Publications by authors named "April Deng"

82 Publications

Topical 5% 5-fluorouracil versus procedural modalities for squamous cell carcinoma in situ and superficial basal cell carcinoma: A retrospective cohort analysis.

J Am Acad Dermatol 2021 Aug 31. Epub 2021 Aug 31.

Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2021.08.045DOI Listing
August 2021

Gene Expression Profiling in the Skin Reveals Strong Similarities between Subacute and Chronic Cutaneous Lupus that Are Distinct from Lupus Nephritis.

J Invest Dermatol 2021 Jun 18. Epub 2021 Jun 18.

Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. Electronic address:

Subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus are represented in the majority of cutaneous lupus subtypes, each of which has variable implications for systemic manifestations such as lupus nephritis. On dermatologic examination, subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus are distinct. However, it is often difficult to diagnose the subtype from histology alone. Our study utilized whole-genome microarray expression analysis on human skin samples of subacute cutaneous lupus erythematosus, on human skin samples of chronic cutaneous lupus erythematosus, and on healthy controls, along with analysis on human samples of lupus nephritis and normal kidney tissue to compare cutaneous lupus subtypes with each other as well as with lupus nephritis. The data revealed that cutaneous lupus subtypes were distinct from healthy control skin, with gene expression predominantly characterized by upregulation of IFN-1 and T-cell chemotactic genes. However, the cutaneous lupus subtypes were very similar to one another; comparative analyses revealed few statistically significant differences in gene expression. There were also distinct differences between the gene signatures of cutaneous lupus and lupus nephritis. Cutaneous lupus samples revealed gene signatures demonstrating a prominent inflammatory component that may suggest the skin as an early site of initiation of lupus pathogenesis, whereas lupus nephritis reflected the recruitment and activation of M2 macrophages and a wound healing signature.
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http://dx.doi.org/10.1016/j.jid.2021.04.030DOI Listing
June 2021

Sweet syndrome with perifollicular involvement because of koebnerization from facial hair plucking.

J Cutan Pathol 2021 Sep 2;48(9):1189-1192. Epub 2021 Jul 2.

Department of Dermatology, UMass Memorial Health Care, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is an uncommon skin eruption characterized by fever, leukocytosis, and tender erythematous papules, nodules, and plaques. Histopathologically, SS lesions are characterized by marked superficial papillary edema with a dense neutrophilic infiltrate. SS is known to demonstrate both the Koebner phenomenon and pathergy. The majority of reported cases of these phenomena occur following significant cutaneous injury (e.g., biopsies, burns) rather than minor trauma such as pressure and friction. Here, we present the first known reported case of SS koebnerization secondary to minor grooming-related hair plucking. In addition, this is also the first reported case to our knowledge of SS with perifollicular involvement on histopathology.
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http://dx.doi.org/10.1111/cup.14061DOI Listing
September 2021

BMP Signaling Promotes Neural Crest Identity and Accelerates Melanoma Onset.

J Invest Dermatol 2021 Aug 19;141(8):2067-2070.e1. Epub 2021 Feb 19.

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2021.01.021DOI Listing
August 2021

Employing immunohistochemical staining to labial minor salivary gland biopsies from patients with Sjogren's syndrome increases diagnostic certainty.

J Oral Pathol Med 2021 Jan 27;50(1):98-102. Epub 2020 Nov 27.

Department of Pathology, University of Massachusetts Medical School, UMass Memorial Medical Center, Worcester, MA, USA.

Background: Sjogren's syndrome (SjS) is an autoimmune disease characterized clinically by dry eyes and dry mouth, and histopathologically by lymphocytic infiltrates in the salivary glands. Labial minor salivary gland biopsy (MSGB) is a major diagnostic test for SjS, deemed positive by a focus score of ≥1, meaning that ≥50 lymphocytes were found in 4 mm tissue on hematoxylin and eosin (H&E)-stained slides. The diagnosis can be challenging, and the above diagnostic criteria has low and variable sensitivity.

Methods: We performed a retrospective study on MSGBs done for possible SjS. We compared the percent of MSGBs which met the histologic criteria by H&E stain alone and that with the addition of CD45, CD3, and CD20 immunohistochemical (IHC) staining for these patients. A total of 45 cases with complete data were analyzed.

Results: Thirty-five of the 45 patients had the diagnosis of Sjogren's syndrome (SjS+) based on ACR criteria. However, based on H&E staining alone, only 22/35 cases (63%) met the histologic criteria. After adding IHC staining with CD45, CD3, and CD20 to MSGBs of SjS + patients, 29/35 (83%) cases met the histological criteria for SjS. All MSGBs from patients without SjS had no significant lymphocyte infiltrate on either H&E or IHC stains.

