Publications by authors named "Sara C Shalin"

67 Publications

Hyperkeratotic Plaques of Distal Extremities as a Presenting Sign of Autoimmune Hepatitis: Challenge.

Am J Dermatopathol 2021 Sep;43(9):e101

Department of Dermatology and Pathology, University of Arkansas for Medical Sciences, Little Rock, AR.

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http://dx.doi.org/10.1097/DAD.0000000000001867DOI Listing
September 2021

Hyperkeratotic Plaques of Distal Extremities as a Presenting Sign of Autoimmune Hepatitis: Answer.

Am J Dermatopathol 2021 Sep;43(9):672-673

Dermatology, University of Arkansas for Medical Sciences, Little Rock, AR.

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http://dx.doi.org/10.1097/DAD.0000000000001866DOI Listing
September 2021

Deep Herpes.

Am J Surg Pathol 2021 Oct;45(10):1357-1363

Pathology Service, Massachusetts General Hospital and Harvard Medical School, Boston.

Herpes viruses are known for infecting epithelial cells and manifesting as vesicles. However, herpes viruses can also infect stromal cells. While established in the ocular setting, cutaneous stromal herpes (deep herpes) is previously unreported and may evade clinical and microscopic detection. We searched for skin biopsies with herpes stromal disease. Clinical information was retrieved via electronic medical records and pathology records system. Hematoxylin and eosin slides, immunohistochemical staining, and polymerase chain reaction detection of viral DNA was performed. We identified 12 specimens from 10 patients with cutaneous stromal herpes simplex virus 1/2 (n=7) or varicella-zoster virus infection (n=5). The most common site involved was the buttocks/perianal region (n=6). Ulceration was a frequent dermatologic finding (n=8). Pyoderma gangrenosum was clinically suspected in 6 specimens (50%). Eight patients (80%) were immunosuppressed. Biopsies frequently demonstrated a dense dermal mixed inflammatory infiltrate with subcutaneous extension and enlarged cells with viral cytopathic changes confirmed by herpes simplex virus 1/2 or varicella-zoster virus immunohistochemistry (n=10) or polymerase chain reaction (n=2). Most specimens (67%) lacked evidence of characteristic epidermal keratinocyte infection. This study presents the first known report of the ability of herpes virus to infect deep stromal cells of the dermis. We raise awareness of cutaneous stromal herpes in patients presenting with atypical clinical lesions, particularly while immunocompromised. Establishing the correct diagnosis is critical for initiating therapy.
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http://dx.doi.org/10.1097/PAS.0000000000001733DOI Listing
October 2021

Dermal melanocytic tumor with CRTC1-TRIM11 fusion: Report of two additional cases with review of the literature of an emerging entity.

J Cutan Pathol 2021 Jul 7;48(7):915-924. Epub 2021 Mar 7.

Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA.

"Cutaneous melanocytic tumor with CRTC1-TRIM11 fusion" (CMTCT) is a newly described, potentially novel entity that typically presents as a dermal nodule on the head and neck, extremities, and trunk of adults. Histopathologically, it is reported as a nodular or multinodular tumor composed of epithelioid and spindle cells that are variably immunoreactive for S100-protein, SOX10, and MITF along with more specific melanocytic markers such as MelanA and HMB45. With only 11 cases reported in the English literature so far, the neoplasm appears to behave in a relatively indolent fashion. Nevertheless, in one case, local recurrence and synchronous distant metastasis were evident after 13 years. Additional cases with longer follow-up are essential to determine the neoplasm's biologic behavior with more accuracy. Herein, two cases of CMTCT, one arising on the lower back of a 65-year-old female and the other on the arm of a 33-year-old female in addition to a comprehensive literature review are reported.
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http://dx.doi.org/10.1111/cup.13984DOI Listing
July 2021

Cervical dysplasia in a patient with inherited epidermodysplasia verruciformis-A mere coincidence?

J Cutan Pathol 2021 Jun 22;48(6):763-770. Epub 2020 Dec 22.

Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

Epidermodysplasia verruciformis (EV) is a rare inherited or acquired genodermatosis caused by increased susceptibility to infection by the beta subtypes of human papillomavirus (HPV). The co-occurrence of EV with high-risk (HR) HPV infection leading to cervical dysplasia is unreported in the literature to date. We report a patient with inherited EV who developed extensive anogenital and cervical dysplasia linked to concurrent HR-HPV infection. Literature review suggests that there is a negative correlation of cervical dysplasia and cervical cancer with EV, which suggests that this patient's presentation and course are exceptional.
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http://dx.doi.org/10.1111/cup.13937DOI Listing
June 2021

Prospective Consensus Reporting by Gynecologic Pathology and Dermatopathology Improves Diagnosis of Vulvar Biopsies.

Arch Pathol Lab Med 2020 11;144(12)

From the Department of Pathology, University of Arkansas for Medical Sciences, Little Rock.

Context.—: Vulvar biopsy interpretation and reporting, particularly of vulvar dermatoses, can be challenging in daily practice for both surgical pathologists (SPs) and dermatopathologists (DPs).

Objective.—: To investigate whether prospective consensus reporting of vulvar biopsies by SPs and DPs would provide value and improve overall diagnostic concordance.

