Ancillary immunohistochemistry testing for loss of p16 in melanoma: A systematic review and meta-analysis of diagnostic accuracy studies.

BACKGROUND: Ancillary immunohistochemistry testing for p16 loss has been proposed as a diagnostic tool for melanoma, but its accuracy remains uncertain. METHODS: A systematic review and meta-analysis were conducted on 26 studies involving 979 melanomas and 974 nevi. RESULTS: Through bivariate analysis of data across all cut-off values, the sensitivity and specificity were calculated to be 0.55 (95% confidence interval [CI]: 0.38, 0.70) and 0.85 (95% CI: 0.70, 0.94), respectively. Summary estimates of diagnostic accuracy fell below recommended thresholds for effective tests, but subgroup analysis suggested that p16 loss could aid in diagnosing ambiguous lesions as melanoma in certain scenarios. However, the presence of p16 expression in these contexts does not definitively rule out melanoma. The findings were limited by underpowered exploratory study designs at risk for bias in patient selection and test interpretation. CONCLUSIONS: While the use of p16 immunohistochemistry for detecting melanoma is not universally reliable, it may serve as a confirmatory test in differential diagnoses involving common, congenital, acral, Spitz, and deep penetrating nevi. Nevertheless, further studies are needed to validate its utility. Until then, the application of p16 immunohistochemistry in melanoma diagnosis should be regarded as experimental.

Trends in authorship in the Journal of Cutaneous Pathology, 1981-2020.

BACKGROUND: The increase in authors per scientific article in many different medical and scientific disciplines has raised concerns over ethical authorship. Trends in authorship in dermatopathology are unknown. METHODS: Cross-sectional study of a random sample of 200 articles from the Journal of Cutaneous Pathology (1981-2020). RESULTS: The number of authors per article increased by an estimated 96% between 1981 and 2020 (2.7-5.3), while the relative citation ratio decreased by an estimated 56% during the same period (1.19-0.52). Higher author counts were not associated with higher relative citation ratios (p = 0.2349) or analytic study designs (p = 0.2987). Higher relative citation ratios were associated with analytic study designs (p = 0.0374). CONCLUSIONS: There has been significant growth in authorship credit at the journal without a corresponding increase in research impact or study rigor. Remedial measures to stem authorship inflation and promote more impactful studies may be necessary.

Publications on the diagnostic accuracy of dermatopathology tests: A cross-sectional quality analysis.

BACKGROUND: Ancillary diagnostic tests are frequent in dermatopathology practice. Publications on their accuracy influence their utilization. The transparency and completeness of these publications are unknown. METHODS: We performed a cross-sectional study on diagnostic accuracy studies in dermatopathology published between 2020 and 2022 for compliance with Standards for Reporting of Diagnostic Accuracy Studies (STARD) and the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). RESULTS: 14.67 ± 3.02 STARD items were reported in 62 publications (range, 9.5-23.5 out of the recommended total of 30). More items were reported in high-impact factor journals (16.01 vs. 13.32, p = 0.0002) and journals that endorsed STARD in their author instructions (17.22 vs. 14.11, p = 0.0039). Less than 10% of publications reported quantifiable hypotheses, sample size calculations, flow diagrams, or study registrations. The risk of bias by our analysis of QUADAS-2 criteria was high or uncertain for index test interpretation (36/62, 58%) and patient selection (44/62, 71%). CONCLUSIONS: Publications on dermatopathology tests are exploratory studies without prespecified hypotheses or study designs. They do not meet the criteria for transparent reporting. We suggest that medical journal leadership should consider updating their instructions with more explicit guidance on recommended manuscript elements.

PRAME immunohistochemistry for melanoma diagnosis: A STARD-compliant diagnostic accuracy study.

