Creating an atlas of normal tissue for pruning WSI patching through anomaly detection.

Patching whole slide images (WSIs) is an important task in computational pathology. While most of them are designed to classify or detect the presence of pathological lesions in a WSI, the confounding role and redundant nature of normal histology are generally overlooked. In this paper, we propose and validate the concept of an "atlas of normal tissue" solely using samples of WSIs obtained from normal biopsies. Such atlases can be employed to eliminate normal fragments of tissue samples and hence increase the representativeness of the remaining patches. We tested our proposed method by establishing a normal atlas using 107 normal skin WSIs and demonstrated how established search engines like Yottixel can be improved. We used 553 WSIs of cutaneous squamous cell carcinoma to demonstrate the advantage. We also validated our method applied to an external dataset of 451 breast WSIs. The number of selected WSI patches was reduced by 30% to 50% after utilizing the proposed normal atlas while maintaining the same indexing and search performance in leave-one-patient-out validation for both datasets. We show that the proposed concept of establishing and using a normal atlas shows promise for unsupervised selection of the most representative patches of the abnormal WSI patches.

Development and Dosimetric Characterization of a Customizable Shield for Subtotal Skin Electron Beam Therapy.

Purpose: Purpose: Subtotal skin electron beam therapy may be an option for patients with cutaneous lymphoma receiving radiation therapy to treat large areas of their skin but may benefit from sparing specific areas that may have had previous radiation therapy, are of specific cosmetic concern, and/or show no evidence of disease. We report here on the design, implementation, and dosimetric characteristics of a reusable and transparent customizable shield for use with the large fields used to deliver total skin electron beam therapy at extended distance with a conventional linear accelerator. Methods and Materials: A shield was designed and manufactured consisting of acrylic blocks that can be mounted on a steel frame to allow patient-specific shielding. The dosimetry of the device was measured using radiochromic film. Results: The shield is easy to use and well-tolerated for patient treatment, providing minimal electron transmission through the shield with a sharp penumbra at the field edge, with no increase in x-ray dose. We report on the dosimetry of a commercial device that has been used to treat more than 30 patients to date. Conclusions: The customizable shield is well suited to providing patient-specific shielding for subtotal skin electron beam therapy.

Skin Cancer Associated With Chronic Leg Ulcers in the Population of Olmsted County, Minnesota.

Malignant skin tumors in the setting of chronic leg ulcers (CLUs) are often underdiagnosed which may contribute to treatment delay and poor outcomes. The aims of our study were to determine the incidence and clinical characteristics of skin cancers in leg ulcers in the Olmsted County population from 1995 to 2020. We used the Rochester Epidemiology Project (a collaboration between health care providers) infrastructure to describe this epidemiology, allowing "population-based" research. Electronic medical records of adult patients with International Classification of Diseases diagnosis codes for leg ulcers and skin cancers on the legs were queried. Thirty-seven individuals with skin cancers in nonhealing ulcers were identified. The cumulative incidence of skin cancer over the 25-year period was 37:7864 (0.47%). The overall incidence rate was 470 per 100,000 patients. Eleven (29.7%) men and 26 (70.3%) women were identified with mean age of 77 years. History of venous insufficiency was present in 30 (81.1%) patients and diabetes in 13 (35.1%) patients. Clinical characteristics of CLU with skin cancer included abnormal granulation tissue in 36 (94.7%) and irregular borders in 35 (94.6%) cases. Skin cancers among CLUs included 17 (41.5%) basal cell carcinomas, 17 (41.5%) squamous cell carcinomas, 2 (4.9%) melanomas, 2 (4.9%) porocarcinomas, 1 (2.4%) basosquamous cell carcinoma, and 1 (2.4%) eccrine adenocarcinoma. The apparent association between chronic wounds and subsequent biopsy-proven skin cancer of the same site was primarily observed in elderly patients; malignant transformation of wounds favored basal cell carcinoma and squamous cell carcinoma. This retrospective cohort study further characterizes the association between skin cancers and chronic leg wounds.

Artificial intelligence for automatic detection of basal cell carcinoma from frozen tissue tangential biopsies.