Design.—: Consecutive vulvar biopsies during a 6-month period were reviewed prospectively by both gynecologic SPs and DPs. Preliminary, independently generated diagnoses were recorded and then shared in consensus review (SPs+DPs). A third pathologist adjudicated cases without consensus. Multiple data elements were collected for each case: division (SP/DP), age, site, clinical history, diagnostic category, preliminary and final (consensus) diagnosis, need for adjudication, ancillary tests, and diagnostic discrepancy.

Results.—: Eighty-four biopsies (48 SP, 36 DP) from 70 patients were reviewed. Forty-two of 84 cases (50%) were neoplastic, 38 of 84 (45%) were reactive/inflammatory, with the remaining (5%) showing both or other features. Independent diagnoses were discrepant in 22 of 84 cases (26%), but consensus review resulted in an agreed-upon diagnosis in all cases, with adjudication required in 6 cases. Independent diagnostic agreement increased over time with a reduction in major and minor discrepancies between the first and second half of the study period.

Conclusions.—: Prospective review of vulvar biopsies by both SPs and DPs can improve overall reporting. Consensus review allows pathologists to gain diagnostic confidence in interpretation of inflammatory (for SPs) and neoplastic (for DPs) vulvar biopsies; therefore, intradepartmental consultation is of value, particularly in select cases.
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http://dx.doi.org/10.5858/arpa.2020-0331-OADOI Listing
November 2020

Lichenoid dermatoses involving the vulva: A clinical-pathologic correlation.

Semin Diagn Pathol 2021 Jan 5;38(1):3-18. Epub 2020 Sep 5.

Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR.

The lichenoid tissue reaction pattern generally signifies cytotoxic damage to the epithelium. When such reaction pattern occurs on vulvar skin or mucosa, the effects can result in considerable morbidity. None of the entities discussed in this review are entirely unique to the vulva, however, some entities may classically occur at this site, while others tend to be widespread diseases that may incidentally affect vulvar skin and mucosa. Given the complex anatomy of the vulva and the bridging of a site showing both keratinizing squamous epithelium and non-keratinizing squamous mucosa, histopathologic features may display variation in presentation. Although identification of a "lichenoid reaction pattern" alone may provide insight into the disease process, understanding of clinical presentation and specific sites of involvement, along with recognition of the nuanced features of the disease entities can help establish a specific diagnosis. Accurate histopathologic diagnoses by pathologists can improve the ability for treating clinicians to implement timely and effective treatment.
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http://dx.doi.org/10.1053/j.semdp.2020.09.005DOI Listing
January 2021

Proteogenomic analysis of melanoma brain metastases from distinct anatomical sites identifies pathways of metastatic progression.

Acta Neuropathol Commun 2020 09 5;8(1):157. Epub 2020 Sep 5.

Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.

Melanoma brain metastases (MBM) portend a grim prognosis and can occur in up to 40% of melanoma patients. Genomic characterization of brain metastases has been previously carried out to identify potential mutational drivers. However, to date a comprehensive multi-omics approach has yet to be used to analyze brain metastases. In this case report, we present an unbiased proteogenomics analyses of a patient's primary skin cancer and three brain metastases from distinct anatomic locations. We performed molecular profiling comprised of a targeted DNA panel and full transcriptome as well as proteomics using mass spectrometry. Phylogeny demonstrated that all MBMs shared a SMARCA4 mutation and deletion of 12q. Proteogenomics identified multiple pathways upregulated in the MBMs compared to the primary tumor. The protein, PIK3CG, was present in many of these pathways and had increased gene expression in metastatic melanoma tissue from the cancer genome atlas data. Proteomics demonstrated PIK3CG levels were significantly increased in all 3 MBMs and this finding was further validated by immunohistochemistry. In summary, this case report highlights the potential role of proteogenomics in identifying pathways involved in metastatic tumor progression. Furthermore, our multi-omics approach can be considered to aid in precision oncology efforts and provide avenues for therapeutic innovation.
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http://dx.doi.org/10.1186/s40478-020-01029-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487560PMC
September 2020

DNA-PKcs Inhibition Extends Allogeneic Skin Graft Survival.

Transplantation 2021 03;105(3):540-549

Division of Surgical Research, University of Arkansas for Medical Sciences, Little Rock, AR.

Background: Organ transplantation is life-saving and continued investigations into immunologic mechanisms that drive organ rejection are needed to improve immunosuppression therapies and prevent graft failure. DNA-dependent protein kinase catalytic subunit, DNA dependent-protein kinase catalytic subunit (DNA-PKcs), is a critical component of both the cellular and humoral immune responses. In this study, we investigate the contribution of DNA-PKcs to allogeneic skin graft rejection to potentially highlight a novel strategy for inhibiting transplant rejection.

Methods: Fully MHC mismatched murine allogeneic skin graft studies were performed by transplanting skin from BalbC mice to C57bl6 mice and treating with either vehicle or the DNA-PKcs inhibitor NU7441. Graft rejection, cytokine production, immune cell infiltration, and donor-specific antibody formation were analyzed.

Results: DNA-PKcs inhibition significantly reduced necrosis and extended graft survival compared with controls (mean survival 14 d versus 9 d, respectively). Inhibition reduced the production of the cytokines interleukin (IL)-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ and the infiltration of CD3+ lymphocytes into grafts. Furthermore, DNA-PKcs inhibition reduced the number of CD19+ B cells and CD19+ CD138+ plasma cells coinciding with a significant reduction in donor-specific antibodies. At a molecular level, we determined that the immunosuppressive effects of DNA-PKcs inhibition were mediated, in part, via inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells signaling through reduced expression of the p65 subunit.

