Publications by authors named "Michael T Tetzlaff"

211 Publications

Multiplex Tissue Imaging Harmonization: A Multicenter Experience from CIMAC-CIDC Immuno-Oncology Biomarkers Network.

Clin Cancer Res 2021 Sep 12;27(18):5072-5083. Epub 2021 Jul 12.

Translational Molecular Pathology-Dermatopathology Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: The Cancer Immune Monitoring and Analysis Centers - Cancer Immunologic Data Commons (CIMAC-CIDC) network supported by the NCI Cancer Moonshot initiative was established to provide correlative analyses for clinical trials in cancer immunotherapy, using state-of-the-art technology. Fundamental to this initiative is implementation of multiplex IHC assays to define the composition and distribution of immune infiltrates within tumors in the context of their potential role as biomarkers. A critical unanswered question involves the relative fidelity of such assays to reliably quantify tumor-associated immune cells across different platforms.

Experimental Design: Three CIMAC sites compared across their laboratories: (i) image analysis algorithms, (ii) image acquisition platforms, (iii) multiplex staining protocols. Two distinct high-dimensional approaches were employed: multiplexed IHC consecutive staining on single slide (MICSSS) and multiplexed immunofluorescence (mIF). To eliminate variables potentially impacting assay performance, we completed a multistep harmonization process, first comparing assay performance using independent protocols followed by the integration of laboratory-specific protocols and finally, validating this harmonized approach in an independent set of tissues.

Results: Data generated at the final validation step showed an intersite Spearman correlation coefficient () of ≥0.85 for each marker within and across tissue types, with an overall low average coefficient of variation ≤0.1.

Conclusions: Our results support interchangeability of protocols and platforms to deliver robust, and comparable data using similar tissue specimens and confirm that CIMAC-CIDC analyses may therefore be used with confidence for statistical associations with clinical outcomes largely independent of site, antibody selection, protocol, and platform across different sites.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2051DOI Listing
September 2021

Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade.

Nat Med 2021 08 8;27(8):1432-1441. Epub 2021 Jul 8.

Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA.

Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.
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http://dx.doi.org/10.1038/s41591-021-01406-6DOI Listing
August 2021

Resolution of tissue signatures of therapy response in patients with recurrent GBM treated with neoadjuvant anti-PD1.

Nat Commun 2021 06 29;12(1):4031. Epub 2021 Jun 29.

Institute for Systems Biology, Seattle, WA, USA.

The response of patients with recurrent glioblastoma multiforme to neoadjuvant immune checkpoint blockade has been challenging to interpret due to the inter-patient and intra-tumor heterogeneity. We report on a comparative analysis of tumor tissues collected from patients with recurrent glioblastoma and high-risk melanoma, both treated with neoadjuvant checkpoint blockade. We develop a framework that uses multiplex spatial protein profiling, machine learning-based image analysis, and data-driven computational models to investigate the pathophysiological and molecular factors within the tumor microenvironment that influence treatment response. Using melanoma to guide the interpretation of glioblastoma analyses, we interrogate the protein expression in microscopic compartments of tumors, and determine the correlates of cytotoxic CD8+ T cells, tumor growth, treatment response, and immune cell-cell interaction. This work reveals similarities shared between glioblastoma and melanoma, immunosuppressive factors that are unique to the glioblastoma microenvironment, and potential co-targets for enhancing the efficacy of neoadjuvant immune checkpoint blockade.
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http://dx.doi.org/10.1038/s41467-021-24293-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241935PMC
June 2021

Dermatopathology in the Molecular Age.

Surg Pathol Clin 2021 Jun 28;14(2):xiii. Epub 2021 Apr 28.

Dermatopathology and Oral Pathology Unit, The University of California, San Francisco, 1701 Divisadero Street, #280, San Francisco, CA 94115, USA. Electronic address:

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http://dx.doi.org/10.1016/j.path.2021.03.007DOI Listing
June 2021

High sensitivity sanger sequencing detection of BRAF mutations in metastatic melanoma FFPE tissue specimens.

Sci Rep 2021 04 27;11(1):9043. Epub 2021 Apr 27.

Department of Bioengineering, Rice University, 65000 Main St, Houston, TX, 77030, USA.

Mutations in the BRAF gene at or near the p. V600 locus are informative for therapy selection, but current methods for analyzing FFPE tissue DNA generally have a limit of detection of 5% variant allele frequency (VAF), or are limited to the single variant (V600E). These can result in false negatives for samples with low VAFs due to low tumor content or subclonal heterogeneity, or harbor non-V600 mutations. Here, we show that Sanger sequencing using the NuProbe VarTrace BRAF assay, based on the Blocker Displacement Amplification (BDA) technology, is capable of detecting BRAF V600 mutations down to 0.20% VAF from FFPE lymph node tissue samples. Comparison experiments on adjacent tissue sections using BDA Sanger, immunohistochemistry (IHC), digital droplet PCR (ddPCR), and NGS showed 100% concordance among all 4 methods for samples with BRAF mutations at ≥ 1% VAF, though ddPCR did not distinguish the V600K mutation from the V600E mutation. BDA Sanger, ddPCR, and NGS (with orthogonal confirmation) were also pairwise concordant for lower VAF mutations down to 0.26% VAF, but IHC produced a false negative. Thus, we have shown that Sanger sequencing can be effective for rapid detection and quantitation of multiple low VAF BRAF mutations from FFPE samples. BDA Sanger method also enabled detection and quantitation of less frequent, potentially actionable non-V600 mutations as demonstrated by synthetic samples.
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http://dx.doi.org/10.1038/s41598-021-88391-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079675PMC
April 2021

Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti-PD-1 Refractory Melanoma.

