Two months later, the lesions healed [Figure 3]. therapy and overall survival, while it is still not confirmed for other cutaneous manifestations.[1,2,4] Case History A 69-year-old female was observed in our dermatology department owing to leg ulcers evolving for the past six months. Her medical history was amazing for stage IIIa adenocarcinoma of the lung under erlotinib, an EGFR inhibitor, for the past 7 months, with good response. She had been previously medicated with gefitinib, withdrawn because of exuberant paronychia. Clinically, we observed multiple deep ulcers with well-defined borders and a necrotic center, exclusively located on the back of both legs, along with perilesional erythema [Physique 1]. Under the suspicion of EGFR inhibitor toxicity, erlotinib was suspended. Skin biopsy revealed ulceration that extended to subcutaneous excess fat, where a septal panniculitis with predominance of polymorphonuclear neutrophils was present along with fibrinoid necrosis in the vessel walls [Physique ?[Physique2a2a and ?andb].b]. Microbiologic and immunologic studies were normal. Chest x-ray showed stability of the tumor and no indicators of tuberculosis. She initiated 0.5 mg/kg/day prednisolone and local treatment with maltodextrin, with significant improvement. Two months later, the lesions healed [Physique 3]. Meanwhile, afatinib was initiated. After 8 months of therapy, the patient developed new ulcers, similar to the former, located in the submammary and intergluteal folds [Physique 4]. Because of a decline on patient’s general condition, we decided not to biopsy these new lesions as they were clinically similar to the previously reported. She was started on topical betamethasone with significant improvement. At this point, the disease evolved to stage IV and a new mutation, T790M, was identified, forcing the replacement of afatinib for osimertinib, a third generation EGFR inhibitor. After 5 months of treatment with this drug, there are no sign of skin adverse effects. Open in a separate window Physique 1 Deep ulcerated lesions with a necrotic center of the posterior aspects of both legs Open in a separate window Physique 2 On low power, presently there is an ulcer that extends deep into the subcutaneous excess fat (H and E, 10). On high power, note the septal panniculitis-like lesion with an inflammatory infiltrate with neutrophils along with fibrinoid necrosis in the vessel walls (H and E, 200) Open in a separate window Physique 3 Posterior aspects of both legs after healing of the ulcers Open in a separate window Physique 4 Ulcers around the intergluteal fold after 8 months of treatment with afatinib Discussion Skin toxicity among patients under treatment with EGFR inhibitors has protean manifestations because its receptor is usually highly expressed in keratinocytes, sebocytes, and outer root sheath of hair follicle.[1,6,7] Rash is the most frequent cutaneous side effect, usually manifesting as an acneiform eruption.[2,3,4,5,6] Pruritus, xerosis, nail, hair, and mucosal changes are also reported.[3,4] Less common manifestations include leukocytoclastic vasculitis and nonscarring alopecia.[6,7] These adverse events are transversal to the entire pharmacological group and therefore considered class-specific.[1,4] The inhibition of EGFR in basal keratinocytes and hair follicles seems to explain the cutaneous side effects of these drugs, but still remains unclear why only some patients are affected.[8] Although usually mild to moderate, these manifestations interfere with patient’s quality of life and can lead to delay in treatment, dose adjustment, or ultimately drug discontinuation, threatening clinical outcome.[1,3] Previous studies show comparable incidence of cutaneous toxicity between erlotinib and afatinib, with fewer side effects and better tolerability with gefitinib, probably because of the differences in their molecular structures.[1,5] Osimertinib is used in patients with T790M-positive advanced lung malignancies, and according to previous trials has comparable adverse effects to other agents of the class, but less studies are available.[9] Panniculitis represents an inflammatory infiltrate of the subcutaneous fat that may show concomitant septal thickening and vasculitis.[10] Rarely, neutrophilic panniculitis has been described as a drug side effect of chemotherapies and targeted molecular therapies.