Conclusions: Our data confirm that DNA-PKcs contributes to allogeneic graft rejection and highlight a novel immunologic function for DNA-PKcs in the regulation of nuclear factor kappa-light-chain-enhancer of activated B cells and concomitant cytokine production.
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http://dx.doi.org/10.1097/TP.0000000000003442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902289PMC
March 2021

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

J Cutan Pathol 2020 Nov 22;47(11):1096-1102. Epub 2020 Aug 22.

Department of Pathology and Laboratory Medicine, Southern California Permanente Medical Group, Los Angeles, California, USA.

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.
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http://dx.doi.org/10.1111/cup.13769DOI Listing
November 2020

Elastophagocytosis and interstitial granulomatous infiltrate are more common in extragenital vs genital lichen sclerosus.

J Cutan Pathol 2020 Oct 9;47(10):903-912. Epub 2020 Jun 9.

Departments of Pathology and Dermatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

Background: Genital and extragenital lichen sclerosus (LS) share similar histopathologic features. A recent small series documented elastophagocytosis uniquely in extragenital LS. We evaluated a larger series of LS for elastophagocytosis, elastic fiber loss, and other histopathologic features. We evaluated matrix metalloproteinase (MMP) expression to determine if these proteins play an etiologic role.

Methods: Genital (n = 42) and extragenital (n = 41) LS biopsies were examined for histopathologic features, elastic fiber alteration (Verhoeff van Gieson staining), and MMP-2 and MMP-9 expression (immunohistochemistry).

Results: Elastophagocytosis and an interstitial granulomatous pattern were significantly more common in extragenital LS than genital LS (43.9% vs 4.7% and 56.1% vs 9.5%). Extragenital LS had mild/focal elastic fiber loss (43.9%), while genital LS had moderate (61.9%) or marked (19%) loss. MMP-9 was diffusely expressed in histiocytes in both types of LS (genital 97.5%; extragenital 100%). Weak MMP-2 expression was seen in genital (58%) and extragenital (55%) LS.

Conclusions: Extragenital LS, but not genital LS, frequently exhibits elastophagocytosis and interstitial granulomatous infiltrate, and these patterns could contribute to elastic fiber destruction in extragenital LS. While MMP-2 and MMP-9 expression are common in LS, expression did not significantly differ depending on anatomic site and thus is unlikely to explain observed histopathologic differences.
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http://dx.doi.org/10.1111/cup.13741DOI Listing
October 2020

Up-Regulation of PARP1 Expression Significantly Correlated with Poor Survival in Mucosal Melanomas.

Cells 2020 05 5;9(5). Epub 2020 May 5.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Introduction: Mucosal melanoma is rare and associated with poorer prognosis in comparison to conventional melanoma subtypes. Little is known about the prognostic significance as well as possible associations between PARP1 and immunologic response in mucosal melanoma.

Methods: PARP1, PD-L1 and IDO1 immunostains were performed on 192 mucosal melanomas including 86 vulvar, 89 sinonasal, and 17 anorectal melanomas.

Results: By Kaplan-Meier analyses, high PARP1 expression correlated with worse overall and melanoma-specific survival (log-rank values = 0.026 and 0.047, respectively). Tumors with combined PARP1 and IDO1 high expression correlated with worse overall and melanoma-specific survival ( = 0.015, 0.0034 respectively). By multivariate analyses, high PARP1 expression remained a predictor of worse survival independent of stage. By Fisher's exact test, high PARP1 expression correlated with highly mitogenic tumors ( = 0.02). High tumoral PD-L1 and IDO1 expression were associated with ulcerated primary tumors ( = 0.019, 0.0019, respectively). By linear regression analyses, correlations between PARP1 expression versus IDO1 expression ( = 0.0001) and mitotic index ( = 0.0052) were observed.

Conclusion: Increased expression of PARP1 is an independent negative prognostic marker in mucosal melanomas. The association between PARP1 and IDO1 and their combined adverse prognostic role raise the potential of combined therapy in mucosal melanoma.
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http://dx.doi.org/10.3390/cells9051135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290913PMC
May 2020

Epithelioid Fibrous Histiocytoma With Dot-Like Perinuclear ALK Expression and PRKAR2A-ALK Fusion.

Am J Dermatopathol 2020 Nov;42(11):861-864

Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR.

Epithelioid fibrous histiocytoma (EFH) is a rare, benign, cutaneous neoplasm. This fibrohistiocytic tumor was once believed to be a variant of fibrous histiocytoma, but EFH is now known to be a distinct entity based on the presence of ALK gene rearrangements in most cases. The pattern of immunohistochemical expression of ALK in EFH in the literature thus far describes both granular cytoplasmic staining and nuclear staining. We present a case of EFH with dot-like Golgi pattern perinuclear ALK expression, a previously undescribed staining pattern. We surmised this unique staining pattern could be due to a novel fusion partner, and using FISH, we confirmed a rearrangement of the ALK (2p23) locus. Further investigation with whole transcriptome sequencing led to the discovery of PRKAR2A-ALK fusion, and the function of this fusion partner reflects a Golgi-predominant localization of the protein. Attention to the distinct immunohistochemical pattern of ALK expression may provide clues to the function of the fusion partner.
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http://dx.doi.org/10.1097/DAD.0000000000001666DOI Listing
November 2020

Hansen Disease (Leprosy) and Armadillo Exposure in Arkansas: A Case Series.

