Lichen Planus Pemphigoides Associated With PD-1 and PD-L1 Inhibitors: A Case Series and Review of the Literature.

ABSTRACT: Immune checkpoint inhibitors are increasingly being used in the treatment of various solid organ and hematologic malignancies. Dermatologic toxicities associated with programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) therapy have been widely reported in the literature. It is important for clinicians to be aware of these toxicities to ensure prompt recognition and treatment. Herein, we present the clinical, histopathologic, and immunofluorescence findings of 3 patients diagnosed with lichen planus pemphigoides (LPP) after treatment with anti-PD-1 inhibitors. We also reviewed the literature and summarize 7 previously reported cases of LPP associated with anti-PD-1 and anti-PD-L1 inhibitors. LPP was diagnosed at a median time of 24.4 weeks (range: 4-78 weeks) after initiation of immunotherapy. Clinical findings included papules, plaques, erosions, vesicles, and bullae on the trunk and extremities. Oral involvement was present in half the cases. Histopathologic features of immunotherapy-induced LPP included lichenoid or vacuolar interface dermatitis, the presence of eosinophils, and subepidermal bullae. Direct immunofluorescence demonstrated linear deposition of immunoglobulin G (IgG) or C3. Indirect immunofluorescence demonstrated linear IgG along basement membrane zone on monkey esophagus in 2 cases and linear IgG on the epidermal side of salt split skin in 3 cases. Serum anti-BP180 was elevated in all cases in which enzyme-linked immunosorbent assay was performed.

Evaluation of a novel rash scale and a serum proteomic predictor in a randomized phase II trial of sequential or concurrent cetuximab and pemetrexed in previously treated non-small cell lung cancer.

BACKGROUND: Candidate predictive biomarkers for epidermal growth factor receptor inhibitors (EGFRi), skin rash and serum proteomic assays, require further qualification to improve EGFRi therapy in non-small cell lung cancer (NSCLC). In a phase II trial that was closed to accrual because of changes in clinical practice we examined the relationships among candidate biomarkers, quantitative changes in tumor size, progression-free and overall survival. METHODS: 55 patients with progressive NSCLC after platinum therapy were randomized to receive (Arm A) cetuximab, followed by pemetrexed at progression, or (Arm B) concurrent cetuximab and pemetrexed. All received cetuximab monotherapy for the first 14 days. Pre-treatment serum and weekly rash assessments by standard and EGFRi-induced rash (EIR) scales were collected. RESULTS: 43 patients (20-Arm A, 23-Arm B) completed the 14-day run-in. Median survival was 9.1 months. Arm B had better median overall (Arm B = 10.3 [95% CI 7.5, 16.8]; Arm A = 3.5 [2.8, 11.7] months P = 0.046) and progression-free survival (Arm B = 2.3 [1.6, 3.1]; Arm A = 1.6 [0.9, 1.9] months P = 0.11). The EIR scale distributed ratings among 6 rather than 3 categories but ordinal scale rash severity did not predict outcomes. The serum proteomic classifier and absence of rash after 21 days of cetuximab did. CONCLUSIONS: Absence of rash after 21 days of cetuximab therapy and the serum proteomic classifier, but not ordinal rash severity, were associated with NSCLC outcomes. Although in a small study, these observations were consistent with results from larger retrospective analyses.

Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C.

Disruption of the nucleotide excision repair (NER) pathway by mutations can cause xeroderma pigmentosum, a syndrome predisposing affected individuals to development of skin cancer. The xeroderma pigmentosum C (XPC) protein is essential for initiating global genome NER by recognizing the DNA lesion and recruiting downstream factors. Here we show that inhibition of the deacetylase and longevity factor SIRT1 impairs global genome NER through suppressing the transcription of XPC in a SIRT1 deacetylase-dependent manner. SIRT1 enhances XPC expression by reducing AKT-dependent nuclear localization of the transcription repressor of XPC. Finally, we show that SIRT1 levels are significantly reduced in human skin tumors from Caucasian patients, a population at highest risk. These findings suggest that SIRT1 acts as a tumor suppressor through its role in DNA repair.