Cancer Discov 2021 Aug 11;11(8):1996-2013. Epub 2021 Mar 11.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti-PD-1- resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNα gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing. SIGNIFICANCE: Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1546DOI Listing
August 2021

iNOS Associates With Poor Survival in Melanoma: A Role for Nitric Oxide in the PI3K-AKT Pathway Stimulation and PTEN S-Nitrosylation.

Front Oncol 2021 12;11:631766. Epub 2021 Feb 12.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

We previously showed that inducible nitric oxide synthase (iNOS) protein expression in melanoma tumor cells is associated with poor patient prognosis. Here, we analyzed the association between iNOS and the oncogenic PI3K-AKT pathway. TCGA data show that iNOS and phospho-Akt Ser473 expression were associated significantly only in the subset of tumors with genetically intact PTEN. Employing a stage III melanoma TMA, we showed that iNOS protein presence is significantly associated with shorter survival only in tumors with PTEN protein expression. These findings led to our hypothesis that the iNOS product, nitric oxide (NO), suppresses the function of PTEN and stimulates PI3K-Akt activation. Melanoma cells in response to NO exposure exhibited enhanced AKT kinase activity and substrate phosphorylation, as well as attenuated PTEN phosphatase activity. Biochemical analysis showed that NO exposure resulted in a post-translationally modified S-Nitrosylation (SNO) PTEN, which was also found in cells expressing iNOS. Our findings provide evidence that NO-rich cancers may exhibit AKT activation due to post-translational inactivation of PTEN. This unique activation of oncogenic pathway under nitrosative stress may contribute to the pathogenesis of iNOS in melanoma. Our study shows that iNOS expression is associated with increased PI3K-AKT signaling and worse clinical outcomes in melanoma patients with wt (intact) PTEN. Mutated PTEN is already inactivated. We also demonstrate that NO activates the PI3K-AKT pathway by suppressing PTEN suppressor function concurrent with the formation of PTEN-SNO. This discovery provides insight into the consequences of inflammatory NO produced in human melanoma and microenvironmental cells. It suggests that NO-driven modification provides a marker of PTEN inactivation, and represents a plausible mechanism of tumor suppressor inactivation in iNOS expressing subset of cancers.
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http://dx.doi.org/10.3389/fonc.2021.631766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907506PMC
February 2021

Is immunohistochemical expression of GATA3 helpful in the differential diagnosis of transformed mycosis fungoides and primary cutaneous CD30-positive T cell lymphoproliferative disorders?

Virchows Arch 2021 Aug 18;479(2):377-383. Epub 2021 Feb 18.

Department of Pathology, Dermatopathology Section, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Mycosis fungoides with large cell transformation (MFLCT) can be difficult to distinguish from primary cutaneous CD30+ T cell lymphoproliferative disorders (PC CD30+ LPD), especially primary cutaneous anaplastic large cell lymphoma (PC-ALCL). This diagnostic distinction is critical for appropriate patient management. GATA3 has been proposed to be useful in the discrimination between these two entities. We identified 25 cases of MFLCT and 24 cases of PC CD30+ LPDs (including lymphomatoid papulosis (n=14), PC-ALCL (n=6), and CD30+ LPD, not otherwise specified (n=4)) diagnosed at our institution from 2002 to 2019. Sections from archived specimens were stained to evaluate for GATA3 expression by immunohistochemistry and compared among cutaneous CD30+ T cell LPDs. The majority of the MFLCT cohort had strong, diffuse expression of GATA3 ranging from 0 to 100% of dermal T cells (mean 53.20%) with 15/25 cases (60%) showing GATA3 expression greater than 50%, while the PC CD30+ LPD group showed variable, moderate GATA3 labeling ranging from 0 to 60% of dermal T cells (mean 23.26%), with 5/6 cases (83%) showing GATA3 expression less than 40% (p =0.003). The calculated sensitivity and specificity were 56% and 74%, while positive and negative predictive values were 70% and 61%, respectively. Based on the percent staining of positive cells, using 50% as a cutoff value for expression, GATA3 might be a useful immunohistochemical marker to discriminate MFLCT from PC CD30+ LPDs, including PC-ALCL.
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http://dx.doi.org/10.1007/s00428-021-03056-yDOI Listing
August 2021

Discordance in Diagnosis of Melanocytic Lesions and Its Impact on Clinical Management.