Evaluation of basal cell carcinoma (BCC) involves tangential biopsies of a suspicious lesion that is sent for frozen sections and evaluated by a Mohs micrographic surgeon. Advances in artificial intelligence (AI) have made possible the development of sophisticated clinical decision support systems to provide real-time feedback to clinicians which could have a role in optimizing the diagnostic workup of BCC. There were 287 annotated whole-slide images of frozen sections from tangential biopsies, of which 121 contained BCC, that were used to train and test an AI pipeline to recognize BCC. Regions of interest were annotated by a senior dermatology resident, experienced dermatopathologist, and experienced Mohs surgeon, with concordance of annotations noted on final review. Final performance metrics included a sensitivity and specificity of 0.73 and 0.88, respectively. Our results on a relatively small dataset suggest the feasibility of developing an AI system to aid in the workup and management of BCC.

Development of the lichen planus quality of life questionnaire (LPQoL) informed by expert clinician input and patient feedback: a retrospective survey study.

Lichen planus (LP) can affect multiple body sites including skin, mucosae, scalp and nails, causing considerable impact on patients' quality of life. Currently, there are no LP patient-reported outcome measures (PROMs) that address all body sites potentially affected by LP. We developed a LP Quality of Life Questionnaire (LPQoL), informed by an expert consortium and patient survey study, to address this gap. The study was approved by our institution's Institutional Review Board. First, a 22-item LPQoL was designed with input from LP experts at our institution. The tool was then optimized by garnering input from patients recently diagnosed with LP, who were asked to complete the LPQoL, as well as the Dermatology Life Quality Index (DLQI) and a feedback form about the LPQoL. Fifty-eight of 150 patients (39% response rate) returned the questionnaire. Mean DLQI score was 4.9 ± 5.6 SD (range 0-25) and mean LPQoL score was 13.6 ± 10.4 SD (range 0-54). LPQoL score was positively correlated with DLQI score (r = 0.79; p < 0.001). Forty-nine out of 56 (88%) and 6/56 (11%) rated the LPQoL as 'very easy' or 'fairly easy' to complete, respectively. Based on participants' feedback, we increased the recall period from one week to one month and added questions on esophageal involvement. With iterative input from LP experts and patients, we developed a LPQoL to address the gap in a multi-site PROM specific to LP. This is a pilot study and there is ongoing validation studies; therefore, this measure should not be used in clinical practice or research until validated.

Clinical and Pathological Characteristics and Outcomes Among Patients With Subcutaneous Panniculitis-like T-Cell Lymphoma and Related Adipotropic Lymphoproliferative Disorders.

Importance: There is a knowledge gap about subcutaneous panniculitis-like T-cell lymphoma (SPTCL) owing to its rarity and diagnostic difficulty, resulting in an absence of well-documented large case series published to date. Objective: To generate consensus knowledge by a joint multi-institutional review of SPTCL and related conditions. Design, Setting, and Participants: This retrospective clinical and pathological review included cases initially diagnosed as SPTCL at 6 large US academic centers. All cases were reviewed by a group of pathologists, dermatologists, and oncologists with expertise in cutaneous lymphomas. Through a process of group consensus applying defined clinical and pathological diagnostic criteria, the cohort was classified as (1) SPTCL or (2) adipotropic lymphoproliferative disorder (ALPD) for similar cases with incomplete histopathological criteria for SPTCL designation. Exposures: Cases of SPTCL diagnosed between 1998 and 2018. Main Outcomes and Measures: The main outcome was disease presentation and evolution, including response to therapy, disease progression, and development of hemophagocytic lymphohistiocytosis. Results: The cohort of 95 patients (median [range] age, 38 [2-81] years; female-to-male ratio, 2.7) included 75 cases of SPTCL and 20 cases of ALPD. The clinical presentation was similar for both groups with multiple (61 of 72 [85%]) or single (11 of 72 [15%]) tender nodules mostly involving extremities, occasionally resulting in lipoatrophy. Hemophagocytic lymphohistiocytosis (HLH) was only observed in SPTCL cases. With a mean follow-up of 56 months, 60 of 90 patients (67%) achieved complete remission with a median (range) of 3 (1-7) cumulative therapies. Relapse was common. None of the patients died of disease progression or HLH. Two patients with ALPD eventually progressed to SPTCL without associated systemic symptoms or HLH. Conclusions and Relevance: In this case series of patients initially diagnosed as having SPTCL, results showed no evidence of systemic tumoral progression beyond the adipose tissue. The SPTCL experience in this study confirmed an indolent course and favorable response to a variety of treatments ranging from immune modulation to chemotherapy followed by hematopoietic stem cell transplantation. Morbidity was primarily associated with HLH.

