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Idiopathic cutaneous lymphoid hyperplasia: A diagnostic dilemma
4958
5301
Idiopathic cutaneous lymphoid hyperplasia: A diagnostic dilemma Taylor Duke, The George Washington University; Thomas Lee, MD, The George Washington University; Divya Sharma, BS, The George Washington University; Thomas Enelow, MD, The George Washington University; Edgar Khalluf, MD, The George Washington University; Adam Friedman, MD, The George Washington University
IL12Brs6887695-GG genotype is associated to biological treatment response in psoriasis Noemi Eiris, MD, Dermatology Department, Complejo Asistencial Universitario de Le on; Leire Gonzalez-Lara, MD, Dermatology Department, Hospital de Cabue~ nes; Ana Batalla, MD, Dermatology Department, Complejo Hospitalario de Pontevedra; Eliecer Coto, PhD, Department of Molecular Genetics, Hospital Universitario Central de Asturias; Pablo CotoSegura, MD, Dermatology Department, Hospital Universitario Central de Asturias Introduction: Psoriasis treatment has experienced a revolution in the last decades with the arrival of biological therapies whose action mechanism is targeted blocking of cytokines or small molecules. Several targets have been identified and successfully blocked, giving us an array of biological therapies for treating severe psoriasis. Recently there has been an interest in pharmacogenetic studies that analyze effectiveness of biological therapies through the study of genetic variants in psoriasis populations.
Cutaneous lymphoid hyperplasia (CLH) is a rare but often benign polyclonal lymphoproliferative condition that can histologically and even clinically mimic cutaneous lymphoma. Often idiopathic, it can form as a reactive process secondary to arthropod bites, medication use, trauma, vaccination, and infection. The clinical presentation can be diverse, ranging from pink to plum-colored papules, nodules, or plaques, creating a diagnostic challenge. We present two cases of CLH with distinct clinical pictures: the first is a 29-year-old white man who complained of a pruritic, indurated, poorly-demarcated, round, pink, dermal plaque on the posterior neck for 5 months. The second patient, a 43-year-old African American woman, presented with a dome-shaped, smooth, ectatic, well-demarcated, pink nodule above the right eyebrow for 4 weeks. Punch biopsies from both patients showed a diffuse, dense dermal infiltrate of predominantly T-cell lymphocytes without cytologic atypia. These two cases highlight the broad clinical differential of CLH ranging from an epidermal neoplasm to dermal inflammatory processes. Treatment modalities include topical or intralesional glucocorticoids, surgical excision, cytotoxic agents, interferons and antimalarials. Close observation is advised as CLH can rarely progress to frank B-cell lymphoma. Therefore, it is important to consider CLH in the differential of morphologically similar presentations. Commercial support: None identified.
Material and Methods: 126 Spanish psoriasis patients receiving biological therapies (antiTNF: infliximab, adalimumab, etanercept or antiIL12/23: ustekinumab) whose response to initial biological treatment had been recorded and could be retrospectively examined. They were genotyped for two IL12B SNPs (rs6887695 and rs3212227) and a statistical association analysis performed, with treatment success determined as reaching PASI75 at week 24 after drug induction. To compare genetic variants and response to antiTNF treatments versus antiIL12/23 treatment, treatment cycles were used instead, with effectiveness data obtained from the first antiTNF treatment and the antiIL12/23 treatment in patients that had received both. Results: PASI75 was achieved in 68.3% of the patients in their first biological treatment received. We observed a significant association (P ¼ .03; OR, 2.46) between carriers of the genotype IL12Brs6887695-GG and a good response to initial biological treatment, even after HLA-Cw6 correction. Although the small number of treatment cycles did not allow to replicate that finding when studying by treatment kind (anti TNF: 117, antiIL12/23: 42), there was a nonsignificant trend toward antiTNF drugs (P ¼ .087; OR, 2.04 (0.90-4.65)) versus antiIL12/23 treatment (P ¼ .725; OR, 0.77 (0.18-3.34)). Discussion: IL12Brs6887695-GG haplotype has only previously been significantly associated to therapeutic success with ustekinumab in HLA-Cw6 carriers in a 2016 study by Galluzzo et al. We have found that in our population, IL12Brs6887695-GG could be used as a predictor of therapeutic success to biological treatment, independent from HLA-Cw6 status, and our data suggest that the association detected might lean towards the antiTNF treatments instead. Growing evidence from pharmacogenetic studies might help identify in a near future which patients would respond better to biological treatment or even which kind of treatment should be initially selected for a better chance of success. Commercial support: None identified.