Am J Dermatopathol 2020 Oct;42(10):769-773

Hull Dermatology, PA, Rogers, AR.

Background: Although most cases of Hansen disease (HD) in the United States are imported from endemic areas, a subset of cases are relate to exposure to nine-banded armadillos. Several recent cases of HD in Arkansas occurred in patients who had not traveled to endemic areas and who reported variable degrees of armadillo exposure.

Objective: The purpose of this study was to report 6 cases of HD diagnosed in Arkansas between 2004 and 2016. The secondary purpose was to explore the correlation between exposure to the nine-banded armadillo as it pertains to transmission of the disease.

Methods: The referring clinician of each patient was contacted to gather information regarding the patient's clinical presentation, armadillo exposure, and travel history. In addition, the Arkansas Department of Health was consulted to review the demographics of individuals diagnosed with HD in the past 15 years and to review the distribution of HD throughout the state of Arkansas.

Results: Six domestic cases of HD were associated with both direct and indirect exposure to armadillos.

Limitations: Armadillo exposure may be underreported in patients with HD because of fear of stigmatization and/or lack of access to care.

Conclusions: Direct exposure to armadillos does not appear to be required for transmission of HD making a soil-mediated mechanism of indirect exposure plausible.
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http://dx.doi.org/10.1097/DAD.0000000000001660DOI Listing
October 2020

Cutaneous pleomorphic fibromas arising in patients with germline TP53 mutations.

J Cutan Pathol 2020 Aug 6;47(8):734-741. Epub 2020 Apr 6.

Department of Pathology, Stanford University School of Medicine, Stanford, California.

Pleomorphic fibromas are rare benign cutaneous neoplasms associated with deletion/loss of chromosomes 13q and 17p, where RB1 and TP53 are located, respectively. Herein, we report five cases of pleomorphic fibroma arising in patients with germline TP53 mutations, suggesting a potential link with Li-Fraumeni syndrome. All three patients were female and young (mean age 27) with a strong personal and/or family oncologic history and confirmed pathogenic germline TP53 mutations. In two patients, multiple pleomorphic fibromas were diagnosed. Clinically, the lesions arose at various cutaneous sites and were small (≤2 cm) and raised (4/5). Histopathologically, the tumors were paucicellular, composed of atypical spindled to stellate cells with hyperchromatic and variably pleomorphic nuclei. Mitotic activity was exceedingly low, although rare atypical mitotic figures were seen in one case. Immunohistochemically, the tumor cells were diffusely positive for p16 (3/3) and showed loss of Rb expression (5/5). All cases showed aberrant p53 expression (overexpression in 4, complete loss in 1). The tumors have followed a benign clinical course with no evidence of progression or recurrence. In conclusion, the development of multiple pleomorphic fibromas in a young patient may be a clue to an underlying genetic cancer syndrome involving TP53.
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http://dx.doi.org/10.1111/cup.13686DOI Listing
August 2020

Utility of histone H3K27me3 and H4K20me as diagnostic indicators of melanoma.

Melanoma Res 2020 04;30(2):159-165

Department of Biochemistry and Molecular Biology.

Histone posttranslational modifications (PTMs) have been shown to be dysregulated in multiple cancers including melanoma, and as they are abundant and easily detectable, they make ideal biomarkers. The aim of this study was to identify histone PTMs that could be potential biomarkers for melanoma diagnosis. Previously, we utilized mass spectrometry to identify histone PTMs that were dysregulated in matched melanoma cell lines and found two modifications, H3 lysine 27 trimethylation (histone H3K27me3) and H4 lysine 20 monomethylation (histone H4K20me), that were differentially expressed in the more aggressive compared to the less aggressive cell line. In this study, we performed immunohistochemistry on tissue microarrays containing 100 patient tissue spots; 18 benign nevi, 62 primary, and 20 metastatic melanoma tissues. We stained for histone H3K27me3 and histone H4K20me to ascertain whether these histone PTMs could be used to distinguish different stages of melanoma. Loss of histone H4K20me was observed in 66% of malignant patient tissues compared to 14% of benign nevi. A majority (79%) of benign nevi had low histone H3K27me3 staining, while 72% of malignant patient tissues showed either a complete loss or had strong histone H3K27me3 staining. When we analyzed the staining for both marks together, we found that we could identify 71% of the benign nevi and 89% of malignant melanomas. Histone H3K27me3 or histone H4K20me display differential expression patterns that can be used to distinguish benign nevi from melanoma; however, when considered together the diagnostic utility of these PTMs increased significantly. The work presented supports the use of combination immunohistochemistry of histone PTMs to increase accuracy and confidence in the diagnosis of melanoma.
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http://dx.doi.org/10.1097/CMR.0000000000000648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080300PMC
April 2020

Current state of melanoma diagnosis and treatment.

Cancer Biol Ther 2019 1;20(11):1366-1379. Epub 2019 Aug 1.

University of Arkansas for Medical Sciences, Department of Biochemistry and Molecular Biology , Little Rock , AR , USA.

