Publications by authors named "David E Elder"

142 Publications

The Impact of Longitudinal Surveillance on Tumor Thickness for Melanoma-Prone Families with and without Pathogenic Germline Variants of and .

Cancer Epidemiol Biomarkers Prev 2021 Apr;30(4):676-681

Division of Cancer Epidemiology and Genetics, NCI, NIH, Rockville, Maryland.

Background: Skin cancer screening is routinely performed for members of melanoma-prone families, but longitudinal studies evaluating the efficacy of surveillance in this high-risk population are lacking.

Methods: We evaluated thickness for first primary melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) enrolled in NCT00040352 (NCI familial melanoma study) from 1976 through 2014; enrolled patients received routine skin cancer screening and education about skin self-exams. We used linear and ordinal logistic regression models adjusted for gender and age with a generalized estimating equations approach to report changes in thickness and tumor (T) stage over time, comparing outcomes for NCI cases diagnosed before (pre-study) versus after study participation (prospective) and for NCI cases versus nonfamilial cases [Surveillance, Epidemiology, and End Results (SEER) 9 registries].

Results: Tumor thickness was evaluated for 293 NCI (pre-study = 246; prospective = 47) patients. Compared with NCI pre-study cases, NCI prospective melanomas were thinner (0.6 vs. 1.1 mm; < 0.001) and more likely to be T1 stage [39/47 (83%) vs. 98/246 (40%); < 0.001]. Similar findings ( < 0.05) were observed for familial cases with and without germline and mutations. Peters-Belson modeling suggested that calendar period effects of decreasing thickness in the general population (SEER 9) did not fully explain thickness trends in NCI families.

Conclusions: Participation in a longitudinal surveillance program providing skin cancer screening and education about skin self-exams was associated with thinner melanomas for members of melanoma-prone families.

Impact: The study findings support the clinical benefit of screening (physician and self) for this high-risk population.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1521DOI Listing
April 2021

Gazing Into the Crystal Ball: Calciphylaxis Causing Striking Retinal Vascular Calcification, Ocular Ischemic Syndrome, Crystalline Retinopathy, and Ischemic Optic Neuropathy.

J Neuroophthalmol 2020 Oct 22. Epub 2020 Oct 22.

Department of Neurology (NRC, MAT), University of Pennsylvania, Philadelphia, Pennsylvania; Department of Ophthalmology (NRC, DS, MAT), Scheie Eye Institute, Philadelphia, Pennsylvania; and Department of Pathology (AMM, DEE), University of Pennsylvania, Philadelphia, Pennsylvania.

A 72-year-old woman with membranous glomerulonephritis and failed renal transplant on peritoneal dialysis presented with bilateral vision loss. She reported several months of diminishing right eye vision that worsened after cataract extraction. On presentation, visual acuity was hand motion in the right and 20/100 in the left eye with a right afferent pupillary defect. Confrontation visual fields were constricted bilaterally. Intraocular pressure was 23 in the right eye, and there was diffuse right eye central corneal opacity with iris neovascularization. Fundus examination revealed bilateral pale optic nerves with cotton wool spot inferior to the left optic disc and diffuse arteriolar whitening with crystalline deposits in the left macula. Given fundus appearance, concurrent ischemic optic neuropathy, and ocular ischemic syndrome, ocular calciphylaxis was suspected. The patient reported development of painful gluteal nodules a month prior, and biopsy revealed calcinosis cutis, a dermatopathologic finding on the spectrum of calcific vasculitides. Her vision continued to decline in both eyes with left eye vision of 20/400. Intravenous sodium thiosulfate through hemodialysis was started with initial improvement in left eye vision to 20/125, but subsequently declined despite treatment. Pathogenesis of systemic calciphylaxis is poorly understood but believed to result from upregulation of osteogenesis and decreased inhibition of vascular calcification in parathyroid axis dyscrasias due to end-stage renal disease. Excess serum calcium-phosphate deposits in blood vessels causing tissue infarction, most commonly in the skin. Prior case reports have described ischemic optic neuropathy mimicking giant cell arteritis and crystalline retinopathy with ocular ischemic syndrome separately. Treatment with empiric intravenous sodium thiosulfate and calcium chelation may preserve vision in some patients.
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http://dx.doi.org/10.1097/WNO.0000000000001090DOI Listing
October 2020

Terminology for melanocytic skin lesions and the MPATH-Dx classification schema: A survey of dermatopathologists.

J Cutan Pathol 2020 Sep 16. Epub 2020 Sep 16.

Department of Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California, USA.

Background: Diagnostic terms used in histopathology reports of cutaneous melanocytic lesions are not standardized. We describe dermatopathologists' views regarding diverse diagnostic terminology and the utility of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) for categorizing melanocytic lesions.

Methods: July 2018-2019 survey of board-certified and/or fellowship-trained dermatopathologists with experience interpreting melanocytic lesions.

Results: Among 160 participants, 99% reported witnessing different terminology being used for the same melanocytic lesion. Most viewed diverse terminology as confusing to primary care physicians (98%), frustrating to pathologists (83%), requiring more of their time as a consultant (64%), and providing necessary clinical information (52%). Most perceived that adoption of the MPATH-Dx would: improve communication with other pathologists and treating physicians (87%), generally be a change for the better (80%), improve patient care (79%), be acceptable to clinical colleagues (68%), save time in pathology report documentation (53%), and protect from malpractice (51%).

Conclusions: Most dermatopathologists view diverse terminology as contributing to miscommunication with clinicians and patients, adversely impacting patient care. They view the MPATH-Dx as a promising tool to standardize terminology and improve communication. The MPATH-Dx may be a useful supplement to conventional pathology reports. Further revision and refinement are necessary for widespread clinical use.
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http://dx.doi.org/10.1111/cup.13873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960566PMC
September 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

A case of tumor-to-tumor metastasis of cutaneous malignant melanoma.

J Cutan Pathol 2020 Dec 6;47(12):1196-1199. Epub 2020 Sep 6.

Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

We report a case of tumor-to-tumor metastasis of a cutaneous malignant melanoma to a synchronous thyroid Hurthle cell carcinoma. A 42-year-old male underwent a biopsy of right inguinal lymphadenopathy which showed metastatic melanoma. The primary lesion was identified on his right posterior leg, and staging workup discovered a synchronous left thyroid lobe nodule concerning for a follicular neoplasm. He underwent excision of the primary melanoma, right inguinal lymphadenectomy, and total thyroidectomy. The resected thyroid contained a 6.6-cm, well-encapsulated left-sided nodule, red-brown in color and homogenous in consistency, with areas of focal hemorrhage and no grossly identifiable calcification. Microscopically, large tumor cells with distinct cell borders were present, with deeply eosinophilic and granular cytoplasm, large nuclei with prominent nucleoli, and loss of polarity consistent with oncocytes. A microscopic single focus of vascular invasion was identified, and a diagnosis of angioinvasive Hurthle cell carcinoma was made. Within the Hurthle cell carcinoma, multiple deposits of metastatic melanoma were seen. These findings were indicative of tumor-to-tumor metastasis of the cutaneous melanoma to the angioinvasive Hurthle cell carcinoma. Our findings show the ability of melanoma to metastasize to a pre-existing neoplasm.
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http://dx.doi.org/10.1111/cup.13829DOI Listing
December 2020

Urethral involvement is associated with higher mortality and local recurrence in vulvar melanoma: a single institutional experience.

Hum Pathol 2020 10 20;104:1-8. Epub 2020 Jul 20.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA. Electronic address:

Vulvar malignant melanoma (VMM), although uncommon, comprises 5-10% of all vulvar malignancies. Local control is notoriously poor in VMM with recurrence rates of 30-50% compared with approximately 3% in cutaneous melanomas. We studied clinicopathologic features of 37 women with VMM, after reviewing three decades of clinical follow-up data in our institutional databases. Most patients were Caucasian (n = 35) with an average age at diagnosis of 60.6 years (range 23-83). The most common subtype was mucosal lentiginous melanoma (n = 25). We compared Kaplan-Meier survival curves of 31 patients defined by clinical and microscopic attributes using exact log-rank tests. Younger patients at diagnosis (23-64 years), those with thin melanomas (≤1 mm), and those with Clark's level II or III tumors had better 5-year survival rates than older patients (65-83 years) and those with thick melanomas (>1 mm) and those with Clark's level IV or V (P ≤ 0.05), respectively, by exact log-rank test. Local recurrence of melanoma occurred in 15 patients. Nine patients (24%) had eventual urethral involvement by malignant melanoma, and this feature was associated with significantly shorter survival (P = 0.036). Patients with urethral involvement had shorter median time to death and worse 5-year survival rates. Given that spread to the urethra is common in VMM and urethral recurrence is also associated with mortality, pathology excision specimens should be carefully reviewed with attention to urethral involvement as a potentially important prognostic factor.
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http://dx.doi.org/10.1016/j.humpath.2020.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669565PMC
October 2020

Malpractice and Patient Safety Concerns.

Am J Clin Pathol 2020 10;154(5):700-707

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles.

Objectives: "Assurance behaviors," a type of defensive medicine, involve physicians' utilization of additional patient services to avoid adverse legal outcomes. We aim to compare the use of clinical behaviors (such as ordering additional tests, services, and consultations) due to malpractice concerns with the same behaviors due to patient safety concerns.

Methods: A national sample of dermatopathologists (n = 160) completed an online survey.

Results: Participants reported using one or more of five clinical behaviors due to concerns about medical malpractice (95%) and patient safety (99%). Self-reported use of clinical behaviors due to malpractice concerns and patient safety concerns was compared, including ordering additional immunohistochemistry/molecular tests (71% vs 90%, respectively, P < .0001), recommending additional surgical sampling (78% vs 91%, P < .0001), requesting additional slides (81% vs 95%, P < .0001), obtaining second reviews (78% vs 91%, P < .0001), and adding caveats into reports regarding lesion difficulty (85% vs 89%, P > .05).

Conclusions: Dermatopathologists use many clinical behaviors both as assurance behaviors and due to patient safety concerns, with a higher proportion reporting patient safety concerns as a motivation for specific behaviors.
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http://dx.doi.org/10.1093/ajcp/aqaa088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553247PMC
October 2020

Factors associated with use of immunohistochemical markers in the histopathological diagnosis of cutaneous melanocytic lesions.

J Cutan Pathol 2020 Oct 17;47(10):896-902. Epub 2020 Jul 17.

Division of General Internal Medicine and Health Services Research, UCLA David Geffen School of Medicine, Los Angeles, California, USA.

Background: Melanocytic tumors are often challenging and constitute almost one in four skin biopsies. Immunohistochemical (IHC) studies may assist diagnosis; however, indications for their use are not standardized.

Methods: A test set of 240 skin biopsies of melanocytic tumors was examined by 187 pathologists from 10 US states, interpreting 48 cases in Phase I and either 36 or 48 cases in Phase II. Participant and diagnosis characteristics were compared between those who reported they would have ordered, or who would have not ordered IHC on individual cases. Intraobserver analysis examined consistency in the intent to order when pathologists interpreted the same cases on two occasions.

Results: Of 187 participants interpreting 48 cases each, 21 (11%) did not request IHC tests for any case, 85 (45%) requested testing for 1 to 6 cases, and 81 (43%) requested testing for ≥6 cases. Of 240 cases, 229 had at least one participant requesting testing. Only 2 out of 240 cases had more than 50% of participants requesting testing. Increased utilization of testing was associated with younger age of pathologist, board-certification in dermatopathology, low confidence in diagnosis, and lesions in intermediate MPATH-Dx classes 2 to 4. The median intraobserver concordance for requesting tests among 72 participants interpreting the same 48 cases in Phases I and II was 81% (IQR 73%-90%) and the median Kappa statistic was 0.20 (IQR 0.00, 0.39).

Conclusion: Substantial variability exists among pathologists in utilizing IHC.
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http://dx.doi.org/10.1111/cup.13736DOI Listing
October 2020

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.