BACKGROUND: Preferentially expressed antigen in melanoma (PRAME) is a tumor-associated antigen that is frequently expressed in cutaneous melanoma and can be evaluated by immunohistochemistry. Earlier studies on PRAME utilized case-control study designs that may misestimate diagnostic accuracy and lack generalizability. METHODS: Using retrospective cohort selection, a cross-sectional study of diagnostic accuracy of PRAME was conducted according to standards for reporting diagnostic accuracy studies requirements. RESULTS: Mean PRAME positive fraction was higher in 42 malignant melanocytic lesions than 101 benign melanocytic lesions (0.71 ± 0.30 vs. 0.13 ± 0.20, p < 0.01). Receiver operating characteristic curve showed the test was effective (area under the curve = 0.90). Global PRAME 4+ scores (>75%) were associated with sensitivity of 0.63, specificity of 0.97, accuracy of 0.87, and excellent interrater concordance (Kappa = 0.83). Lower cutoffs for PRAME of 2+ (>25%) and 3+ (>50%) produced higher joint sensitivity/specificity (Youden index) than PRAME 4+, but lower accuracy. CONCLUSION: PRAME as it is used in clinical practice is an effective test for melanoma. PRAME is best used as an ordinal variable to calculate the posttest probability of melanoma. PRAME ≤25% (0/1+) favors nevus, PRAME 26%-75% (2/3+) is noncontributory, and PRAME >75% (4+) favors melanoma.

Gamma-Delta and CD20 Mycosis Fungoides: Two Cases Uncovered by Broad-Spectrum Immunostaining.

ABSTRACT: Mycosis fungoides (MF) expresses T-cell markers and the alpha-beta T-cell receptor (TCR) complex. Here, we describe a case of MF with dual expression of TCR delta and TCR beta and a case of MF expressing the B-cell marker CD20. Both anomalies were detected after we instituted a broad-spectrum immunostaining panel for cutaneous T-cell lymphomas. These findings suggest anomalous immunophenotypes may be more common in MF than previously appreciated. Histopathologists should be aware of unexpected malleability in the immunophenotype of MF to avoid confusion with other subtypes of cutaneous lymphoma. Further research into the prevalence and significance of CD20 and TCR-delta expression in MF is encouraged.

Trichilemmal Cysts With Divergent Ductal Differentiation: A Series of 4 Cases.

ABSTRACT: Trichilemmal cysts are common clonal tumors with a predilection for the scalp. They are composed of an outer epithelial wall resembling the outer root sheath in the isthmus of the hair follicle and a central core of compact keratin. Sweat duct differentiation is exceptional with only one convincing case reported to date. Here, we sought to characterize the clinicopathological characteristics of sweat duct differentiation in trichilemmal cysts. We reviewed all cases of trichilemmal cyst diagnosed at our institution between 2008 and 2019. Ductal structures were found in 4 of 411 cases (0.97%). Subjects included 2 male and 2 female patients with a median age of 37.5 years (range 34-55). The ducts were lined by attenuated epithelial cells and immunoreactive for polyclonal carcinoembryonic antigen and cytokeratin 7. Ductal differentiation involved a median of 7.5% (range 1%-50%) of the cyst wall. All 4 cases were from the scalp and treated with local excision. No recurrence was identified with a median follow-up period of 1.5 years (range 1-12 years). In summary, sweat duct differentiation in trichilemmal cysts is rare but likely under recognized. Conceptually, we suggest it represents a type of divergent cellular differentiation within a clonal neoplasm rather than a retention cyst or hybrid cyst.

Plasmacytoid dendritic cells in keratoacanthoma and squamous cell carcinoma: A blinded study of CD123 as a diagnostic marker.

BACKGROUND: Histopathologic distinction between keratoacanthoma (KA) and squamous cell carcinoma (SCC) is challenging. We surmised that a discriminatory immunostain would be clinically meaningful. Previous investigators have found CD123-positive plasmacytoid dendritic cells (PDCs) are more prominent in KA than SCC. We sought to determine if CD123 immunostaining might have value as a diagnostic test for distinguishing KA from SCC. METHODS: We used blinded, semi-automated image analysis to compare CD123 expression in 66 KAs and 63 SCCs in a tissue microarray. RESULTS: PDCs were present in both KA and SCC. Mean PDC frequency was higher in KA than SCC (14.2 vs 11.2 mean cells/0.0945 square mm) but the difference was not statistically significant (P = 0.1240). There was no significant difference in mean PDC cluster frequency, mean intratumoral PDC frequency, or the percentage of PDCs as proportion of the total mononuclear inflammatory cell infiltrate between KA and SCC. CONCLUSION: CD123 immunostaining is not a clinically useful test for distinguishing KA from SCC.