4621 IGF-1R-biased signaling role in melanoma metastasis Ada Girnita, MD, Karolinska University Hospital; Iara Troccoli Dragensjo, MD, Karolinska University Hospital; Leonard Girnita, MD, Karolinska University Hospital In melanoma biology, a major impact in evolution is made by the hyperactivation of the RAS/RAF/MEK/ERK signaling pathway combined with inactivation of the tumor suppressor p53 pathway. The aim of the present study is to investigate the effects of ‘‘Mdm2 reactivation’’ following pharmacological disruption of the Mdm2/p53 complexes, with focus on IGF-1R, the last one known as well as cancer relevant Mdm2 substrate.
5464
Conclusion: This study highlights the complex bidirectional interplay between the IGF and p53 signaling pathways: a control feedback mechanism in normal cells is converted in a feed-forward mechanism in cancer cells. This cross regulation at the level of Mdm2 between p53 and IGF-1R has important implications for therapy targeting either pathway alone or in combination and needs to be fully understood.
Immunohistochemistry of HPV-related markers in cutaneous squamous cell carcinoma Alessio Giubellino, MD, University of Miami; Victoria Billero, University of Miami; Paolo Romanelli, MD, University of Miami Nonmelanoma skin cancers (NMSCs), including squamous cell carcinoma and basal cell carcinoma, are the most common type of cancers, accounting for more than 5 million diagnoses each year in the US alone. In particular, squamous cell carcinoma (SCC) constitutes about 20% of NMSC and is responsible for the majority of NMSC cancer deaths. Among the risk factors for the development of SCC is the infection of the epidermal keratinocytes with human papilloma virus (HPV). The significance of infection with HPV in NMSC is a challenging and controversial topic in dermatology, but scientific evidence is mounting in favor of an etiopathologic role. In contrast to cervical, anogenital and oral squamous lesions, the relationship between HPV infection and cutaneous SCC have not been extensively studied. Precisely, no specific markers have been adopted for routine diagnostic dermatopathologic evaluation of these lesions. In the present study, we explored the use of antibodies targeting the human papillomavirus capsid proteins and other HPV-related targets in biopsies of fifteen patients with cutaneous SCC with histopathologic features suggestive of a viral cytopathic etiology. Capsid and other protein expression was evaluated by immunohistochemistry using commercially available antibodies. Our results illustrate the potential application in routing clinical practice of novel HPVrelated markers for the evaluation of cutaneous squamous cell lesions for the improvement of diagnostic and clinical management of patients suffering from this disease.
Commercial support: None identified.
Commercial support: None identified.
Methods: We analyzed the functional effects of Mdm2 reactivation on the IGF1R intracellular signaling following disruption of the p53/Mdm2 interaction by Nutlin-3. Results: Nutlin-3 treatment reactivates p53 with concomitant Mdm2 increase and caused a dose and time dependent decrease in IGF-1R, most noticeably in p53 wild type cell lines. This decrease is not associated with changes in IGF-1R transcript levels and occurs only in the presence of ligand activated IGF-1R. Nutlin-3 treatment causes IGF-1R/Mdm2 association and ubiquitination, downregulation of the IGF-1R and MAPK signaling. Nutlin-3 induced IGF-1R degradation is paralleled by a reduction in IGF-1einduced melanoma cell invasion and migration.