Bullous pemphigoid in late childhood successfully treated with mycophenolate mofetil as an adjuvant therapy.

Bullous pemphigoid is an acquired subepidermal vesiculobullous disease most commonly seen in the elderly. We report a 16-year-old girl with bullous pemphigoid who achieved disease remission with mycophenolate mofetil as an adjuvant therapy.

Regulation of XPC deubiquitination by USP11 in repair of UV-induced DNA damage.

Nucleotide excision repair (NER) is the most versatile DNA repair pathway for removing DNA damage caused by UV radiation and many environmental carcinogens. NER is essential for suppressing tumorigenesis in the skin, lungs and brain. Although the core NER proteins have been identified and characterized, molecular regulation of NER remains poorly understood. Here we show that ubiquitin-specific peptidase 11 (USP11) positively regulates NER by deubiquitinating xeroderma pigmentosum complementation group C (XPC) and promoting its retention at the DNA damage sites. In addition, UV irradiation induces both USP11 recruitment to the chromatin and USP11 interaction with XPC in an XPC-ubiquitination-dependent manner. Furthermore, we found that USP11 is down-regulated in chronically UV-exposed mouse skin and in skin tumors from mice and humans. Our findings indicate that USP11 plays an important role in maintaining NER capacity, and suggest that USP11 acts as a tumor suppressor via its role in DNA repair.

Autophagy gene ATG7 regulates ultraviolet radiation-induced inflammation and skin tumorigenesis.

Macroautophagy (hereafter autophagy) is a cellular "self-eating" process that is implicated in many human cancers, where it can act to either promote or suppress tumorigenesis. However, the role of autophagy in regulation of inflammation during tumorigenesis remains unclear. Here we show that autophagy is induced in the epidermis by ultraviolet (UV) irradiation and autophagy gene Atg7 promoted UV-induced inflammation and skin tumorigenesis. Atg7 regulated UV-induced cytokine expression and secretion, and promoted Ptgs2/Cox-2 expression through both a CREB1/CREB-dependent cell autonomous mechanism and an IL1B/IL1ß-dependent non-cell autonomous mechanism. Adding PGE2 increased UV-induced skin inflammation and tumorigenesis, reversing the epidermal phenotype in mice with Atg7 deletion in keratinocytes. Similar to ATG7 knockdown in human keratinocytes, ATG5 knockdown inhibited UVB-induced expression of PTGS2 and cytokines. Furthermore, ATG7 loss increased the activation of the AMPK pathway and the phosphorylation of CRTC1, and led to endoplasmic reticulum (ER) accumulation and reduction of ER stress. Inducing ER stress and inhibiting calcium influx into the ER by thapsigargin reverses the inflammation and tumorigenesis phenotype in mice with epidermal Atg7 deletion. Taken together, these findings demonstrate that deleting autophagy gene Atg7 leads to a suppression of carcinogen-induced protumorigenic inflammatory microenvironment and tumorigenesis of the epithelium.

The promise of molecular targeted therapies: protein kinase inhibitors in the treatment of cutaneous malignancies.

A new revolution in cancer therapy has arrived with the development of agents targeting cancer-related protein kinases, critical regulators of malignant behavior. These drugs are selective inhibitors of protein kinases, which mediate most signal transduction pathways in malignant cells and result in increased proliferation, evasion of apoptosis, invasion, and metastasis. Protein kinases are the second largest group of drug targets and they account for 20% to 30% of the drug discovery programs of many biotechnology and pharmaceutical companies. A critical review of the literature is performed, highlighting selective inhibitors of signal transduction molecules involved in nonmelanoma skin cancer, melanoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, Kaposi's sarcoma, and systemic mastocytosis. Clinical studies were identified by searches of the Proceedings of the American Society of Clinical Oncology Annual Meetings, MedLine, and www.clinicaltrials.gov. Clinical trials of kinase inhibitors in study populations are illustrated, highlighting early results, side effects, and potential improvements in outcomes. Case series and case reports were included for rare diseases. These drugs will have important implications in clinical dermatology, based on their expected frequent use in the treatment of dermatologic malignancies, and their associated cutaneous side effects.

