Priyadharsini Nagarajan

Diverse types of dermatologic toxicities from immune checkpoint blockade therapy

Immunomodulatory drugs that leverages host immune mechanisms to destroy tumor cells have been met with great promise in the treatment of cancer. Immunotherapy, targeting cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4) and the programmed cell death 1 (PD‐1) receptor and its ligand (PD‐L1) have shown tremendous improvements in the survival of patients with advanced solid tumors. However, the development of dermatologic toxicity (DT) is a consequence to immunotherapy. Review of published reports of the DT to immunotherapy revealed patients receiving anti‐CTCLA‐4 antibody or anti‐PD‐1/PD‐L1 antibody often develop a DT of any type and grade. In this article, of the 3825 patients who were treated with anti‐PD‐1 and of 556 patients receiving anti‐PD‐L1, DT of any type and grade were reported in 1474 (∼39%) and 95 (∼17%) of patients, respectively. The emergence of specific types of DT to immunotherapy is beginning to be recognized can be categorized into four groups: (a) inflammatory, (b) immunobullous, (c) alteration of keratinocytes and (d) alteration of melanocytes. Lichenoid dermatitis and bullous pemphigoid appear to be DT more associated with anti‐PD‐1/PD‐L1 antibody. The DT profile in patients receiving immunotherapy is diverse, and early recognition of specific types of DT that clinicians may encounter is critical for optimal patient care

Density, Distribution, and Composition of Immune Infiltrates Correlate with Survival in Merkel Cell Carcinoma.

Purpose: Merkel cell carcinoma (MCC) is an aggressive cancer with frequent metastasis and death with few effective therapies. Because programmed death ligand-1 (PD-L1) is frequently expressed in MCC, immune checkpoint blockade has been leveraged as treatment for metastatic disease. There is therefore a critical need to understand the relationships between MCPyV status, immune profiles, and patient outcomes. Experimental Design: IHC for CD3, CD8, PD-1, PD-L1, and MCPyV T-antigen (to determine MCPyV status) was performed on 62 primary MCCs with annotated clinical outcomes. Automated image analysis quantified immune cell density (positive cells/mm2) at discrete geographic locations (tumor periphery, center, and hotspot). T-cell receptor sequencing (TCRseq) was performed in a subset of MCCs. Results: No histopathologic variable associated with overall survival (OS) or disease-specific survival (DSS), whereas higher CD3+ (P = 0.004) and CD8+ (P = 0.037) T-cell density at the tumor periphery associated with improved OS. Higher CD8+ T-cell density at the tumor periphery associated with improved DSS (P = 0.049). Stratifying MCCs according to MCPyV status, higher CD3+ (P = 0.026) and CD8+ (P = 0.015) T-cell density at the tumor periphery associated with improved OS for MCPyV+ but not MCPyV− MCC. TCRseq revealed clonal overlap among MCPyV+ samples, suggesting an antigen-specific response against a unifying antigen. Conclusions: These findings establish the tumor-associated immune infiltrate at the tumor periphery as a robust prognostic indicator in MCC and provide a mechanistic rationale to further examine whether the immune infiltrate at the tumor periphery is relevant as a biomarker for response in ongoing and future checkpoint inhibitor trials in MCC. Clin Cancer Res; 22(22); 5553–63. ©2016 AACR.

Loss of CD30 expression after treatment with brentuximab vedotin in a patient with anaplastic large cell lymphoma: a novel finding

Anaplastic large cell lymphoma (ALCL) is an aggressive T‐cell lymphoma characterized by strong and uniform expression of CD30. Brentuximab vedotin (BV), an anti‐CD30 antibody‐drug conjugate has been approved by the U.S. FDA for relapsed/refractory systemic ALCL and achieves improved outcomes. We report a 44‐year‐old African‐American man who presented with lymphadenopathy, lip and chest nodules diagnosed as CD30+, ALK‐negative ALCL. The patient was treated with BV upon recurrence. While on treatment, the patient developed new‐onset nodules on the chest and back. Skin biopsy showed a diffuse dermal infiltrate of medium‐to‐large atypical lymphocytes with frequent mitosis and scattered eosinophils. Immunohistochemically, the atypical cells displayed the same immunophenotype as previous specimens (CD3+, CD4−/CD8−, CD56−, ALK− and TCR γ−), except for lack of CD30 expression which was attributed to BV treatment effect. The diagnosis was thought to be consistent with ALK‐negative ALCL and the patient was continued on BV along with total skin electron beam radiation and the lesions cleared. The patient relapsed 2 months later with extensive disease and expired. In summary, this is the first report in the literature of loss of CD30 expression in ALCL after BV therapy. Awareness of this may prevent a mistaken diagnosis of a CD30‐negative secondary T‐cell lymphoma.

Primary Cutaneous T-Cell Lymphomas Showing Gamma-Delta (γδ) Phenotype and Predominantly Epidermotropic Pattern are Clinicopathologically Distinct From Classic Primary Cutaneous γδ T-Cell Lymphomas.

