Dermatopathologic features of cutaneous squamous cell carcinoma and actinic keratosis: Consensus criteria and proposed reporting guidelines.

BACKGROUND: There is considerable variation in the literature regarding the dermatopathologic diagnostic features of and reporting guidelines for actinic keratosis (AK) and cutaneous squamous cell carcinoma (cSCC). OBJECTIVE: To develop consensus recommendations regarding diagnostic criteria, nomenclature, and reporting of AK and cSCC. METHODS: Literature review and cross-sectional multiround Delphi process including an international group of expert dermatopathologists followed by a consensus meeting. RESULTS: Consensus was achieved regarding the key dermatopathologic features necessary for diagnosing cSCC, AK, and associated variants; grading of degree of cellular differentiation in cSCC; utility of immunohistochemistry for diagnosis of cSCC; and pathologic features that should be reported for cSCC and AK. LIMITATIONS: Consensus was not achieved on all questions considered. CONCLUSION: Despite the lack of clarity in the literature, there is consensus among expert dermatopathologists regarding diagnostic criteria and appropriate reporting of AK and cSCC. Widespread implementation of these consensus recommendations may improve communication between dermatopathologists and clinicians, facilitating appropriate treatment of AK and cSCC.

Appropriate use criteria for ancillary diagnostic testing in dermatopathology: New recommendations for 11 tests and 220 clinical scenarios from the American Society of Dermatopathology Appropriate Use Criteria Committee.

BACKGROUND: Appropriate 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. METHODS: RAND/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. RESULTS: For 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." LIMITATIONS: The 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. CONCLUSIONS: AUC 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.

Preferentially expressed antigen in melanoma expression in nonmelanoma skin cancers and melanocytes in surrounding skin.

BACKGROUND: Immunohistochemistry for preferentially expressed antigen in melanoma (PRAME) has been studied in melanocytic lesions but not nonmelanoma skin cancers (NMSCs). This study evaluated PRAME expression in NMSCs and dermoepidermal junction (DEJ) melanocytes in the surrounding skin. METHODS: Ninety-nine NMSCs were studied: 23 Merkel cell carcinomas (MCCs), 25 well to poorly differentiated squamous cell carcinomas (SCCs), 14 basal cell carcinomas (BCCs), five basosquamous carcinomas, four sebaceous carcinomas, ten atypical fibroxanthomas, 11 dermatofibrosarcoma protuberans, and seven leiomyosarcomas. Staining quality was considered low or high intensity. Staining quantity was reported as negative 0%, 1% to 24%, 25% to 50%, and >50%. DEJ melanocyte PRAME expression was recorded. RESULTS: Forty-eight percent of NMSCs showed PRAME expression, mostly low intensity in fewer than 25% of cells. High-intensity expression was noted in one poorly differentiated SCC, six BCCs, and seven MCCs. Only MCCs showed expression in greater than 25% of tumor cells. Focal DEJ melanocytes expressed high-intensity PRAME in 18% of cases, most commonly SCCs (11/23). CONCLUSIONS: PRAME is negative or expressed with low intensity in a small percentage of NMSCs, with the exception of some MCC showing high-intensity and diffuse staining. Focal DEJ melanocytes showed high-intensity PRAME reactivity in the skin surrounding some NMSCs.

PAS and GMS utility in dermatopathology: Review of the current medical literature.

The American Society of Dermatopathology has established an Appropriate Use Criteria (AUC) Committee with the intention of establishing evidence-based recommendations regarding the appropriateness of various ancillary tests commonly utilized by dermatopathologists. Periodic acid Schiff (PAS) and Grocott (or Gomori) methenamine silver (GMS) stains represent some of the most commonly employed ancillary tests in dermatopathology. The utility of these tests was targeted for evaluation by the AUC. This literature review represents a comprehensive evaluation of available evidence for the utility of PAS and/or GMS staining of skin and nail biopsies. In concert with expert opinion, these data will be incorporated into future recommendations by the AUC for PAS and GMS staining in routine dermatopathology practice.

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

BACKGROUND: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy, and physician decision-making. OBJECTIVES: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology. METHODS: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience, and expert judgment, was used to develop AUC in dermatopathology. RESULTS: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate" and 52 (25%) "rarely appropriate" and 43 (20%) having "uncertain appropriateness." LIMITATIONS: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost. CONCLUSIONS: The ultimate decision to order specific tests rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-the AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.