AB402
J AM ACAD DERMATOL
JUNE 2017
5301
Idiopathic cutaneous lymphoid hyperplasia: A diagnostic dilemma Taylor Duke, The George Washington University; Thomas Lee, MD, The George Washington University; Divya Sharma, BS, The George Washington University; Thomas Enelow, MD, The George Washington University; Edgar Khalluf, MD, The George Washington University; Adam Friedman, MD, The George Washington University
IL12Brs6887695-GG genotype is associated to biological treatment response in psoriasis Noemi Eiris, MD, Dermatology Department, Complejo Asistencial Universitario de Le on; Leire Gonzalez-Lara, MD, Dermatology Department, Hospital de Cabue~ nes; Ana Batalla, MD, Dermatology Department, Complejo Hospitalario de Pontevedra; Eliecer Coto, PhD, Department of Molecular Genetics, Hospital Universitario Central de Asturias; Pablo CotoSegura, MD, Dermatology Department, Hospital Universitario Central de Asturias Introduction: Psoriasis treatment has experienced a revolution in the last decades with the arrival of biological therapies whose action mechanism is targeted blocking of cytokines or small molecules. Several targets have been identified and successfully blocked, giving us an array of biological therapies for treating severe psoriasis. Recently there has been an interest in pharmacogenetic studies that analyze effectiveness of biological therapies through the study of genetic variants in psoriasis populations.
Cutaneous lymphoid hyperplasia (CLH) is a rare but often benign polyclonal lymphoproliferative condition that can histologically and even clinically mimic cutaneous lymphoma. Often idiopathic, it can form as a reactive process secondary to arthropod bites, medication use, trauma, vaccination, and infection. The clinical presentation can be diverse, ranging from pink to plum-colored papules, nodules, or plaques, creating a diagnostic challenge. We present two cases of CLH with distinct clinical pictures: the first is a 29-year-old white man who complained of a pruritic, indurated, poorly-demarcated, round, pink, dermal plaque on the posterior neck for 5 months. The second patient, a 43-year-old African American woman, presented with a dome-shaped, smooth, ectatic, well-demarcated, pink nodule above the right eyebrow for 4 weeks. Punch biopsies from both patients showed a diffuse, dense dermal infiltrate of predominantly T-cell lymphocytes without cytologic atypia. These two cases highlight the broad clinical differential of CLH ranging from an epidermal neoplasm to dermal inflammatory processes. Treatment modalities include topical or intralesional glucocorticoids, surgical excision, cytotoxic agents, interferons and antimalarials. Close observation is advised as CLH can rarely progress to frank B-cell lymphoma. Therefore, it is important to consider CLH in the differential of morphologically similar presentations. Commercial support: None identified.
Material and Methods: 126 Spanish psoriasis patients receiving biological therapies (antiTNF: infliximab, adalimumab, etanercept or antiIL12/23: ustekinumab) whose response to initial biological treatment had been recorded and could be retrospectively examined. They were genotyped for two IL12B SNPs (rs6887695 and rs3212227) and a statistical association analysis performed, with treatment success determined as reaching PASI75 at week 24 after drug induction. To compare genetic variants and response to antiTNF treatments versus antiIL12/23 treatment, treatment cycles were used instead, with effectiveness data obtained from the first antiTNF treatment and the antiIL12/23 treatment in patients that had received both. Results: PASI75 was achieved in 68.3% of the patients in their first biological treatment received. We observed a significant association (P ¼ .03; OR, 2.46) between carriers of the genotype IL12Brs6887695-GG and a good response to initial biological treatment, even after HLA-Cw6 correction. Although the small number of treatment cycles did not allow to replicate that finding when studying by treatment kind (anti TNF: 117, antiIL12/23: 42), there was a nonsignificant trend toward antiTNF drugs (P ¼ .087; OR, 2.04 (0.90-4.65)) versus antiIL12/23 treatment (P ¼ .725; OR, 0.77 (0.18-3.34)). Discussion: IL12Brs6887695-GG haplotype has only previously been significantly associated to therapeutic success with ustekinumab in HLA-Cw6 carriers in a 2016 study by Galluzzo et al. We have found that in our population, IL12Brs6887695-GG could be used as a predictor of therapeutic success to biological treatment, independent from HLA-Cw6 status, and our data suggest that the association detected might lean towards the antiTNF treatments instead. Growing evidence from pharmacogenetic studies might help identify in a near future which patients would respond better to biological treatment or even which kind of treatment should be initially selected for a better chance of success. Commercial support: None identified.
