Publications by authors named "Drazen Jukic"

71 Publications

Cutaneous Secondary Syphilis Resembling Non-Melanoma Skin Cancer.

Cureus 2020 Oct 2;12(10):e10774. Epub 2020 Oct 2.

Dermatology, University of Florida, Gainesville, USA.

The cutaneous manifestations of secondary syphilis can vary significantly between patients, leading to a more difficult or delayed diagnosis. Here we present an instructive case of secondary syphilis in a 45-year-old, HIV-positive male patient. He presented with a solitary, crusted anterior neck nodule without concomitant systemic symptoms. Together, history and physical exam were concerning for non-melanoma skin cancer. Histopathologic evaluation of the lesion revealed an extensive infiltrate of plasma cells at the dermoepidermal junction, and immunohistochemical staining revealed numerous microorganisms. Physicians must keep syphilis in the differential diagnosis when evaluating atypical nodular lesions resembling non-melanoma skin cancer for the purpose of initiating appropriate antibiotic treatment and preventing future infectious complications.
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http://dx.doi.org/10.7759/cureus.10774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532864PMC
October 2020

Concordance of somatic mutation profiles (BRAF,NRAS, and TERT) and tumoral PD-L1 in matched primary cutaneous and metastatic melanoma samples.

Hum Pathol 2018 12 16;82:206-214. Epub 2018 Aug 16.

Dermatopathology Section, VA Integrated Systems Network (VISN1), Department of Pathology and Laboratory Medicine, West Roxbury, MA 02132, USA. Electronic address:

Despite the efficacy of BRAF-targeted and PD-L1-related immune therapies in tackling metastatic melanoma, a significant number of patients exhibit resistance. Given this, the objective of the current study was to ascertain concordance of somatic mutations in BRAF/NRAS/TERT and immunohistochemical PD-L1 and CD8 in matched primary cutaneous and metastatic melanoma. A total of 43 archival paired samples with sufficient material for genetic and immunohistochemical analyses met the criteria for inclusion in the study. Immunohistochemistry was performed for PD-L1 and CD8 and direct-DNA Sanger sequencing for BRAF/NRAS/TERT promoter mutational analyses. Agreement between paired samples was assessed using Cohen κ. Poor concordance among primary and corresponding metastases was noted in BRAF (9/42 cases discordant, κ = 0.49; 95% confidence interval [CI], 0.21-0.77; P = .0013), TERT promoter mutations (13/41 cases discordant, κ = 0.33; 95% CI, 0.04-0.62; P = .033), tumoral PD-L1 immunoexpression (9/43 cases discordant, κ = 0.39; 95% CI, 0.07-0.72; P = .0099), and immunoexpression of CD8 T lymphocytes (12/43 cases discordant, κ = 0.44; 95% CI, 0.19-0.69; P = .002). Although NRAS1 and NRAS2 were highly concordant (42/43 and 39/43 cases, respectively), discordant NRAS2 mutational status was associated with a median time to metastasis of 90 versus 455 days for pairs with concordant status (P = .07). Although limited by sample size, our findings suggest that consideration be given to mutational analysis of metastatic tissue rather than the primary to guide BRAF-targeted therapy and question the roles of TERT promoter mutations and PD-L1 as predictive biomarkers in malignant melanoma.
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http://dx.doi.org/10.1016/j.humpath.2018.08.002DOI Listing
December 2018

Two Cases of Lepromatous Leprosy from Exposure to Armadillos in Florida.

Skinmed 2017;15(5):391-393. Epub 2017 Oct 1.

Department of Dermatopathology, James A. Haley Veterans Hospital, Tampa, FL.

The first patient was a 41-year-old white man who was referred to the dermatology clinic with a 2-year history of numerous erythematous, hypoesthetic, poorly demarcated papules and plaques present on the trunk, buttocks, and bilateral upper and lower extremities (Figures 1 and 2). The lesions had initially begun as localized erythematous plaques on the right flank, and were diagnosed and treated as cellulitis and allergic contact dermatitis by primary care on separate occasions, with no resolution and continued gradual but persistent spread.
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July 2019

Eccrine-Centric Melanocytic Nevus.

Am J Dermatopathol 2018 May;40(5):375-377

Pathology and Laboratory Medicine Service, James A. Haley VA Hospital, Tampa, FL.

Benign melanocytic neoplasms present with a diverse array of well-known histopathologic patterns. It is imperative to recognize the benign patterns to render accurate diagnoses. We describe here an interesting and hitherto not described low-power architectural pattern of a benign melanocytic lesion: eccrine-centric melanocytic nevus. The patient was a 50-year-old African American woman who noticed a new mole on her foot that began as a dark speck but quickly grew larger. The lesion was excised to exclude the possibility of melanoma. Upon review of the specimen, the lesion was noted to demonstrate a distinctive pattern consistent with a melanocytic nevus of possible congenital onset. Remarkably, the ducts of eccrine glands were increased in density and the nests of melanocytes were found solely in a peri-eccrine distribution without melanocytes in any other locations (ie, interstitial, perifollicular). Additionally, all melanocytes in the nevus were rather heavily pigmented. Although this pattern demonstrated no atypical features that would cause one to consider it malignant to the trained eye, this presentation could implicate a metastatic disease (well-delineated nests in the dermis without concomitant interstitial component) and it is important to recognize.
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http://dx.doi.org/10.1097/DAD.0000000000001045DOI Listing
May 2018

Whole Slide Imaging.

Am J Dermatopathol 2018 Dec;40(12):938-939

Pathology and Laboratory Medicine Service, James A Haley VA Hospital, Tampa, FL.

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http://dx.doi.org/10.1097/DAD.0000000000001008DOI Listing
December 2018

Feasibility study in teledermatopathology: An examination of the histopathologic features of mycosis fungoides and spongiotic dermatitis.