Muir-Torre syndrome appropriate use criteria: Effect of patient age on appropriate use scores.

BACKGROUND: Muir-Torre syndrome (MTS) is a rare inherited syndrome, with an increased risk of sebaceous and visceral malignancy. Prior reports suggest screening for mismatch repair (MMR) deficiency may be warranted in patients <50 years and when sebaceous neoplasms are located on a non-head and neck location. Previously, appropriate use criteria (AUC) were developed for clinical scenarios in patients >60 years concerning the use of MMR protein immunohistochemistry (MMRP-IHC). This analysis explores the appropriateness of testing in patients ≤60 years. METHODS: Panel raters from the AUC Task Force rated the use of MMRP-IHC testing for MTS for previously rated scenarios with the only difference being age. RESULTS: Results verify the previously developed AUC for the use of MMRP-IHC in neoplasms associated with MTS in patients >60 years. Results also show that in patients ≤60 years with a single sebaceous tumor on a non-head and neck site, MMRP-IHC testing should be considered. Testing can also be considered with a 2-antibody panel on periocular sebaceous carcinoma in younger patients. CONCLUSIONS: Our findings align with known evidence supporting the need to incorporate clinical parameters in identifying patients at risk for MTS, with age being a factor when considering MMRP-IHC testing.

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

BACKGROUND: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy and physician decision-making. OBJECTIVES: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology. METHODS: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience and expert judgment, was used to develop AUC in dermatopathology. RESULTS: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate," 52 (25%) "rarely appropriate" and 43 (20%) "uncertain appropriateness." LIMITATIONS: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost. CONCLUSIONS: The ultimate decision of when to order specific test rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.

Educational Gaps in Molecular Diagnostics, Genomics, and Personalized Medicine in Dermatopathology Training: A Survey of U.S. Dermatopathology Fellowship Program Directors.

BACKGROUND: Molecular technologies offer clinicians the tools to provide high-quality, cost-effective patient care. We evaluated education focused on molecular diagnostics, genomics, and personalized medicine in dermatopathology fellowship training. DESIGN: A 20-question online survey was emailed to all (n = 53) Accreditation Council for Graduate Medical Education (ACGME)-accredited dermatopathology training programs in the United States. RESULTS: Thirty-one of 53 program directors responded (response rate = 58%). Molecular training is undertaken in 74% of responding dermatopathology fellowships, with levels of instruction varying among dermatology-based and pathology-based programs. Education differed for dermatology- and pathology-trained fellows in approximately one-fifth (19%) of programs. Almost half (48%) of responding program directors believe that fellows are not currently receiving adequate molecular education, although the majority (97%) expect to incorporate additional instruction in the next 2-5 years. Factors influencing the incorporation of relevant education include perceived clinical utility and Accreditation Council for Graduate Medical Education/residency review committee (RRC) requirements. Potential benefits of molecular education include increased medical knowledge, improved patient care, and promotion of effective communication with other healthcare professionals. More than two-thirds (68%) of responding program directors believe that instruction in molecular technologies should be required in dermatopathology fellowship training. CONCLUSIONS: Although all responding dermatopathology fellowship program directors agreed that molecular education is important, only a little over half of survey participants believe that their fellows receive adequate instruction. This represents an important educational gap. Discussion among those who oversee fellow education is necessary to best integrate and evaluate teaching of molecular dermatopathology.

Clinical Follow-up of Atypical Spitzoid Tumors Analyzed by Fluorescence In Situ Hybridization.

Many neoplasms with spitzoid features remain enigmatic, especially those with intermediate grade features or "atypical spitzoid tumors" (ASTs). Fluorescence in situ hybridization (FISH) has emerged as a complementary technique to conventional microscopy, with certain chromosomal patterns conveying diagnostic information. In this study, we examined 36 ASTs analyzed by FISH for specific abnormalities in chromosomes 6, 9, and 11. Aberrations were detected in 11 cases, 7 of which met FISH criteria for spitzoid melanoma. These had homozygous deletion of 9p21, partial deletion of 11q13, gain of 6p25, and gain of 11q13. All 3 patients with positive sentinel lymph nodes, including one with progression beyond the sentinel lymph node, had homozygous deletion of chromosome 9p21, but there were no deaths in an average of 28 months of follow-up of these cases. Other aberrations in the chromosomal pattern of ASTs were heterozygous deletion of 9p21, partial deletion of 6p23, and tetraploidy. We found that ASTs, including those eventually diagnosed as spitzoid melanoma, had a more indolent course in our cohort than conventional malignant melanoma. Moreover, the addition of FISH results led to a more definitive diagnosis in 7 cases, 4 of which had abnormalities on FISH consistent with spitzoid melanoma.