Conclusions: Immunohistochemical better identifies lymphocytic infiltrates in MSGB and increases diagnostic certainty. Due to high cost, their use should be restricted to cases where there is high clinical suspicion of SjS and negative H&E evaluation alone, or if the diagnosis is uncertain.
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http://dx.doi.org/10.1111/jop.13119DOI Listing
January 2021

Defining the Histologic Support Structures of the Nasal Ala and Soft Triangle: Toward Understanding the Cause of Iatrogenic Alar Retraction.

Plast Reconstr Surg 2020 09;146(3):283e-291e

From the Division of Plastic Surgery, Division of Hand and Upper Extremity Surgery, Beth Israel Deaconess Medical Center; the University of Wisconsin School of Medicine and Public Health; the Department of Plastic Surgery, University of Virginia Health System; and the Department of Pathology and the Division of Plastic Surgery, University of Massachusetts Medical Center.

Background: As rhinoplasty techniques have evolved to more extensive dissections, the incidence of iatrogenic deformities, such as alar rim retraction, has risen. Its mechanism is presently unknown. This study examined the microscopic anatomy of the nasal ala to define architectural support elements at the histologic level to determine why rhinoplasty dissection creates such deformities.

Methods: Eight cadaveric noses were harvested and sectioned through the soft triangle and ala. Various tissue stains were performed. Slides were examined using light microscopy. Anatomical features pertaining to cartilage, skin, mucosa, elastic fibers, and muscle were documented.

Results: Four male and four female noses were sectioned. The median cadaver age was 64 years (range, 47 to 83 years). On Elastica van Gieson stain, distinct elastic fibers span from the vestibular lining to the caudal margin of the lower lateral cartilage, and from the caudal edge of the lower lateral cartilage to the external alar skin. In the nasal ala midsection, trichrome stains reveal that skeletal muscle is located far beyond the lower lateral cartilage, close to the free alar margin. The soft triangle shows a distinct microanatomical structure, with heavy longitudinal condensations of elastin. These histologic findings have not been previously reported.

Conclusions: A distinct anatomical alar wall endoskeleton has been identified. It is obligatorily disrupted by specific rhinoplasty maneuvers when dissection is carried out over the lateral crura and into areas without cartilaginous support. This microanatomy may explain factors that contribute to postoperative alar wall retraction. Leaving this area undisturbed or performing adjunctive measures with rhinoplasty can provide structural support to the external valves, thus minimizing the risk of deformity.
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http://dx.doi.org/10.1097/PRS.0000000000007050DOI Listing
September 2020

Sarcoid-like reaction in a patient recovering from coronavirus disease 19 pneumonia.

JAAD Case Rep 2020 Sep 24;6(9):915-917. Epub 2020 Jul 24.

Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts.

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http://dx.doi.org/10.1016/j.jdcr.2020.07.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378473PMC
September 2020

Jak Inhibition Prevents Bleomycin-Induced Fibrosis in Mice and Is Effective in Patients with Morphea.

J Invest Dermatol 2020 07 16;140(7):1446-1449.e4. Epub 2020 Jan 16.

Department of Dermatology, Yale University, New Haven, Connecticut, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2019.12.019DOI Listing
July 2020

YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression.

Cell Rep 2019 12;29(10):3200-3211.e4

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address:

Uveal melanoma (UM), the most common ocular malignancy, is characterized by GNAQ/11 mutations. Hippo/YAP and Ras/mitogen-activated protein kinase (MAPK) emerge as two important signaling pathways downstream of G protein alpha subunits of the Q class (GαQ/11)-mediated transformation, although whether and how they contribute to UM genesis in vivo remain unclear. Here, we adapt an adeno-associated virus (AAV)-based ocular injection method to directly deliver Cre recombinase into the mouse uveal tract and demonstrate that Lats1/2 kinases suppress UM formation specifically in uveal melanocytes. We find that genetic activation of YAP, but not Kras, is sufficient to initiate UM. We show that YAP/TAZ activation induced by Lats1/2 deletion cooperates with Kras to promote UM progression via downstream transcriptional reinforcement. Furthermore, dual inhibition of YAP/TAZ and Ras/MAPK synergizes to suppress oncogenic growth of human UM cells. Our data highlight the functional significance of Lats-YAP/TAZ in UM initiation and progression in vivo and suggest combination inhibition of YAP/TAZ and Ras/MAPK as a new therapeutic strategy for UM.
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http://dx.doi.org/10.1016/j.celrep.2019.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871510PMC
December 2019

Verruciform xanthoma in recessive dystrophic epidermolysis bullosa and keratitis-ichthyosis-deafness syndrome: Report of two cases and a review of the literature.

