The Immune Checkpoint Inhibitor LAG-3 and Its Ligand GAL-3 in Vulvar Squamous Neoplasia.

Vulvar squamous cell carcinoma (vSCC), although rare, carries significant morbidity and a high rate of recurrence. Treatment options beyond surgical excision remain limited. Lymphocyte activation gene-3 (LAG-3) and its binding partner galectin-3 (GAL-3) are an immuno-inhibitory checkpoint pair that represent potential immunotherapy targets for the treatment of vSCC. This study examined the expression of LAG-3 and GAL-3 alongside programmed cell death ligand-1 expression in invasive SCC and vulvar intraepithelial neoplasia (VIN) by immunohistochemical analysis of formalin-fixed paraffin-embedded tissue. A total of 35 cases were selected for evaluation: 13 VIN3 [human papillomavirus (HPV)-associated VIN/usual-type VIN], 2 differentiated VIN (dVIN), 16 HPV-associated vSCC, and 4 dVIN-associated vSCC. LAG-3+ tumor-infiltrating lymphocytes were identified in 91% (32/35) of cases of vulvar squamous neoplasia. Tumor cells were positive for GAL-3 in 71% of the vulvar neoplasia cases. HPV-associated vSCC was more likely to demonstrate GAL-3 tumoral positivity when compared with dVIN-associated vSCC (24/29 vs. 1/6, P=0.004). We observed co-expression of all 3 immunomarkers in 40% (14/35) of cases evaluated. In light of these findings, use of immunomodulatory drugs that target the LAG-3/GAL-3 pathway may be potentially beneficial in vSCC and efficacy may be increased when combined with anti-programmed cell death ligand-1 therapy.

Quality assurance in dermatopathology: A review of report amendments.

BACKGROUND: Systematic review of amended reports in surgical pathology has been recommended as a valuable exercise in promoting quality assurance and improvement. Examination of report amendments can identify defects in the surgical pathology process and inspire new approaches to decreasing error rates and improving overall patient care. METHODS: We performed a retrospective review of all amended dermatopathology reports over a 1.5-year period at a large academic institution. RESULTS: During the study period, 86 amended reports out of a total 7950 skin-specific reports were issued (1.08%). Of these amended reports, about 59% (51/86) were because of non-interpretative errors (eg, wrong site, chin vs shin, etc.) while 41% (35/86) were diagnostic misinterpretations. Of these 35, 24 were considered major diagnostic changes while six were minor. Five amendments provided additional diagnostic information. Of those amended reports with diagnostic misinterpretations, 14/35 involved melanocytic lesions, 8/35 involved non-melanoma skin cancers or keratinocyte atypia, 10/35 were inflammatory lesions and 3/35 involved other tumors. CONCLUSION: Our review points to several quality improvement areas that can be targeted to potentially avoid diagnostic errors in dermatopathology, including standardizing certain anatomic sites to prevent misidentification and seeking out clinicopathologic correlation in challenging melanocytic cases.

Necrobiosis lipoidica associated with sarcoidosis.

We report the case of a 40-year-old African-American female with biopsy-proven pulmonary sarcoidosis who developed atrophic plaques on her shins, trunk, and scalp that were clinically and histologically consistent with necrobiosis lipoidica (NL). The lesions appeared 3 years after her diagnosis of sarcoidosis, and progressed despite chronic prednisone. Sarcoidosis and NL are granulomatous skin disorders reported to coexist in the same patient only 10 times in the literature. Including the current case, patients have been exclusively females around middle age, and have greater tendencies to develop typical cutaneous sarcoidosis. The incidence of diabetes is rare in this group. Like typical NL, NL associated with sarcoidosis tends to ulcerate, and is difficult to treat. Interestingly, there are six similar cases reported in the literature of patients with sarcoidosis who developed lesions clinically and behaviorally consistent with NL, but received a final histological diagnosis of sarcoidosis. These cases share very similar demographics and clinical features with cases of true NL associated with sarcoidosis, and often have more ambiguous histology containing features of both cutaneous sarcoidosis and NL. Comparing the two sets of cases raises the possibility of a final common disease pathway shared by these two granulomatous skin disorders.