J Cutan Pathol 2017 Nov 5;44(11):919-924. Epub 2017 Sep 5.

Pathology and Laboratory Medicine Service, James A Haley VA Hospital, Tampa, Florida.

Background: Digital pathology offers numerous advantages, allowing remote information sharing using whole slide imaging (WSI) to digitize an entire glass slide (GS) at high resolution, creating a digital slide (DS).

Methods: In this study, we examine the concordance in diagnoses made on 40 digital slides (DSs) vs traditional GSs in differentiating between spongiotic dermatitis (SD) and patch/plaque-stage mycosis fungoides (MF).

Results: Greater interobserver concordance rate in final diagnosis of SD vs MF was observed with the utilization of DS (86.7%) compared with the utilization of GS (80%). Intraobserver concordance rate between the diagnoses rendered by a particular dermatopathologist on GS and DS was 86.7%. For all histopathological criteria, a correlation in the magnitudes of interobserver vs intraobserver discordances suggests that discordance between glass vs digital evaluation of these criteria may be largely expected subjective read variation independent of the media. Discordance in identification of histopathological features did not have a statistically significant link to discordance in diagnosis for 7 out of the 8 features.

Conclusions: The similarity between interobserver and intraobserver discordances suggests that WSI does not introduce additional barriers or variability to accurately identify histopathologic feature and to discriminate between MF and SD beyond interobserver variability.
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http://dx.doi.org/10.1111/cup.13018DOI Listing
November 2017

Comparing whole slide digital images versus traditional glass slides in the detection of common microscopic features seen in dermatitis.

J Pathol Inform 2016 26;7:30. Epub 2016 Jul 26.

Department of Pathology and Cell Biology, University of South Florida, Tampa, USA; Department of Dermatology and Cutaneous Surgery, University of South Florida, Tampa, USA; Department of Pathology and Laboratory Medicine Service, James A Haley VA Hospital, Tampa, USA; Georgia Dermatopathology, Savannah, GA, USA; Department of Dermatology, University of Florida, Gainesville, FL, USA.

Background: The quality and limitations of digital slides are not fully known. We aimed to estimate intrapathologist discrepancy in detecting specific microscopic features on glass slides and digital slides created by scanning at ×20.

Methods: Hematoxylin and eosin and periodic acid-Schiff glass slides were digitized using the Mirax Scan (Carl Zeiss Inc., Germany). Six pathologists assessed 50-71 digital slides. We recorded objective magnification, total time, and detection of the following: Mast cells; eosinophils; plasma cells; pigmented macrophages; melanin in the epidermis; fungal bodies; neutrophils; civatte bodies; parakeratosis; and sebocytes. This process was repeated using the corresponding glass slides after 3 weeks. The diagnosis was not required.

Results: The mean time to assess digital slides was 176.77 s and 137.61 s for glass slides (P < 0.001, 99% confidence interval [CI]). The mean objective magnification used to detect features using digital slides was 18.28 and 14.07 for glass slides (P < 0.001, 99.99% CI). Parakeratosis, civatte bodies, pigmented macrophages, melanin in the epidermis, mast cells, eosinophils, plasma cells, and neutrophils, were identified at lower objectives on glass slides (P = 0.023-0.001, 95% CI). Average intraobserver concordance ranged from κ = 0.30 to κ = 0.78. Features with poor to fair average concordance were: Melanin in the epidermis (κ = 0.15-0.58); plasma cells (κ = 0.15-0.49); and neutrophils (κ = 0.12-0.48). Features with moderate average intrapathologist concordance were: parakeratosis (κ = 0.21-0.61); civatte bodies (κ = 0.21-0.71); pigment-laden macrophages (κ = 0.34-0.66); mast cells (κ = 0.29-0.78); and eosinophils (κ = 0.31-0.79). The average intrapathologist concordance was good for sebocytes (κ = 0.51-1.00) and fungal bodies (κ = 0.47-0.76).

Conclusions: Telepathology using digital slides scanned at ×20 is sufficient for detection of histopathologic features routinely encountered in dermatitis cases, though less efficient than glass slides.
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http://dx.doi.org/10.4103/2153-3539.186909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977977PMC
August 2016

Role of histological findings and pathologic diagnosis for detection of human papillomavirus infection in men.

J Med Virol 2015 Oct 6;87(10):1777-87. Epub 2015 May 6.

Center for Infection Research in Cancer, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Early HPV infection in males is difficult to detect clinically and pathologically. This study assessed histopathology in diagnosing male genital HPV. External genital lesions (n = 352) were biopsied, diagnosed by a dermatopathologist, and HPV genotyped. A subset (n = 167) was diagnosed independently by a second dermatopathologist and also re-evaluated in detail, tabulating the presence of a set of histopathologic characteristics related to HPV infection. Cases that received discrepant diagnoses or HPV-related diagnoses were evaluated by a third dermatopathologist (n = 163). Across dermatopathologists, three-way concordance was fair (k = 0.30). Pairwise concordance for condyloma was fair to good (k = 0.30-0.67) and poor to moderate for penile intraepithelial neoplasia (k = -0.05 to 0.42). Diagnoses were 44-47% sensitive and 65-72% specific for HPV 6/11-containing lesions, and 20-37% sensitive and 98-99% specific for HPV 16/18. Presence of HPV 6/11 was 75-79% sensitive and 35% specific for predicting pathologic diagnosis of condyloma. For diagnosis of penile intraepithelial neoplasia, HPV 16/18 was 95-96% specific but only 40-64% sensitive. Rounded papillomatosis, hypergranulosis, and dilated vessels were significantly (P < 0.05) associated with HPV 6/11. Dysplasia was significantly (P = 0.001) associated with HPV 16/18. Dermatopathologists' diagnoses of early male genital HPV-related lesions appear discordant with low sensitivity, while genotyping may overestimate clinically significant HPV-related disease. Rounded papillomatosis, hypergranulosis, and dilated vessels may help establish diagnosis of early condyloma.
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http://dx.doi.org/10.1002/jmv.24238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780420PMC
October 2015

Glomus-like bodies within a neurofibroma: a novel neoplasm arising in neurofibromatosis type 1 or a coincidence?