Pediatr Dermatol 2020 Jan 11;37(1):176-179. Epub 2019 Nov 11.

Departments of Dermatology and Pediatrics, University of Massachusetts Medical School, Worcester, MA, USA.

Verruciform xanthoma is a benign, wart-like lesion that can clinically mimic squamous cell carcinoma. We describe two teenage patients with severe genodermatoses, recessive dystrophic epidermolysis bullosa (RDEB), and keratitis-ichthyosis-deafness (KID) syndrome, respectively, each found to have plaques suspicious for malignancy, later demonstrated on histopathologic examination to be verruciform xanthoma. We discuss the connection between these severe genodermatoses and the suspected pathophysiology of verruciform xanthoma. In addition, we highlight the importance of recognizing verruciform xanthoma as a clinical mimicker of squamous cell carcinoma, for which patients with RDEB and KID syndrome are at increased risk.
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http://dx.doi.org/10.1111/pde.14046DOI Listing
January 2020

Widespread presentation and spontaneous regression of porokeratotic eccrine ostial and dermal duct nevus.

JAAD Case Rep 2018 Nov 29;4(10):972-975. Epub 2018 Oct 29.

Department of Dermatology, University of Massachusetts Medical School, UMass Memorial Healthcare, Worcester, Massachusetts.

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http://dx.doi.org/10.1016/j.jdcr.2018.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214893PMC
November 2018

Expression of TLE1 in Malignant Melanoma With Spindle Cell Morphology: A Potential Diagnostic Pitfall.

Int J Surg Pathol 2019 May 10;27(3):259-262. Epub 2018 Oct 10.

1 University of Massachusetts Medical School, UMass Memorial Medical Center, Worcester, MA, USA.

Objectives: Transducer-like enhancer of split 1 (TLE1) immunohistochemistry is widely used as a biomarker of synovial sarcoma. Spindle cell or desmoplastic melanoma can morphologically mimic synovial sarcoma. The aim of this study was to investigate the expression of TLE1 in melanomas with a spindle cell morphology.

Methods: A search of the surgical pathology files resulted in 57 cases of melanomas diagnosed with a spindle cell or desmoplastic component. After review, 8 cases had no definitive dermal spindle cell component and 7 cases had insufficient tissue remaining and were excluded from the study. A total of 42 melanomas were examined for TLE1 immunohistochemistry using a mouse monoclonal antibody (Cell Marque, clone 1F5). Strength and percentage of nuclear TLE1 positivity was graded on a scale from 0 to 3+. Staining for TLE1 was considered positive for 2 to 3+ and negative for 0 to 1+.

Results: Nuclear TLE1 expression was identified in 24 (57%) of the 42 melanoma cases with spindle cell morphology (2+, n = 14; 3+, n = 10). TLE1 was considered negative in 18 cases (43%), of which most contained weak staining (1+, n = 14 [33%]) and only a small subset did not show any staining (0, n = 4 [10%]).

Conclusion: TLE1 frequently highlights melanomas with spindle cell morphology and is a potential diagnostic pitfall. Therefore, when evaluating spindle cell tumors in which the differential may include both a melanoma and synovial sarcoma, TLE1 expression should be interpreted with caution and in conjunction with an immunohistochemical panel.
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http://dx.doi.org/10.1177/1066896918805137DOI Listing
May 2019

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

Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus-like inflammation.

J Clin Invest 2018 07 11;128(7):2966-2978. Epub 2018 Jun 11.

Department of Medicine, University of Massachusetts School of Medicine, Worcester, Massachusetts, USA.

Toll-like receptors TLR7 and TLR9 are both implicated in the activation of autoreactive B cells and other cell types associated with systemic lupus erythematosus (SLE) pathogenesis. However, Tlr9-/- autoimmune-prone strains paradoxically develop more severe disease. We have now leveraged the negative regulatory role of TLR9 to develop an inducible rapid-onset murine model of systemic autoimmunity that depends on T cell detection of a membrane-bound OVA fusion protein expressed by MHC class II+ cells, expression of TLR7, expression of the type I IFN receptor, and loss of expression of TLR9. These mice are distinguished by a high frequency of OVA-specific Tbet+, IFN-γ+, and FasL-expressing Th1 cells as well as autoantibody-producing B cells. Unexpectedly, contrary to what occurs in most models of SLE, they also developed skin lesions that are very similar to those of human cutaneous lupus erythematosus (CLE) as far as clinical appearance, histological changes, and gene expression. FasL was a key effector mechanism in the skin, as the transfer of FasL-deficient DO11gld T cells completely failed to elicit overt skin lesions. FasL was also upregulated in human CLE biopsies. Overall, our model provides a relevant system for exploring the pathophysiology of CLE as well as the negative regulatory role of TLR9.
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http://dx.doi.org/10.1172/JCI98219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025993PMC
July 2018

Emperipolesis and S100 expression may be seen in cutaneous xanthogranulomas: A multi-institutional observation.