How to take better photomicrographs: A step-wise approach.

The objective of our study was to establish a detailed photomicrographing protocol for pathologists and dermatopathologists using standard overhead camera and image editing packages. Through a trial-and-error approach we devised a series of steps that comprise our photomicrographing protocol. Descriptive and interpretive data analyses were performed to highlight how each step improves tinctorial quality of digital photomicrographs.

Structured Case-Based Ethics Discussion for Trainees and Faculty on Dermatopathology.

Introduction: Ethical and professional dilemmas are part of the day-to-day practice of medicine, including within dermatopathology (e.g., ethical implications of self-referring skin biopsies for pathology interpretation). There is a need for teaching aids that dermatology educators can easily access to help provide ethics education. Methods: We held an hour-long, faculty-facilitated, interactive, virtual discussion about ethical issues in dermatopathology. The session followed a structured, case-based format. We administered anonymous online feedback surveys after the session and used the Wilcoxon signed rank test to compare participants' before and after responses. Results: Seventy-two individuals from two academic institutions participated in the session. We collected 35 total responses (49%) from dermatology residents (n = 15), dermatology faculty (n = 14), medical students (n = 2), and other providers and learners (n = 4). Feedback was largely positive, with 21 attendees (60%) indicating they learned a few things and 11 (31%) indicating they learned a great deal. Additionally, 32 participants (91%) indicated they would recommend the session to a colleague. Our analysis showed that attendees had a greater self-perceived level of achievement for each of our three objectives after the session. Discussion: This dermatoethics session is structured so as to be easily shared, deployed, and built on by other institutions. We hope that other institutions will use our materials and results to improve upon the foundation presented here and that this framework will be used by other medical specialties seeking to foster ethics education in their training programs.

A Starter Guide to Immunofluorescence Testing in Dermatology.

Immunodermatology laboratory testing, including direct immunofluorescence (DIF), indirect immunofluorescence (IIF), and enzyme-linked immunosorbent assay (ELISA) are powerful tools that can aide dermatologists when diagnosing autoimmune blistering diseases. Understanding these tests is important to ensure appropriate use and optimum results. This article is intended to serve as a helpful primer for immunofluorescence testing in dermatology, with an overview of the tests available as well as pragmatic tips for optimal biopsy sites and specimen transport.

Dermatoethics for Dermatology Residents.

Dermatology residents are expected to demonstrate professional behavior and an understanding of ethical principles as part of Accreditation Council for Graduate Medical Education (ACGME)- accredited training programs. Incorporating this education into an already full curriculum can be challenging, but there are several dermatoethics resources available, including model curricula and textbooks that can be utilized to design custom formal curricula. This article reviews these available resources and also considers why dermatoethics training is useful in dermatology residency.

The Genital Examination in Dermatologic Practice.

The genital area is not routinely included in the total-body skin examination (TBSE) despite malignancies and inflammatory conditions involving the genital skin. This article explores some of the reasons for this omission and highlights why examining the genital area during routine dermatologic evaluation is important. It also provides an approach to performing the genital examination that can be adapted for everyday practice.

Immune checkpoint status and tumor microenvironment in vulvar squamous cell carcinoma.

Vulvar squamous cell carcinoma accounts for 5% of cancers of the female genital tract. Current guidelines recommend wide local excision with negative surgical margins as the standard treatment. However, the extent of the tumor-free resection margin after wide local excision is still controversial in many cases. Drugs targeting immune checkpoints such as PD-1 or its ligand PD-L1 have potential clinical utility in these patients. We examined the expression of PD-L1 in tumor cells and immune cells, as well as the proportion of PD-1, CD8, and FOXP3 positive lymphocytes. Twenty-one cases of invasive vulvar squamous cell carcinomas were reviewed. Whole slides of representative formalin-fixed, paraffin-embedded archival material were used for analysis. Odds ratios (OR) and hazard ratios (HR) were used to estimate risk for disease recurrence, overall mortality, and cancer mortality. PD-L1 expression was found in 43% of tumor cells, with higher proportions in intratumoral (67%) and peritumoral (81%) immune cells. OR and HR for disease recurrence and cancer mortality were higher in tumors with higher CD8 expression. OR and HR for overall mortality were also higher in tumors with higher PD-L1 and CD8 expression. In conclusion, nearly half of cases were PD-L1 positive in tumor cells with over two-third of cases demonstrating PD-L1 positivity in immune cells. Immunohistochemical expression of PD-L1 and CD8 could be used to suggest higher risk of disease recurrence, overall mortality, and cancer mortality. Furthermore, our data contributes to the growing evidence that targeting the PD-1/PD-L1 pathway may be beneficial in vulvar squamous cell carcinomas.