4621 IGF-1R-biased signaling role in melanoma metastasis Ada Girnita, MD, Karolinska University Hospital; Iara Troccoli Dragensjo, MD, Karolinska University Hospital; Leonard Girnita, MD, Karolinska University Hospital In melanoma biology, a major impact in evolution is made by the hyperactivation of the RAS/RAF/MEK/ERK signaling pathway combined with inactivation of the tumor suppressor p53 pathway. The aim of the present study is to investigate the effects of ‘‘Mdm2 reactivation’’ following pharmacological disruption of the Mdm2/p53 complexes, with focus on IGF-1R, the last one known as well as cancer relevant Mdm2 substrate.
5464
Conclusion: This study highlights the complex bidirectional interplay between the IGF and p53 signaling pathways: a control feedback mechanism in normal cells is converted in a feed-forward mechanism in cancer cells. This cross regulation at the level of Mdm2 between p53 and IGF-1R has important implications for therapy targeting either pathway alone or in combination and needs to be fully understood.
Immunohistochemistry of HPV-related markers in cutaneous squamous cell carcinoma Alessio Giubellino, MD, University of Miami; Victoria Billero, University of Miami; Paolo Romanelli, MD, University of Miami Nonmelanoma skin cancers (NMSCs), including squamous cell carcinoma and basal cell carcinoma, are the most common type of cancers, accounting for more than 5 million diagnoses each year in the US alone. In particular, squamous cell carcinoma (SCC) constitutes about 20% of NMSC and is responsible for the majority of NMSC cancer deaths. Among the risk factors for the development of SCC is the infection of the epidermal keratinocytes with human papilloma virus (HPV). The significance of infection with HPV in NMSC is a challenging and controversial topic in dermatology, but scientific evidence is mounting in favor of an etiopathologic role. In contrast to cervical, anogenital and oral squamous lesions, the relationship between HPV infection and cutaneous SCC have not been extensively studied. Precisely, no specific markers have been adopted for routine diagnostic dermatopathologic evaluation of these lesions. In the present study, we explored the use of antibodies targeting the human papillomavirus capsid proteins and other HPV-related targets in biopsies of fifteen patients with cutaneous SCC with histopathologic features suggestive of a viral cytopathic etiology. Capsid and other protein expression was evaluated by immunohistochemistry using commercially available antibodies. Our results illustrate the potential application in routing clinical practice of novel HPVrelated markers for the evaluation of cutaneous squamous cell lesions for the improvement of diagnostic and clinical management of patients suffering from this disease.
Commercial support: None identified.
Commercial support: None identified.
Methods: We analyzed the functional effects of Mdm2 reactivation on the IGF1R intracellular signaling following disruption of the p53/Mdm2 interaction by Nutlin-3. Results: Nutlin-3 treatment reactivates p53 with concomitant Mdm2 increase and caused a dose and time dependent decrease in IGF-1R, most noticeably in p53 wild type cell lines. This decrease is not associated with changes in IGF-1R transcript levels and occurs only in the presence of ligand activated IGF-1R. Nutlin-3 treatment causes IGF-1R/Mdm2 association and ubiquitination, downregulation of the IGF-1R and MAPK signaling. Nutlin-3 induced IGF-1R degradation is paralleled by a reduction in IGF-1einduced melanoma cell invasion and migration.
AB402
J AM ACAD DERMATOL
JUNE 2017