Treatment of hemorrhagic lymphatic malformation of the tongue with a pulsed-dye laser.

Hemorrhagic lymphatic malformation (formerly called hemolymphangioma) of the tongue is an uncommon malformation that may pose both functional and cosmetic problems for the patient. The challenge has been to find a conservative treatment with low morbidity and better results than those achieved with surgical excision, which has been the mainstay of therapy. We report a case of successful treatment of a hemorrhagic lymphatic malformation of the tongue with a variable-pulse 595-nm pulsed-dye laser (Vbeam; Candela Corp, Wayland, Mass). In this patient, pulsed-dye laser treatment of the hemorrhagic lymphatic malformation achieved satisfactory functional and cosmetic outcomes. Its use in superficial vascular lesions of the mucosa should be considered.

Digital anesthesia with epinephrine: an old myth revisited.

BACKGROUND: The prohibition against the use epinephrine with local anesthetics for digital blocks or infiltrative anesthesia is an established dogma in dermatologic surgery. Major textbooks reinforce this teaching suggesting that there is substantial risk of digital gangrene caused by local anesthesia containing epinephrine. OBJECTIVE: To provide a comprehensive literature review of the cases of digital necrosis associated with the use of local anesthesia containing epinephrine. METHODS: A PubMed search of the National Library of Medicine database using the terms "lidocaine" and "epinephrine" and "finger" with no specified limits was performed. RESULTS: A total of 16 papers were referenced and only 6 papers dealt with digital anesthesia. A total of 50 cases of digital gangrene were reported, mostly in the early part of the 20th century. In 21 cases digital gangrene was associated with anesthetic mixed with epinephrine. Actual concentration of epinephrine was known in only 4 cases. Careful analysis of all cases of necrosis did not support epinephrine itself as a cause. Other contributing factors including older compounds (cocaine, eukaine, and procaine), non-standardized inaccurate methods of mixing epinephrine with lidocaine, inappropriate use of a tourniquet, postoperative hot soaks, infection, or large anesthetic volume were also present. None of the reported cases were associated with the use of a commercial lidocaine-epinephrine mixture. CONCLUSION: A literature review failed to provide evidence to support the dogma that block or infiltrative anesthesia with lidocaine and epinephrine produces digital necrosis. Proper injection technique and adequate selection of patients (absence of thrombotic, vasospastic conditions, or uncontrolled hypertension) are mandatory to minimize complications. The addition of epinephrine, in fact, reduces the need for the use of tourniquets and large volumes of anesthetic and provides better and longer pain control during digital procedures.

Dermatologic and dental aspects of the 2012 International Tuberous Sclerosis Complex Consensus Statements.

IMPORTANCE: The 2012 International Tuberous Sclerosis Complex Clinical Consensus Conference was convened to update the last consensus statement in 1998. Skin and dental lesions are common in tuberous sclerosis complex (TSC) and are a frequent concern for patients. Recognition of these lesions is imperative for early diagnosis, given the treatment advances that may improve patient outcomes. OBJECTIVE: To detail recommendations for the diagnosis, surveillance, and management of skin and dental lesions in TSC. EVIDENCE REVIEW: The TSC Dermatology and Dentistry Subcommittee, 1 of 12 subcommittees, reviewed the relevant literature from 1997 to 2012. FINDINGS: A consensus on skin and dental issues was achieved within the Dermatology and Dentistry Subcommittee before recommendations were presented, discussed, and agreed on in a group meeting of all subcommittees from June 14 to 15, 2012. CONCLUSIONS AND RELEVANCE: Skin and dental findings comprise 4 of 11 major features and 3 of 6 minor features in the diagnostic criteria. A definite diagnosis of TSC is defined as the presence of at least 2 major features or 1 major and 2 or more minor features; in addition, a pathological mutation in TSC1 or TSC2 is diagnostic. Skin and oral examinations should be performed annually and every 3 to 6 months, respectively. Intervention may be indicated for TSC skin or oral lesions that are bleeding, symptomatic, disfiguring, or negatively affecting function. Options presented include surgical excision, laser(s), or use of a mammalian target of rapamycin inhibitor.