J Cutan Pathol 2018 May 24. Epub 2018 May 24.

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

Cutaneous Rosai-Dorfman disease (RDD) can be difficult to distinguish from other non-Langerhans cell histiocytoses, particularly xanthogranuloma (XG). Pathologists use S100 immunoreactivity, abundant plasma cells, and the presence of emperipolesis to distinguish RDD from XG. However, S100 expression has been reported in XG and, in practice, we have occasionally observed emperipolesis in cases that were otherwise clinically and pathologically consistent with XG. We present 10 cases of XG with emperipolesis and variable S100 immunoreactivity. Histologically, 7 cases were most in keeping with XG, and a histologic differential of XG versus RDD was raised in the remaining 3 cases. All 10 cases were clinically consistent with XG. Notably, none of these cases showed abundant plasma cells. Nine cases showed variable S100 immunostaining, ranging from focal/weak expression, to focal/strong, diffuse/moderate, and diffuse/strong expression. Histiocytes in all cases were CD68 positive and CD1a negative. We conclude that emperipolesis and S100 expression in a skin biopsy cannot reliably distinguish XG from cutaneous manifestations of RDD. Clinical correlations are essential, as are histologic clues to a diagnosis of classic XG that include an abundance of foamy mononuclear cells, Touton giant cells, and an absence of pale-stained histiocytes, abundant plasma cells, fibrosis, or vascular proliferation.
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http://dx.doi.org/10.1111/cup.13285DOI Listing
May 2018

Distinguishing between irritated seborrheic keratosis and squamous cell carcinoma in situ using BCL-2 and IMP3 immunohistochemistry.

J Cutan Pathol 2018 Aug 12;45(8):603-609. Epub 2018 Jun 12.

Department of Pathology, University of Massachusetts Medical School, UMass Memorial Medical Center, Worcester, Massachusetts.

Background: Distinguishing an irritated seborrheic keratosis (ISK) from a squamous cell carcinoma in situ (SCCIS) can occasionally be challenging, both histologically and clinically. The purpose of this study was to determine if an immunohistochemical profile of select markers can aid in differentiating these two entities.

Methods: We randomly selected and stained 103 ISK and 111 SCCIS for EGFR, IMP3, and BCL-2. IMP3 staining was scored as negative or 0 (0% positive), 1+ (1%-25% positive), 2+ (26%-50% positive), and 3+ (>50% positive). BCL-2 and EGFR were graded as either positive or negative.

Results: Sixty five out of 103 (63%) ISKs were positive for BCL-2, none (0%) were positive for IMP3, and 18 (18%) were positive for EGFR. Fifteen out of 111 (14%) SCCISs were positive for BCL-2, 26 (23%) were positive for IMP3, and 27 (24%) were positive for EGFR. BCL-2 was moderately sensitive (63%) and specific (87%) in identifying ISK. IMP3 was specific (100%) but not sensitive (23%) for SCCIS.

Conclusion: Our findings indicate that the combination of IMP3 and BCL-2 may be of diagnostic utility in distinguishing between ISK and SCCIS in daily clinical practice. EGFR immunohistochemistry did not appear to be useful in this setting.
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http://dx.doi.org/10.1111/cup.13269DOI Listing
August 2018

Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma.

J Clin Invest 2018 01 4;128(1):294-308. Epub 2017 Dec 4.

Program in Molecular Medicine.