Authors:
Maria Teresa Landi D Timothy Bishop Stuart MacGregor Mitchell J Machiela Alexander J Stratigos Paola Ghiorzo Myriam Brossard Donato Calista Jiyeon Choi Maria Concetta Fargnoli Tongwu Zhang Monica Rodolfo Adam J Trower Chiara Menin Jacobo Martinez Andreas Hadjisavvas Lei Song Irene Stefanaki Richard Scolyer Rose Yang Alisa M Goldstein Miriam Potrony Katerina P Kypreou Lorenza Pastorino Paola Queirolo Cristina Pellegrini Laura Cattaneo Matthew Zawistowski Pol Gimenez-Xavier Arantxa Rodriguez Lisa Elefanti Siranoush Manoukian Licia Rivoltini Blair H Smith Maria A Loizidou Laura Del Regno Daniela Massi Mario Mandala Kiarash Khosrotehrani Lars A Akslen Christopher I Amos Per A Andresen Marie-Françoise Avril Esther Azizi H Peter Soyer Veronique Bataille Bruna Dalmasso Lisa M Bowdler Kathryn P Burdon Wei V Chen Veryan Codd Jamie E Craig Tadeusz Dębniak Mario Falchi Shenying Fang Eitan Friedman Sarah Simi Pilar Galan Zaida Garcia-Casado Elizabeth M Gillanders Scott Gordon Adele Green Nelleke A Gruis Johan Hansson Mark Harland Jessica Harris Per Helsing Anjali Henders Marko Hočevar Veronica Höiom David Hunter Christian Ingvar Rajiv Kumar Julie Lang G Mark Lathrop Jeffrey E Lee Xin Li Jan Lubiński Rona M Mackie Maryrose Malt Josep Malvehy Kerrie McAloney Hamida Mohamdi Anders Molven Eric K Moses Rachel E Neale Srdjan Novaković Dale R Nyholt Håkan Olsson Nicholas Orr Lars G Fritsche Joan Anton Puig-Butille Abrar A Qureshi Graham L Radford-Smith Juliette Randerson-Moor Celia Requena Casey Rowe Nilesh J Samani Marianna Sanna Dirk Schadendorf Hans-Joachim Schulze Lisa A Simms Mark Smithers Fengju Song Anthony J Swerdlow Nienke van der Stoep Nicole A Kukutsch Alessia Visconti Leanne Wallace Sarah V Ward Lawrie Wheeler Richard A Sturm Amy Hutchinson Kristine Jones Michael Malasky Aurelie Vogt Weiyin Zhou Karen A Pooley David E Elder Jiali Han Belynda Hicks Nicholas K Hayward Peter A Kanetsky Chad Brummett Grant W Montgomery Catherine M Olsen Caroline Hayward Alison M Dunning Nicholas G Martin Evangelos Evangelou Graham J Mann Georgina Long Paul D P Pharoah Douglas F Easton Jennifer H Barrett Anne E Cust Goncalo Abecasis David L Duffy David C Whiteman Helen Gogas Arcangela De Nicolo Margaret A Tucker Julia A Newton-Bishop Ketty Peris Stephen J Chanock Florence Demenais Kevin M Brown Susana Puig Eduardo Nagore Jianxin Shi Mark M Iles Matthew H Law

Nat Genet 2020 05 27;52(5):494-504. Epub 2020 Apr 27.

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
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http://dx.doi.org/10.1038/s41588-020-0611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255059PMC
May 2020

Histologic features of melanoma associated with germline mutations of CDKN2A, CDK4, and POT1 in melanoma-prone families from the United States, Italy, and Spain.

J Am Acad Dermatol 2020 Sep 10;83(3):860-869. Epub 2020 Apr 10.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.

Background: CDKN2A, CDK4, and POT1 are well-established melanoma-susceptibility genes.

Objective: We evaluated melanoma histopathology for individuals with germline mutations of CDKN2A, CDK4, and POT1.

Methods: We assessed histopathology for melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) from the United States, Italy, and Spain. Comparisons between mutation carriers and noncarriers (no mutation) were adjusted for age, sex, Breslow depth, and correlations among individuals within the same family.

Results: Histologic slides were evaluated for 290 melanomas (139 from 132 noncarriers, 122 from 68 CDKN2A carriers, 10 from 6 CDK4 carriers, and 19 from 16 POT1 carriers). Superficial spreading was the predominant subtype for all groups. Spitzoid morphology (>25% of tumor) was observed in 10 of 15 invasive melanomas (67%) from POT1 carriers (P < .0001 vs noncarriers). This finding was independently confirmed by 3 expert melanoma dermatopathologists in 9 of 15 invasive melanomas (60%). In situ and invasive melanomas from CDKN2A and CDK4 carriers were histologically similar to melanomas from noncarriers.

Limitations: Limited sample sizes for rare melanoma-susceptibility syndromes (CDK4, POT1).

Conclusion: Spitzoid morphology was associated with POT1 mutations suggesting that telomere dysfunction (POT1 mutations) may contribute to spitzoid differentiation in melanocytic tumors.
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http://dx.doi.org/10.1016/j.jaad.2020.03.100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505133PMC
September 2020

The 2018 World Health Organization Classification of Cutaneous, Mucosal, and Uveal Melanoma: Detailed Analysis of 9 Distinct Subtypes Defined by Their Evolutionary Pathway.

Arch Pathol Lab Med 2020 04 14;144(4):500-522. Epub 2020 Feb 14.

From the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia (Dr Elder); the Department of Dermatology, University of California San Francisco, San Francisco (Dr Bastian); International Agency for Research on Cancer, Lyon, France (Dr Cree); Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy (Dr Massi); and the Department of Pathology and Melanoma Institute Australia, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia (Dr Scolyer).

Context.—: There have been major advances in the understanding of melanoma since the last revision of the World Health Organization (WHO) classification in 2006.

Objective.—: To discuss development of the 9 distinct types of melanoma and distinguishing them by their epidemiology, clinical and histologic morphology, and genomic characteristics. Each melanoma subtype is placed at the end of an evolutionary pathway that is rooted in its respective precursor, wherever appropriate and feasible, based on currently known data. Each precursor has a variable risk of progression culminating in its fully evolved, invasive melanoma.

Data Sources.—: This review is based on the "Melanocytic Tumours" section of the 4th edition of the , published in 2018.