[10] To our knowledge, this is the first report of panniculitis related to EGFR inhibitors. We attributed the panniculitis to a side effect of EGFR inhibitors because there were no confounding elements explaining the cutaneous findings. The higher incidence of erlotinib and afatinib cutaneous effects in comparison with gefinitib, could justify why the panniculitis did not occur in the first place under treatment with gefitinib. Considering that skin lesions have reproduced simultaneously with cancer progression, it is likely that this side effect may not be considered a marker of efficacy as opposed to previously acknowledged cutaneous effects. Given the potential severity of the cutaneous lesions, there may be implications in the maintenance of long-term tumor-targeted therapy. The increasing Rabbit Polyclonal to GLCTK use of these drugs in oncology and future occurrence of comparable cases will clarify the importance of this side effect in the progression of oncologic disease..The increasing use of these drugs in oncology and future occurrence of similar cases will clarify the importance of this side effect in the progression of oncologic disease. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.. EGFR inhibitor, for the past 7 months, with good response. She had been previously medicated with gefitinib, withdrawn because of exuberant paronychia. Clinically, we observed multiple deep ulcers with well-defined borders and a necrotic center, exclusively located on the back of both legs, along with perilesional erythema [Figure 1]. Under the suspicion of EGFR inhibitor toxicity, erlotinib was suspended. Skin biopsy revealed ulceration that extended to subcutaneous fat, where a septal panniculitis with predominance of polymorphonuclear neutrophils was present along SU6656 with fibrinoid necrosis in the vessel walls [Figure ?[Figure2a2a and ?andb].b]. Microbiologic and immunologic studies were normal. Chest x-ray showed stability of the tumor and no signs of tuberculosis. She initiated 0.5 mg/kg/day prednisolone and local treatment with maltodextrin, with significant improvement. Two months later, the lesions healed [Figure 3]. Meanwhile, afatinib was initiated. After 8 months of therapy, the patient developed new ulcers, similar to the former, located in the submammary and intergluteal folds [Figure 4]. Because of a decline on patient’s general condition, we decided not to biopsy these new lesions as they were clinically similar to the previously reported. She was started on topical betamethasone with significant improvement. At this point, the disease evolved to stage IV and a new mutation, T790M, was identified, forcing the replacement of afatinib for osimertinib, a third generation EGFR inhibitor. After 5 months of treatment with this drug, there are no sign of skin adverse effects. Open in a separate window Figure 1 Deep ulcerated lesions with a necrotic center of the posterior SU6656 aspects of both legs Open in a separate SU6656 window Figure 2 On low power, there is an ulcer that extends deep into the subcutaneous fat (H and E, 10). On high power, note the septal panniculitis-like lesion with an inflammatory infiltrate with neutrophils along with fibrinoid necrosis in the vessel walls (H and E, 200) Open in a separate window Figure 3 Posterior aspects of both legs after healing of the ulcers Open in a separate window Figure 4 Ulcers on the intergluteal fold after 8 months of treatment with afatinib Discussion Skin toxicity among patients under treatment with EGFR inhibitors has protean manifestations because its receptor is highly expressed in keratinocytes, sebocytes, and outer root sheath of hair follicle.[1,6,7] Rash is the most frequent cutaneous side effect, usually manifesting as an SU6656 acneiform eruption.[2,3,4,5,6] Pruritus, xerosis, nail, hair, and mucosal changes are also reported.[3,4] Less common manifestations include leukocytoclastic vasculitis and nonscarring alopecia.[6,7] These adverse events are transversal to the entire pharmacological group and therefore considered class-specific.[1,4] The inhibition of EGFR in basal keratinocytes and hair follicles seems to explain the cutaneous side effects of these drugs, but still remains unclear why only some patients are affected.[8] Although usually mild to moderate, these manifestations interfere with patient’s quality of life and can lead to delay in treatment, dose adjustment, or ultimately drug discontinuation, threatening clinical outcome.[1,3] Previous studies show comparable incidence of cutaneous toxicity between erlotinib and afatinib, with fewer side effects and better tolerability with gefitinib, probably because of the differences in their molecular structures.[1,5] Osimertinib is used in patients with T790M-positive advanced lung malignancies, and according to previous trials has similar adverse effects to other agents of the class, but less studies are available.[9] Panniculitis represents an inflammatory infiltrate of the subcutaneous fat that may show concomitant septal thickening and vasculitis.[10] Rarely, neutrophilic panniculitis has been described as a drug side effect of chemotherapies and targeted molecular therapies.