Measuring Scholastic Production by Dermatopathologists Using the H-Index: A Cross-Sectional Study.

Academic advancement in dermatopathology requires evidence of scientific production. The H-index is a useful bibliometric for measuring scientific production because it weights both volume and impact of an individual's scholastic production. The H-index distribution among academic dermatopathologists is unknown. In this cross-sectional study of 299 dermatopathologists with academic appointments in North America, H-index, publication counts, and citation counts were retrieved from Thomas Reuters Web of Science. Analytic statistics were performed to identify best predictors of academic rank and cutoff points between academic ranks. The H-index was a superior predictor of overall academic rank than publication or citation counts. The median H-index for assistant, associate, and full professors was 4, 6, and 11, respectively. H-index cutoff scores of 8 and 10 favored associate and full professor rank, respectively. These data provide benchmarks for dermatopathologists to gauge their scientific productivity against that of their peers. Although advancement decisions will depend on a careful examination of the scope and impact of a candidate's work, assistant professors of dermatopathology with H-index scores of >7 and associate professors of dermatopathology with H-index scores of >9 may wish to consider application for promotion.

Histopathologic features of melanoma in difficult-to-diagnose lesions: A case-control study.

BACKGROUND: Dermatopathology is considered the gold standard for melanoma diagnosis, but a subset of cases is difficult to diagnose by histopathology. OBJECTIVE: The goals of this study were to measure the accuracy of histopathologic features in difficult-to-diagnose melanocytic tumors and the interobserver agreement of those features. METHODS: This is a case-control study of histopathologic features of melanoma in 100 difficult-to-diagnose melanocytic neoplasms (40 melanomas and 60 nevi). Slides were blindly evaluated by 5 dermatopathologists. Frequencies, predictive values, and interobserver agreement were calculated. Univariate and multivariate logistic regression analyses were performed to identify the most influential features in arriving at a diagnosis of melanoma. RESULTS: Asymmetry, single-cell melanocytosis, solar elastosis, pagetoid melanocytosis, and broad surface diameter were most influential in arriving at a diagnosis of melanoma. Asymmetry and single-cell melanocytosis were most predictive of melanoma. Fleiss kappa was <0.6 for interobserver agreement in 9/10 histopathologic features of melanoma. LIMITATIONS: This study is limited by the small sample size, selection bias, and binary classification of melanocytic lesions. CONCLUSION: Our results indicate histopathologic features of melanoma in difficult-to-diagnose lesions vary in accuracy and reproducibility.

Cutaneous Adenomyoepithelioma: Report of a Case and Review of the Literature.

Adenomyoepithelioma (AME) is a biphasic neoplasm of epithelial and myoepithelial cells. It is most commonly found in the breast, although rare cases have been reported from the lung, salivary glands, and skin. There are 5 well-documented cases of cutaneous AME in the literature. We report a new case of cutaneous AME. Our case was commingled with apocrine hidrocystoma. This is the first report of cutaneous AME in a male patient and the first to describe SOX10 immunostaining in cutaneous AME. We review the literature on cutaneous AME and note the greater than chance colocalization with other adnexal tumors. We speculate that AME may represent localized overgrowth of myoepithelial cells within a pre-existent sweat gland tumor. Histopathologists should be aware of the potential of SOX10-positive myoepithelial neoplasms to mimic nodular melanocytic proliferations.

Economic Costs Avoided by Diagnosing Melanoma Six Months Earlier Justify >100 Benign Biopsies.