A challenging and rewarding time: The early days of graduate medical education in dermatology.

Specialized residency training was still in its infancy in mid-20th century America. While specialty boards in various fields such as ophthalmology and otolaryngology had been established in the 1920s and 1930s, the details of training programs were still being fine-tuned and formal curricula were lacking. In dermatology, three prominent physicians including Harry L. Arnold Jr., J. Lamar Callaway and Walter B. Shelley trained during these experimental days of medical education. Each of them captured personal reflections of their own training experiences in brief memoirs published in scientific journals. A closer examination of these texts provides unique insights into how dermatology subspecialty training in particular and medical education more broadly evolved during this period.

Recent Advances in Cutaneous T-cell Lymphoma: Diagnostic and Prognostic Considerations.

This review describes the latest advances in the diagnosis of cutaneous T-cell lymphoma focusing on the most clinically useful features introduced since the publication of the World Health Organization revision in 2017. Clinical entities described include mycosis fungoides, Sézary syndrome, lymphomatoid papulosis, primary cutaneous anaplastic large cell lymphoma, primary cutaneous gamma delta T-cell lymphoma, primary cutaneous acral CD8+ T-cell lymphoma, primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, and hydroa-vacciniforme-like lymphoproliferative disorder. Distinguishing histologic clues to diagnosis are discussed, and important molecular advances are described. Key prognostic indicators that may assist clinicians with timely and appropriate management options are presented.

Frequency of Dermatologic Findings at Autopsy.

A complete academic autopsy includes an external examination with inspection of gross dermatologic findings. At our institution, the postmortem examination also includes a standard skin biopsy. We determined the microscopic yield of this standard postmortem skin biopsy and the overall frequency of macroscopic dermatologic diagnoses. We reviewed 389 complete autopsies conducted between 2012 and 2014. Both microscopic and macroscopic dermatologic diagnoses were analyzed. A macroscopic dermatologic diagnosis was made in 32% of cases while a microscopic diagnosis was recorded in 10% of cases. Dermatologic diagnoses were identified as leading directly to cause of death in 4% of patients and as contributing to death in another 20%. Targeted biopsies were more likely to reveal histologic abnormalities than routine biopsies from a standard anatomic site. Better training in skin gross examination in addition to systematic sampling of both skin lesions and grossly normal skin may improve diagnostic accuracy and enhance clinical pathologic correlations.

Bizarre parosteal osteochondromatous proliferation: 16 Cases with a focus on histologic variability.

Bizarre parosteal osteochondromatous proliferation (BPOP) is a benign bone and cartilage forming tumor occurring on the surface of bones, predominantly on the hands and feet. A defining feature of BPOP is the purplish-blue mineralization of cartilaginous tissue, known as 'blue bone.' Here, we report on an institutional series of 16 cases of BPOP, including radiographic, histologic, and histomorphometric features. All tumors were composed of some element of bone, cartilage, fibrous tissue and 'blue bone,' though the amount of each tissue sub-type varied widely. Some cases showed focal 'blue bone' only, however this was a defining feature in all cases.

IgG4-Related Disease of Bilateral Temporal Bones.