Arch Pathol Lab Med 2021 Feb 12. Epub 2021 Feb 12.

From the Departments of Pathology (Ronen, Al-Rohil, Keiser, Jour, Nagarajan, Tetzlaff, Curry, Ivan, Middleton, Torres-Cabala, Aung, Prieto).

Context.—: Accurate diagnosis of melanocytic lesions is fundamental for appropriate clinical management.

Objective.—: To evaluate the degree of discordance, if any, between histopathologic diagnoses of melanocytic lesions at referring institutions and at a tertiary referral cancer center and the potential impact of such discordance on clinical management.

Design.—: We retrospectively identified all patients referred to our comprehensive cancer center for evaluation of a melanocytic lesion from January 2010 to January 2011. For each patient, the histopathologic diagnosis from the referring institution was compared with the histopathologic diagnosis from a dermatopathologist at our center. Discordances were classified as major if they resulted in a change in clinical management and minor if they did not.

Results.—: A total of 1521 cases were included. The concordance rates were 72.2% (52 of 72) for dysplastic nevus, 75.0% (15 of 20) for all other types of nevi, 91.1% (143 of 157) for melanoma in situ, 96.1% (758 of 789) for invasive melanoma, and 99.6% (478 of 480) for metastatic melanoma. Major discordances were found in 20.2% of cases (307 of 1521), and minor discordances were found in 48.8% of cases (742 of 1521). Compared with the guideline-based treatment recommendation based on the referring-institution diagnosis, the guideline-based treatment recommendation based on the cancer center diagnosis was more extensive in 5.9% (89 of 1521) of patients and less extensive in 5.0% (76 of 1521) of patients.

Conclusions.—: Our findings underscore the importance of secondary histopathologic review of melanocytic lesions by expert dermatopathologists because significant changes in the diagnosis, tumor classification, and/or staging may be identified; thus, resulting in critical changes in recommendations for clinical management.
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http://dx.doi.org/10.5858/arpa.2020-0620-OADOI Listing
February 2021

Clinical, molecular, metabolic, and immune features associated with oxidative phosphorylation in melanoma brain metastases.

Neurooncol Adv 2021 Jan-Dec;3(1):vdaa177. Epub 2021 Jan 6.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Recently, we showed that melanoma brain metastases (MBMs) are characterized by increased utilization of the oxidative phosphorylation (OXPHOS) metabolic pathway compared to melanoma extracranial metastases (ECMs). MBM growth was inhibited by a potent direct OXPHOS inhibitor, but observed toxicities support the need to identify alternative therapeutic strategies. Thus, we explored the features associated with OXPHOS to improve our understanding of the pathogenesis and potential therapeutic vulnerabilities of MBMs.

Methods: We applied an OXPHOS gene signature to our cohort of surgically resected MBMs that had undergone RNA-sequencing (RNA-seq) ( = 88). Clustering by curated gene sets identified MBMs with significant enrichment (High-OXPHOS; = 21) and depletion (Low-OXPHOS; = 25) of OXPHOS genes. Clinical data, RNA-seq analysis, and immunohistochemistry were utilized to identify significant clinical, molecular, metabolic, and immune associations with OXPHOS in MBMs. Preclinical models were used to further compare melanomas with High- and Low-OXPHOS and for functional validation.

Results: High-OXPHOS MBMs were associated with shorter survival from craniotomy compared to Low-OXPHOS MBMs. High-OXPHOS MBMs exhibited an increase in glutamine metabolism, and treatment with the glutaminase inhibitor CB839 improved survival in mice with MAPKi-resistant, High-OXPHOS intracranial xenografts. High-OXPHOS MBMs also exhibited a transcriptional signature of deficient immune activation, which was reversed in B16-F10 intracranial tumors with metformin treatment, an OXPHOS inhibitor.

Conclusions: OXPHOS is associated with distinct clinical, molecular, metabolic, and immune phenotypes in MBMs. These associations suggest rational therapeutic strategies for further testing to improve outcomes in MBM patients.
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http://dx.doi.org/10.1093/noajnl/vdaa177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865080PMC
January 2021

Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC).

Nat Med 2021 02 8;27(2):301-309. Epub 2021 Feb 8.

Melanoma Institute Australia, The University of Sydney, Sydney, Australia.

The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%, P < 0.001) and OS (pCR 2-year OS 95% versus no pCR 83%, P = 0.027). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and, at this writing, no patient has died from melanoma, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%. Pathological response should be an early surrogate endpoint for clinical trials and a new benchmark for development and approval in melanoma.
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http://dx.doi.org/10.1038/s41591-020-01188-3DOI Listing
February 2021

Perianal condylomata lata mimicking carcinoma.

J Cutan Pathol 2021 Jan 20. Epub 2021 Jan 20.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

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http://dx.doi.org/10.1111/cup.13865DOI Listing
January 2021

Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy.

Nat Commun 2021 01 12;12(1):346. Epub 2021 Jan 12.

The Wistar Institute, Philadelphia, PA, USA.

Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34 cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγ (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3 Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8/Granz B T cells homeostasis are observed in tumor regions where FOXP3 Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.
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http://dx.doi.org/10.1038/s41467-020-20600-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804257PMC
January 2021

Tertiary lymphoid structures with overlapping histopathologic features of cutaneous marginal zone lymphoma during neoadjuvant cemiplimab therapy are associated with antitumor response.

J Cutan Pathol 2021 May 13;48(5):674-679. Epub 2021 Jan 13.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

The development of immune checkpoint inhibitor (ICI) therapy with anti-CTLA-4 and anti-PD-1/L1 monoclonal antibodies has led to a paradigm shift in cancer therapy. ICI neoadjuvant therapy followed by surgery has become the standard of care for several advanced-stage cancers. The pathology associated with ICI therapy is vast and includes neoadjuvant-associated tissue reactions and activation of tertiary lymphoid structures (TLSs) at the site of the tumor bed and off-target immune-related adverse events. TLSs are thought to recapitulate lymph node function and may act as localized immune machinery to mount an antitumor response. B-cell activation in TLSs during neoadjuvant ICI therapy has been correlated with antitumor response. We report a patient with a history of sarcomatoid squamous cell carcinoma treated with neoadjuvant ICI cemiplimab who developed clonal expansion of B-cells in the TLSs of the tumor bed. The TLSs morphologically mimicked a cutaneous marginal zone lymphoma with plasmacytic differentiation. Awareness of clonal expansion of B-cells in TLSs during neoadjuvant ICI therapy is critical to recognize a response to ICI therapy and to avoiding an incorrect diagnosis of low-grade B-cell lymphoma.
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http://dx.doi.org/10.1111/cup.13953DOI Listing
May 2021

Immune profiling of uveal melanoma identifies a potential signature associated with response to immunotherapy.

J Immunother Cancer 2020 11;8(2)

Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Background: To date, no systemic therapy, including immunotherapy, exists to improve clinical outcomes in metastatic uveal melanoma (UM) patients. To understand the role of immune infiltrates in the genesis, metastasis, and response to treatment for UM, we systematically characterized immune profiles of UM primary and metastatic tumors, as well as samples from UM patients treated with immunotherapies.

Methods: Relevant immune markers (CD3, CD8, FoxP3, CD68, PD-1, and PD-L1) were analyzed by immunohistochemistry on 27 primary and 31 metastatic tumors from 47 patients with UM. Immune gene expression profiling was conducted by NanoString analysis on pre-treatment and post-treatment tumors from patients (n=6) receiving immune checkpoint blockade or 4-1BB and OX40 dual costimulation. The immune signature of UM tumors responding to immunotherapy was further characterized by Ingenuity Pathways Analysis and validated in The Cancer Genome Atlas data set.

Results: Both primary and metastatic UM tumors showed detectable infiltrating lymphocytes. Compared with primary tumors, treatment-naïve metastatic UM showed significantly higher levels of CD3+, CD8+, FoxP3+ T cells, and CD68+ macrophages. Notably, levels of PD-1+ infiltrates and PD-L1+ tumor cells were low to absent in primary and metastatic UM tumors. No metastatic organ-specific differences were seen in immune infiltrates. Our NanoString analysis revealed significant differences in a set of immune markers between responders and non-responders. A group of genes relevant to the interferon-γ signature was differentially up-expressed in the pre-treatment tumors of responders. Among these genes, suppressor of cytokine signaling 1 was identified as a marker potentially contributing to the response to immunotherapy. A panel of genes that encoded pro-inflammatory cytokines and molecules were expressed significantly higher in pre-treatment tumors of non-responders compared with responders.

Conclusion: Our study provides critical insight into immune profiles of UM primary and metastatic tumors, which suggests a baseline tumor immune signature predictive of response and resistance to immunotherapy in UM.
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http://dx.doi.org/10.1136/jitc-2020-000960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674090PMC
November 2020

Neoadjuvant Therapy for Melanoma: A U.S. Food and Drug Administration-Melanoma Research Alliance Public Workshop.

Clin Cancer Res 2021 01 13;27(2):394-401. Epub 2020 Nov 13.

Melanoma Research Alliance, Washington, DC.

Tremendous progress has been made in treating patients with metastatic melanoma over the past decade. In that timeframe, the FDA has approved 12 novel treatments for patients with advanced unresectable melanoma, comprising both kinase-targeted therapies and immune checkpoint inhibitors (ICI), and five treatments for adjuvant (postoperative) use in patients with high-risk resectable stage III melanoma. It is not known whether outcomes can be further improved by administering kinase inhibitors or ICI in the neoadjuvant (presurgical) setting in patients with high-risk resectable melanomas. Noting research community interest in exploring the neoadjuvant approach for treating melanoma and recognizing that early harmonization of methodologies may expedite the development of therapeutics in this space, the FDA and Melanoma Research Alliance convened a public workshop on November 6, 2019, in National Harbor, Maryland, to discuss key issues. The workshop consisted of 23 faculty and included more than 250 live participants. Topics discussed included opportunities for advancing novel endpoints for regulatory purposes as well as translational research, clinical trial design considerations, and strategies for optimizing patient selection while mitigating risk.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3285DOI Listing
January 2021

Molecular and immunological associations of elevated serum lactate dehydrogenase in metastatic melanoma patients: A fresh look at an old biomarker.