Immune biomarkers are more accurate in prediction of survival in ulcerated than in non-ulcerated primary melanomas.

INTRODUCTION: Ulcerated melanomas may have a unique biology and microenvironment. We test whether markers of immune infiltration correlate with clinical outcome in ulcerated compared to non-ulcerated primary melanoma tumors. METHODS: Sixty-two stage II-III cutaneous melanomas, 32 ulcerated and 30 non-ulcerated, were analyzed for tumor-infiltrating lymphocytes (TILs). Immunohistochemistry (IHC) was performed for CD2, a marker previously shown to correlate with overall survival (OS) and recurrence-free survival (RFS) in this patient population. IHC using antibody, VE1, to BRAF V600E was also performed on a subset of 41 tumors to assess the relationship of BRAF mutation to immune markers. RESULTS: We found, using Cox regression models, that the presence of TILs was associated with improved OS (p = 0.034) and RFS (p = 0.002) in ulcerated melanoma tumors, but not in non-ulcerated melanoma (p = 0.632, 0.416). CD2 expression also was correlated with improved OS (p = 0.021) and RFS (p = 0.001) in ulcerated melanoma, but no relationship was seen in non-ulcerated melanoma (p = 0.427, 0.682). In this small population, BRAF status did not correlate with TILs or CD2+ count. CONCLUSION: Our data show that immune markers including TILs and CD2 count correlate more closely with survival in ulcerated melanomas than that in non-ulcerated melanomas. We propose that immune biomarkers may be particularly relevant to ulcerated, as compared to non-ulcerated, melanomas and that this merits study in larger populations.

What's eating you? Cutaneous larva migrans.

This article provides a focused update and clinical review on cutaneous larva migrans (CLM), including atypical clinical presentations and newer management recommendations. The results and recommendations are subject to modification based on future studies.

Histopathologic evaluation of the sentinel lymph node for malignant melanoma: the unstandardized process.

Metastasis from malignant melanoma (MM) usually first presents in the draining lymph node basin and thus sentinel lymph node (SLN) biopsy is a staging tool used to predict risk of metastases and death in higher risk tumors and has become the standard of care. Differences in the processing and methods used in the histopathological examination of SLNs can affect the positivity rate for metastatic MM because isolated MM deposits may be small and variably distributed in the SLN. The examination of SLNs is not standardized. The authors surveyed institutions across the United States who process SLNs for MM to better characterize the current methods used and to suggest a standardized approach to improve the reliability of the SLN biopsy. A survey of 142 academic institutions in the United States regarding the methods used in the evaluation of the SLN biopsy for MM was conducted. Thirty-two institutions responded. Eighty-one percent of the institutions (26 of 32) had a protocol that they used for SLN examination. In regards to gross dissection, 28% of the responders (9 of 32) initially bivalve (cut the SLN in half), whereas 59% (19 of 32) use a bread loaf technique, cutting the SLN at even intervals without specifically commenting about orientation to the hilum. The number of levels initially cut from the SLN block varied from 1 to 8 levels per block. Thirty-nine percent of the respondents (12 of 31) routinely order immunohistochemistry before evaluation of the initial hematoxylin- and eosin-stained sections. Eighty percent of the respondents (24 of 30) report the maximum dimension of the metastatic tumor deposit. The response rate was low (22%), and most respondents did not indicate how many SLN accessions were performed at their institution each year. Histologic protocols for processing SLNs for MM vary among institutions. Different methods of handling SLNs result in varying sensitivities for detection of metastases. Data derived from these varied approaches to develop and determine prognostic and staging categories may be inconsistent. A standardized yet practical approach is needed to provide reliable information on which prognosis can be determined and therapeutic guidelines can be based. The hope is for dermatologists and those treating patients with MM to understand the intricacies and inconsistencies involved in performance and interpretation of this key staging tool.