Melanoma is the deadliest form of skin cancer. In the early stages, melanoma can be treated successfully with surgery alone and survival rates are high, but after metastasis survival rates drop significantly. Therefore, early and correct diagnosis is key for ensuring patients have the best possible prognosis. Melanoma misdiagnosis accounts for more pathology and dermatology malpractice claims than any cancer other than breast cancer, as an early misdiagnosis can significantly reduce a patient's chances of survival. As far as treatment for metastatic melanoma goes, there have been several new drugs developed over the last 10 years that have greatly improved the prognosis of patients with metastatic melanoma, however, a majority of patients do not show a lasting response to these treatments. Thus, new biomarkers and drug targets are needed to improve the accuracy of melanoma diagnosis and treatment. This article will discuss the major advancements of melanoma diagnosis and treatment from antiquity to the present day.
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http://dx.doi.org/10.1080/15384047.2019.1640032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804807PMC
August 2020

Pearls and Updates in Dermatopathology for the General Surgical Pathologist: Experts Weigh In on What You Need to Know.

Arch Pathol Lab Med 2019 07;143(7):786-788

From the Departments of Pathology and Dermatology, University of Arkansas for Medical Sciences, Little Rock, (Drs Shalin, Gardner, Kaley); and Hull Dermatology, Rogers, Arkansas (Dr Kaley).

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http://dx.doi.org/10.5858/arpa.2019-0099-EDDOI Listing
July 2019

Dermatologic Urgencies and Emergencies: What Every Pathologist Should Know.

Arch Pathol Lab Med 2019 08 20;143(8):919-942. Epub 2019 Feb 20.

From the Department of Dermatology, Saint Louis University, St Louis, Missouri (Dr Abate); the Departments of Dermatology (Dr Battle), and Pathology (Drs Gardner and Shalin), University of Arkansas for Medical Sciences, Little Rock; and the Department of Dermatology, University of Mississippi Medical Center, Jackson (Dr Emerson).

Context.—: Fatal dermatologic diseases and ones with high morbidity can occur in the inpatient setting. In such cases, prompt and accurate assessment of a bedside skin biopsy is required. This may be challenging for many pathologists who are not familiar with the complexity of skin pathology and skin terminology within the fields of dermatopathology and dermatology.

Objective.—: To provide the pathologist with a practical, up-to-date, and "must-know" reference guide on dermatologic urgencies and emergencies from a real-world perspective, highlighting diagnostic pearls, diagnostic pitfalls, and commonly encountered practice gaps. This review will focus on key diseases with which every pathologist should be familiar, including angioinvasive fungal infections, Stevens-Johnson syndrome/toxic epidermal necrolysis, staph-scalded-skin syndrome, acute graft-versus-host disease, bullous pemphigoid, calciphylaxis, Sweet syndrome and its histiocytoid variant, pyoderma gangrenosum, and leukocytoclastic vasculitis, as well as those in their clinical and histopathologic differential.

Data Sources.—: This review is based on peer-reviewed literature and our personal experiences with these diseases at major academic institutions, including one where a large number of stem cell transplants are performed. This review is unique as it represents collaborative expert opinion from both a dermatopathology and a dermatology standpoint.

Conclusions.—: This review outlines the critical role that the pathologist plays in the outcomes of patients with dermatologic urgencies and emergencies. Improved patient care will result from prompt and accurate histopathologic diagnoses as well as an open line of communication with the dermatologist.
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http://dx.doi.org/10.5858/arpa.2018-0239-RADOI Listing
August 2019

Loss of E-Cadherin Inhibits CD103 Antitumor Activity and Reduces Checkpoint Blockade Responsiveness in Melanoma.

Cancer Res 2019 03 23;79(6):1113-1123. Epub 2019 Jan 23.

Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Identifying controlling features of responsiveness to checkpoint blockade therapies is an urgent goal in oncology research. Our group and others have previously shown melanoma tumors resistant to checkpoint blockade display features of mesenchymal transition, including E-cadherin loss. Here, we present the first evidence that E-cadherin from tumor cells facilitate immune attack, using a B16F10 melanoma mouse model in which E-cadherin is exogenously expressed (B16.Ecad). We find, compared with vector control, B16.Ecad exhibits delayed tumor growth, reduced metastatic potential, and increased overall survival . Transplantation of B16.Ecad into Rag1 and CD103 mice abrogated the tumor growth delay. This indicates the anti-melanoma response against B16.Ecad is both immune and CD103 mediated. Moreover, B16.Ecad showed increased responsiveness to combination immune checkpoint blockade (ICB) compared with vector control. This work establishes a rationale for ICB responses observed in high E-cadherin-expressing tumors and suggests therapeutic advancement through amplifying CD103 immune cell subsets. These findings identify the mechanism behind checkpoint blockade resistance observed in melanoma that has undergone mesenchymal transition and suggest activation of CD103 immune cells as a therapeutic strategy against other E-cadherin-expressing malignancies. http://cancerres.aacrjournals.org/content/canres/79/6/1113/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420873PMC
March 2019

Consecutive Immunohistochemical Staining on a Single Slide is Effective in Confirming Melanocytic Derivation.

Appl Immunohistochem Mol Morphol 2020 10;28(9):e76-e81

Departments of Pathology.

