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ImportanceA standardized pathology classification system for melanocytic lesions is needed to aid both pathologists and clinicians in cataloging currently existing diverse terminologies and in the diagnosis and treatment of patients. The Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) has been developed for this purpose.ObjectiveTo revise the MPATH-Dx version 1.0 classification tool, using feedback from dermatopathologists participating in the National Institutes of Health-funded Reducing Errors in Melanocytic Interpretations (REMI) Study and from members of the International Melanoma Pathology Study Group (IMPSG).Evidence reviewPracticing dermatopathologists recruited from 40 US states participated in the 2-year REMI study and provided feedback on the MPATH-Dx version 1.0 tool. Independently, member dermatopathologists participating in an IMPSG workshop dedicated to the MPATH-Dx schema provided additional input for refining the MPATH-Dx tool. A reference panel of 3 dermatopathologists, the original authors of the MPATH-Dx version 1.0 tool, integrated all feedback into an updated and refined MPATH-Dx version 2.0.FindingsThe new MPATH-Dx version 2.0 schema simplifies the original 5-class hierarchy into 4 classes to improve diagnostic concordance and to provide more explicit guidance in the treatment of patients. This new version also has clearly defined histopathological criteria for classification of classes I and II lesions; has specific provisions for the most frequently encountered low-cumulative sun damage pathway of melanoma progression, as well as other, less common World Health Organization pathways to melanoma; provides guidance for classifying intermediate class II tumors vs melanoma; and recognizes a subset of pT1a melanomas with very low risk and possible eventual reclassification as neoplasms lacking criteria for melanoma.Conclusions and relevanceThe implementation of the newly revised MPATH-Dx version 2.0 schema into clinical practice is anticipated to provide a robust tool and adjunct for standardized diagnostic reporting of melanocytic lesions and management of patients to the benefit of both health care practitioners and patients.

BackgroundAppropriate use criteria (AUC) provide patient-centered physician guidance in test selection. An initial set of AUC was reported by the American Society of Dermatopathology (ASDP) in 2018. AUC reflect evidence collected at single timepoints and may be affected by evolving evidence and experience. The objective of this study was to update and expand AUC for selected tests.MethodsRAND/UCLA (RAND Corporation [Santa Monica, CA]/University of California Los Angeles) methodology used includes the following: (a) literature review; (b) review of previously rated tests and previously employed clinical scenarios; (c) selection of previously rated tests for new ratings; (d) development of new clinical scenarios; (e) selection of additional tests; (f) three rating rounds with feedback and group discussion after rounds 1 and 2.ResultsFor 220 clinical scenarios comprising lymphoproliferative (light chain clonality), melanocytic (comparative genomic hybridization, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, telomerase reverse transcriptase promoter), vascular disorders (MYC), and inflammatory dermatoses (periodic acid-Schiff, Gömöri methenamine silver), consensus by panel raters was reached in 172 of 220 (78%) scenarios, with 103 of 148 (70%) rated "usually appropriate" or "rarely appropriate" and 45 of 148 (30%), "appropriateness uncertain."LimitationsThe study design only measures appropriateness. Cost, availability, test comparison, and additional clinical considerations are not measured. The possibility that the findings of this study may be influenced by the inherent biases of the dermatopathologists involved in the study cannot be excluded.ConclusionsAUC are reported for selected diagnostic tests in clinical scenarios that occur in dermatopathology practice. Adhering to AUC may reduce inappropriate test utilization and improve healthcare delivery.

Some solid tumors have reduced posttranscriptional RNA editing by adenosine deaminase acting on RNA (ADAR) enzymes, but the functional significance of this alteration has been unclear. Here, we found the [...]

Metastatic melanoma is one of the most aggressive forms of cutaneous cancers. Although recent therapeutic advances have prolonged patient survival, the prognosis remains dismal. C-MER proto-oncogene tyrosine kinase (MERTK) is [...]

Malignant melanoma is characterized by a propensity for early lymphatic and hematogenous spread. The hypoxia-inducible factor (HIF) family of transcription factors is upregulated in melanoma by key oncogenic drivers. HIFs [...]