New melanoma drugs bring enormous benefits but do so at significant costs. Because melanoma grows deeper and deadlier over time, deeper lesions are costlier due to increased sentinel lymph node biopsy, chemotherapy, and disease-associated income loss. Prior studies have justified pigmented lesion biopsies on a "value per life" basis; by contrast we sought to assess how many biopsies are justified per melanoma found on a purely economic basis. We modeled how melanomas in the United States would behave if diagnosis were delayed by 6 months, eg, not biopsied, only observed until the next surveillance visit. Economic loss from delayed biopsy is the obverse of economic benefit of performing biopsy earlier. Growth rates were based on Liu et al. The results of this study can be applied to all patients presenting to dermatologists with pigmented skin lesions suspicious for melanoma. In-situ melanomas were excluded because no studies to date have modeled growth rates analogous to those for invasive melanoma. We assume conservatively that all melanomas not biopsied initially will be biopsied and treated 6 months later. Major modeled costs are (1) increased sentinel lymph node biopsy, (2) increased chemotherapy for metastatic lesions using increased 5-yr death as metastasis marker, and (3) income loss per melanoma death at $413,370 as previously published. Costs avoided by diagnosing melanoma earlier justify 170 biopsies per melanoma found. Efforts to penalize "unnecessary" biopsies may be economically counterproductive.

J Drugs Dermatol. 2016;15(5):527-532.

BAM! Utilizing the frequency of Benign, Atypical and Malignant diagnoses for quality improvement in the histopathologic diagnosis of melanocytic neoplasms.

BACKGROUND: Healthcare quality measures are metrics that quantify medical outcomes. There is a need for performance indicators in the diagnosis of melanocytic neoplasms. We sought to determine whether the atypical to malignant diagnosis ratio (AMR) and benign to malignant diagnosis ratio (BMR) could identify differences between practitioners within a group as well as individual diagnostic drift. METHODS: Diagnoses of melanocytic neoplasms from 2013 and 2014 by two dermatopathologists were prospectively subclassified as benign, atypical or malignant and reported on a monthly basis to the pathologists. Case diagnoses of melanocytic neoplasms from 2012 and 2009 were retrospectively subclassified as benign, atypical or malignant for comparison. RESULTS: A total of 33,169 cases were used in this study. Interpathologist AMR and BMR were significantly different. One pathologist demonstrated a significant increase in AMR over time. CONCLUSION: AMR and BMR metrics are potential performance indicators that can measure pathologist uncertainty, identify diagnostic drift and provide a surrogate measure of the relative risk level of laboratory patient populations. If applied to multiple laboratories, AMR and BMR metrics could help inform physicians' choice of dermatopathology laboratory and provide a method for comparative analysis between laboratories.

Pleomorphic spindle cell dermal neoplasm with dot-like keratin reactivity: keratin-positive AFX or carcinoma?

Atypical fibroxanthoma (AFX) is an uncommon cutaneous neoplasm of pleomorphic myofibroblast-like cells. Diagnosis requires exclusion of other undifferentiated spindle and pleomorphic cell neoplasms by immunohistochemistry. We report two patients with p63-non-reactive spindle cell neoplasms which resembled AFX but demonstrated anomalous dot-like immunolabeling with antibodies to high molecular weight keratin and keratin 5. One case recurred locally, suggesting such lesions may behave aggressively. Whether these lesions represent keratin-positive dermal sarcomas or poorly differentiated carcinomas is debatable. Regardless of exact classification, our experience suggests such cases should be managed as high-risk non-melanoma skin cancers.

Pressure-induced isomorphic sclerodermoid graft-versus-host disease from brassiere underwire and tight-fitting watch.

Sclerodermoid chronic graft-versus-host disease (scGVHD) is a rare form of cGVHD with an estimated prevalence of 3% to 11% in patients receiving allogeneic bone marrow transplants. scGVHD is believed to be an immune-mediated response characterized by aberrant T-cell function and dysregulation of tyrosine kinase cascades. Published literature on scGVHD is still limited and the mechanisms are yet to be fully understood. Thus, successful treatment of scGVHD remains largely unknown and many current options are hindered by potential side effects. This case provides an example of scGVHD localizing to areas of trauma and friction as a potential mechanism behind scGVHD and provides several case reports that document similar findings.

Leukemia cutis with lymphoglandular bodies: a clue to acute lymphoblastic leukemia cutis.