Oncogenomic studies indicate that copy number variation (CNV) alters genes involved in tumor progression; however, identification of specific driver genes affected by CNV has been difficult, as these rearrangements are often contained in large chromosomal intervals among several bystander genes. Here, we addressed this problem and identified a CNV-targeted oncogene by performing comparative oncogenomics of human and zebrafish melanomas. We determined that the gene encoding growth differentiation factor 6 (GDF6), which is the ligand for the BMP family, is recurrently amplified and transcriptionally upregulated in melanoma. GDF6-induced BMP signaling maintained a trunk neural crest gene signature in melanomas. Additionally, GDF6 repressed the melanocyte differentiation gene MITF and the proapoptotic factor SOX9, thereby preventing differentiation, inhibiting cell death, and promoting tumor growth. GDF6 was specifically expressed in melanomas but not melanocytes. Moreover, GDF6 expression levels in melanomas were inversely correlated with patient survival. Our study has identified a fundamental role for GDF6 and BMP signaling in governing an embryonic cell gene signature to promote melanoma progression, thus providing potential opportunities for targeted therapy to treat GDF6-positive cancers.
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http://dx.doi.org/10.1172/JCI92513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749509PMC
January 2018

Indolent, waxing and waning cutaneous presentation of HTLV-1-associated adult T-cell leukemia/lymphoma in an HIV-1-positive patient.

J Cutan Pathol 2018 Feb 10;45(2):171-175. Epub 2017 Dec 10.

Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts.

We present an unusual case of human T-cell leukemia-lymphoma virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma in an human immunodeficiency virus (HIV) patient who presented with non-diffuse, papular, waxing and waning cutaneous eruptions. The patient is a 61-year-old Haitian male with history of HIV on highly active antiretroviral therapy (HAART) who presented with multiple painful pink papules on his distal fingers and back for more than a year with a waxing and waning course. Skin biopsy demonstrated a CD4+, CD25+, CD8- lymphocytic proliferation with a clonal T-cell receptor gene rearrangement. Peripheral blood demonstrated lymphocytosis with a CD4:CD8 ratio greater than 20:1 and an identical T-cell receptor (TCR) clone as that in the biopsy. HTLV-1 antibodies and PCR testing for HTLV virus were positive. Retrospective review of CBCs during the past 8 years demonstrated chronic lymphocytosis with a sharp increase in absolute CD4 counts corresponding to the onset of rash. The patient lacked systemic symptoms after 6 months follow-up.
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http://dx.doi.org/10.1111/cup.13078DOI Listing
February 2018

The Value of Direct Immunofluorescence on Proteinase-Digested Formalin-Fixed Paraffin-Embedded Skin Biopsies.

Am J Dermatopathol 2018 Feb;40(2):111-117

Department of Pathology, University of Massachusetts Medical School, UMass Memorial Medical Center, Worcester, MA.

Direct immunofluorescence (DIF) on frozen tissue (DIF-F) is the method of choice for the identification of immune deposits present in skin and other tissues. DIF can also be performed on formalin-fixed paraffin-embedded tissue (DIF-P) after antigen retrieval with proteases and has proven to be of value in renal pathology. However, its utility in skin biopsies has not been fully examined. In this study, we performed DIF-P on 60 skin biopsies that comprised of bullous pemphigoid (n = 18), pemphigoid gestationis (n = 1), pemphigus (n = 7), linear IgA disease (n = 7), vasculitis (n = 20), lupus erythematosus (n = 3), and dermatitis herpetiformis (n = 4) cases. We compared the results of DIF-P with those of DIF-F from the same patients. The diagnostic features were found in 15 of 19 (79%) pemphigoid (bullous pemphigoid and pemphigoid gestationis), 3 of 7 (43%) pemphigus, 3 of 7 (43%) linear IgA disease, 14 of 20 (70%) vasculitis, 1 of 3 (33%) lupus erythematosus, and none (0%) of the dermatitis herpetiformis cases tested. Overall, DIF-P is less sensitive than DIF-F but seems to be a valuable technique that could aid in the diagnosis of vasculitides, immunobullous, and connective tissue disorders when fresh tissue is unavailable.
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http://dx.doi.org/10.1097/DAD.0000000000000934DOI Listing
February 2018

Lichen planus pigmentosus in a blaschkoid distribution.

Dermatol Online J 2017 Jun 15;23(6). Epub 2017 Jun 15.

University of Massachusetts Medical School, Worcester, Massachusetts.

Lichen planus pigmentosus is a pigmentary disorder of unknown etiology, with diffuse hyperpigmentation of sun-exposed areas, more commonly seen in some ethnic and racial groups. We report an unusual case of lichen planus pigmentosus in a 40-year-old man with Fizpatrick type III skin that was present in a blaschkoid distribution on the trunk, a distribution that has been rarely reported. This unique presentation of lichen planus pigmentosus may contribute to better understanding of the etiology, as the blaschkoid distribution may reflect underlying cutaneous mosaicism that renders those cells more susceptible to an insult that results in lichen planus pigmentosus. This disorder should be considered in the differential diagnosis of macular hyperpigmentation, especially in those from more commonly affected ethnic and racial groups, even when the distribution is atypical and in the absence of history of sun exposure.
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June 2017

Pregnancy-associated morphea: a case report and literature review.