Conclusions.—: Melanomas were divided into those etiologically related to sun exposure and those that are not, as determined by their mutational signatures, anatomic site, and epidemiology. Melanomas on the sun-exposed skin were further divided by the histopathologic degree of cumulative solar damage (CSD) of the surrounding skin, into low and high CSD, on the basis of degree of associated solar elastosis. Low-CSD melanomas include superficial spreading melanomas and high-CSD melanomas incorporate lentigo maligna and desmoplastic melanomas. The "nonsolar" category includes acral melanomas, some melanomas in congenital nevi, melanomas in blue nevi, Spitz melanomas, mucosal melanomas, and uveal melanomas. The general term is proposed to encompass "intermediate" tumors that have an increased (though still low) probability of disease progression to melanoma.
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http://dx.doi.org/10.5858/arpa.2019-0561-RADOI Listing
April 2020

Dermatopathologists' Experience With and Perceptions of Patient Online Access to Pathologic Test Result Reports.

JAMA Dermatol 2020 03;156(3):320-324

David Geffen School of Medicine, Department of Medicine, University of California, Los Angeles.

Importance: Many patients presently have access to their pathologic test result reports via online patient portals, yet little is known about pathologists' perspective on this topic.

Objective: To examine dermatopathologists' experience and perceptions of patient online access to pathology reports.

Design, Setting, And Participants: A survey of 160 dermatopathologists currently practicing in the United States who are board certified and/or fellowship trained in dermatopathology was conducted between July 15, 2018, and September 23, 2019. Those who reported interpreting skin biopsies of melanocytic lesions within the previous year and expected to continue interpreting them for the next 2 years were included.

Main Outcomes And Measures: Dermatopathologists' demographic and clinical characteristics, experiences with patient online access to pathologic test result reports, potential behaviors and reactions to patient online access to those reports, and effects on patients who read their pathologic test result reports online.

Results: Of the 160 participating dermatopathologists from the 226 eligible for participation (71% response rate), 107 were men (67%); mean (SD) age was 49 (9.7) years (range, 34-77 years). Ninety-one participants (57%) reported that patients have contacted them directly about pathologic test reports they had written. Some participants noted that they would decrease their use of abbreviations and/or specialized terminology (57 [36%]), change the way they describe lesions suspicious for cancer (29 [18%]), and need specialized training in communicating with patients (39 [24%]) if patients were reading their reports. Most respondents perceived that patient understanding would increase (97 [61%]) and the quality of patient-physician communication would increase (98 [61%]) owing to the availability of online reports. Slightly higher proportions perceived increased patient worry (114 [71%]) and confusion (116 [73%]). However, on balance, most participants (114 [71%]) agreed that making pathologic test result reports available to patients online is a good idea.

Conclusions And Relevance: Dermatopathologists in this survey study perceived both positive and negative consequences of patient online access to pathologic test result reports written by the respondents. Most participants believe that making pathologic test result reports available to patients online is a good idea; however, they also report concerns about patient worry and confusion increasing as a result. Further research regarding best practices and the effect on both patients and clinicians is warranted.
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http://dx.doi.org/10.1001/jamadermatol.2019.4194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990839PMC
March 2020

Staging for Melanoma - Toward a New Paradigm?

J Natl Cancer Inst 2020 09;112(9):873-874

Melanoma Institutes Australia, The University of Sydney Royal Prince Alfred Hospital and New South Wales Health Pathology, Faculty of Health and Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1093/jnci/djaa009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492757PMC
September 2020

Neoadjuvant Versus Adjuvant Immune Checkpoint Blockade in the Treatment of Clinical Stage III Melanoma.

Ann Surg Oncol 2020 Aug 2;27(8):2915-2926. Epub 2020 Jan 2.

Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: Immune checkpoint blockade (ICB) has transformed melanoma treatment, but optimal sequencing of ICB and surgery for clinically evident nodal metastasis remains undefined. We evaluated adjuvant-only (AT) and neoadjuvant/adjuvant (NAT) ICB with respect to survival outcomes in this patient population.

Methods: Patients who underwent lymphadenectomy (1 January 2011 to 31 July 2018) and received perioperative ICB at an academic center were identified. AT was defined as postoperative ICB, and NAT was defined as one to two cycles of ICB prior to resection with continuation of therapy following surgery. Three-year disease-free survival (DFS), locoregional recurrence-free survival (LRFS), distant disease-free survival (DDFS), and melanoma-specific survival (MSS) were estimated.

Results: Of 59 patients, 18 (31%) received AT and 41 (69%) received NAT. The AT and NAT groups did not differ in age (median 53 vs. 62 years, p = 0.16) or stage (IIIB 33% vs. 29%, IIIC 56% vs. 68%, IIID 11% vs. 2%, p = 0.34). Although 3-year DFS did not differ significantly by treatment sequencing (NAT vs. AT, hazard ratio [HR] 0.56, p = 0.17), NAT was associated with improved 3-year DDFS (HR 0.38, p = 0.028). Of 39 NAT patients with evaluable pathologic response, 23 (59%) and 5 (13%) had a pathologic partial response (pPR) and pathologic complete response (pCR), respectively. Patients with pPR/pCR experienced improved 3-year DFS (HR 0.16, p = 0.001), LRFS (HR 0.17, p = 0.003), and DDFS (HR 0.26, p = 0.029) compared with those with no response. Three-year MSS did not differ significantly by response (p = 0.062).

Conclusion: NAT may be associated with improved 3-year DDFS compared with AT sequencing, and allows for early assessment of pathologic response. Further prospective evaluation of treatment sequencing is warranted.
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http://dx.doi.org/10.1245/s10434-019-08174-1DOI Listing
August 2020

Pathologists' agreement on treatment suggestions for melanocytic skin lesions.

J Am Acad Dermatol 2020 Jun 17;82(6):1435-1444. Epub 2019 Dec 17.

Department of Medicine, University of Washington School of Medicine, Seattle, Washington; Department of Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California. Electronic address:

Background: Although treatment guidelines exist for melanoma in situ and invasive melanoma, guidelines for other melanocytic skin lesions do not exist.

Objective: To examine pathologists' treatment suggestions for a broad spectrum of melanocytic skin lesions and compare them with existing guidelines.