Primary cutaneous gamma-delta (&ggr;&dgr;) T-cell lymphoma is a rare disease that typically involves the dermis and subcutis. Cases of primary cutaneous T-cell lymphomas showing &ggr;&dgr; phenotype and predominantly epidermotropic pattern (E&ggr;&dgr;TCL) are not well defined. In this series, cases of primary cutaneous T-cell lymphomas showing &ggr;&dgr; phenotype were reviewed and classified as predominantly epidermotropic (E&ggr;&dgr;TCL) when >75% of lymphoma cells resided in the epidermis or predominantly dermal and/or subcutaneous (DS&ggr;&dgr;TCL). Clinical, pathologic, and immunophenotypic features were compared in 27 biopsies from 13 patients of E&ggr;&dgr;TCL and 13 biopsies from 7 patients of DS&ggr;&dgr;TCL. The lymphoma cells were diffusely positive for CD3 and T-cell receptor (TCR)&ggr;, mostly positive for granzyme B and TIA-1, variably positive for CD8, CD7, and CD30, and negative for CD4 and TCR&bgr;. Two patients with E&ggr;&dgr;TCL had dissemination to lymph nodes and 1 to the lung; 1 patient with DS&ggr;&dgr;TCL had gastrointestinal involvement. The median survival of patients with E&ggr;&dgr;TCL was not reached, and with a median follow-up of 19.2 months, 3/13 died. In contrast, the median survival of patients with DS&ggr;&dgr;TCL was 10 months, and after a median follow-up of 15.6 months, 5/5 died (P<0.01). E&ggr;&dgr;TCL is a rare presentation of cutaneous T-cell lymphoma that can be distinguished from DS&ggr;&dgr;TCL based on the extent of epidermotropism and has a better prognosis and longer median survival than DS&ggr;&dgr;TCL. However, although E&ggr;&dgr;TCL resembles mycosis fungoides clinically and histologically, a subset of E&ggr;&dgr;TCL is more likely to behave more aggressively than typical mycosis fungoides.

Erythema nodosum-like panniculitis mimicking disease recurrence: A novel toxicity from immune checkpoint blockade therapy—Report of 2 patients

Immunotherapies targeting cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4) and the programmed cell death 1 (PD‐1) receptor and its ligand (PD‐L1) have showed substantial therapeutic benefit in patients with clinically advanced solid malignancies. However, autoimmune toxicities are common and often significant adverse events with these agents. While rash and pruritus remain the most common cutaneous complications in treated patients, novel dermatologic toxicities related to immune checkpoint blockade continue to emerge as the number of patients exposed to immunotherapy increases. Here, we describe 2 patients treated with combination immunotherapy with ipilimumab and nivolumab who developed painful subcutaneous nodules. Although the findings were clinically concerning for disease recurrence, histopathologic examination of biopsies from the lesions revealed a subcutaneous mixed septal and lobular erythema nodosum‐like panniculitis. Notably, neither patient received immunosuppressive therapy for these lesions, which subsequently remained stable, and both patients’ cancer remained controlled. These cases show that the dermatologic toxicity profile of immune checkpoint blockade is diverse and continues to expand, and illustrates that recognition of such toxicities is critical to optimal patient management.

Prognostic implication of lymphovascular invasion detected by double immunostaining for D2-40 and MITF1 in primary cutaneous melanoma

Background:Lymphovascular invasion (LVI) is associated with adverse outcomes in primary cutaneous melanoma (PCM). Detection of LVI by hematoxylin and eosin staining alone is 0%–6%, but targeting lymphovascular structures increases the detection rate. Objective:To examine the prognostic significance of LVI detected by immunostaining for D2-40 and microphthalmia-associated transcription factor 1 (MITF1) in PCM. Methods:The authors retrospectively analyzed 120 PCM samples. We compared the LVI detection rates of immunostaining for D2-40 only (22%), double staining for D2-40 and MITF1 (38%), and hematoxylin and eosin, and examined the association of LVI with clinicopathologic variables and clinical outcomes. Results:Immunolabeling with both methods significantly increased the LVI detection rate. Double staining for D2-40 and MITF1 as well as D2-40–detected LVI was significantly associated with increased Breslow thickness, number of mitoses, and sentinel lymph node (SLN) metastasis. D2-40–detected LVI was also associated with ulceration. Although the difference was not significant, double staining for D2-40 and MITF1 allowed for easier detection of LVI than D2-40 alone. Limitations:This study was conducted in a tertiary referral institution; therefore, a referral bias cannot be excluded. Conclusions:Immunolabeling increased detection of LVI in PCM. Because LVI is a positive predictive marker for SLN metastasis, the authors propose using anti-D2-40 and anti-MITF1 in the evaluation of LVI in patients with PCM with a certain risk of SLN metastasis.

Differential mutation frequencies in metastatic cutaneous squamous cell carcinomas versus primary tumors

Exome and targeted sequencing studies have identified potential driver mutations for a variety of tumor types. Cutaneous squamous cell carcinoma (cSCC) is one of the most highly mutated cancers but typically is associated with low rates of metastasis and high survival rates. Nevertheless, metastatic cSCC is a significant health threat; up to 8800 individuals die each year of this disease.