Author(s): Tobias Schatton [1]; George F. Murphy [2]; Natasha Y. Frank [1, 3]; Kazuhiro Yamaura [1]; Ana Maria Waaga-Gasser [4]; Martin Gasser [4]; Qian Zhan [2]; Stefan Jordan [1]; Lyn [...]

Metastatic variants are characterized with an acquired focal chromosomal amplification that corresponds to a much larger amplification in human metastatic melanomas and the analyses has identified Nedd9, an adaptor protein related to p130CAS, as the only gene within the minimal common region that displayed amplification-associated overexpression. The comparative oncogenomics has helped in the identification and has facilitated the validation of a highly relevant cancer gene governing metastatic potential in human melanoma.

Context.--Assessment of accuracy and feasibility of whole slide imaging (WSI) for interinstitutional consultation in surgical pathology. Objectives.--To train technical and pathologist staff in WSI technology, establish and evaluate a WSI workflow using training cases and second-opinion consultations, and assess diagnostic accuracy. Design.--First, WSI training and evaluation using selected subspecialty service cases were performed and compared with the clinical glass slide (GS) diagnosis. Second, WSI and GS diagnoses of consecutive, second-opinion consultation cases were compared. Discrepancies underwent adjudication to determine a reference diagnosis. Participant observations on WSI initiation to practice were gathered. Results.--There were 130 cases evaluated, with 123 correlations (94.6%) and 6 minor (4.6%) and 1 major (0.8%) discrepancies. The 74 consultation cases interpreted had 52 correlations (70.3%), and 18 minor (24.3%) and 4 major (5.4%) discrepancies. The WSI and GS adjusted major discrepancy rates in second-opinion consultations were 2.7% (2 of 74) and 4.1% (3 of 74), respectively. Statistical analysis showed that WSI was not inferior to GS interpretation. Pathologists agreed the software was easy to use and the images were adequate, but more time was spent rendering WSI interpretations. Conclusions.--A significant learning curve was observed in the transition from the training set to clinical consultation cases associated both with WSI interpretation and adjustments to the digital analogs of routine GS workflow. Results from second-opinion consultations indicated that WSI interpretation was as accurate as GS interpretation among properly trained and experienced users. Overall, WSI-based practice appears feasible for second-opinion consultations. (Arch Pathol Lab Med. 2015; 139:627-635; doi: 10.5858/arpa.2014-0133-OA), The use of whole slide imaging (WSI) technology for surgical pathology diagnosis is being investigated in many laboratories around the world. Improvements in the technology during the past several years, [...]

Abstract Serum lactate dehydrogenase (LDH) is a prognostic factor for patients with stage IV melanoma. To gain insights into the biology underlying this prognostic factor, we analyzed total serum LDH, serum LDH isoenzymes, and serum lactate in up to 49 patients with metastatic melanoma. Our data demonstrate that high serum LDH is associated with a significant increase in LDH isoenzymes 3 and 4, and a decrease in LDH isoenzymes 1 and 2. Since LDH isoenzymes play a role in both glycolysis and oxidative phosphorylation (OXPHOS), we subsequently determined using tissue microarray (TMA) analysis that the levels of proteins associated with mitochondrial function, lactate metabolism, and regulators of glycolysis were all elevated in advanced melanomas compared with nevic melanocytes. To investigate whether in advanced melanoma, the glycolysis and OXPHOS pathways might be linked, we determined expression of the monocarboxylate transporters (MCT) 1 and 4. Analysis of a nevus-to-melanoma progression TMA revealed that MCT4, and to a lesser extend MCT1, were elevated with progression to advanced melanoma. Further analysis of human melanoma specimens using the Seahorse XF24 extracellular flux analyzer indicated that metastatic melanoma tumors derived a large fraction of energy from OXPHOS. Taken together, these findings suggest that in stage IV melanomas with normal serum LDH, glycolysis and OXPHOS may provide metabolic symbiosis within the same tumor, whereas in stage IV melanomas with high serum LDH glycolysis is the principle source of energy.