Methods: Pathologists (N = 187) completed a survey and then provided diagnoses and treatment suggestions for 240 melanocytic skin lesions. Physician characteristics associated with treatment suggestions were evaluated with multivariable modeling.

Results: Treatment suggestions were concordant with National Comprehensive Cancer Network guidelines for the majority of cases interpreted as melanoma in situ (73%) and invasive melanoma (86%). Greater variability of treatment suggestions was seen for other lesion types without existing treatment guidelines. Characteristics associated with provision of treatment suggestions discordant with National Comprehensive Cancer Network guidelines were low caseloads (invasive melanoma), lack of fellowship training or board certification (melanoma in situ), and more than 10 years of experience (invasive melanoma and melanoma in situ).

Limitations: Pathologists could not perform immunohistochemical staining or other diagnostic tests; only 1 glass side was provided per biopsy case.

Conclusions: Pathologists' treatment suggestions vary significantly for melanocytic lesions, with lower variability for lesion types with national guidelines. Results suggest the need for standardization of treatment guidelines for all melanocytic lesion types.
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http://dx.doi.org/10.1016/j.jaad.2019.12.020DOI Listing
June 2020

Draining dorsal hand pustules, nodules, and ulcers in a patient with immunosuppression.

JAAD Case Rep 2019 Oct 24;5(10):846-848. Epub 2019 Sep 24.

Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1016/j.jdcr.2019.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804474PMC
October 2019

Assessment of Second-Opinion Strategies for Diagnoses of Cutaneous Melanocytic Lesions.

JAMA Netw Open 2019 10 2;2(10):e1912597. Epub 2019 Oct 2.

Department of Translational Research, Institut Curie, Paris, France.

Importance: Histopathologic criteria have limited diagnostic reliability for a range of cutaneous melanocytic lesions.

Objective: To evaluate the association of second-opinion strategies by general pathologists and dermatopathologists with the overall reliability of diagnosis of difficult melanocytic lesions.

Design, Setting, And Participants: This diagnostic study used samples from the Melanoma Pathology Study, which comprises 240 melanocytic lesion samples selected from a dermatopathology laboratory in Bellevue, Washington, and represents the full spectrum of lesions from common nevi to invasive melanoma. Five sets of 48 samples were evaluated independently by 187 US pathologists from July 15, 2013, through May 23, 2016. Data analysis was performed from April 2016 through November 2017.

Main Outcomes And Measures: Accuracy of diagnosis, defined as concordance with an expert consensus diagnosis of 3 experienced pathologists, was assessed after applying 10 different second-opinion strategies.

Results: Among the 187 US pathologists examining the 24 lesion samples, 113 were general pathologists (65 men [57.5%]; mean age at survey, 53.7 years [range, 33.0-79.0 years]) and 74 were dermatopathologists (49 men [66.2%]; mean age at survey, 46.4 years [range, 33.0-77.0 years]). Among the 8976 initial case interpretations, physicians desired second opinions for 3899 (43.4%), most often for interpretation of severely dysplastic nevi. The overall misclassification rate was highest when interpretations did not include second opinions and initial reviewers were all general pathologists lacking subspecialty training (52.8%; 95% CI, 51.3%-54.3%). When considering different second opinion strategies, the misclassification of melanocytic lesions was lowest when the first, second, and third consulting reviewers were subspecialty-trained dermatopathologists and when all lesions were subject to second opinions (36.7%; 95% CI, 33.1%-40.7%). When the second opinion strategies were compared with single interpretations without second opinions, the reductions in misclassification rates for some of the strategies were statistically significant, but none of the strategies eliminated diagnostic misclassification. Melanocytic lesions in the middle of the diagnostic spectrum had the highest misclassification rates (eg, moderately or severely dysplastic nevus, Spitz nevus, melanoma in situ, and pathologic stage [p]T1a invasive melanoma). Variability of in situ and thin invasive melanoma was relatively intractable to all examined strategies.

Conclusions And Relevance: The results of this study suggest that second opinions rendered by dermatopathologists improve reliability of melanocytic lesion diagnosis. However, discordance among pathologists remained high.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.12597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804025PMC
October 2019

Stromal inflammatory cells are associated with poorer prognosis in primary cutaneous melanoma.

Hum Pathol 2019 06 6;88:78-86. Epub 2019 Apr 6.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

We observed that non-tumor-infiltrating inflammatory cells are often present in the stroma of melanoma. The role of these stromal inflammatory cells (SIC) in cancer has not been studied. We evaluated the prognostic significance of SIC in 299 patients with vertical growth phase primary melanomas with at least 10 years of clinical follow-up. Lymphatic density and lymphatic invasion in the areas with SIC was quantified. The prognostic significance of these factors was evaluated using univariable and multivariable Cox models for melanoma-specific death and the time to first recurrence. Of the 299 melanomas, 161 exhibited areas with SIC. Percentages of vertical growth phase tumor-infiltrating lymphocytes and radial growth phase regression were significantly higher in cases with SIC compared to those without SIC (P = .005); lymphatic invasion was also detected more frequently in cases with SIC (P = .001). Lymphatic density in SIC areas was higher than that in other areas of the melanomas. Patients with SIC had poorer clinical outcome. Vascular endothelial growth factor-C (VEGFC) staining in a subset of these melanoma patients showed that VEGFC expression in the stromal macrophages was associated with lymphatic invasion in SIC areas. In conclusion, SIC in melanoma is associated with poorer prognosis, and the prognostic effect is partially mediated through induction of lymphangiogenesis with increased lymphatic invasion.
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http://dx.doi.org/10.1016/j.humpath.2019.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579677PMC
June 2019

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT.

J Am Acad Dermatol 2019 Aug 5;81(2):386-394. Epub 2019 Feb 5.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Electronic address:

Background: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved.

Methods: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics.

Results: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance.

Conclusion: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling.
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http://dx.doi.org/10.1016/j.jaad.2019.01.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634996PMC
August 2019

Concordance and Reproducibility of Melanoma Staging According to the 7th vs 8th Edition of the .