J Cutan Pathol 2015 Apr 24;42(4):285-8. Epub 2015 Feb 24.

Department of Dermatology and Cutaneous Surgery, University of South Florida, Tampa, FL, USA.

Neurofibromatosis type 1 is a relatively common genetic disorder with variable phenotypes. Tumors with features of both glomus tumors and neurofibromas are exceedingly rare in literature. Herein, we report a not yet described neoplasm with features of both a glomangioma/glomus tumor and a neurofibroma arising in a patient with segmental neurofibromatosis. Our case report supports the theory of a common lineage/ancestor cell between neurofibromas and glomus tumors and adds it to the spectrum of neoplasms that may arise in the setting of Von Recklinghausen's disease.
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http://dx.doi.org/10.1111/cup.12439DOI Listing
April 2015

Adenoid cystic carcinoma of the base of the tongue metastasizing to the scalp.

Dermatol Online J 2014 Mar 17;20(3). Epub 2014 Mar 17.

The University of South Florida Morsani College of Medicine.

Adenoid cystic carcinoma is a rare neoplasm that originates from secretory glands, most commonly from the salivary glands. We present a 76 year-old white man with a history of adenoid cystic carcinoma from the base of the tongue diagnosed 15 years prior to the development of the metastatic lesion on his mid-posterior scalp. The present case represents the second reported instance of an extracutaneous adenoid cystic carcinoma metastasizing to the scalp. Differentiating between a primary cutaneous adenoid cystic carcinoma and an extracutaneous adenoid cystic carcinoma metastasizing to cutaneous structures is crucial in determining prognosis and management.
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March 2014

Analysis of tumor mitotic rate in thin metastatic melanomas compared with thin melanomas without metastasis using both the hematoxylin and eosin and anti-phosphohistone 3 IHC stain.

Am J Dermatopathol 2014 Jan;36(1):64-7

*Department of Dermatology, University of South Florida, Tampa, FL; †Department of Cutaneous Oncology, Sarcoma Program, Moffitt Cancer Center; ‡University of Central Florida College of Medicine, Tampa, FL; §Emory University College of Medicine; ¶Biostatistics Core, Clinical and Translational Science Institute, University of South Florida College of Medicine, Tampa, FL; ‖University of South Florida College of Medicine, Tampa, FL; **Department of Pathology and Cell Biology, University of South Florida, Tampa, FL; ††Department of Dermatology, James A. Haley VAMC; ‡‡Department of Dermatology, Moffitt Cancer Center; §§Department of Dermatology, University of South Florida, Tampa, FL; and ¶¶Department of Pathology, Cell Biology and Dermatology, University of South Florida Morsani College of Medicine, Tampa, FL.

Studies have suggested that elevated tumor mitotic rate (MR) is linked to overall survival in thin melanoma. Recently, promising data regarding anti-phosphohistone 3 (pHH3) immunohistochemistry and its ability to aid in calculation of MR have emerged. The authors retrospectively analyzed original biopsies from 13 thin melanomas with positive sentinel node (SN) status and 16 thin melanomas with negative SN status. Both anti-pHH3 immunohistochemistry and the hematoxylin and eosin (H&E) stain were used to evaluate MR by 2 dermatopathologists blinded to SN status using the "hot spot" method. Intraclass coefficient values were attained to measure interobserver concordance and reliability of the pHH3 stain. By generating a receiver operating characteristic curve and analyzing the overall area under the curve, pHH3 was found to have good interobserver reliability. The relationship between MR and SN involvement was also evaluated, but this correlation was not statistically significant.
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http://dx.doi.org/10.1097/DAD.0b013e31829433b6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764097PMC
January 2014

Hyperspectral imaging of melanocytic lesions.

Am J Dermatopathol 2014 Feb;36(2):131-6

*Department of Pathology and Cell Biology, University of South Florida Morsani College of Medicine, Tampa, FL; †Department of Pediatrics, Children's National Medical Center, Washington, DC; ‡Science Applications International Corporation, Surveillance and Reconnaissance Business Unit, Arlington, VA; and §Dermatopathology Service, James A. Haley Veterans' Hospital, Tampa, FL.

Hyperspectral imaging (HSI) allows the identification of objects through the analysis of their unique spectral signatures. Although first developed many years ago for use in terrestrial remote sensing, this technology has more recently been studied for application in the medical field. With preliminary data favoring a role for HSI in distinguishing normal and lesional skin tissues, we sought to investigate the potential use of HSI as a diagnostic aid in the classification of atypical Spitzoid neoplasms, a group of lesions that often leave dermatopathologists bewildered. One hundred and two hematoxylin and eosin-stained tissue samples were divided into 1 of 4 diagnostic categories (Spitz nevus, Spitz nevus with unusual features, atypical Spitzoid neoplasm, and Spitzoid malignant melanoma) and 1 of 2 control groups (benign melanocytic nevus and malignant melanoma). A region of interest was selected from the dermal component of each sample, thereby maximizing the examination of melanocytes. Tissue samples were examined at ×400 magnification using a spectroscopy system interfaced with a light microscope. The absorbance patterns of wavelengths from 385 to 880 nm were measured and then analyzed within and among groups. All tissue groups demonstrated 3 common absorbance spectra at 496, 533, and 838 nm. Each sample group contained at least one absorption point that was unique to that group. The Spitzoid malignant melanoma category had the highest number of total and unique absorption points for any sample group. The data were then clustered into 12 representative spectral classes. Although each of the sample groups contained all 12 spectral vectors, they did so in differing proportions. These preliminary results reveal differences in the spectral signatures of the Spitzoid lesions examined in this study. Further investigation into a role for HSI in classifying atypical Spitzoid neoplasms is encouraged.
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http://dx.doi.org/10.1097/DAD.0b013e31829bad10DOI Listing
February 2014

OpenSlide: A vendor-neutral software foundation for digital pathology.