[10] To our knowledge, this is the first report of panniculitis related to EGFR inhibitors. We attributed the panniculitis to a side effect of EGFR inhibitors because there were no confounding elements explaining the cutaneous findings. The higher incidence of erlotinib and afatinib cutaneous effects in comparison with gefinitib, could justify why the panniculitis did not occur in the first place under treatment with gefitinib. Considering that skin lesions have reproduced simultaneously with cancer progression, it is likely that this side effect may not be considered a marker of efficacy as opposed to previously recognized cutaneous effects. Given the potential severity of the cutaneous lesions, there may be implications in the maintenance.The increasing use of these drugs in oncology and future occurrence of similar cases will clarify the importance of this side effect in the progression of oncologic disease. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.. the rash correlates significantly with tumor response to therapy and overall survival, while it is still not proven for other cutaneous manifestations.[1,2,4] Case History A 69-year-old female was observed in our dermatology department owing to leg ulcers evolving for the past six months. Her medical history was remarkable for stage IIIa adenocarcinoma of the lung under erlotinib, an EGFR inhibitor, for the past 7 months, with good response. She had been previously medicated with gefitinib, withdrawn because of exuberant paronychia. Clinically, we observed multiple deep ulcers with well-defined borders and a necrotic center, exclusively located on the back of both legs, along with perilesional erythema [Figure 1]. Under the suspicion of EGFR inhibitor toxicity, erlotinib was suspended. Skin biopsy revealed ulceration that extended to subcutaneous fat, where a septal panniculitis with predominance of polymorphonuclear neutrophils was present along with fibrinoid necrosis in SU6656 the vessel walls [Figure ?[Figure2a2a and ?andb].b]. Microbiologic and immunologic studies were normal. Chest x-ray showed stability of the tumor and no signs of tuberculosis. She initiated 0.5 mg/kg/day prednisolone and local treatment with maltodextrin, with significant improvement. Two months later, the lesions healed [Figure 3]. Meanwhile, afatinib was initiated. After 8 months of therapy, the patient developed new ulcers, similar to the former, located in the submammary and intergluteal folds [Figure 4]. Because of a decrease on patient’s general condition, we decided not to biopsy these fresh lesions as they were clinically similar to the previously reported. She was started on topical betamethasone with significant improvement. At this point, the disease developed to stage IV and a new mutation, T790M, was recognized, forcing the alternative of afatinib for osimertinib, a third generation EGFR inhibitor. After 5 weeks of treatment with this drug, you will find no sign of skin adverse effects. Open in a separate window Number 1 Deep ulcerated lesions having a necrotic center of the posterior aspects of both legs Open in a separate window Number 2 On low power, right now there is an ulcer that stretches deep into the subcutaneous extra fat (H and E, 10). On high power, notice the septal panniculitis-like lesion with an inflammatory infiltrate with neutrophils along with fibrinoid necrosis in the vessel walls (H and E, 200) Open in a separate window Number 3 Posterior aspects of both legs after healing of the ulcers Open in a separate window Number 4 Ulcers within the intergluteal collapse after 8 weeks of treatment with afatinib Conversation Pores and skin toxicity among individuals under treatment with EGFR inhibitors offers protean manifestations because its receptor is definitely highly indicated in keratinocytes, sebocytes, and outer root sheath of hair follicle.[1,6,7] Rash is the most frequent cutaneous side effect, usually manifesting as an acneiform eruption.[2,3,4,5,6] Pruritus, xerosis, toenail, hair, and mucosal changes will also be reported.[3,4] Less common manifestations include leukocytoclastic vasculitis and nonscarring alopecia.[6,7] These adverse events are transversal to the entire pharmacological group and therefore considered class-specific.[1,4] The inhibition of EGFR in basal keratinocytes and hair follicles seems to explain the cutaneous side effects of these medicines, but still remains unclear why only some patients are affected.[8] Although usually mild to moderate, these manifestations interfere with patient’s quality of life and can lead to hold off in treatment, dose adjustment, or ultimately drug discontinuation, threatening clinical outcome.[1,3] Earlier studies show similar incidence of cutaneous toxicity between erlotinib and afatinib, with fewer side effects and better tolerability with gefitinib, probably because of the differences in their molecular structures.[1,5] Osimertinib is used in individuals with T790M-positive advanced lung malignancies, and according to earlier trials has related adverse effects to additional agents of the class, but less studies are available.[9].