Tumor thickness and mitotic rate robustly predict melanoma-specific survival in patients with primary vulvar melanoma: A retrospective review of 100 cases

Purpose: Primary vulvar melanoma (PVM) is the second most common vulvar malignancy. Despite their distinct anatomic site and unique molecular–genetic alterations, PVMs are staged according to the American Joint Committee on Cancer (AJCC) guidelines for primary cutaneous melanomas (PCM). However, whether parameters derived for PCM also apply to PVM remain a critical yet largely unexplored clinical question. The objective of this study was to determine the parameters predictive of survival in PVM. Experimental Design: We retrospectively reviewed 100 patients with PVM and determined associations between clinical and histopathologic parameters and disease-specific survival (DSS) and overall survival (OS). Results: Univariate Cox regression analysis demonstrated older age (>56 years), greater tumor thickness, higher dermal mitotic rate, ulceration, lymphovascular invasion, perineural invasion, microscopic satellitosis, and absence of precursor nevus associated with decreased OS. Furthermore, age, midline, and/or multifocal involvement, greater tumor thickness, higher dermal mitotic rate, ulceration, lack of regression, lymphovascular invasion, perineural invasion, and microscopic satellitosis associated with decreased DSS. Multivariate analysis demonstrated tumor thickness, dermal mitotic rate, lymphovascular invasion, microscopic satellitosis, and absence of precursor nevus independently predicted shorter OS. Only tumor thickness and increased dermal mitotic rate (≥2/mm2) independently predicted reduced DSS. In comparison with the AJCC T-category, a novel, bivariate T-category based only on tumor thickness and dermal mitotic rate robustly predicted OS and DSS in our patient cohort. Conclusions: In the largest single institutional study of PVM, we demonstrate a combination of tumor thickness and mitotic rate comprise a simple but robust T-category to direct staging and prognosis. Clin Cancer Res; 23(8); 2093–104. ©2016 AACR.

Spectrum of immune-related conditions associated with risk of keratinocyte cancers among elderly adults in the United States

Background: Elevated keratinocyte carcinoma risk is present with several immune-related conditions, e.g., solid organ transplantation and non-Hodgkin lymphoma. Because many immune-related conditions are rare, their relationships with keratinocyte carcinoma have not been studied. Methods: We used Medicare claims to identify cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) cases in 2012, and controls matched on sex and age. All subjects were aged 65 to 95 years, of white race, and had attended ≥1 dermatologist visit in 2010–2011. Immune-related conditions were identified during 1999–2011 using Medicare claims. Associations were estimated with logistic regression, with statistical significance determined after Bonferroni correction for multiple comparisons. Results: We included 258,683 SCC and 304,903 BCC cases. Of 47 immune-related conditions, 21 and 9 were associated with increased SCC and BCC risk, respectively. We identified strongly elevated keratinocyte carcinoma risk with solid organ transplantation (SCC OR = 5.35; BCC OR = 1.94) and non-Hodgkin lymphoma (SCC OR = 1.62; BCC OR = 1.25). We identified associations with common conditions, e.g., rheumatoid arthritis [SCC OR = 1.06, 95% confidence interval (95% CI), 1.04–1.09] and Crohns disease (SCC OR = 1.33, 95% CI, 1.27–1.39; BCC OR = 1.10, 95% CI, 1.05–1.15), and rare or poorly characterized conditions, e.g., granulomatosis with polyangiitis (SCC OR = 1.88; 95% CI, 1.61–2.19), autoimmune hepatitis (SCC OR = 1.81; 95% CI, 1.52–2.16), and deficiency of humoral immunity (SCC OR = 1.51, 95% CI, 1.41–1.61; BCC OR = 1.22, 95% CI, 1.14–1.31). Most conditions were more positively associated with SCC than BCC. Associations were generally consistent regardless of prior keratinocyte carcinoma history. Conclusions: Many immune-related conditions are associated with elevated keratinocyte carcinoma risk and appear more tightly linked to SCC. Impact: Immunosuppression or immunosuppressive treatment may increase keratinocyte carcinoma risk, particularly SCC. Cancer Epidemiol Biomarkers Prev; 26(7); 998–1007. ©2017 AACR.

MicroRNA expression profiling in metastatic cutaneous squamous cell carcinoma

or sinecatechin may take up to 3 to 16 weeks for complete clearing of AGWs, treatment with IM was much more rapid. This could be explained by the loss of mitochondrial respiration mediated by IM leading to cell death and a cytotoxic reaction within hours. Our histological examination 18 h after treatment confirmed this direct cytotoxic effect of IM in AGWs. So far only surgical therapies show clearance rates approaching 100%. However, only single, protruding AGWs can be treated properly with surgical therapies and cautery can lead to scarring since it is difficult to restrict the effect to the skin lesions only. All those treatments bear the risk of high relapse rates after one to three months, whereas we could show that our patients are still in remission after up to 240 days. Further clinical trials with a longer follow-up period are required to confirm this persistent remission.