Histopathology of autoimmune bullous dermatoses: what's new?

Autoimmune bullous dermatoses are characterized by the presence of tissue-bound and often circulating pathogenic autoantibodies targeting structural components of the skin and/or mucous membranes. The diagnostic workup for this heterogeneous group of disorders consists of a multi-step process, of which the light microscopic examination is a crucial component. This review is organized following a classification scheme that is based on two main histopathologic features, namely level of intraepithelial split and composition of the inflammatory infiltrate. Overall, we aim to place emphasis on the histopathologic clues that can assist pathologists in differential diagnosis and review the updates in the literature.

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.

Impact of adding an IgG4 conjugate to routine direct immunofluorescence testing for subepithelial and intraepithelial autoimmune blistering disorders.

BACKGROUND: Certain autoimmune bullous dermatoses are mediated by autoantibodies of the IgG4 subclass. We determined the diagnostic impact of adding IgG4 to our conventional direct immunofluorescence (DIF) panel. METHODS: For all cases submitted to our referral laboratory for DIF over 1 month (n = 630), we performed IgG4 testing and collected consecutive biopsy specimens showing definite or indeterminate linear or cell-surface deposition of IgG, IgG4, and/or C3. On retrospective blinded review, we classified the pattern and whether the findings were definite, indeterminate, or negative. When present, substantial background staining was recorded. RESULTS: Seventy DIF specimens met the inclusion criteria. Of 22 (31.4%) specimens equivocal for linear or cell-surface deposition, 9 (40.9%) had definitive IgG4 findings, either linear (3 of 14 equivocal linear cases; 21.4%) or cell-surface (6 of 8 equivocal cell-surface cases; 75.0%). Background deposition was substantial in 14 cases (20.0%) for IgG but in none for C3 or IgG4. CONCLUSION: IgG4 allowed the classification of over 40% of DIF cases that were otherwise equivocal by IgG and C3. IgG4 staining showed lower levels of non-specific background staining than IgG or C3. IgG4 appears to contribute most value in cases with cell-surface deposition or with equivocal linear IgG deposition and negative C3 results.

Cutaneous eccrine inflammation and necrosis: review of inflammatory disorders affecting the eccrine apparatus including new associations.

Despite being frequently overlooked during the examination of histopathological sections, eccrine sweat glands can offer clues for diagnosing various skin conditions. They provide important functions and can lead to several diseases when inflamed or injured. This review article provides information regarding eccrine physiology as well as well-established and novel entities that occur in association with eccrine gland pathology.

Kaposi sarcoma misdiagnosed as granuloma annulare: A case of mistaken identity.

The microscopic features of patch stage Kaposi sarcoma (KS) and interstitial granuloma annulare (GA) may be difficult to differentiate, because both may exhibit a subtle "busy" dermis due to infiltration of spindled cells between collagen bundles. The clinical distinction is particularly challenging in human immunodeficiency virus (HIV)-affected individuals, as the incidence of GA appears to be greater in the HIV-infected population. KS is the most common neoplasm in this population. Despite the significant decrease in the incidence of KS since the advent of highly active antiretroviral therapy (HAART), KS tends to occur with late onset and indolent progression in patients with preserved immune function and minimal viral load. We present a 47-year-old homosexual HIV-positive man, under virologic and immunologic control on long-term HAART therapy, with a 5-year history of progressive red-brown patches and plaques on the legs, feet, hands, and trunk. Prior skin biopsy specimens were interpreted as interstitial GA. Histopathology on new skin biopsy specimens along with review specimens supported the diagnosis of plaque and patch stages of KS, respectively, supported by immunohistochemical expression of human herpes virus-8 (HHV-8). This case underscores the importance of maintaining a high suspicion for KS in progressive, treatment-recalcitrant skin lesions, particularly in HIV-infected individuals.

Utility of TRBC1 Expression in the Diagnosis of Peripheral Blood Involvement by Cutaneous T-Cell Lymphoma.