JAMA Netw Open 2018 05;1(1)

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (Elmore); Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia (Elder); Department of Pathology, Institut Curie, Paris, France (Barnhill); Paris Sciences and Lettres Research University, Paris, France (Barnhill); Faculty of Medicine, University of Paris Descartes, Paris, France (Barnhill); Pathology Associates, Clovis, California (Knezevich); Program in Biostatistics and Biomathematics, Fred Hutchinson Cancer Research Center, Seattle, Washington (Longton, Pepe); Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (Titus); Department of Pediatrics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire (Titus); Norris Cotton Cancer Center, Lebanon, New Hampshire (Titus); Center for Dermatoepidemiology, Providence Veterans Affair Medical Center, Providence, Rhode Island (Weinstock); Department of Dermatology, Brown University, Providence, Rhode Island (Weinstock); Department of Epidemiology, Brown University, Providence, Rhode Island (Weinstock); Department of Medical Informatics and Clinical Epidemiology, School of Medicine, Oregon Health and Science University, Portland (Nelson); Department of Medicine, School of Medicine, Oregon Health and Science University, Portland (Nelson); Department of Medicine, University of Washington School of Medicine, Seattle (Reisch, Radick, Piepkorn); Dermatopathology Northwest, Bellevue, Washington (Piepkorn).

Importance: The recently updated American Joint Committee on Cancer (AJCC) classification of cancer staging, the , 8th edition (), includes revisions to definitions of T1a vs T1b or greater. The Melanoma Pathology Study database affords a comparison,of pathologists' concordance and reproducibility in the microstaging of melanoma according to both the existing 7th edition ) and the new .

Objective: To compare and to examine whether changes to the definitions of T1a and T1b or greater are associated with changes in concordance and reproducibility.

Design Setting And Participants: In this diagnostic study conducted as part of the national Melanoma Pathology Study across US states, 187 pathologists interpreting melanocytic skin lesions in practice completed 4342 independent case interpretations of 116 invasive melanoma cases. A consensus reference diagnosis and participating pathologists' interpretations were classified into the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis class IV (T1a) or class V ( T1b) using both the and criteria.

Main Outcomes And Measures: Concordance with consensus reference diagnosis, interobserver reproducibility, and intraobserver reproducibility.

Results: For T1a diagnoses, participating pathologists' concordance with the consensus reference diagnosis increased from 44% (95% CI, 41%-48%) to 54% (95% CI, 51%-57%) using and criteria, respectively. The concordance for cases of T1b or greater increased from 72% (95% CI, 69%-75%) to 78% (95% CI, 75%-80%). Intraobserver reproducibility of diagnoses also improved, increasing from 59% (95% CI, 56%-63%) to 64% (95% CI, 62%-67%) for T1a invasive melanoma, and from 74% (95% CI, 71%-76%) to 77% (95% CI, 74%-79%) for T1b or greater invasive melanoma cases.

Conclusions And Relevance: Melanoma staging in shows greater reproducibility and higher concordance with a reference standard. Improved classification of invasive melanoma can be expected after implementation of , suggesting a positive impact on patients. However, despite improvement, concordance and reproducibility remain low.
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http://dx.doi.org/10.1001/jamanetworkopen.2018.0083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294444PMC
May 2018

NRAS Q61R and BRAF G466A mutations in atypical melanocytic lesions newly arising in advanced melanoma patients treated with vemurafenib.

J Cutan Pathol 2019 Mar 27;46(3):190-194. Epub 2018 Dec 27.

Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Background: BRAF inhibition has improved overall survival in patients with BRAF mutant melanoma, but this is associated with a range of known and predictable cutaneous side effects, including squamous cell carcinomas associated with RAS mutations.

Methods: We identified three severely dysplastic nevi, one atypical intraepidermal melanocytic proliferation, and four melanoma in situ lesions, newly arising in four patients undergoing treatment with vemurafenib. To characterize mutations in these atypical melanocytic lesions, we used a custom iPlex panel detecting 74 mutations in 13 genes known to play a role in melanoma pathogenesis.

Results: We identified an NRAS mutation at codon 61 (Q61R) and a rare BRAF exon 11 mutation (G466A) in atypical melanocytic lesions that arose in patients treated with vemurafenib.

Conclusion: There appears to be development or accelerated growth of atypical melanocytic lesions in the setting of BRAF inhibition. Our results underscore the need for careful surveillance for melanocytic lesions in patients on BRAF inhibitor therapy and shed light on potential mechanisms for melanoma pathogenesis in the context of BRAF pathway blockade. Further studies are warranted to show a causal relationship.
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http://dx.doi.org/10.1111/cup.13401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367041PMC
March 2019

Guidelines of care for the management of primary cutaneous melanoma.

J Am Acad Dermatol 2019 01 1;80(1):208-250. Epub 2018 Nov 1.

American Academy of Dermatology, Rosemont, Illinois.

The incidence of primary cutaneous melanoma continues to increase each year. Melanoma accounts for the majority of skin cancer-related deaths, but treatment is usually curative following early detection of disease. In this American Academy of Dermatology clinical practice guideline, updated treatment recommendations are provided for patients with primary cutaneous melanoma (American Joint Committee on Cancer stages 0-IIC and pathologic stage III by virtue of a positive sentinel lymph node biopsy). Biopsy techniques for a lesion that is clinically suggestive of melanoma are reviewed, as are recommendations for the histopathologic interpretation of cutaneous melanoma. The use of laboratory, molecular, and imaging tests is examined in the initial work-up of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, recommendations for surgical margins and the concepts of staged excision (including Mohs micrographic surgery) and nonsurgical treatments for melanoma in situ, lentigo maligna type (including topical imiquimod and radiation therapy), are updated. The role of sentinel lymph node biopsy as a staging technique for cutaneous melanoma is described, with recommendations for its use in clinical practice. Finally, current data regarding pregnancy and melanoma, genetic testing for familial melanoma, and management of dermatologic toxicities related to novel targeted agents and immunotherapies for patients with advanced disease are summarized.
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http://dx.doi.org/10.1016/j.jaad.2018.08.055DOI Listing
January 2019

Relationship between age and likelihood of lymph node metastases in patients with intermediate thickness melanoma (1.01-4.00 mm): A National Cancer Database study.

J Am Acad Dermatol 2019 Feb 27;80(2):433-440. Epub 2018 Aug 27.

Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Background: There is large variability in the risk of sentinel lymph node (SLN) positivity among patients with intermediate thickness melanoma (ITM), with a subgroup of patients exhibiting a low risk of nodal disease.

Objective: To identify a group of patients with ITM for whom the risk of nodal disease is low.

Methods: A retrospective cohort of patients with ITM who underwent wide excision and nodal evaluation from 2010 to 2013 was identified by using the National Cancer Database and analyzed for the presence of nodal disease. Classification and regression tree analysis identified the most important factors used in a model to identify groups at low risk of SLN positivity.

Results: Of 23,440 patients, 14.7% were found to have nodal metastasis. On classification and regression tree analysis, patients older than 55 years without lymphovascular invasion and with a lesion thickness less than 1.7 mm had an SLN positivity rate of 4.9%. A model using age and thickness in nonulcerated patients identified a low-risk subgroup with a corresponding SLN positivity rate of 4.7%.

Limitations: This was a retrospective study, and the model developed requires prospective validation.

Conclusions: Patient age is an important factor in estimating risk of SLN in patients with ITM and may help identify patients without ulceration who may be safely spared an SLN biopsy.
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http://dx.doi.org/10.1016/j.jaad.2018.08.022DOI Listing
February 2019

Characteristics and diagnostic performance of pathologists who enjoy interpreting melanocytic lesions.

Dermatol Online J 2018 Jun 15;24(6). Epub 2018 Jun 15.

Department of Medicine, University of Washington School of Medicine, Seattle, Washington.

Diagnostic discrepancy among pathologists interpreting melanocytic skin lesions (MSL) is an ongoing concern for patient care. Given that job satisfaction could impact patient care, this study aimed to characterize which pathologists enjoy interpreting MSL and estimate the association between enjoyment and diagnostic accuracy. Pathologists' demographics, training, and experience were obtained by a cross-sectional survey. Associations between these characteristics and self-reported enjoyment when interpreting MSL were estimated by Pearson's Chi-square tests. Diagnostic accuracy was determined by comparing pathologists' MSL interpretations with reference standard diagnoses. Associations between enjoyment and diagnostic accuracy were evaluated by generalized estimating equations (GEE) models. One hundred and eighty-seven (90%) pathologists completed the study. Seventy percent agreed that interpreting MSL is enjoyable. Pathologists who enjoyed interpreting MSL were more likely to be board certified and/or fellowship trained in dermatopathology (P=0.008), have ?10 years of experience (P=0.010) and have an MSL caseload of ?60 per month (P=<0.001). After adjustment, there was no association between enjoyment and diagnostic accuracy. Our data suggest that job dissatisfaction does not adversely affect diagnostic accuracy in the interpretation of melanocytic lesions, which is of importance given the progressive increase in annual biopsy rates and the attendant work demands imposed on pathologists.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463485PMC
June 2018

Accuracy of Digital Pathologic Analysis vs Traditional Microscopy in the Interpretation of Melanocytic Lesions.

JAMA Dermatol 2018 10;154(10):1159-1166

Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.

Importance: Use of digital whole-slide imaging (WSI) for dermatopathology in general has been noted to be similar to traditional microscopy (TM); however, concern has been noted that WSI is inferior for interpretation of melanocytic lesions. Since approximately 1 of every 4 skin biopsies is of a melanocytic lesion, the use of WSI requires verification before use in clinical practice.

Objective: To compare pathologists' accuracy and reproducibility in diagnosing melanocytic lesions using Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) categories when analyzing by TM vs WSI.

Design, Setting, And Participants: A total of 87 pathologists in community-based and academic settings from 10 US states were randomized with stratification based on clinical experience to interpret in TM format 180 skin biopsy cases of melanocytic lesions, including 90 invasive melanoma, divided into 5 sets of 36 cases (phase 1). The pathologists were then randomized via stratified permuted block randomization with block size 2 to interpret cases in either TM (n = 46) or WSI format (n = 41), with each pathologist interpreting the same 36 cases on 2 separate occasions (phase 2). Diagnoses were categorized as MPATH-Dx categories I through V, with I indicating the least severe and V the most severe.

Main Outcomes And Measures: Accuracy with respect to a consensus reference diagnosis and the reproducibility of repeated interpretations of the same cases.

Results: Of the 87 pathologists in the study, 46% (40) were women and the mean (SD) age was 50.7 (10.2) years. Except for class III melanocytic lesions, the diagnostic categories showed no significant differences in diagnostic accuracy between TM and WSI interpretation. Discordance was lower among class III lesions for the TM interpretation arm (51%; 95% CI, 46%-57%) than for the WSI arm (61%; 95% CI, 53%-69%) (P = .05). This difference is likely to have clinical significance, because 6% of TM vs 11% of WSI class III lesions were interpreted as invasive melanoma. Reproducibility was similar between the traditional and digital formats overall (66.4%; 95% CI, 63.3%-69.3%; and 62.7%; 95% CI, 59.5%-65.7%, respectively), and for all classes, although class III showed a nonsignificant lower intraobserver agreement for digital. Significantly more mitotic figures were detected with TM compared with WSI: mean (SD) TM, 6.72 (2.89); WSI, 5.84 (2.56); P = .002.

Conclusions And Relevance: Interpretive accuracy for melanocytic lesions was similar for WSI and TM slides except for class III lesions. We found no clinically meaningful differences in reproducibility for any of the diagnostic classes.
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http://dx.doi.org/10.1001/jamadermatol.2018.2388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233746PMC
October 2018

Prediction of Residual Nodal Disease at Completion Dissection Following Positive Sentinel Lymph Node Biopsy for Melanoma.

Ann Surg Oncol 2018 Nov 24;25(12):3469-3475. Epub 2018 Jul 24.

Department of Surgery, Endocrine and Oncologic Surgery Division, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

Introduction: While recent trial data have demonstrated no survival benefit to immediate completion lymph node dissection (CLND) for positive sentinel lymph node (SLN) disease in melanoma, prediction of non-SLN disease may help risk-stratify patients for more intensive observation of the nodal basin.

Patients And Methods: A retrospective cohort of patients with positive SLN biopsy (SLNB) who underwent CLND was identified (1996-2016). A risk score for likelihood of CLND-positive disease was developed based on factors associated with presence of CLND metastases identified on logistic regression. Survival outcomes were analyzed.