J Pathol Inform 2013 27;4:27. Epub 2013 Sep 27.

School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States ; Google, Pittsburgh, PA, USA.

Although widely touted as a replacement for glass slides and microscopes in pathology, digital slides present major challenges in data storage, transmission, processing and interoperability. Since no universal data format is in widespread use for these images today, each vendor defines its own proprietary data formats, analysis tools, viewers and software libraries. This creates issues not only for pathologists, but also for interoperability. In this paper, we present the design and implementation of OpenSlide, a vendor-neutral C library for reading and manipulating digital slides of diverse vendor formats. The library is extensible and easily interfaced to various programming languages. An application written to the OpenSlide interface can transparently handle multiple vendor formats. OpenSlide is in use today by many academic and industrial organizations world-wide, including many research sites in the United States that are funded by the National Institutes of Health.
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http://dx.doi.org/10.4103/2153-3539.119005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815078PMC
November 2013

Cutaneous human papillomavirus types detected on the surface of male external genital lesions: a case series within the HPV Infection in Men Study.

J Clin Virol 2013 Dec 16;58(4):652-9. Epub 2013 Oct 16.

Center for Infection Research in Cancer, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Background: Cutaneous human papillomaviruses (HPVs) may be associated with cutaneous epithelial lesions and non-melanoma skin cancers. No study has systematically evaluated the presence of genus beta [β]-HPV in male genital skin or external genital lesions (EGLs)

Objectives: To examine cutaneous β-HPV types detected on the surface of EGLs in men and describe their presence prior to EGL development.

Study Design: A retrospective case series was conducted among 69 men with pathologically confirmed EGLs (n=72) who participated in the HPV Infection in Men Study. Archived exfoliated cells collected from the surface of each EGL and normal genital skin specimens 6-12 months preceding EGL development were tested for β-HPV DNA using a type-specific multiplex genotyping assay.

Results: β-HPV DNA was detected on 61.1% of all EGLs, with types 38 (16.7%), 5 (15.3%), and 12 (12.5%) most commonly identified. HPV prevalence differed across pathological diagnoses, with the largest number of β-HPV types detected on condylomas. Most β-HPV types were detected on normal genital skin prior to EGL development, though the prevalence was lower on EGLs compared to preceding normal genital skin.

Conclusions: EGLs and the normal genital skin of men harbor a large number of β-HPV types; however, it appears that β-HPVs are unrelated to EGL development in men. Despite evidence to support a causal role in skin carcinogenesis at UVR-exposed sites, cutaneous HPV appears unlikely to cause disease at the UVR-unexposed genitals.
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http://dx.doi.org/10.1016/j.jcv.2013.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866698PMC
December 2013

Pediatric melanoma: analysis of an international registry.

Cancer 2013 Nov 10;119(22):4012-9. Epub 2013 Sep 10.

Department of Surgery, Division of Surgical Oncology, MetroHealth Medical Center, Cleveland, Ohio; Department of Surgery, Case Western Reserve University, Cleveland, Ohio.

Background: The management of pediatric melanoma (PM) has largely been extrapolated from adult data. However, the behavior of PM appears to differ from its adult counterparts. Therefore, an international PM registry was created and analyzed.

Methods: Twelve institutions contributed deidentified clinicopathologic and outcome data for patients diagnosed with PM from 1953 through 2008.

Results: Overall survival (OS) data were reported for 365 patients with invasive PM who had adequate follow-up data. The mean age of the patients was 16 years (range 1 year-21 years). The 10-year OS rate, 80.6%, tended to vary by patient age: 100% for those aged birth to 10 years, 69.7% for those aged > 10 years to 15 years, and 79.5% for those aged > 15 years to 20 years (P = .147). Patients with melanomas measuring ≤ 1 mm had a favorable prognosis (10-year OS rate of 97%), whereas survival was lower but similar for patients with melanomas measuring > 1 mm to 2 mm, > 2 mm to 4 mm, and > 4 mm (70%, 78%, and 80%, respectively; P = .0077). Ulceration and lymph node metastasis were found to be correlated with worse survival (P = .022 and P = .017, respectively). The 10-year OS rate was 94.1% for patients with American Joint Committee on Cancer stage I disease, 79.6% for those with stage II disease, and 77.1% for patients with stage III disease (P < .001).

Conclusions: Tumor thickness, ulceration, lymph node status, and stage were found to be significant predictors of survival in patients with PM, similar to adult melanoma. There is a trend toward increased survival in children aged ≤ 10 years versus adolescents aged > 10 years. Further analyses are needed to probe for potential biological and behavioral differences in pediatric versus adult melanoma.
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http://dx.doi.org/10.1002/cncr.28289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096292PMC
November 2013

Composite hemangioendothelioma and its classification as a low-grade malignancy.

Am J Dermatopathol 2013 Jun;35(4):517-22

Department of Pathology and Cell Biology, University of South Florida College of Medicine, Tampa, FL 33612, USA.