Dermatol Online J 2017 Jan 15;23(1). Epub 2017 Jan 15.

Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA.

Morphea, also known as localized scleroderma, is arare fibrosing disorder of the skin, the pathogenesisof which is incompletely understood. It is thought,however, to involve interplay of genetic dispositionand triggering environmental factors, such asinfections and autoimmunity. Pregnancy as a potentialtrigger has only been reported in four cases. Herein,we present a patient who developed morphea of thebreasts during pregnancy, which rapidly resolvedwith a normal delivery. Our patient was distinct fromsome of the reported patients because her conditionwas tightly correlated with her pregnancy, as judgingby rapid resolution after delivery. In addition, therewas no apparent infection, history of autoimmunity,or development of autoimmunity during or afterpregnancy. Although the pathogenesis of pregnancyassociatedmorphea is largely unknown, we exploredpotential mechanisms of this condition, which mayinvolve mechanical injury, "microchimerism," andshifts in intrapartum hormones, such as TGF-β.
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January 2017

Hypercholesterolemia Increases Colorectal Cancer Incidence by Reducing Production of NKT and γδ T Cells from Hematopoietic Stem Cells.

Cancer Res 2017 05 1;77(9):2351-2362. Epub 2017 Mar 1.

Diabetes Center of Excellence and Division of Vascular and Endovascular Surgery, University of Massachusetts Medical School, Worcester, Massachusetts.

Obesity will soon surpass smoking as the most preventable cause of cancer. Hypercholesterolemia, a common comorbidity of obesity, has been shown to increase cancer risk, especially colorectal cancer. However, the mechanism by which hypercholesterolemia or any metabolic disorder increases cancer risk remains unknown. In this study, we show that hypercholesterolemia increases the incidence and pathologic severity of colorectal neoplasia in two independent mouse models. Hypocholesterolemia induced an oxidant stress-dependent increase in miR101c, which downregulated Tet1 in hematopoietic stem cells (HSC), resulting in reduced expression of genes critical to natural killer T cell (NKT) and γδ T-cell differentiation. These effects reduced the number and function of terminally differentiated NKT and γδ T cells in the thymus, the colon submucosa, and during early tumorigenesis. These results suggest a novel mechanism by which a metabolic disorder induces epigenetic changes to reduce lineage priming of HSC toward immune cells, thereby compromising immunosurveillance against cancer. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193767PMC
May 2017

Tumoral PD-L1 expression in desmoplastic melanoma is associated with depth of invasion, tumor-infiltrating CD8 cytotoxic lymphocytes and the mixed cytomorphological variant.

Mod Pathol 2017 03 13;30(3):357-369. Epub 2017 Jan 13.

Dermatopathology Section, Department of Pathology and Laboratory Medicine (113), VA Integrated Service Networks (VISN1), West Roxbury, MA, USA.

Recently, patients with metastatic desmoplastic melanoma (DM) have been shown to respond more favorably to anti-PD1/PD-L1 therapy than other melanoma subtypes. Given this, we evaluated PD-L1/2 expression in primary DM samples and correlated these with subtype, CD8+ lymphocyte status, histopathological prognosticators, and select genetic alterations. Eighty-six (36 mixed DM, 50 pure DM) archival annotated samples met inclusion criteria and were immunohistochemically semiquantitatively evaluated. Per established criteria, for PD-L1/L2, cases with ⩾5% tumoral expression, and for CD8, cases with a predominantly peri/intratumoral CD8+ infiltrate were scored positive. Univariate analysis (chi-square and Wilcoxon) identified potential confounders and a nested case-control study was accomplished using multiple logistic regression. For PD-L1, 49% of cases were positive and 71% of cases with thickness >4 mm were positive; PD-L1 expression differed by median depth (3.29 mm, interquartile range=3.58 mm for PD-L1 positives vs 1.75 mm, interquartile range=2.04 mm for PD-L1 negatives, P=0.0002) and was linearly associated with increasing depth of invasion (P=0.0003). PD-L1-positive cases were more likely to display CD8+ lymphocytes (60 vs 28% P=0.0047).The presence of CD8+ lymphocytes correlated significantly with depth of invasion >1 mm (P=0.022). On multivariate analysis, PD-L1 was 6.14 × more likely to be expressed in mixed DM than pure DM (P=0.0131), CD8+ staining was 6.22 × more likely in PD-L1 positive cases than in PD-L1 negative (P=0.0118), and tumor depth was associated with greater odds of PD-L1 expression (OR=1.61, P=0.0181). PD-L2 expression was observed in 48% of cases but did not correlate with any variables. Correlation of tumoral PD-L1 with increased depth and CD8+ lymphocytes implicates the tumoral immune microenvironment with advancing disease in DM. Enhanced tumoral PD-L1 expression in the mixed cytomorphological variant provides an insight into the differential pathogenesis of the subtypes and suggests that these patients are likely better candidates for anti-PD/PD-L1 therapy.
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http://dx.doi.org/10.1038/modpathol.2016.210DOI Listing
March 2017