Cancer Med 2020 11 5;9(22):8650-8661. Epub 2020 Oct 5.

Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Elevated serum lactate dehydrogenase (sLDH) is associated with poor clinical outcomes in patients with stage IV metastatic melanoma (MM). It is currently unknown if sLDH elevation correlates with distinct molecular, metabolic, or immune features of melanoma metastases. The identification of such features may identify rational therapeutic strategies for patients with elevated sLDH. Thus, we obtained sLDH levels for melanoma patients with metastases who had undergone molecular and/or immune profiling. Our analysis of multi-omics data from independent cohorts of melanoma metastases showed that elevated sLDH was not significantly associated with differences in immune cell infiltrate, point mutations, DNA copy number variations, promoter methylation, RNA expression, or protein expression in melanoma metastases. The only significant association observed for elevated sLDH was with the number of metastatic sites of disease. Our data support that sLDH correlates with disease burden, but not specific molecular or immunological phenotypes, in metastatic melanoma.
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http://dx.doi.org/10.1002/cam4.3474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666738PMC
November 2020

Bullous Pemphigoid-like Eruption Triggered by Targeted Therapy for Metastatic Melanoma.

Acta Derm Venereol 2020 Nov 26;100(18):adv00334. Epub 2020 Nov 26.

Oncology-Pathology and Department of Oncology/Skin Cancer Center, Theme Cancer, Karolinska Institutet, Karolinska University Hospital Solna, SE-176 76 Stockholm, Sweden. E-mail:

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http://dx.doi.org/10.2340/00015555-3648DOI Listing
November 2020

Clinical validity of a gene expression signature in diagnostically uncertain neoplasms.

Per Med 2020 09 17;17(5):361-371. Epub 2020 Jun 17.

Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Evaluate the accuracy of a 23-gene expression signature in differentiating benign nevi from melanoma by comparing test results with clinical outcomes. Seven dermatopathologists blinded to gene expression test results and clinical outcomes examined 181 lesions to identify diagnostically uncertain cases. Participants independently recorded diagnoses and responses to questions quantifying diagnostic certainty. Test accuracy was determined through comparison with clinical outcomes (sensitivity and percent negative agreement). Overall, 125 cases fulfilled criteria for diagnostic uncertainty (69.1%; 95% CI: 61.8-75.7%). Test sensitivity and percent negative agreement in these cases were 90.4% (95% CI: 79.0-96.8%) and 95.5% (95% CI: 87.3-99.1%), respectively. The 23-gene expression signature has high diagnostic accuracy in diagnostically uncertain cases when evaluated against clinical outcomes.
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http://dx.doi.org/10.2217/pme-2020-0048DOI Listing
September 2020

Osteonecrosis of the jaw induced by treatment with anti-PD-1 immunotherapy: a case report.

Immunotherapy 2020 12 9;12(17):1213-1219. Epub 2020 Sep 9.

Department of Translational & Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Recognizing rare but clinically significant toxicity of immunotherapy is critical. Here we describe the first detailed case of severe osteonecrosis of the jaw due to anti-PD-1. A 75-year-old man with metastatic melanoma, with no prior radiation or treatment with bone-targeting agents, experienced jaw pain 1 week after his first dose of nivolumab. Imaging studies were negative, and treatment was resumed after pain was controlled. 4 months later, the patient experienced acute exacerbation of pain and malocclusion of the jaw. Imaging showed bilateral fractures of the angle of mandible with extensive disruption of the normal trabecular architecture, requiring total mandibulectomy. The patient's metastatic melanoma responded to treatment and remains controlled >20 months after treatment cessation without further therapy.
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http://dx.doi.org/10.2217/imt-2020-0108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658614PMC
December 2020

Prognostic significance of acral lentiginous histologic type in T1 melanoma.

Mod Pathol 2021 03 5;34(3):572-583. Epub 2020 Aug 5.