Hemangioendotheliomas are vascular neoplasms occupying a spectrum of biological potential ranging from benign to low-grade malignancy. Composite hemangioendothelioma (CH) is one of the less commonly encountered variants exhibiting a mixture of elements of other hemangioendothelioma subtypes, such as epithelioid, retiform, and spindle cell. Some authors have identified areas histopathologically equivalent to angiosarcoma within CH, raising the question of the true nature of this neoplasm. Although CH recurs locally, there are only 3 reported cases which metastasized. To date, 26 cases (including the present case) have been described in the literature. Herein, we describe a unique case of CH arising in the background of previous radiation therapy and long-standing lymphedema (classically associated with the development of angiosarcoma-Stewart-Treves syndrome) that harbored higher grade areas but behaved as a low-grade malignant neoplasm. This, in conjunction with the many reported cases of CH-harboring angiosarcoma-like areas, and the occasional association with a history of lymphedema, raises the question of whether this variant of hemangioendothelioma may actually be an angiosarcoma that behaves prognostically better than the conventional type. After careful study of the natural disease progression of the current case and review of the literature, we discuss justification for the continued classification of CH as a low-grade malignancy.
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http://dx.doi.org/10.1097/DAD.0b013e31827a0d37DOI Listing
June 2013

Discrepancies in dermatopathology diagnoses: the role of second review policies and dermatopathology fellowship training.

J Am Acad Dermatol 2013 Jan 11;68(1):119-28. Epub 2012 Aug 11.

Department of Pathology and Cell Biology, University of South Florida, Tampa, Florida 33612, USA.

Background: Expert consultation and institutional policies mandating second review of pathologic diagnoses in the course of referral have been advocated to optimize patient care.

Objective: We sought to investigate the rate of diagnostic discrepancies between pathologists with and without dermatopathology fellowship training.

Methods: All available outside pathology reports were reviewed for material sent to the University of Pittsburgh Medical Center Dermatopathology Unit during 1 year. The outside diagnosis was compared with the diagnosis rendered by the referral dermatopathology service. Cases were assigned into 1 of 4 categories: melanocytic neoplasm, nonmelanocytic neoplasm, inflammatory, and other. For each case, the outside pathologist's level of dermatopathology training was noted. Any change in diagnosis resulting in significant alteration in therapy or prognosis, as dictated by the accepted standard of care, was considered a major discrepancy.

Results: A total of 405 cases were reviewed. In 51 cases (13%), no preliminary diagnosis was rendered at the outside facility. The referral diagnosis differed from the outside diagnosis in 226 cases (56%), and major discrepancies were identified in 91 cases (22%). Of these 91 cases, 84 were received from outside pathologists who were not dermatopathology trained and 7 were received from pathologists with dermatopathology training. The 91 cases with major discrepancies were categorized as: 36 nonmelanocytic neoplasms (40%), 30 inflammatory (33%), 23 melanocytic neoplasms (25%), and 2 other (2%).

Limitations: This was a retrospective study limited to 2 consultant dermatopathologists at an academic referral center, which typically receives and reviews select cases.

Conclusion: Dermatopathology fellowship training is associated with a substantial decrease in major diagnostic discrepancies. Pathologists without dermatopathology fellowship training tend to successfully identify those cases for which expert consultation is most useful.
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http://dx.doi.org/10.1016/j.jaad.2012.06.034DOI Listing
January 2013

Automated detection of heuristics and biases among pathologists in a computer-based system.

Adv Health Sci Educ Theory Pract 2013 Aug 23;18(3):343-63. Epub 2012 May 23.

Department of Biomedical Informatics, University of Pittsburgh School of Medicine, UPMC Shadyside Cancer Pavilion-Room 313, 5150 Centre Avenue, Pittsburgh, PA 15232, USA.

The purpose of this study is threefold: (1) to develop an automated, computer-based method to detect heuristics and biases as pathologists examine virtual slide cases, (2) to measure the frequency and distribution of heuristics and errors across three levels of training, and (3) to examine relationships of heuristics to biases, and biases to diagnostic errors. The authors conducted the study using a computer-based system to view and diagnose virtual slide cases. The software recorded participant responses throughout the diagnostic process, and automatically classified participant actions based on definitions of eight common heuristics and/or biases. The authors measured frequency of heuristic use and bias across three levels of training. Biases studied were detected at varying frequencies, with availability and search satisficing observed most frequently. There were few significant differences by level of training. For representativeness and anchoring, the heuristic was used appropriately as often or more often than it was used in biased judgment. Approximately half of the diagnostic errors were associated with one or more biases. We conclude that heuristic use and biases were observed among physicians at all levels of training using the virtual slide system, although their frequencies varied. The system can be employed to detect heuristic use and to test methods for decreasing diagnostic errors resulting from cognitive biases.
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http://dx.doi.org/10.1007/s10459-012-9374-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728442PMC
August 2013

High-definition hematoxylin and eosin staining in a transition to digital pathology.

J Pathol Inform 2011 19;2:45. Epub 2011 Oct 19.

Department of Dermatology, University of Pittsburgh, Pennsylvania, United States, Tampa, Florida.

Introduction: A lot of attention has been generated in recent years by digital pathology and telepathology. Multiple reasons for and barriers to effective adoption are discussed in the current literature. Digital slides are the most promising medium at this time. The goal of our study was to evaluate whether the change in the methodology, particularly utilizing the so-called high-definition hematoxylin and eosin (H and E) slides, enhanced the quality of the final digital slide, and whether pathologists who tested the results perceived this as a difference in quality.

Methods: THE STUDY WAS A BLINDED COMPARISON OF DIGITAL SLIDES PREPARED USING TWO METHODS: standard H&E batch staining and automated individual "high definition" HD HE staining. Four pathologists have compared 80 cases stained with each method.