Helminths: a clinical review and update.

This article provides a focused update and clinical review on select helminth infections. The goal is to report atypical clinical presentations and newer management recommendations. The results and recommendations should be interpreted with the understanding that future studies may alter what is presented.

Diffuse dermal angiomatosis of the thigh as the presenting sign of critical limb ischemia.

Diffuse dermal angiomatosis (DDA) is a rare, benign disease that can serve as the precursor to critical limb ischemia. Pruritic, erythematous plaques form from a proliferation of endothelial cells in response to dermal hypoxia. We present the case of a 63-year-old female patient with DDA of the left medial thigh, followed by ischemia of her distal extremities. Revascularization of her left leg resulted in resolution of the DDA and healing of her ulcers. DDA can be an important clue to identify significant peripheral vascular disease.

Eosinophils in mycosis fungoides: an uncommon finding in the patch and plaque stages.

Early diagnosis of mycosis fungoides (MF) is one of the most challenging problems in dermatopathology, as the histopathologic features of inflammatory dermatoses and MF may show significant overlap. One criterion used to distinguish early MF (patch stage) from dermatitis, which may be currently underutilized, is the presence of eosinophils. A search was performed for cases with a preoperative diagnosis of MF, cutaneous T-cell lymphoma, or dermatitis, which included 29 cases "diagnostic" for MF, 25 cases "suspicious" for MF, and 55 cases of spongiotic dermatitis. We examined tissue sections blinded to diagnosis to obtain an exact eosinophil count. Twenty-nine cases were diagnostic for MF (12 patch, 9 plaque, and 8 tumor stage). The average eosinophil count for cases diagnostic for patch stage MF was 1 eosinophil in 10 (0.11) sections examined. For plaque MF, there was 1 eosinophil in 5 (0.24) sections examined. All tumor stage MF cases showed abundant eosinophils within each section. Twenty-five cases were suspicious for MF (15 patches, 9 plaques, and 1 folliculotropic). The average eosinophil count for the patch lesions was 1 eosinophil in 4 (0.25) sections examined and 2 eosinophils per section for plaque lesions. Forty-five of 55 cases of spongiotic dermatitis had at least scattered eosinophils (>3) in each section. Twenty-three (47%) had eosinophils around most postcapillary venules. Only 3 of 45 patients (6.6%) with biopsies diagnostic or suspicious for patch or plaque stage MF showed >3 eosinophils per tissue section, whereas 45 of 55 (81.8%) biopsies of spongiotic dermatitis had >3. The presence of eosinophils (>3 per tissue section) is statistically significant in differentiating cases diagnostic or suspicious for patch or plaque stage MF from dermatitis (P < 0.0001). Our data indicate that eosinophils are uncommon in cases of patch and plaque MF. When a pathologist is faced with evaluating a biopsy that lacks some of the criteria used to make the diagnosis of patch stage MF, yet demonstrates >3 eosinophils per tissue section, dermatitis is the likely diagnosis. However, in cases where fewer than 3 eosinophils are present in sections, patch stage MF cannot be excluded.

The staining pattern of pigmented spindle cell nevi with S100A6 protein.

BACKGROUND: Spitz nevi typically show strong diffuse staining with S100A6, whereas staining in melanomas is commonly patchy and weak. To our knowledge, S100A6 has not been studied in pigmented spindle cell nevus (PSCN), considered by many to be a variant of Spitz nevus. METHODS: Forty-six archived PSCNs were stained with S100A6 and then categorized by predominant cell size and staining pattern. RESULTS: Eighteen (55%) of the small cell predominant nevi showed patchy staining, eight showed diffuse staining and seven were negative for S100A6. Two predominantly large-celled 'PSCNs' were diffusely positive and had many histopathological attributes of classical Spitz nevi. On review, these two cases were reclassified as Spitz nevi and excluded from the remainder of this study. Of the nevi with mixed cell size, one had no expression of S100A6. In the remaining tumors, the small cells showed patchy staining in eight (80%) and diffuse staining in two (20%). The large cells showed patchy staining in four (40%) and diffuse staining in six (60%). CONCLUSION: In contrast to the strong diffuse S100A6 staining typical of Spitz nevi, the small spindle cells of PSCN commonly show patchy staining or fail to stain completely. In melanocytic neoplasms composed of small spindle cells, patchy S100A6 staining should not be interpreted as evidence of supporting a diagnosis of melanoma.