Department of Pathology, Dermatopathology Section, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Acral lentiginous melanoma (ALM) is a rare type of cutaneous melanoma with a poor prognosis. It is unclear whether the poor outcome of ALM is due to its inherent disease characteristics or advanced stage at initial diagnosis. To address this question, we retrospectively analyzed the clinicopathologic factors of 828 thin (T1; Breslow thickness ≤1.0 mm) melanomas [129 (15.6%) ALMs and 699 (84.4%) non-ALMs] and their nodal and distance metastases and local recurrence rates and determined their relationship with the disease-specific (DSS), overall (OS), and recurrence-free survivals (RFS) at the pathologic stages T1, T1a, and T1b with a median follow-up time of 84.5 months. With the exception of OS at T1b stage, ALM patients showed significantly lower 5- and 10-year DSS, OS, and RFS rates at every pathologic stage when compared with non-ALM. In multivariable analysis, ALM histologic type, SLN positivity, age, and the use of systemic therapy were detected as independent poor prognostic factors associated with significantly lower survival rates. ALM histologic type was associated with lower DSS and OS rates at T1 and T1a stages and lower RFS rates at T1b stage. SLN positivity was associated with lower DSS, OS, and RFS rates at T1, T1a, and T1b stages. Age was associated with lower OS rates at T1 and T1b stages. Whereas the use of systemic therapy was associated with lower DSS rates at T1a stage and RFS rates at T1b stage. In addition, the ALM group showed significantly older median age patients and higher rates of female sex, Hispanic ethnicity, nevoid cytology, non-brisk tumor-infiltrating lymphocytes, nodal metastasis, and local recurrence at every pathologic stage of thin melanoma. Our findings suggest that ALM is inherently more aggressive than other types of cutaneous melanoma. This information may be useful for prognostic stratification of patients with thin melanomas, especially to help guide the clinical decision-making for SLN biopsy and patients entering clinical trials.
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http://dx.doi.org/10.1038/s41379-020-0641-xDOI Listing
March 2021

Langerhans cell sarcoma involving skin and showing epidermotropism: A comprehensive review.

J Cutan Pathol 2021 Apr 7;48(4):547-557. Epub 2020 Sep 7.

Department of Pathology, Dermatopathology Section, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Langerhans cell sarcoma (LCS) is rare and aggressive; patients have an overall survival rate of less than 50%. We present a 62-year-old man with a history of superficial spreading melanoma of the upper back with sentinel lymph node metastasis, Langerhans cell histiocytosis, and LCS. The patient presented with erythematous papules and scaly areas on his face, neck, arms, chest, abdomen, and legs. A skin biopsy revealed a proliferation of large neoplastic cells involving the dermis and with epidermotropism. These cells had atypical bean-shaped nuclei, with ample cytoplasm and abundant mitotic figures including atypical forms. Immunohistochemical studies showed the tumor to be diffusely positive for CD1a, S100 protein, and langerin (CD207) and negative for melanocytic markers. Some tumor cells were positive for cyclin D1. A diagnosis of LCS involving the skin was established. The present study is a very unusual case of LCS showing epidermotropism. The patient's history of metastatic melanoma posed additional challenges for diagnosis, underlying the need of immunophenotyping in these cases. Consensus for optimal standard therapy has not been established in LCS, and thus, early recognition is important since these neoplasms tend to recur and metastasize. LCS in skin is discussed and published cases are comprehensively reviewed.
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http://dx.doi.org/10.1111/cup.13803DOI Listing
April 2021

Without Missing a Beat: Absence of Cilia Informs the Diagnosis of Histopathologically Challenging Spitzoid Melanocytic Neoplasms.

J Invest Dermatol 2020 07;140(7):1320-1323

Department of Dermatology, Boston University Medical School, Boston, Massachusetts, USA.

The diagnosis of Spitzoid melanocytic lesions remains a formidable challenge in dermatopathology. Numerous ancillary tests have evolved to improve accurate classification of histopathologically ambiguous lesions. A study by Lang et al. (2020b) demonstrates loss of primary cilia in Spitzoid melanoma compared with Spitz nevi and positions ciliation index as an informative ancillary test for Spitzoid lesions.
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http://dx.doi.org/10.1016/j.jid.2020.01.009DOI Listing
July 2020

Cutaneous adnexal carcinosarcoma: Immunohistochemical and molecular evidence of epithelial mesenchymal transition.

J Cutan Pathol 2021 Apr 14;48(4):526-534. Epub 2020 Sep 14.

Department of Pathology, Dermatopathology Section, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Cutaneous carcinosarcomas are rare biphenotypic tumors that simultaneously show epithelial and mesenchymal differentiation. The most common carcinomatous components in skin carcinosarcomas are basal cell carcinoma and squamous cell carcinoma; adnexal carcinomas are rarely encountered. We report a case of an adnexal carcinoma with ductal and squamous differentiation and spindle cell component, which is interpreted as carcinosarcoma. Loss of immunohistochemical expression of E-cadherin and β-catenin detected in the sarcomatous component suggested epithelial mesenchymal transition (EMT). RNA sequencing analysis identified several gene mutations and alterations such as translocations and upregulations/downregulations, either shared by the two components of the tumor or differentially present in the carcinoma or the sarcoma parts. Thus, mutations in genes, such as TP53, were found in both components of the tumor while mutations in PDGFRA and RB1 (a pathogenic missense mutation) were exclusively present in the sarcomatous areas, further supporting EMT. EMT is a dynamic process by which tumors acquire mesenchymal phenotype while simultaneously losing epithelial properties. Although the pathways involved in EMT have been extensively studied, this phenomenon still needs to be investigated in cutaneous tumors of adnexal origin for a better understanding of their pathogenesis. These molecular changes may represent promising targets for personalized therapies.
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http://dx.doi.org/10.1111/cup.13782DOI Listing
April 2021

The Society for Immunotherapy of Cancer statement on best practices for multiplex immunohistochemistry (IHC) and immunofluorescence (IF) staining and validation.