OBJECTIVE: IgG4-related disease (IgG4-RD) is an idiopathic inflammatory condition that causes pseudotumor formation in single or multiple organs, including those of the head and neck. Temporal bone involvement is rare, with only 3 cases of unilateral temporal bone IgG4-RD described in the literature. We report the first known case of IgG4-RD of bilateral temporal bones and describe its clinical presentation, diagnosis, and treatment. METHODS: The patient was a 52-year-old man with latent tuberculosis (TB) who presented with a 10-year history of bilateral profound hearing loss and vestibular dysfunction. Computed tomography and magnetic resonance imaging demonstrated bilateral labyrinthine destruction with invasion of the posterior fossa. RESULTS: Immunoglobulin level testing showed elevated total serum IgG levels with normal IgG4 levels. Bilateral mastoidectomies were performed, with biopsy samples demonstrating IgG4 staining with IgG4-positive plasma cells up to 40/HPF (high power field) on the right and 20/HPF on the left, consistent with bilateral IgG4-RD. CONCLUSION: IgG4-RD of bilateral temporal bones presents with chronic and progressive bilateral hearing loss and vestibular dysfunction. Clinical presentation and radiologic findings are nonspecific, and definitive diagnosis must be made with histopathology and immunostaining. Corticosteroids are therapeutic, but surgical resection may be necessary for temporal bone IgG4-RD to improve long-term remission.

Vascular patterning in human heterotopic ossification.

Heterotopic ossification (HO, also termed myositis ossificans) is the formation of extra-skeletal bone in muscle and soft tissues. HO is a tissue repair process gone awry, and is a common complication of surgery and traumatic injury. Medical strategies to prevent and treat HO fall well short of addressing the clinical need. Better characterization of the tissues supporting HO is critical to identifying therapies directed against this common and sometimes devastating condition. The physiologic processes of osteogenesis and angiogenesis are highly coupled and interdependent. However, few efforts have been made to document the vascular patterning within heterotopic ossification. Here, surgical pathology case files of 29 human HO specimens were examined by vascular histomorphometric analysis. Results demonstrate a temporospatial patterning of HO vascularity that depends on the "maturity" of the bony lesion. In sum, human HO demonstrates a time- and space-dependent pattern of vascularization suggesting a coupled pathophysiologic process involving the coordinate processes of osteogenesis and angiogenesis. Further imaging studies may be used to further characterize vasculogenesis within HO and whether anti-angiogenic therapies are a conceivable future therapy for this common condition.

Immune-checkpoint status in penile squamous cell carcinoma: a North American cohort.

Penile squamous cell carcinoma (SCC) is primarily treated by surgical resection. Locally advanced and metastatic diseases require a multidisciplinary treatment approach. However, mortality and morbidity remain high, and novel molecular and immunotherapeutic targets are actively being sought. We investigated the expression of immune-checkpoint markers in penile cancers. Fifty-three invasive penile SCCs diagnosed between 1985 and 2013 were retrieved from our surgical pathology archives. Representative formalin-fixed, paraffin-embedded archival blocks were used for the construction of 2 high-density tissue microarrays. Tissue microarrays were stained with immunohistochemistry for PD-L1, FOXP3, CD8, and Ki-67. PD-L1 was investigated using rabbit monoclonal anti-PD-L1 antibody (Cell Signaling, Boston, MA; E1L3N, 1:100). Overall, 21 (40%) of 53 penile SCCs had positive PD-L1 expression. PD-L1 was expressed by a significant proportion of advanced penile SCC. Forty-four percent (15/34) of stage pT2 or more SCC and 38% (6/16) of tumors with lymph node metastasis were positive for PD-L1. PD-L1 expression did not correlate with patient age, tumor location, histologic subtype, tumor stage, anatomic depth of invasion, or tumor grade. FOXP3 expression in tumoral immune cells was found in 26 (49%) of 53 cases. FOXP3 expression in stromal immune cells correlated with tumor thickness (P = .0086). The ratio of CD8/FOXP3 was greater than 1 in 62% of cases in tumor-infiltrating immune cells and 34% of cases in stromal immune cells. Our current study is the largest to assess expression of PD-L1 in a clinically well-annotated North American cohort of penile SCC. Our findings support a rationale for targeting immune-checkpoint inhibitor pathways in advanced penile SCC.