Results: The results discussed in this study show potential promise that the utilization of protocol(s) adapted for tissue and for imaging might be preferable for digital pathology in at least some of the pathology subspecialties. In particular, the protocol evaluated here was capable of turning out digital slides that had more contrast and detail, and therefore were perceived to provide enhanced diagnostically significant information for the pathologist.
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http://dx.doi.org/10.4103/2153-3539.86284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205517PMC
November 2011

Primary cutaneous CD30+ T-cell lymphoproliferative disorder presenting as paraphimosis: a case report and review of the literature.

Dermatol Online J 2011 Jul 15;17(7). Epub 2011 Jul 15.

Department of Pathology and Cell Biology, University of South Florida, Tampa, Florida, USA.

Primary cutaneous CD30+ T-cell lymphoproliferative disorders (PC-CD30+ LPD) as a group are one of the more common types of T-cell lymphoma. More specifically primary cutaneous anaplastic lymphoma (PC-ALCL), one of these lymphoproliferative disorders, is the second most common cutaneous T-cell lymphoma. We report an unusual presentation of PC-ALCL. A 90-year-old, uncircumcised male presented with a 3-week history of painful penile swelling and discharge. The patient was treated with cephalexin and underwent emergent circumcision for paraphimosis. The diagnosis of ALCL was made on microscopic evaluation of the foreskin along with follow-up staging studies. A literature review revealed 31 previously reported cases of penile lymphoma, one of which reported a primary penile CD30+ T-cell lymphoma similar to ours. Only one case report described a lymphoma presenting as paraphimosis. Our case is the second reported case of PC-ALCL of the penis and the first of its kind to present as paraphimosis. Lymphomas must be included in the differential diagnosis of penile lesions and paraphimosis. When present, clinicians should be able to differentiate primary cutaneous lymphoma from lymphomas with secondary skin involvement. All foreskins should be submitted to pathology for proper evaluation of penile lesions.
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July 2011

An immunohistochemical panel to differentiate metastatic breast carcinoma to skin from primary sweat gland carcinomas with a review of the literature.

Arch Pathol Lab Med 2011 Aug;135(8):975-83

Department of Pathology, University of Pittsburgh Medical Center, Pennsylvania 15261, USA.

Context: Approximately 25% of patients with breast cancer develop cutaneous metastases. Sweat gland carcinomas (SGCs) account for about 0.05% of all cutaneous neoplasms. Cutaneous metastases of breast carcinoma (CMBCs) (especially the ductal type) can be difficult to distinguish from SGCs. Treatment and prognoses for these 2 types of tumors differ radically, making accurate histologic diagnosis crucial. Although a few studies attempt to differentiate these entities employing immunohistochemical (IHC) studies (some of which we review here), to date, no panel of IHC stains exists, to our knowledge, to distinguish these entities.

Objective: To devise a panel of IHC stains to distinguish CMBC from SGC.

Design: Twelve cases of ductal CMBCs (11 not otherwise specified type, and 1 basal phenotype), 11 cases of SGCs (5 eccrine carcinomas, 3 porocarcinomas, and 3 microcystic adnexal carcinomas), 2 benign sweat gland neoplasm cases, and 2 primary breast cancer cases were retrieved and analyzed with the following IHC panel: mammaglobin, gross cystic disease fluid protein (GCDFP) 15, p63, basal cytokeratins (CK5, CK14, and CK17), androgen receptor, and PAX5.

Results: The p63 was only weakly expressed in 1 of 12 CMBC cases (8.3%), whereas it was strongly expressed in 10 of 11 SGC cases (90.9%) (P < .001). Basal cytokeratins demonstrated a similar immunoprofile in the SGC group, with 10 of 11 cases (90.9%) expressing all 3 markers, and a variable immunoprofile in the CMBC group with 0% (CK14) (P < .001) to 16.7% (2 of 12 cases; CK5 and CK17) (P < .001) expression. Mammaglobin was expressed in 8 of 12 cases (66.7%) of CMBC.

Conclusions: Together, these 5 IHC stains were combined to make a panel that was 100% sensitive and 91% specific in distinguishing between CMBC and SGC.
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http://dx.doi.org/10.5858/2009-0445-OAR2DOI Listing
August 2011

Clinical examination and validation of primary diagnosis in anatomic pathology using whole slide digital images.

Arch Pathol Lab Med 2011 Mar;135(3):372-8

Department of Dermatology, University of Pittsburgh School of Medicine, Pennsylvania, 15213, USA.

Context: Novel anatomic pathology technologies allow pathologists to digitally view and diagnose cases. Although digital pathology advocates champion its strengths and move to integrate it into practice and workflow, the capabilities and limitations of digital slides have not been fully investigated.

Objectives: To estimate intrapathologist diagnostic discrepancy between glass and digital slides and to determine pathologists' diagnostic certainty when diagnosing with the 2 formats.

Design: Intrapathologist diagnostic consistency between glass and digital slides was measured. Three pathologists diagnosed 101 cases digitally and with corresponding glass slides. Discrepancies between formats were evaluated, and diagnostic precision and certainty were compared.

Results: A total of 606 diagnoses were evaluated in pairs (202 per pathologist). Seven cases did not transfer to the database and were eliminated from further study. We report no discrepancies between media in 75%, 87%, and 83% of the cases diagnosed by the 3 pathologists, respectively; significant discrepancies were identified in 3%, 3%, and 7% of cases by each pathologist. In total, we identified significant clinical and therapeutic discrepancies in 13 of 296 cases (4.4%). The certainty values provided by each pathologist were similar between formats.

Conclusions: This study did not detect significant differences between diagnoses based on digital and glass slides. We believe that this study further supports the integration of digital slides into pathology workflow, particularly considering the low rate of discrepancy documented here.
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http://dx.doi.org/10.5858/2009-0678-OA.1DOI Listing
March 2011

Cutaneous anaplastic large-cell lymphoma should be evaluated for systemic involvement regardless of ALK-1 status: case reports and review of literature.