Statistical analysis of the concordance of immunohistochemical stains with the final diagnosis in spitzoid neoplasms.

INTRODUCTION: The classification of spitzoid melanocytic tumors can be difficult, and pathologists rely on both histological features and clinical information to arrive at a diagnosis. We proposed that an immunohistochemical panel could be useful in classifying these neoplasms and designed a study to test the independent contribution of the panel to the final diagnosis. METHODS: We identified 121 cases previously signed out either as (1) Spitz nevus, (2) atypical spitzoid neoplasm, favor Spitz nevus, (3) atypical spitzoid neoplasm of uncertain malignant potential, (4) atypical spitzoid neoplasm, favor melanoma, and (5) spitzoid melanoma. The slides were reveiwed in random order by 4 pathologists. For the first review, the pathologists received only hematoxylin and eosin sections and patient age. Subsequently, the same pathologists interpreted the immunohistochemically stained slides (S-100A6, HMB-45, and MIB-1) on the same cases in randomized order without the benefit of either hematoxylin and eosin sections or patient age. The original diagnosis (based on a combination of clinical information, hematoxylin and eosin-stained sections and immunohistochemical stains) was the gold standard used for statistical analysis. The primary aim of the study was to determine the level of agreement between interpretions based on hematoxylin and eosin sections and age, the immunostains alone, and the gold standard, thus providing a measurement of the degree to which each of these elements contributes to the final diagnosis. The agreement between the gold standard and external review was also determined for those cases sent for external review. RESULTS: The generalized kappa statistic was 0.95 for both the hematoxylin and eosin-stained slides alone and the immunohistochemical stains alone, implying a high level of agreement among the 4 pathologists. The combined weighted kappa statistic for the comparison of hematoxylin and eosin sections and patient age to the gold standard was 0.49, and for the immunohistochemically stained slides to the gold standard 0.48, indicating that a diagnosis based on hematoxylin and eosin sections alone or immunostains alone show only a moderate and similar level of agreement with the gold standard diagnosis. Only the most controversial cases were sent for external review. The weighted kappa statistic estimate was 0.30 for the gold standard diagnosis on those cases and the external review. CONCLUSIONS: Spitzoid neoplasms remain a difficult area in dermatopathology and experts frequently disagree on the most challenging cases. An immunohistochemical panel contributes to the diagnosis of spitzoid tumors, and the contribution is statistically similar to that of hematoxylin and eosin sections and age. Interpretation remains subjective, as evidenced by the comparison of the gold standard and external review.

Automated digital TIL analysis (ADTA) adds prognostic value to standard assessment of depth and ulceration in primary melanoma.

Accurate prognostic biomarkers in early-stage melanoma are urgently needed to stratify patients for clinical trials of adjuvant therapy. We applied a previously developed open source deep learning algorithm to detect tumor-infiltrating lymphocytes (TILs) in hematoxylin and eosin (H&E) images of early-stage melanomas. We tested whether automated digital (TIL) analysis (ADTA) improved accuracy of prediction of disease specific survival (DSS) based on current pathology standards. ADTA was applied to a training cohort (n = 80) and a cutoff value was defined based on a Receiver Operating Curve. ADTA was then applied to a validation cohort (n = 145) and the previously determined cutoff value was used to stratify high and low risk patients, as demonstrated by Kaplan-Meier analysis (p ≤ 0.001). Multivariable Cox proportional hazards analysis was performed using ADTA, depth, and ulceration as co-variables and showed that ADTA contributed to DSS prediction (HR: 4.18, CI 1.51-11.58, p = 0.006). ADTA provides an effective and attainable assessment of TILs and should be further evaluated in larger studies for inclusion in staging algorithms.

Nodal blue nevus: a pitfall in lymph node biopsies.

The sentinel lymph node from a 72-year-old female with melanoma revealed a pigmented and spindled melanocytic proliferation in the capsule that extended into the trabeculae. Benign nodal nevi are uncommon but have been reported in lymph nodes of melanoma patients and less often in lymph nodes removed for other reasons. Nodal blue nevi are particularly rare. These melanocytic proliferations can be distinguished from metastatic melanoma by evaluation of the distribution in the node, morphologic characteristics and the assistance of immunohistochemistry.