Deregulation of XPC and CypA by cyclosporin A: an immunosuppression-independent mechanism of skin carcinogenesis.

Skin cancer is the most common malignancy in organ transplant recipients, causing serious morbidity and mortality. Preventing and treating skin cancer in these individuals has been extraordinarily challenging. Following organ transplantation, cyclosporin A (CsA) has been used as an effective immunosuppressive to prevent rejection. Therefore immunosuppression has been widely assumed to be the major cause for increased skin carcinogenesis. However, the mechanism of skin carcinogenesis in organ transplant recipients has not been understood to date; specifically, it remains unknown whether these cancers are immunosuppression dependent or independent. Here, using both immunocompromised nude mice which are defective in mature T lymphocytes as an in vivo model and human keratinocytes as an in vitro model, we showed that CsA impairs genomic integrity in the response of keratinocytes to ultra violet B (UVB). Following UVB radiation, CsA inhibited UVB-induced DNA damage repair by suppressing the transcription of the DNA repair factor xeroderma pigmentosum C (XPC). In addition, CsA compromised the UVB-induced checkpoint function by upregulating the molecular chaperone protein cyclophilin A (CypA). XPC mRNA levels were lower, whereas CypA mRNA and protein levels were higher in human skin cancers than in normal skin. CsA-induced phosphoinositide 3-kinase(PI3K)/AKT activation was required for both XPC suppression and CypA upregulation. Blocking UVB damage or inhibiting the PI3K/AKT pathway prevented CsA-sensitized skin tumorigenesis. Our findings identified deregulation of XPC and CypA as key targets of CsA, and UVB damage and PI3K/AKT activation as two principal drivers for CsA-sensitized skin tumorigenesis, further supporting an immunosuppression-independent mechanism of CsA action on skin tumorigenesis.

Immunohistochemistry for immunoglobulin G4 on paraffin sections for the diagnosis of pemphigus.

CONTEXT: Pemphigus is a group of autoimmune vesiculobullous diseases characterized by immunoglobulin G (IgG) antibodies directed against desmosomal adhesion proteins, with IgG4 being the predominant subclass in active diseases. Direct immunofluorescence for IgG performed on fresh-frozen tissue plays a crucial role in diagnosing pemphigus. However, the diagnosis might be hindered when frozen tissue is not available. OBJECTIVE: To evaluate the usefulness of immunohistochemistry for IgG4 performed on paraffin sections as a diagnostic test for pemphigus. DESIGN: Eighteen immunofluorescence-proven pemphigus cases (12 pemphigus vulgaris, 6 pemphigus foliaceus) were studied. Four normal skin specimens and 32 nonpemphigus vesiculobullous disease specimens served as controls. Paraffin sections of all cases were examined immunohistochemically for IgG4 expression. Positivity was defined as distinct, condensed, continuous immunoreactivity localized to the intercellular junctions of keratinocytes. RESULTS: The immunostains were independently evaluated in a masked manner by 3 pathologists, with a 100% interobserver agreement. Nine of 12 pemphigus vulgaris cases (sensitivity 75.0%), and 4 of 6 pemphigus foliaceus cases (sensitivity 66.7%), were positive for IgG4 immunostain. The overall sensitivity was 72.2%. One control specimen (bullous pemphigoid) showed IgG4 positivity (specificity 97.2%). In specimens demonstrating acantholysis, 8 of 10 pemphigus vulgaris cases (sensitivity 80.0%) and 4 of 4 pemphigus foliaceus cases (sensitivity 100.0%) were positive for IgG4. The overall sensitivity for specimens with acantholytic lesions was 85.7%. CONCLUSION: Immunohistochemistry for IgG4 provides a reasonably sensitive and highly specific test for diagnosing pemphigus, especially when frozen tissue is not available, and active acantholytic lesions are examined.

PTEN positively regulates UVB-induced DNA damage repair.