Am J Clin Dermatol 2011 Jun;12(3):203-9

Department of Dermatology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Anaplastic large-cell lymphoma (ALCL) is a lymphoma that expresses CD30. Cutaneous ALCL presents either as primary cutaneous disease or as secondary skin involvement due to the systemic disease. Herein, we describe two patients who presented to dermatology for evaluation of skin lesions diagnosed by non-dermatologists as a cutaneous abscess and lupus erythematosus, respectively. Upon investigation by a team of medical dermatologists and dermatopathologists, systemic ALCL with secondary skin involvement was discovered in both patients. The majority of cases of systemic ALCL with cutaneous involvement express anaplastic lymphoma kinase-1 (ALK-1), and are associated with a more favorable prognosis than ALK-1-negative cases. However, cutaneous ALCL regardless of ALK-1 status may be secondary to systemic lymphoma. This article stresses the importance of dermatologists being aware of the diagnosis of systemic lymphoma based on cutaneous findings, and being aggressive in initiating appropriate diagnostic testing. Primary cutaneous ALCL and systemic ALCL are reviewed.
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http://dx.doi.org/10.2165/11537520-000000000-00000DOI Listing
June 2011

Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.

J Clin Invest 2011 Mar;121(3):976-84

Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.

Defects in cholesterol synthesis result in a wide variety of symptoms, from neonatal lethality to the relatively mild dysmorphic features and developmental delay found in individuals with Smith-Lemli-Opitz syndrome. We report here the identification of mutations in sterol-C4-methyl oxidase–like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay. This gene encodes a sterol-C4-methyl oxidase (SMO), which catalyzes demethylation of C4-methylsterols in the cholesterol synthesis pathway. C4-Methylsterols are meiosis-activating sterols (MASs). They exist at high concentrations in the testis and ovary and play roles in meiosis activation. In this study, we found that an accumulation of MASs in the patient led to cell overproliferation in both skin and blood. SMO deficiency also substantially altered immunocyte phenotype and in vitro function. MASs serve as ligands for liver X receptors α and β(LXRα and LXRβ), which are important in regulating not only lipid transport in the epidermis, but also innate and adaptive immunity. Deficiency of SMO represents a biochemical defect in the cholesterol synthesis pathway, the clinical spectrum of which remains to be defined.
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http://dx.doi.org/10.1172/JCI42650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049385PMC
March 2011

NGFR (p75) expression in cutaneous scars; Further evidence for a potential pitfall in evaluation of reexcision scars of cutaneous neoplasms, in particular desmoplastic melanoma.

Am J Dermatopathol 2011 Feb;33(1):65-71

Lake Erie College of Osteopathic Medicine and School of Pharmacy, Erie, PA, USA.

Desmoplastic melanoma is a rare variant of malignant melanoma composed of spindle cells in a collagenous matrix. The antibody against NGFR (low affinity nerve growth factor receptor, also known as p75) stains cells of desmoplastic melanoma with high sensitivity; however, the specificity of this marker is not well established. Although there are established histologic criteria for recognition of desmoplastic melanoma, the evaluation of residual disease in cutaneous reexcision scars can be challenging. If residual spindle cells in scar are sufficiently atypical and NGFR positive, their presence could be interpreted as residual desmoplastic melanoma. In this study, we reevaluated the use of antibody against NGFR to detect residual disease in reexcision specimens of melanocytic neoplasms as the previously published works are contradictory. Our data indicate that anti-NGFR antibody stains many cells in the scar, some of which seem to be myofibroblasts, nerve twigs, and Schwann cells. Our findings further suggest that NGFR is not a suitable marker to evaluate reexcision scars for desmoplastic melanoma, especially as a sole marker, as its specificity is low.
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http://dx.doi.org/10.1097/DAD.0b013e3181dfcb9fDOI Listing
February 2011

Cytologic evaluation of image-guided fine needle aspiration biopsies via robotic microscopy: A validation study.

J Pathol Inform 2010 May 26;1. Epub 2010 May 26.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA Yale University School of Medicine, New Haven, CT,USA.

Background: This study carried out was to assess the feasibility of using robotic microscopy (RM) for cytologic evaluation of direct smears from fine needle aspiration biopsy (FNAB).

Methods: Three board-certified cytopathologists reviewed representative direct smears from 40 image-guided FNABs using RM and subsequently re-reviewed the same smears using conventional microscopy. Adequacy of the smears and cytologic diagnosis, as determined using the two approaches, were compared for each individual cytopathologist (intraobserver) and between the three cytopathologists (interobserver). The intraobserver and interobserver discrepancies were analyzed and discussed in a follow-up consensus conference.

Results: FOR ASSESSMENT OF ADEQUACY, THERE WERE HIGH CONCORDANCE RATES (INTRAOBSERVER: 92.5-97.5%; interobserver: 90-92.5%), with a few discrepancies involving distinctions between suboptimal and satisfactory smears. Analysis of diagnostic interpretations showed correct classification of 92.5-95% (intraobserver) or 90-92.5% (interobserver) of benign and malignant cases combined, with the discrepancies being between benign and atypical cells in the benign group, and between suspicious and malignant in the malignant group. Within the malignant group, 94% of cases were accurately subclassified via RM. The quality of images viewed by using RM was rated adequate (fair or good) for 95% of the slides.

Conclusions: The results demonstrate that cytologic evaluation of direct smears from FNABs using RM is feasible. Problems encountered included the longer times needed to evaluate cases with thick, bloody smears and/or low numbers of diagnostic cells, and difficulties in recognizing neuroendocrine differentiation and mimics of hepatocellular carcinoma.
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http://dx.doi.org/10.4103/2153-3539.63826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929544PMC
May 2010

A principal case of multiple lymphoid collision tumors involving both B-cell chronic lymphocytic leukemia and metastatic malignant melanoma.