J Immunother Cancer 2020 05;8(1)

Providence Portland Medical Center, Portland, Oregon, USA.

Objectives: The interaction between the immune system and tumor cells is an important feature for the prognosis and treatment of cancer. Multiplex immunohistochemistry (mIHC) and multiplex immunofluorescence (mIF) analyses are emerging technologies that can be used to help quantify immune cell subsets, their functional state, and their spatial arrangement within the tumor microenvironment.

Methods: The Society for Immunotherapy of Cancer (SITC) convened a task force of pathologists and laboratory leaders from academic centers as well as experts from pharmaceutical and diagnostic companies to develop best practice guidelines for the optimization and validation of mIHC/mIF assays across platforms.

Results: Representative outputs and the advantages and disadvantages of mIHC/mIF approaches, such as multiplexed chromogenic IHC, multiplexed immunohistochemical consecutive staining on single slide, mIF (including multispectral approaches), tissue-based mass spectrometry, and digital spatial profiling are discussed.

Conclusions: mIHC/mIF technologies are becoming standard tools for biomarker studies and are likely to enter routine clinical practice in the near future. Careful assay optimization and validation will help ensure outputs are robust and comparable across laboratories as well as potentially across mIHC/mIF platforms. Quantitative image analysis of mIHC/mIF output and data management considerations will be addressed in a complementary manuscript from this task force.
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http://dx.doi.org/10.1136/jitc-2019-000155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239569PMC
May 2020

TERT amplification but not activation of canonical Wnt/β-catenin pathway is involved in acral lentiginous melanoma progression to metastasis.

Mod Pathol 2020 10 13;33(10):2067-2074. Epub 2020 May 13.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Acral lentiginous melanoma (ALM) is a rare tumor that occurs on non-sun exposed skin areas of the hands and feet. Reports suggest that ALM exhibits poor prognosis, although mechanisms driving this remain poorly understood. Alterations in TERT and the Wnt/β-catenin (Wnt) pathway have been suggested to correlate with prognosis of ALM. Thus, immunohistochemical expression of β-catenin and LEF1 along with TERT amplification by FISH was investigated in 34 primary ALMs, 20 metastatic ALMs, 10 primary non-ALMs, and 15 acral nevi. Foot/toe was the most common primary tumor location (85%) for ALM. TERT amplification was detected in 6 of 28 (21.4%) primary ALM, 2 of 8 (25%) primary non-ALM, and 8 of 18 (44.4%) metastatic ALM, the latter showing significantly higher frequency compared with primary melanomas (P = 0.043). Most metastatic ALMs positive for TERT amplification lacked BRAF V600E (87.5%). Cytoplasmic and nonnuclear expression of β-catenin was variably detected in all cases. Metastatic ALM revealed lower expression of β-catenin compared with primary ALM (P = 0.017). No differences in LEF1 expression were detected among the groups; however, acral nevi showed decreased labeling with dermal descent, in contrast to melanoma. No molecular-genetic alteration correlated with prognosis. TERT amplification by FISH is a frequent finding in primary ALM and appears to increase in metastatic tumors, suggesting a role in tumor progression to metastasis. Although TERT amplification has been reported to be infrequent in primary non-ALM, it showed comparable frequency with ALM in our series. Our immunohistochemical findings are not fully supportive of activation of either canonical or noncanonical Wnt cascades in ALM. TERT amplification by FISH and LEF1 immunohistochemistry may help in the differential diagnosis between primary ALM and acral nevus. TERT amplification appears to be a promising target for therapy in patients with metastatic ALM.
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http://dx.doi.org/10.1038/s41379-020-0565-5DOI Listing
October 2020

Hypertrophic lichenoid dermatitis immune-related adverse event during combined immune checkpoint and exportin inhibitor therapy: A diagnostic pitfall for superficially invasive squamous cell carcinoma.

J Cutan Pathol 2020 Oct 10;47(10):954-959. Epub 2020 Jun 10.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Immune checkpoint inhibitors (ICIs) for cancer treatment have revolutionized the field of medicine. However, an unintended but frequent consequence of ICI therapy is the development of cutaneous immune-related adverse events (irAEs), such as lichenoid dermatitis irAEs (LD-irAEs). The hypertrophic variant of LD-irAE may be a diagnostic challenge since it can mimic superficially invasive squamous cell carcinoma (SCC). A 79-year-old woman with metastatic melanoma who began treatment with an ICI-pembrolizumab-plus exportin-1 (XPO1) inhibitor presented after 1 month of therapy with symmetrical violaceous papules coalescing into plaques and with two nodules of the bilateral dorsal hands. Biopsy of the nodules revealed an actinic keratosis and atypical epidermal proliferation concerning for SCC. However, in the ensuing 3 weeks, the patient developed multiple new erythematous, violaceous, and scaly macules and papules, some coalescing into plaques on the extremities. Biopsies of these lesions revealed exuberant irregular epidermal hyperplasia with hypermaturation and lichenoid infiltrate concentrated at the base of the elongated, broadened rete ridges, consistent with hypertrophic LD-irAE. Treatment included topical fluocinonide ointment, intralesional triamcinolone injections and oral acitretin. Distinguishing hypertrophic LD-irAE and SCC can be challenging since both entities share histopathologic features; thus, correlation with clinical presentation is essential for diagnosis and optimal patient management.
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http://dx.doi.org/10.1111/cup.13739DOI Listing
October 2020

BAP-1 Expression Status by Immunohistochemistry in Cellular Blue Nevus and Blue Nevus-like Melanoma.