Complete Spontaneous Regression of Merkel Cell Carcinoma After Biopsy: A Case Report and Review of the Literature.

Am J Dermatopathol 2016 Nov;38(11):e154-e158

Department of Pathology, University of Massachusetts Medical School, Worcester, MA.

Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine tumor that typically occurs on the head and neck of the elderly and follows an aggressive clinical course. Merkel cell polyomavirus (MCPyV) has been identified in up to 80% of cases and has been shown to participate in MCC tumorigenesis. Complete spontaneous regression of MCC has been rarely reported in the literature. We describe a case of a 79-year-old man that presented with a rapidly growing, 3-cm mass on the left jaw. An incisional biopsy revealed MCC. Additional health issues were discovered in the preoperative workup of this patient which delayed treatment. One month after the biopsy, the lesion showed clinical regression in the absence of treatment. Wide excision of the biopsy site with sentinel lymph node dissection revealed no evidence of MCC 2 months later. The tumor cells in the patient's biopsy specimen were negative for MCPyV by polymerase chain reaction and immunohistochemistry (CM2B4 antibody, Santa Cruz, CA). The exact mechanism for complete spontaneous regression in MCC is unknown. To our knowledge, only 2 previous studies evaluated the presence of MCPyV by polymerase chain reaction in MCC with spontaneous regression. Whether the presence or absence of MCPyV correlates with spontaneous regression warrants further investigation.
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http://dx.doi.org/10.1097/DAD.0000000000000614DOI Listing
November 2016

Ki-67, p53, and p16 expression, and G691S RET polymorphism in desmoplastic melanoma (DM): A clinicopathologic analysis of predictors of outcome.

J Am Acad Dermatol 2016 Sep;75(3):595-602

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

Background: The prognostic role Ki-67, p53, and p16 immunostains and RET (rearranged during transfection) polymorphism in desmoplastic melanoma has not been evaluated.

Objective: We sought to identify potential prognostic markers.

Methods: We performed Ki-67, p53, and p16 immunostains on 66 desmoplastic melanomas, and sequenced RET G691 polymorphism and recurrent mutations of 17 cancer genes in 55 and 20 cases, respectively.

Results: Recurrence and metastasis were documented in 11 of 66 (17%) and 26 of 66 (39%) patients, respectively. Death was noted in 25 of 55 (45%) patients. Ki-67 expression (≥10%, 43%) correlated with male gender (P = .009), ulceration (P = .002), and Breslow depth (P = .009). p53 Expression (≥50%, 28%) correlated with male gender (P = .002) and head and neck location (P = .0228). Using Kaplan-Meier plots, Ki-67 expression (P = .0425) and mitosis (P = .00295) correlated with overall survival, whereas vascular invasion (P = .0292) correlated with disease progression. There was a significant correlation between Ki-67 and p53 expression (P = .003). RET polymorphism was present in 10 of 46 (22%) cases and inversely correlated with Breslow depth (P = .024).

Limitation: Our study is small and lacks power to perform a multivariate analysis.

Conclusion: Although Ki-67 expression correlated with overall survival, additional studies are needed to determine whether Ki-67 would be an independent prognostic marker in addition to the current routine histopathologic assessment.
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http://dx.doi.org/10.1016/j.jaad.2016.04.059DOI Listing
September 2016

Azathioprine hypersensitivity presenting as neutrophilic dermatosis and erythema nodosum.

Cutis 2016 Jul;98(1):E7-9

Division of Dermatology, University of Massachusetts Medical School, Worcester, USA.

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July 2016

A Private Investigation: Radiologic-Pathologic Correlation of Testicular Tumors.

Curr Probl Diagn Radiol 2017 May - Jun;46(3):242-256. Epub 2016 May 20.

Department of Radiology, University of Massachusetts Medical School, Worcester, MA.