Dermatol Online J 2010 Jul 15;16(7). Epub 2010 Jul 15.

Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

B-cell chronic lymphocytic leukemia/small lymphocytic B-cell lymphoma (CLL/B-SLL) is a neoplasm of B-cell lymphocytes that occurs frequently in the older population as an asymptomatic elevation of the white blood cell count (WBC) and has a good overall prognosis. Malignant melanoma of the skin is a neoplasm derived from cutaneous melanocytes that frequently arises among the elderly and, depending on certain histopathologic features, may metastasize loco-regionally or distally. However, only one report describes synchronous presentation of these two malignancies within the same lymph node. In this report, we present the unique case of an 87-year-old male with a presumed history of indolent CLL/B-SLL, in which metastatic malignant melanoma and CLL/B-SLL both involved 112 of 145 dissected regional lymph nodes. Possible explanations regarding the mechanisms that can lead to this rare presentation of both CLL/B-SLL and melanoma in the same lymph nodes are discussed.
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July 2010

Expression analysis of Ubc9, the single small ubiquitin-like modifier (SUMO) E2 conjugating enzyme, in normal and malignant tissues.

Hum Pathol 2010 Sep 18;41(9):1286-98. Epub 2010 Jun 18.

Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.

Unlike ubiquitination, which targets proteins for degradation, sumoylation modulates protein-protein interactions of target proteins. Although there are multiple E2 enzymes required for ubiquitination, there is only one E2-conjugating enzyme for sumoylation, which is Ubc9. In line with increasing evidence that sumoylation plays an important role in tumorigenesis, we recently demonstrated that Ubc9 is expressed at high levels in advanced melanomas and that blocking expression of Ubc9 sensitizes melanomas to the cytotoxic effects of chemotherapeutic drugs. To determine whether and to what extent Ubc9 is expressed in other malignancies and their normal tissue counterparts, we undertook a detailed analysis of colon, lung, prostate, and breast cancer tissue microarrays. The findings, presented here, document that in primary colon and prostate cancer, Ubc9 expression is increased compared with their normal tissue counterparts, whereas in metastatic breast, prostate, and lung cancer, it is decreased in comparison with their corresponding normal and primary adenocarcinoma tissues. We also provide evidence that Ubc9 expression correlates positively with Dukes' stage and negatively with the Gleason score as well as breast cancer grade and that Ubc9 expression is substantially higher in the luminal than in the nonluminal type of breast cancer.
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http://dx.doi.org/10.1016/j.humpath.2010.02.007DOI Listing
September 2010

Posttransplant cutaneous T-cell lymphoma: case reports and review of the association of calcineurin inhibitor use with posttransplant lymphoproliferative disease risk.

Arch Dermatol 2010 May;146(5):513-6

Department of Dermatology, University of Pittsburgh School of Medicine, Presby South Tower, Ste 3880, 200 Lothrop St, Pittsburgh, PA 15213, USA.

Background: Cutaneous T-cell lymphoma occurring in the context of posttransplant immunosuppression is rare, with 27 cases documented to date.

Observations: We report 2 new cases of posttransplant cutaneous T-cell lymphoma in patients treated at our institution. Both were male recipients of renal transplants who had undergone transplantation a mean of 5.3 years previously and were taking various multidrug immunosuppressive regimens, including cyclosporine, tacrolimus, mycophenolate mofetil, and prednisone.

Conclusions: These cases underscore the association of posttransplant cutaneous T-cell lymphoma with renal transplantation, cyclosporine and tacrolimus therapy, male sex, and later onset compared with B-cell posttransplant lymphoproliferative disease. Relative to the general population, the incidence of cutaneous T-cell lymphoma seems increased among transplant recipients receiving immunosuppressive medications.
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http://dx.doi.org/10.1001/archdermatol.2010.60DOI Listing
May 2010

Pharmacodynamic (phase 0) study using etaracizumab in advanced melanoma.

J Immunother 2010 Apr;33(3):316-25

University of Pittsburgh Cancer Institute, PA, USA.

AlphaVbeta3 (alphavbeta3) is an important molecule for tumor-induced angiogenesis and is upregulated in metastatic melanoma (MM). We proposed to study the mechanism of action of etaracizumab, a monoclonal antibody targeting alphavbeta3, in MM. Patients with MM and biopsiable tumor were treated with etaracizumab in 3 dose cohorts starting from 8 mg/kg. Tumor saturation by etaracizumab using LM609 immunohistochemical staining of tumor sections was the primary endpoint. Subsequent dose cohorts were defined based on the tumor saturation by etaracizumab. Secondary end points were analysis of clinical benefit and changes from baseline of several tumor and peripheral blood biomarkers. Eighteen patients were enrolled at 3 dose levels. Etaracizumab showed better melanoma cell saturation at the 8mg/kg and 1 mg/kg dose compared with the 4 mg/kg dose and better vascular endothelial cell saturation at 8 mg/kg compared with lower dose groups. Etaracizumab demonstrated an acceptable safety profile. The optimal biologic dose out of those selected for investigation was 8 mg/kg. Patients treated at the highest dose may have had better clinical benefit secondary to suppression of the activated immediate downstream effector of alphavbeta3 signaling, FAK, in melanoma cells, but this alone did not ultimately affect melanoma cell proliferation or apoptosis. No apparent antiangiogenic or immunomodulatory effects of etaracizumab were noted.
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http://dx.doi.org/10.1097/CJI.0b013e3181c1f216DOI Listing
April 2010
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