Leukemia cutis describes cutaneous lesions produced by infiltrates of leukemic cells. It usually manifests contemporaneously with the initial diagnosis of systemic leukemia, but may also precede or follow systemic leukemia. Most cases are associated with acute myeloid leukemia. Adult B-cell lymphoblastic leukemia cutis is very rare. We report a 59-year-old woman with a history of B-cell acute lymphoblastic leukemia who relapsed with aleukemic lymphoblastic leukemia cutis. Lymphoglandular bodies were conspicuous on biopsy and may serve as a morphologic clue to lymphocytic differentiation while molecular and immunophenotypic studies are pending. The patient was successfully treated with local radiation therapy and oral ponatinib.

Large cell acanthoma: a variant of solar lentigo with cellular hypertrophy.

BACKGROUND: Large cell acanthoma (LCA) is an epidermal proliferation of enlarged keratinocytes. There is a lack of consensus on whether it represents a unique neoplasm or not. To determine whether it is a variant of solar lentigo, we compared macroscopic, microscopic and immunophenotypic attributes of LCA with conventional solar lentigo, seborrheic keratosis, actinic keratosis and Bowen disease. METHODS: We constructed tissue microarrays containing multiple cores of LCA, solar lentigo, seborrheic keratosis, actinic keratosis and Bowen disease. Tissue microarray sections were blindly analyzed for microscopic morphologic variables. Corresponding ex vivo dermoscopic images from the original cases were blindly analyzed for macroscopic morphologic variables. Immunostained sections from the tissue microarray were tested for keratin 10, keratin 5/6, Bcl-2 and Ki-67 expression by image analysis. RESULTS: There were no significant differences in the studied morphologic attributes between LCA and solar lentigo. All other tumor classes showed at least one significant morphologic difference with LCA. LCA and solar lentigo showed different keratin 10 and Bcl-2 signal intensities. CONCLUSIONS: LCA is best considered a variant of solar lentigo with cellular hypertrophy. The differences in immunophenotype and cell size could be because of differences in cell kinetics.

Diagnostic concordance rates in the subtyping of basal cell carcinoma by different dermatopathologists.

BACKGROUND: There are numerous subtypes of basal cell carcinoma (BCC). Defining the histopathologic subtype is an essential element in patient management, but there is little known data regarding interobserver precision in subtyping BCC. METHODS: We studied interobserver variance between six board-certified dermatopathologists who subtyped 100 BCCs in a blinded fashion. We used kappa statistic to calculate the concordance in suggested subtype by different dermatopathologists. Provided diagnoses were then re-categorized into low-risk and high-risk phenotypes, and kappa statistic for concordance on high-risk BCC was determined. RESULTS: The overall κ statistic was 0.301, indicating fair agreement among the six observers. Superficial and fibroepithelial BCC had the highest individual kappa statistics. When subtypes were re-classified into a two-tier system of high-risk and low-risk phenotypes, there was substantial interobserver agreement on high-risk BCC with a κ statistic of 0.699. CONCLUSION: These results suggest only fair agreement among dermatopathologists on specific BCC subtypes, but substantial agreement on superficial, fibroepithelial and high-risk BCC growth patterns. A simplified classification system comprised of superficial, fibroepithelial, nodular and infiltrative subtypes would increase interobserver precision and facilitate clinical decision-making.

How accurate are the suggested diagnoses on biopsy requisitions for inflammatory skin disease? A retrospective study of 348 cases.

Clinical information is often critical to the histopathologic interpretation of cutaneous biopsies for inflammatory skin diseases. This information is often conveyed to the dermatopathologist as list of possible diagnoses. We reviewed 348 cases of biopsied inflammatory skin disease and measured the correlation between the original clinical differential diagnoses on the pathology requisition and the patient's final diagnosis. The final diagnosis was included among the suggested diagnoses in 270 of 348 (78%) cases reviewed. In 191 of 270 (71%) correctly diagnosed cases, the final diagnosis was listed first among those included in the differential diagnoses. The total number of suggested diagnoses did not correlate with overall diagnostic accuracy. The most commonly neglected diagnoses were eczematous dermatitis, psoriasis, lichen planus, and granuloma annulare. We conclude that the differential diagnosis submitted with pathology specimens for inflammatory skin disease includes the final diagnosis in a majority of cases. The first listed diagnosis has the highest positive predictive value. Submitting longer differential diagnosis lists did not improve diagnostic accuracy.