patient have a similar reaction to the same or similar drugs in any previous                      1        0         0
        exposure?
 10.    Was the adverse event confirmed by any objective evidence?                                                1        0         0

Figure 3. Naranjo Adverse Drug Reaction Probability Scale.




published: one of them defined as acute localized exanthem-                3. Naranjo CA, Busto U, Sellers EM, et al. A method for estimat-
atous pustulosis (ALEP) [5], while two reported as AGEP                       ing the probability of adverse drug reactions. Clin Pharmacol
                                                                              Ther. 1981;30(2):239-245. DOI: 10.1038/clpt.1981.154. PMID:
[6,7]. These evidence may suggest an increasing incidence of
                                                                              7249508.
sorafenib-induced AGEP due to the relatively recent intro-
                                                                           4. Bracarda S, Ruggeri EM, Monti M, et al. Early detection, pre-
duction use of this kinase-inhibitor. We therefore underline                  vention and management of cutaneous adverse events due to
the importance of early diagnosis of AGEP during sorafenib                    sorafenib: recommendations from the Sorafenib Working Group.
therapy, in order to promptly withdraw the causative drug                     Crit Rev Oncol Hematol. 2012;82(3):378-386. DOI: 10.1016/j.
and at the same time to consider other therapeutic options                    critrevonc.2011.08.005. PMID: 21944842.
                                                                           5. Liang CP, Yang CS, Shen JL, Chen YJ. Sorafenib-induced acute
for metastatic cancer.
                                                                              localized exanthematous pustulosis in a patient with hepatocel-
                                                                              lular carcinoma. Br J Dermatol. 2011;165(2):443-445. DOI:
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Research Letter | Dermatol Pract Concept. 2023;13(2):e2023130                                                                              3