Results: Among 312 patients with positive SLN, 192 underwent CLND and had complete pathologic data for evaluation. The median age of the study cohort was 53 years [interquartile range (IQR) 43-66 years], and 112 (58%) were male. Thirty-one (16%) had non-SLN metastatic disease on CLND. The four factors independently associated with CLND positivity and thus included in the risk score were Breslow thickness ≥ 3 mm [odds ratio (OR) 2.56, p = 0.047], presence of primary tumor-infiltrating lymphocytes (OR 0.33, p = 0.013), ≥ 2/3 positive-to-total SLN ratio (OR 4.35, p = 0.003), and combined subcapsular and parenchymal metastatic SLN location or metastatic deposit ≥ 1 mm (OR 4.45, p = 0.013). The four-point risk score predicted CLND positivity well with area under the curve of 0.82 (0.80-0.85). Increasing risk score was independently associated with increasingly worse melanoma-specific survival [hazard ratio (HR) = 1.54, p = 0.001].

Conclusions: Likelihood of residual nodal disease after positive SLNB and survival can be predicted from primary tumor and SLN characteristics. High-risk patients may warrant more intensive surveillance of the nodal basin to reduce risk of loss of regional control.
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http://dx.doi.org/10.1245/s10434-018-6647-7DOI Listing
November 2018

Malpractice Concerns, Defensive Medicine, and the Histopathology Diagnosis of Melanocytic Skin Lesions.

Am J Clin Pathol 2018 Aug;150(4):338-345

Department of Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA.

Objectives: The impact of malpractice concerns on pathologists' use of defensive medicine and interpretations of melanocytic skin lesions (MSLs) is unknown.

Methods: A total of 207 pathologists interpreting MSLs responded to a survey about past involvement in malpractice litigation, influence of malpractice concerns on diagnosis, and use of assurance behaviors (defensive medicine) to alleviate malpractice concerns. Assurance behaviors included requesting second opinions, additional slides, additional sampling, and ordering specialized tests.

Results: Of the pathologists, 27.5% reported that malpractice concerns influenced them toward a more severe MSL diagnosis. Nearly all (95.2%) pathologists reported practicing at least one assurance behavior due to malpractice concerns, and this practice was associated with being influenced toward a more severe MSL diagnosis (odds ratio, 2.72; 95% confidence interval, 1.41-5.26).

Conclusions: One of four US skin pathologists upgrade MSL diagnosis due to malpractice concerns, and nearly all practice assurance behaviors. Assurance behaviors are associated with rendering a more severe MSL diagnosis.
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http://dx.doi.org/10.1093/ajcp/aqy057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116884PMC
August 2018

Melanoma Screening and Mortality.

Authors:
David E Elder

J Natl Cancer Inst 2018 10;110(10):1135-1136

Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.1093/jnci/djy056DOI Listing
October 2018

Complexities of perceived and actual performance in pathology interpretation: A comparison of cutaneous melanocytic skin and breast interpretations.

J Cutan Pathol 2018 Jul 26;45(7):478-490. Epub 2018 Apr 26.

Department of Internal Medicine, University of Washington, Seattle, Washington.

Background: Little is known about how pathologists process differences between actual and perceived interpretations.

Objective: To compare perceived and actual diagnostic agreement before and after educational interventions.

Methods: Pathologists interpreted test sets of skin and/or breast specimens that included benign, atypical, in situ and invasive lesions. Interventions involved self-directed learning, one skin and one breast, that showed pathologists how their interpretations compared to a reference diagnoses. Prior to the educational intervention, participants estimated how their interpretations would compare to the reference diagnoses. After the intervention, participants estimated their overall agreement with the reference diagnoses. Perceived and actual agreements were compared.

Results: For pathologists interpreting skin, mean actual agreement was 52.4% and overall pre- and postinterventional mean perceived agreement was 72.9% vs 54.2%, an overestimated mean difference of 20.5% (95% confidence interval [CI] 17.2% to 24.0%) and 1.8% (95% CI -0.5% to 4.1%), respectively. For pathologists interpreting breast, mean actual agreement was 75.9% and overall pre- and postinterventional mean perceived agreement was 81.4% vs 76.9%, an overestimation of 5.5% (95% CI 3.0% to 8.0%) and 1.0% (95% CI 0.0% to 2.0%), respectively.

Conclusions: Pathologists interpreting breast tissue had improved comprehension of their performance after the intervention compared to pathologists interpreting skin lesions.
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http://dx.doi.org/10.1111/cup.13147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013368PMC
July 2018

Pathologist characteristics associated with accuracy and reproducibility of melanocytic skin lesion interpretation.

J Am Acad Dermatol 2018 Jul 7;79(1):52-59.e5. Epub 2018 Mar 7.

Department of Medicine, University of Washington School of Medicine, Seattle, Washington. Electronic address:

Background: Diagnostic interpretations of melanocytic skin lesions vary widely among pathologists, yet the underlying reasons remain unclear.

Objective: Identify pathologist characteristics associated with rates of accuracy and reproducibility.

Methods: Pathologists independently interpreted the same set of biopsy specimens from melanocytic lesions on 2 occasions. Diagnoses were categorized into 1 of 5 classes according to the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis system. Reproducibility was determined by pathologists' concordance of diagnoses across 2 occasions. Accuracy was defined by concordance with a consensus reference standard. Associations of pathologist characteristics with reproducibility and accuracy were assessed individually and in multivariable logistic regression models.

Results: Rates of diagnostic reproducibility and accuracy were highest among pathologists with board certification and/or fellowship training in dermatopathology and in those with 5 or more years of experience. In addition, accuracy was high among pathologists with a higher proportion of melanocytic lesions in their caseload composition and higher volume of melanocytic lesions.

Limitations: Data gathered in a test set situation by using a classification tool not currently in clinical use.

Conclusion: Diagnoses are more accurate among pathologists with specialty training and those with more experience interpreting melanocytic lesions. These findings support the practice of referring difficult cases to more experienced pathologists to improve diagnostic accuracy, although the impact of these referrals on patient outcomes requires additional research.
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http://dx.doi.org/10.1016/j.jaad.2018.02.070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016831PMC
July 2018