Am J Dermatopathol 2020 May;42(5):313-321

Associate Professor, Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.

The family of blue nevi includes the common blue nevus (BN), cellular blue nevus (CBN), and atypical BN, while melanomas with BN-like morphology can either arise in association with a blue nevus (MABN) or in the de novo setting mimicking cellular blue nevus (MMCBN). Recent molecular and immunohistochemical studies have demonstrated loss of BAP-1 in MABN/MMCBN but not in BN/CBN, suggesting that loss of BAP-1 correlates with a malignant phenotype in these lesions. In this study, we applied anti-BAP-1 antibodies to a series of CBN/BN (n = 11) and MABN/MMCBN (n = 4). Nuclear BAP-1 expression was detected in the majority of CBN/BN (n = 10/11) but was lost in 1 case. Most cases of MABN/MMCBN showed loss of nuclear BAP-1 expression (n = 3/4), with one case of MMCBN showing preserved BAP-1 expression. Demonstration of BAP-1 loss in a single case of CBN and preservation of BAP-1 expression in 1 case of MMCBN may indicate that detection of alterations in BAP-1 protein expression by immunohistochemistry may not be a completely reliable biomarker for the distinction of BN/CBN from MABN/MMCBN. Further investigation of the significance of BAP-1 loss/preservation in BN-like tumors is warranted.
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http://dx.doi.org/10.1097/DAD.0000000000001551DOI Listing
May 2020

T-Cell Repertoire in Combination with T-Cell Density Predicts Clinical Outcomes in Patients with Merkel Cell Carcinoma.

J Invest Dermatol 2020 11 15;140(11):2146-2156.e4. Epub 2020 Apr 15.

Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Electronic address:

The integrity of the immune system represents a pivotal risk factor and prognostic biomarker for Merkel cell carcinoma. A higher density of tumor-associated T cells correlates with improved Merkel cell carcinoma-specific survival, but the prognostic importance of the T-cell infiltrate reactivity is unknown. We evaluated the T-cell receptor repertoire associated with 72 primary Merkel cell carcinomas and correlated metrics of the T-cell receptor repertoire with clinicopathologic characteristics and patient outcomes. We showed that a high Simpson's Dominance index (SDom) was significantly associated with fewer metastases (P = 0.01), lower stage at presentation (P = 0.02), lower final stage at last follow-up (P = 0.05), and longer time to first lymph node metastasis (P = 0.04). These correlations were mostly preserved in the Merkel cell polyomavirus-negative subgroup. Combining SDom with CD3 or CD8 T-cell density revealed three distinct prognostic groups with respect to disease-specific survival. Patients with both high SDom and high CD3 or CD8 T-cell density had markedly improved disease-specific survival compared with patients with low SDom and low CD3 or CD8 T-cell density (P = 0.002 and P = 0.03, respectively). Patients with either high SDom or high CD3 or CD8 had intermediate disease-specific survival. Our findings demonstrate that the quality of the tumor-associated T-cell infiltrate informs patient prognosis in primary Merkel cell carcinoma beyond the T-cell density.
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http://dx.doi.org/10.1016/j.jid.2020.02.031DOI Listing
November 2020

Spatially resolved analyses link genomic and immune diversity and reveal unfavorable neutrophil activation in melanoma.

Nat Commun 2020 04 15;11(1):1839. Epub 2020 Apr 15.

Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Complex tumor microenvironmental (TME) features influence the outcome of cancer immunotherapy (IO). Here we perform immunogenomic analyses on 67 intratumor sub-regions of a PD-1 inhibitor-resistant melanoma tumor and 2 additional metastases arising over 8 years, to characterize TME interactions. We identify spatially distinct evolution of copy number alterations influencing local immune composition. Sub-regions with chromosome 7 gain display a relative lack of leukocyte infiltrate but evidence of neutrophil activation, recapitulated in The Cancer Genome Atlas (TCGA) samples, and associated with lack of response to IO across three clinical cohorts. Whether neutrophil activation represents cause or consequence of local tumor necrosis requires further study. Analyses of T-cell clonotypes reveal the presence of recurrent priming events manifesting in a dominant T-cell clonotype over many years. Our findings highlight the links between marked levels of genomic and immune heterogeneity within the physical space of a tumor, with implications for biomarker evaluation and immunotherapy response.
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http://dx.doi.org/10.1038/s41467-020-15538-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160105PMC
April 2020
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