Background: Metastatic melanoma in sentinel lymph nodes is often elusive to detect with morphology alone. Per American Joint Committee on Cancer staging guidelines, a single atypical melanocyte in lymph node qualifies as metastasis, whether identified by morphology or immunohistochemistry, but single cell staining must be convincing. We propose that the use of a second immunohistochemical run performed on a single slide will allow for more confident diagnosis of micrometastases.

Materials And Methods: We designed a technical study to determine whether a second antibody application on previously stained slides can successfully detect the same population of cells. Melanocytic neoplasms were stained with SOX-10 using Ventana Benchmark Ultra stainers, coverslipped, and examined, followed by coverslip removal and application of MART-1 (Ventana A103). The order of antibody application and chromagen detection kit (AP-RED vs. DAB) was reversed to establish reliability and robustness of the protocol.

Results: All melanocytes marked with SOX-10 and MART-1, and produced a range of staining quality that varied based on order of stain application and chromagen kit were used. The optimal combination was red MART-1 applied first followed by brown SOX-10 applied second.

Conclusions: Consecutive staining of melanocytes with SOX-10 and MART-1 may improve diagnostic confidence of melanocyte identification, particularly in detection of single cell, micrometastases in sentinel lymph nodes or in situations where dual immunohistochemical stains may be unavailable.
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http://dx.doi.org/10.1097/PAI.0000000000000665DOI Listing
October 2020

ALK Rearrangements Are Infrequent in Cellular Blue Nevus and Deep Penetrating Nevus.

Am J Dermatopathol 2018 Jul;40(7):469-478

Chief Resident (A.L.J.D.), Associate Professor (J.M.G., S.C.S.), Assistant Professor (J.R.K.), Professor (W.B.), Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR.

Recent studies have identified kinase fusions in Spitzoid melanocytic neoplasms, and approximately 10% of Spitzoid neoplasms harbor anaplastic lymphoma kinase (ALK) rearrangements and corresponding ALK immunoreactivity. Deep penetrating nevi (DPN), a subset of melanocytic neoplasms, have histologic and immunohistochemical overlap that have historically supported classification of DPN with blue/cellular blue nevi (CBN). However, HRAS mutations have rarely been detected in DPN, thereby also linking them to Spitz nevi. The purpose of this study was to see if DPN or CBN possess ALK rearrangements, thereby providing more evidence that these melanocytic lesions may be pathogenetically related to Spitzoid neoplasms. Using ALK immunohistochemistry as a surrogate for ALK rearrangement, the authors examined 26 DPN, 30 CBN, and 4 conventional blue nevi. ALK immunoreactive cases underwent fluorescent in situ hybridization to investigate for the presence of ALK gene rearrangement. Patchy and focal ALK immunostaining was found in only 1 case of DPN (1/26, 3.8%). Seven cases of CBN (7/30; 23%) showed ALK immunostaining (6 focal/patchy, 1 strong and diffuse). Fluorescent in situ hybridization using ALK break-apart probes showed various degrees of gain of 2p23 and rare ALK break-apart signals. Four CBN showed ALK rearrangement in 2%-4% of cells. Two cases of CBN showed gain of 2p23 in 10%-20% of cells. In our study, ALK rearrangements are uncommon in both CBN and DPN, making ALK an unlikely driver in tumorigenesis and classification of these melanocytic variants. However, our study did identify ALK molecular changes and immunohistochemical staining patterns that have not been previously described in CBN or DPN.
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http://dx.doi.org/10.1097/DAD.0000000000001014DOI Listing
July 2018

Conventional Versus Giant Basal Cell Carcinoma, a Review of 57 Cases: Histologic Differences Contributing to Excessive Growth.

Indian J Dermatol 2018 Mar-Apr;63(2):147-154

Department of Dermatology, University of Alabama, Birmingham, AL, USA.

Background: Giant basal cell carcinoma (GBCC) is defined as a basal cell carcinoma (BCC) exceeding 5 cm in size. While these tumors impart significant morbidity due to local tissue destruction and have a higher rate of metastatic disease than their conventional (smaller) counterparts, reasons for their large size remain unclear. While theories relating to neglect or faster growth rate are often invoked; to date, there has not been a comprehensive evaluation of the histologic features of these large tumors that may contribute to their size.

Methods: Histologic features of GBCCs ( = 29) were evaluated and compared to those of conventional BCC ( = 28). Available clinical demographic data were also reviewed.

Results: GBCCs, in addition to overall larger size, more often were thicker, displayed ulceration, and showed a more infiltrative growth pattern than their conventional counterparts. These rare tumors also displayed an insignificant increased propensity for a brisk host immune response, and the infiltrate significantly more often included clusters of plasma cells.

Conclusions: Most histologic features seen in GBCCs likely reflect their large size. Histologic features alone are unlikely to explain the size of these rare tumors. The possibility of an altered host immune response contributing to the growth of these tumors requires further investigation.
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http://dx.doi.org/10.4103/ijd.IJD_165_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903045PMC
April 2018

Colliding, colonizing or combining? Four cases illustrating the unique challenges presented by melanoma arising in conjunction with basal cell carcinoma.

J Cutan Pathol 2018 Jun 25;45(6):443-452. Epub 2018 Mar 25.

Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Biphasic lesions comprised of melanocytic and epithelial components are rare entities believed to arise either as a collision of 2 histologically distinct lesions in the same anatomic location or as a singular progenitor tumor differentiating along 2 differing lineages. Regardless of mechanism of origin, these tumors present unique challenges in pathologic interpretation and in determining appropriate measurements, which assigns subsequent prognosis to the patient. We present 4 tumors of melanoma co-existing with basal cell carcinoma (BCC) and discuss relevant literature regarding these biphasic entities. Patients consisted of 3 males and 1 female, ranging in age from 62 to 93, with lesions located on the shoulder, frontal scalp, forearm and nose. Three of 4 lesions showed melanoma cells limited to BCC tumor lobules, without evidence of direct dermal invasion by melanoma cells, raising the question of whether or not these tumors should be classified as in situ or invasive melanoma. These cases highlight the complexity that such lesions pose to dermatopathologists, in terms of their uncertain origin and variable microscopic appearance. In the absence of data regarding outcomes for these tumors (given their rarity), it is important to utilize a case-by-case approach, with careful clinical correlation and appropriate use of ancillary techniques.
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http://dx.doi.org/10.1111/cup.13137DOI Listing
June 2018

Impact of Pathologist Involvement in Sarcoma and Rare Tumor Patient Support Groups on Facebook: A Survey of 542 Patients and Family Members.

Arch Pathol Lab Med 2018 09 29;142(9):1113-1119. Epub 2018 Jan 29.

From the College of Medicine, University of Arkansas for Medical Sciences, Little Rock (Ms Haller); the Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas (Dr David); Pathology Associates, Huntsville, Alabama (Dr Lee); and the Departments of Pathology & Dermatology, University of Arkansas for Medical Sciences, Little Rock (Drs Shalin and Gardner).

Context: - Patients with rare tumors have difficulty finding reliable information about their disease. Facebook patient support groups allow patients to educate one another.

Objective: - To investigate how these patients perceive the value of pathologists, both in Facebook groups and real-world patient care.

Design: - Survey links were posted in 12 Facebook patient groups: 6 with an active pathologist member (angiosarcoma, epithelioid hemangioendothelioma, epithelioid sarcoma, dermatofibrosarcoma protuberans [×2], and desmoid fibromatosis), and 6 without "active" pathologist involvement (aggressive angiomyxoma, chondrosarcoma, Ewing sarcoma, leiomyosarcoma, liposarcoma, and osteosarcoma).

Results: - A total of 542 people responded (403 were patients): 264 from groups with a pathologist, and 278 from groups without active pathologist involvement. Of groups with an active pathologist, respondents agreed the pathologist's posts helped them better understand their disease (107 of 119; 90%) and relieved some of their disease-related anxiety (92 of 119; 77%). And for these groups 98% (117 of 119) of respondents agreed that having a pathologist in their group was a good thing; 83% (192 of 232) wanted more pathologists involved. More respondents from groups with an active pathologist (219 of 236; 93%) than without one (215 of 252; 85%) agreed: "pathologists are an important part of the patient care team for patients with cancer and other rare tumors" ( P = .008).

Conclusions: - This study is the first to evaluate the impact of pathologist interaction with Facebook patient support groups and to assess perceptions about the specialty of pathology from a large group of patients with rare tumors. Pathologist involvement in Facebook patient groups appears to positively influence patient perception of the importance of pathologists. We hope these data will encourage more pathologists to participate in Facebook patient support groups.
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http://dx.doi.org/10.5858/arpa.2017-0408-OADOI Listing
September 2018

Prognostic role of tumoral PDL1 expression and peritumoral FoxP3+ lymphocytes in vulvar melanomas.

Hum Pathol 2018 03 4;73:176-183. Epub 2018 Jan 4.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA. Electronic address:

The prognostic role of PDL1 expression, CD8+ and FoxP3+ lymphocytes in vulvar melanomas has not been studied. We correlated PDL1 expression and CD8+ and FoxP3+ immune infiltrates with clinicopathologic variables and patient outcomes in a series of 75 vulvar melanomas. Tumoral PDL1 expression (>5%) was seen in 23% of cases. By Fisher exact test, PDL1 expression and peritumoral FoxP3+ lymphocytes significantly correlated with less disease-specific death. By linear regression analysis, correlations between tumoral PDL1 expression with the density of tumoral CD8+ and peritumoral CD8+ lymphocytes, tumoral FoxP3+ with tumoral CD8+ lymphocytes, and peritumoral FoxP3+ with peritumoral CD8+ lymphocytes were observed. By univariate analyses, tumor thickness >4 mm predicted poorer progression-free survival, melanoma-specific survival, and overall survival. PDL1 expression >5% and peritumoral CD8+, peritumoral FoxP3+, and tumoral FoxP3+ lymphocytes correlated with better overall survival. By multivariate analyses, high peritumoral FoxP3+ lymphocytes independently predicted better melanoma-specific survival (P = .023), and tumor thickness independently predicted poorer progression-free survival (P = .05) and overall survival (P = .039). In conclusion, our study shows that, independent from tumor thickness, an increased density of peritumoral FoxP3+ lymphocytes may positively impact survival in a subset of vulvar melanomas. Tumoral PDL1 expression correlated with tumoral as well as peritumoral CD8+ and FoxP3+ lymphocytes, supportive of an adaptive immune response. Although the frequency of PDL1 expression is low in vulvar melanoma, its expression may identify a subset of vulvar melanoma that might respond to immunotherapy.
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http://dx.doi.org/10.1016/j.humpath.2017.12.022DOI Listing
March 2018

Dermatopathology and Social Media: Improving Participation by Increasing Clarity.

