Lentigo maligna melanoma mapping using reflectance confocal microscopy correlates with staged excision: A prospective study.

BACKGROUND: Lentigo maligna/lentigo maligna melanoma (LM/LMM) can present with subclinical extension that may be difficult to define preoperatively and lead to incomplete excision and potential recurrence. Preliminarily studies have used reflectance confocal microscopy (RCM) to assess LM/LMM margins. OBJECTIVE: To evaluate the correlation of LM/LMM subclinical extension defined by RCM compared with the gold standard histopathology. METHODS: Prospective study of LM/LMM patients referred for dermatologic surgery. RCM was performed at the clinically defined initial surgical margin followed by margin-controlled staged excision with paraffin-embedded tissue, and histopathology was correlated with RCM results. RESULTS: Seventy-two patients were included. Mean age was 66.8 years (standard deviation, 11.1; range, 38-89); 69.4% were men. Seventy of 72 lesions (97.2%) were located on the head and neck with mean largest clinical diameter of 1.3 cm (range, 0.3-5). Diagnostic accuracy for detection of residual melanoma in the tumor debulk (after biopsy) had a sensitivity of 96.7% and a specificity of 66.7% when compared with histopathology. RCM margin assessment revealed an overall agreement with final histopathology of 85.9% (κ = 0.71; P < .001). LIMITATIONS: No RCM imaging beyond initial planned margins was performed. CONCLUSION: RCM showed moderate to excellent overall agreement between RCM imaging of LM/LMM and histopathology of staged excision margins.

FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation.

Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed with regions of divergent histomorphology, most commonly squamous differentiation. To define the biologic basis for and clinical significance of this morphologic heterogeneity, here we perform integrated genomic analyses of mixed histology bladder cancers with separable regions of urothelial and squamous differentiation. We find that squamous differentiation is a marker of intratumoral genomic and immunologic heterogeneity in patients with bladder cancer and a biomarker of intrinsic immunotherapy resistance. Phylogenetic analysis confirms that in all cases the urothelial and squamous regions are derived from a common shared precursor. Despite the presence of marked genomic heterogeneity between co-existent urothelial and squamous differentiated regions, no recurrent genomic alteration exclusive to the urothelial or squamous morphologies is identified. Rather, lineage plasticity in bladder cancers with squamous differentiation is associated with loss of expression of FOXA1, GATA3, and PPARG, transcription factors critical for maintenance of urothelial cell identity. Of clinical significance, lineage plasticity and PD-L1 expression is coordinately dysregulated via FOXA1, with patients exhibiting morphologic heterogeneity pre-treatment significantly less likely to respond to immune checkpoint inhibitors.

Genomic Alterations as Potential Therapeutic Targets in Extramammary Paget's Disease of the Vulva.

PURPOSE: To identify genomic alterations as potential therapeutic targets in extramammary Paget disease (EMPD) of the vulva. METHODS: We identified all patients with primary vulvar EMPD who were treated at our institution and underwent paired tumor-normal massively parallel sequencing of 410-468 cancer-related genes (MSK-IMPACT assay). EMPD of the vulva samples sequenced from 2014 to 2019 were reviewed and somatic mutations identified, with specific focus on mutations of potential therapeutic targets. Clinical data were abstracted from electronic medical records. Microsatellite instability (MSI) was assessed by MSIscore. RESULTS: Tumors of 26 patients with EMPD underwent genomic sequencing. At diagnosis, all patients had noninvasive or microinvasive (< 1 mm) disease; invasive disease eventually developed in 2 patients. Primary treatment was surgery for 19 patients (73%) and imiquimod topical therapy for 7 (27%). Seven patients had ≥ 2 surgeries as part of clinical course (1 patient had 5 vulvar resections). Samples had a median of 2 coding mutations in the genes analyzed (range, 0-29). The most common mutations were in PIK3CA (n = 9; 35%), ERBB2 (4 mutations and 3 copy number alterations; 27%), and TP53 (n = 7; 27%). MSIscore was available for 23 samples; all were microsatellite stable. After tumor genomic profiling, a patient who was initially treated with multiple resections and imiquimod was found to have a PIK3CA p.E542K mutation. She underwent PI3K-inhibitor treatment for 18 months before disease progression. CONCLUSION: EMPD of the vulva has a chronic and relapsing course, often requiring multiple surgical resections. Effective topical treatments are lacking. We identified targetable mutations (PIK3CA or ERBB2) in > 25% of a real-world clinical cohort. Additional prospective research implementing targetable therapies for EMPD treatment is warranted.

Cancer biology as revealed by the research autopsy.

A research autopsy is a post-mortem medical procedure performed on a deceased individual with the primary goal of collecting tissue to support basic and translational research. This approach has increasingly been used to investigate the pathophysiological mechanisms of cancer evolution, metastasis and treatment resistance. In this Review, we discuss the rationale for the use of research autopsies in cancer research and provide an evidence-based discussion of the quality of post-mortem tissues compared with other types of biospecimens. We also discuss the advantages of using post-mortem tissues over other types of biospecimens, including the large amounts of tissue that can be obtained and the extent of multiregion sampling that is achievable, which is not otherwise possible in living patients. We highlight how the research autopsy has supported the identification of the clonal origins and modes of spread among metastases, the extent that selective pressures imposed by treatments cause bottlenecks leading to parallel and convergent tumour evolution, and the creation of rare tissue banks and patient-derived model systems. Finally, we comment on the future of the research autopsy as an integral component of precision medicine strategies.