Peripheral blood involvement by cutaneous T-cell lymphoma is typically assessed by flow cytometry and plays a critical role in diagnosis, classification, and prognosis. Simplified strategies to detect tumor cells (Sezary cells) fail to exclude reactive subsets, whereas tumor-specific abnormalities are subtle and inconsistently present. We implemented a flow cytometric strategy to detect clonal Sezary cells based on the monotypic expression of one of two mutually exclusive TCR constant ß chains, TRBC1 and TRBC2. Analysis of CD4+ T-cell subsets and TCR variable ß classes from healthy donors showed polytypic TRBC1 staining. Clonal Sezary cells were identified by TRBC1 staining in 56 of 111 (50%) samples from patients with cutaneous T-cell lymphoma, accounting for 7-18,155 cells/µl and including 13 cases (23%) lacking tumor-specific immunophenotypic abnormalities. CD4+ T-cell subsets from 86 patients without T-cell lymphoma showed polytypic TRBC1 staining, except for five patients (6%) with minute T-cell clones of uncertain significance accounting for 53-136 cells/µl. Assessment of TRBC1 expression within a comprehensive single-tube flow cytometry assay effectively overcomes interpretative uncertainties in the identification of Sezary cells without the need for a separate T-cell clonality assay.

Resurrecting the Hospital Autopsy: Impact of an Office of Decedent Affairs on Consent Rates, Providers, and Next-of-Kin.

CONTEXT.­: Autopsy rates have decreased dramatically despite providing important clinical information to medical practices and social benefits to decedents' families. OBJECTIVE.­: To assess the impact of an institutional Office of Decedent Affairs (ODA), a direct communication link between pathology and decedents' families, on hospital autopsy consent rates, autopsy-related communication, practitioner views, and next-of-kin experiences. DESIGN.­: A before and after study involving all hospital decedents whose deaths did not fall within the jurisdiction of the medical examiner's office from 2013 to 2018. A pathology-run ODA launched in May 2016 to guide next-of-kin through the hospital death process (including autopsy-related decisions) and serve as the next-of-kin's contact for any subsequent autopsy-related communication. Critical care and hematology/oncology practitioners were assessed for their autopsy-related views and decedents' next-of-kin were assessed for their autopsy-related experiences. Autopsy consent rates for non-medical examiner hospital deaths, autopsy-related communication rates, practitioner views on the role and value of autopsy, and next-of-kin autopsy experiences and decisions factors were compared prior to and after ODA launch. RESULTS.­: Autopsy consent rates significantly increased from 13.2% to 17.3% (480 of 3647 deaths versus 544 of 3148 deaths; P < .001). There were significant increases in the rate of autopsy-related discussions and bereavement counseling provided to decedents' families. Practitioner views on the positive role of autopsy for any hospital death and those with advanced stage cancer also significantly increased. Next-of-kin indicated more consistent autopsy-related discussions with the potential benefits of autopsy discussed becoming key decision factors. CONCLUSIONS.­: An ODA improves hospital autopsy consent rates, autopsy-related communication, providers' autopsy-related views, and next-of-kins autopsy experiences.

Kappa and lambda immunohistochemistry and in situ hybridization in the evaluation of atypical cutaneous lymphoid infiltrates.

BACKGROUND: Atypical cutaneous lymphoid infiltrates are challenging lesions in dermatopathology. We present a summary of the literature regarding kappa and lambda immunohistochemistry (IHC) and in situ hybridization (ISH) in the evaluation of atypical cutaneous or mucosal lymphoid infiltrates. METHODS: Relevant articles from 1967 to 2018 in the English language were identified and summarized. In the absence of larger studies, case series of n ≥ 3 were included. RESULTS: Sixty-three articles assessing kappa and lambda IHC and/or ISH were identified. Most focused on marginal zone lymphomas. Other lymphomas included follicle center lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, lymphoplasmacytic lymphoma, plasmablastic lymphoma, multiple myeloma, monoclonal gammopathy of undetermined significance, and polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS). Non-neoplastic lesions included reactive lymphoid hyperplasia, cutaneous plasmacytosis, connective tissue disease, IgG4-related disease, acrodermatitis chronic atrophicans, Zoon balanitis, dermatitides, and infiltrates around epithelial dysplasias/neoplasias. CONCLUSION: Kappa and lambda IHC and ISH are useful tools in the evaluation of cutaneous B-cell lymphomas and plasma cell neoplasms. The literature supports that the detection of light-chain restriction by IHC and ISH is one of the most useful findings in the differential diagnosis of reactive lymphoid hyperplasia vs B-cell lymphoma with plasmacytic differentiation.