* Context.--Detection of microscopic melanoma metastases in sentinel lymph nodes drives clinical care; patients without metastases are observed, and patients with metastases are offered completion lymphadenectomy and adjuvant therapy. Objective.--We sought to determine common elements in currently used analytic platforms for sentinel lymph nodes in melanoma patients. Design.--An electronic survey was distributed to 83 cancer centers in North America. Results.--Seventeen responses (20%) were received. The number of sentinel lymph node mapping procedures for melanoma ranged from less than 11 to more than 100 patients per year, with 72% of institutions mapping more than 50 melanoma patients a year. Uniform practices included (1) processing all of the lymph node tissue rather than submitting representative sections and (2) use of immunohistochemical stains if no tumor was identified on the hematoxylin-eosin-stained sections. Significant variability existed regarding the method of sectioning lymph nodes at grossing and in the histology laboratory; most bisected nodes longitudinally (94%) and performed deeper levels into the block (67%), but these were not uniform practices. S-100 was the most commonly used immunohistochemical stain (78%), followed by Melan-A (56%), MART-1 (50%), HMB-45 (44%), tyrosinase (33%), MiTF (11%), and pan-melanoma (6%). Conclusions.--There is a need for a standardized platform for detecting melanoma in sentinel lymph nodes. Current practices by a majority of laboratories and findings in the reported literature support the following: histologic evaluation of all lymph node tissue, use of immunohistochemical stains, bisecting lymph nodes longitudinally, and performing deeper levels into the tissue block. (Arch Pathol Lab Med. 2013;137:1603-1609; doi: 10.5858/arpa.2012-0550-OA), More than 80% of patients diagnosed with primary cutaneous melanoma are without clinical evidence of metastatic disease at the time of diagnosis. (1) Patients with localized disease at presentation have [...]

* Context.--Basaloid squamous cell carcinoma (bSCC) is an uncommon variant of squamous cell carcinoma, which may overlap histologically with basal cell carcinoma with squamous metaplasia (BCCm). Objective.--To aid in the differentiation of these neoplasms using immunohistochemical staining because of the worse prognosis associated with bSCC. Design.--Using immunohistochemical techniques, we investigated BerEp4, cytokeratin 17 (CK17), and cytokeratin 14 (CK14) protein expression in 25 cases of bSCC (8 cutaneous [32%], 12 aerodigestive tract [48%], and 5 lymph node metastases [20%]) and 43 cases of BCCm (39 cutaneous [91%], and 4 metastases [9%]). An immunoreactivity score was assigned using the percentage of tumor cells staining and the pattern of expression. Interobserver agreement for 2 independent pathologists was assessed using a κ coefficient. Results.--The mean percentage of staining was significantly higher in BCCm, compared with bSCC (BerEp4, P = .006; CK17, P < .001; CK14, P < .001; unpaired t test), with 58% of BCCm cases (25 of 43) displaying diffuse staining for all markers, and nearly all (98%; 42 of 43) displaying diffuse staining for CK17 and CK14. In contrast, no bSCC cases (0%) displayed diffuse staining for all 3 markers, and only 8% (2 of 25) displayed diffuse staining for CK17 and CK14. High interobserver agreement was determined. Conclusions.--BerEp4 alone is unreliable for differentiation between BCCm and bSCC, and the addition of either CK14 or CK17 will augment the sensitivity and negative predictive value of BerEp4 staining in BCCm and bSCC diagnosis. (Arch Pathol Lab Med. 2013; 137:1591-1598; doi: 10.5858/arpa.2012-0424-OA), Basaloid malignancies of the skin include basaloid squamous cell carcinoma (bSCC) and basal cell carcinoma with squamous metaplasia (BCCm), 2 lesions with morphologic overlap but vastly different potential outcomes clinically. [...]