Nonmelanoma skin cancer is the most common cancer in the United States, where DNA-damaging ultraviolet B (UVB) radiation from the sun remains the major environmental risk factor. However, the critical genetic targets of UVB radiation are undefined. Here we show that attenuating PTEN in epidermal keratinocytes is a predisposing factor for UVB-induced skin carcinogenesis in mice. In skin papilloma and squamous cell carcinoma (SCC), levels of PTEN were reduced compared with skin lacking these lesions. Likewise, there was a reduction in PTEN levels in human premalignant actinic keratosis and malignant SCCs, supporting a key role for PTEN in human skin cancer formation and progression. PTEN downregulation impaired the capacity of global genomic nucleotide excision repair (GG-NER), a critical mechanism for removing UVB-induced mutagenic DNA lesions. In contrast to the response to ionizing radiation, PTEN downregulation prolonged UVB-induced growth arrest and increased the activation of the Chk1 DNA damage pathway in an AKT-independent manner, likely due to reduced DNA repair. PTEN loss also suppressed expression of the key GG-NER protein xeroderma pigmentosum C (XPC) through the AKT/p38 signaling axis. Reconstitution of XPC levels in PTEN-inhibited cells restored GG-NER capacity. Taken together, our findings define PTEN as an essential genomic gatekeeper in the skin through its ability to positively regulate XPC-dependent GG-NER following DNA damage.

Risk of nonmelanoma skin cancer with azathioprine use.

While often life-saving for many complex diseases, iatrogenic immunosuppression has been associated with life-threatening infections and malignancies. Among these malignancies is skin cancer. Skin cancer is the most common form of cancer in the United States; the nonmelanoma skin cancers have an annual incidence of greater than 1,000,000 people in the US. It is well documented that the risk of nonmelanoma skin cancer (NMSC) is increased in those who are immunosuppressed. While many articles have been published on skin cancer risk in organ transplant recipients, little has been written regarding the incidence of nonmelanoma skin cancer in inflammatory bowel disease. A review of the literature of patients who are immunosuppressed for autoimmune disorders, and specifically, inflammatory bowel diseases, is discussed, as well as clinical presentations and treatment options.

KSHV/HHV8-associated primary cutaneous plasmablastic lymphoma in a patient with Castleman's disease and Kaposi's sarcoma.

We report a unique case of Kaposi's sarcoma (KS)-associated herpesvirus (KSHV)/human herpesvirus (HHV)8-associated lymphoma in a 56-year-old man with a history of acquired immune deficiency syndrome, Castleman's disease, KS, and idiopathic thrombocytopenic purpura. Three months following the diagnosis of KS affecting a left cervical lymph node and Castleman's disease with bone marrow involvement, he presented with a subcutaneous, tender lesion on his left arm. A skin biopsy demonstrated a superficial and deep, interstitial-nodular infiltrate of severely atypical lymphoid cells showing plasmacytoid features, numerous mitotic figures, and frequent individual apoptotic tumor cells. The morphologic features were those of plasmablastic lymphoma (PBL). Immunohistochemical study showed that the lymphoma cells strongly expressed CD45, CD30, and KSHV/HHV8 latency-associated nuclear antigen. KSHV/HHV8 was also detected in the biopsy sections of the patient's KS and Castleman's disease. Epstein-Barr virus in situ hybridization was diffusely positive. In situ hybridization demonstrated kappa-light chain restriction. Although KSHV/HHV8 has been individually associated with KS, Castleman's disease, and PBL, this appears to be the first reported case in which all three entities were present simultaneously in one person, suggesting a critical role of KSHV/HHV8 as a common denominator in the pathogenesis of these diseases.

Ossified soft tissue leiomyoma in a patient with sickle cell anemia.

Osseous metaplasia in leiomyomas is extremely rare. Here, we report the case of an ossified subcutaneous leiomyoma in a 34-year-old African American man with sickle cell thalassemia who presented with a painful nodule of the scapular region, which appeared as a heavily mineralized soft tissue mass on chest radiographs. Histopathologic and immunohistochemical examination of the resected nodule revealed a benign soft tissue leiomyoma composed of intersecting fascicles of spindle cells that strongly expressed smooth muscle actin and caldesmon. Extensive intratumoral calcification and ossification were noticed. Only eight cases of ossified leiomyoma have been reported, of which two arose in the deep soft tissue.