Arch Pathol Lab Med 2018 01;142(1):11

2   Department of Pathology, University of Arkansas for Medical Sciences, Little Rock.

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http://dx.doi.org/10.5858/arpa.2017-0331-LEDOI Listing
January 2018

Metastatic laryngeal large cell neuroendocrine carcinoma: A rare case of presentation and extreme tumor burden.

J Cutan Pathol 2018 Mar 28;45(3):229-233. Epub 2017 Dec 28.

Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Large cell neuroendocrine carcinoma (LCNEC) of the larynx is an aggressive form of neuroendocrine carcinoma that affects smokers at an average age of 60 years. LCNEC is characterized by large cells with round to ovoid nuclei distributed in a trabecular or nested growth pattern. Previously, laryngeal LCNEC and atypical carcinoid tumors were considered identical; however, laryngeal LCNEC has been shown to have higher mitotic rates and worse prognosis, which has led to laryngeal LCNEC's being separated from atypical carcinoid and classified as a poorly differentiated neuroendocrine carcinoma in the most recent World Health Organization classification. We present a case of a 56-year-old female who presented with painful subcutaneous skin lesions that were diagnosed as metastatic carcinoma at an outside facility. Subsequent workup revealed a primary epiglottic lesion. Over the next 4 years, she continued to develop over 100 similar subcutaneous nodules. Additional workup confirmed neuroendocrine differentiation, thus clarifying the diagnosis of metastatic LCNEC. Review of literature has revealed only 1 reported case of LCNEC with skin metastasis. This is the first reported case in which skin metastasis was the initial presenting symptom; moreover, our case is unique with regard to the heavy metastatic burden to the skin.
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http://dx.doi.org/10.1111/cup.13090DOI Listing
March 2018

Effects of supramaximal balloon dilatation pressures on adult cricoid and tracheal cartilage: A cadaveric study.

Laryngoscope 2018 06 8;128(6):1304-1309. Epub 2017 Oct 8.

Department of Otolaryngology and Head and Neck Surgery, University of Arkansas Medical Sciences, Little Rock, Arkansas, U.S.A.

Objectives/hypothesis: Cricoid fracture is a serious concern for balloon dilatation in airway stenosis. Furthermore, there are no studies examining tracheal rupture in balloon dilatation of stenotic segments. The aim of this study was to evaluate the effect of supramaximal pressures of balloons on the cricoid and tracheal rings.

Study Design: Prospective cadaveric study.

Methods: Seven cadaveric laryngotracheal complexes of normal adults with intact cricothyroid membranes were acquired. Noncompliant vascular angioplasty balloons (BARD-VIDA) were used for dilatation. The subglottis and trachea were subjected to supramaximal dilatation pressures graduated to nominal burst pressure (NBP) and, if necessary, rated burst pressure (RBP). Larger-diameter balloons, starting from 18 mm size to 24 mm, were used. Dilatations were maintained for 3 minutes.

Results: The cricoid ring was disrupted by larger-diameter balloons (22 mm and 24 mm) even at lower pressures (less than NBP) in six cases. Tracheal cartilages were very distensible, and external examination after supramaximal dilatation (24 mm close to RBP) revealed no obvious cartilage fractures or trachealis tears. Histopathological examination revealed sloughing of mucosa in the areas corresponding to balloon placement, but no microfractures or disruption of the perichondrium of tracheal ring cartilages.

Conclusions: These results indicate that the cricoid is vulnerable to injury from larger balloons even at lower dilatation pressures. The tracheal cartilages and the membranous wall of the trachea remained resilient to supramaximal dilatation and larger balloons.

Level Of Evidence: NA. Laryngoscope, 128:1304-1309, 2018.
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http://dx.doi.org/10.1002/lary.26872DOI Listing
June 2018

Dermatopathology and Social Media: A Survey of 131 Medical Professionals From 29 Countries.

Arch Pathol Lab Med 2018 Feb 28;142(2):184-190. Epub 2017 Jun 28.

Context: - Use of social media in the medical profession is an increasingly prevalent and sometimes controversial practice. Many doctors believe social media is the future and embrace it as an educational and collaborative tool. Others maintain reservations concerning issues such as patient confidentiality, and legal and ethical risks.

Objective: - To explore the utility of social media as an educational and collaborative tool in dermatopathology.

Design: - We constructed 2 identical surveys containing questions pertaining to the responders' demographics and opinions regarding the use of social media for dermatopathology. The surveys were available on Twitter and Facebook for a period of 10 days.

Results: - The survey was completed by 131 medical professionals from 29 different countries: the majority (81%, 106 of 131) were 25 to 45 years of age. Most replied that they access Facebook or Twitter several times a day (68%, 89 of 131) for both professional and social purposes (77%, 101 of 131). The majority agreed that social media provides useful and relevant information, but stated limitations they would like addressed.

Conclusions: - Social media is a powerful tool with the ability to instantaneously share dermatopathology with medical professionals across the world. This study reveals the opinions and characteristics of the population of medical professionals currently using social media for education and collaboration in dermatopathology.
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http://dx.doi.org/10.5858/arpa.2017-0064-OADOI Listing
February 2018
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