* Context.--Wolf isotopic response has infrequently been reported in the literature, mainly as isolated case reports. Objective.--To aid in recognition of the occurrence of postherpetic granuloma annulare for accurate histologic interpretation of granulomatous dermatitides. Design.--We report 5 cases of patients with Wolf isotopic response manifesting as granuloma annulare, developing in a site of previous herpes zoster, and discuss the clinicopathologic findings. Results.--Previous infection with herpes zoster or herpes simplex virus was found in 5 of 5 cases reported. The differential diagnosis of a dermal lymphohistiocytic infiltrate with multinucleated giant cells includes postherpetic granuloma annulare. Conclusions.--All cases of postherpetic Wolf isotopic response reported in this series revealed granuloma annulare, with a perineurovascular or perifollicular pattern of lymphohistiocytic infiltration including multinucleated giant cells, and occurred following herpes zoster or herpes simplex infection, although herpes viral infection was not always associated with a subsequent isotopic eruption. Awareness of this entity can aid in the clinicopathologic diagnosis of granuloma annulare occurring at the site of prior herpes viral infection. (Arch Pathol Lab Med. 2013; 137:255-258; doi: 10.5858/arpa.2011-0643-OA), The phenomenon of developing a unique skin disease at the site of another unrelated and healed skin disease was first termed isotopic response by Wolf et al (1) in 1995. [...]

Context.--Whole-slide imaging technology offers promise for rapid, Internet-based telepathology consultations between institutions. Before implementation, technical issues, pathologist adaptability, and morphologic pitfalls must be well characterized. Objective.--To determine whether interpretation of whole-slide images differed from glass-slide interpretation in difficult surgical pathology cases. Design.--Diagnostically challenging pathology slides from a variety of anatomic sites from an outside laboratory were scanned into whole digital format. Digital and glass slides were independently diagnosed by 2 subspecialty pathologists. Reference, digital, and glass-slide interpretations were compared. Operator comments on technical issues were gathered. Results.--Fifty-three case pairs were analyzed. There was agreement among digital, glass, and reference diagnoses in 45 cases (85%) and between digital and glass diagnoses in 48 (91%) cases. There were 5 digital cases (9%) discordant with both reference and glass diagnoses. Further review of each of these cases indicated an incorrect digital whole-slide interpretation. Neoplastic cases showed better correlation (93%) than did cases of nonneoplastic disease (88%). Comments on discordant cases related to digital whole technology focused on issues such as fine resolution and navigating ability at high magnification. Conclusions.--Overall concordance between digital whole-slide and standard glass-slide interpretations was good at 91%. Adjustments in technology, case selection, and technology familiarization should improve performance, making digital whole-slide review feasible for broader telepathology subspecialty consultation applications. (Arch Pathol Lab Med. 2009;133:1949-1953), Whole-slide imaging at resolutions comparable to standard microscopic evaluation is now technologically feasible. (1) A variety of commercial systems that perform technically simple and rapid image capture and viewing are [...]

* Context.--Nephrogenic systemic fibrosis (NSF) is a rare but serious disorder initially described as a purely dermatologic process. Isolated autopsy reports have described multiorgan involvement by this disease. Objective.--To further illustrate the varied and systemic involvement of NSF by describing the autopsy experience at the Massachusetts General Hospital. Design.--We describe the findings in a series of 4 autopsy cases of patients diagnosed with NSF. This report describes the history of renal dysfunction, exposure to gadolinium-containing contrast agents, specific laboratory parameters, and the extent of systemic involvement identified by postmortem examination. Results.--Causes of death included systemic thromboembolic disease (n = 3) and pneumonia (n = 1). Laboratory parameters and type, dose, or timing of gadolinium containing contrast-agent exposure did not correlate with clinical findings and outcomes. All patients demonstrated cutaneous manifestations of the disease and nephrocalcinosis, with some exhibiting calcification and fibrosis of the dura, thyroid, and heart including the cardiac conduction system, on postmortem examination. Soft tissue calcification was associated with concurrent hyperparathyroidism or high serum parathyroid hormone levels. Conclusions.--Thromboembolic disease can be a significant clinical complication of NSF. Patients with NSF may also develop characteristic histologic features of fibrosis and calcification in multiple organs, with significant morbidity and mortality. This autopsy series highlights the variability of systemic manifestations of NSF. (Arch Pathol Lab Med. 2009;133:1943-1948), Nephrogenic systemic fibrosis (NSF) is a recently identified fibrosing disorder affecting patients with chronic kidney disease and occasionally those with acute renal failure. (1) Clinically, the disease manifests as rapidly [...]