To review the classification of testicular tumors, describe the sonographic and pathologic features of each tumor type, and discuss the mimics, diagnostic pitfalls, and management of testicular tumors. Method consists of pictorial review. We review sonographic and pathologic findings of several testicular tumors and tumorlike entities. Although ultrasound is the first-line imaging modality to differentiate between intratesticular and extratesticular location of an intrascrotal mass, it is not specific for intratesticular lesion characterization. Therefore, correlation with histology sampling is often necessary.
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http://dx.doi.org/10.1067/j.cpradiol.2016.05.002DOI Listing
November 2017

Frequency of telomerase reverse transcripter promoter mutations in desmoplastic melanoma subtypes: analyses of 76 cases.

Melanoma Res 2016 08;26(4):361-6

aDepartment of Pathology, Boston University of Medicine bBoston University School of Public Health and Ragon Institute of MGH, MIT and Harvard cDepartment of Pathology, Massachusetts General Hospital, Boston dMiraca Life Sciences, Newton Upper Falls eDepartment of Pathology, University of Massachusetts Medical School, Worcester fDermatopathology Section, VA Integrated Systems Network (VISN1), Department of Pathology and Laboratory Medicine, West Roxbury, Massachusetts gCarver College of Medicine, University of Iowa, Iowa City, Iowa hDepartment of Pathology and Dermatology, Icahn School of Medicine Mount Sinai, New York, New York iAurora Diagnostics GPA Laboratories, Greensboro, North Carolina, USA jDepartment of Pathology, Western General Hospital, Edinburgh, Scotland, UK.

Estimates of the frequency of telomerase reverse transcripter (TERT) mutations in desmoplastic melanoma (DM) are limited. DM is categorized into subtypes, pure and mixed, differing in prognosis, suggesting genetic heterogeneity. Given this, our aims were to determine the incidence of TERT promoter mutations in DM subtypes and to evaluate its relationship with established histopathologic prognosticators, BRAF and RETp status, and neurofibromin protein expression. Of the archival annotated samples retrieved, 76 cases of DM (48 pure and 28 mixed) fulfilled the criteria for inclusion. PCR amplification of the TERT promoter region was performed on DNA extracted from formalin-fixed paraffin-embedded tissue using primers5'-GCCGATTCGACCTCTCTCC-3' (forward) and 5'-CAGCGCTGCCTGAAACTC-3' (reverse). For each case, appropriate C>T mutations were identified on the electropherograms. Univariate analysis using χ-test was carried out to identify potential confounders; a nested case-control study of demographic, clinical, histopathological, and genetic determinants was carried out using multiple logistic regression. Significant differences in TERT promoter mutation frequencies were noted in the subtypes (mixed vs. pure; 15/28, 54% vs. 11/48, 23%, respectively, P=0.0066). After adjusting for potential confounding, multivariate analyses indicated a three-fold increase in the odds of the TERT mutation for those with the mixed subtype compared with the pure subtype (P=0.04, adjusted odds ratio =3.32). No other significant associations were noted (sex/junctional component/Breslow depth/ulceration/mitoses/host response/RETp, BRAF status, and neurofibromin protein expression). Our findings, the largest to date investigating TERT promoter mutations in DM, support the hypothesis that the subtypes have distinct genetic drivers and underscore the relevance of telomere integrity in the etiopathogenesis of the mixed variant.
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http://dx.doi.org/10.1097/CMR.0000000000000272DOI Listing
August 2016

Neurofibromin protein loss in desmoplastic melanoma subtypes: implicating NF1 allelic loss as a distinct genetic driver?

Hum Pathol 2016 07 9;53:82-90. Epub 2016 Mar 9.

Dermatopathology Section, Department of Pathology and Laboratory Medicine, VA Consolidated Laboratories, West Roxbury, MA 02132. Electronic address:

Loss of the NF1 allele, coding for the protein neurofibromin, and polymorphism in the proto-oncogene RET (RETp) are purportedly common in desmoplastic melanoma (DM). DM is categorized into pure (PDM) and mixed (MDM) subtypes, which differ in prognosis. Most NF1 mutations result in a truncated/absent protein, making immunohistochemical screening for neurofibromin an ideal surrogate for NF1 allelic loss. Using antineurofibromin, our aims were to ascertain the incidence of neurofibromin loss in DM subtypes and to evaluate the relationship with RET, perineural invasion (PNI) and established histopathologic prognosticators. A total of 78 archival samples of DM met criteria for inclusion (54 cases of non-DM serving as controls). Immunohistochemistry was performed for neurofibromin, whereas direct DNA sequencing was used for RETp and BRAF mutation status. Statistical analyses included χ(2) test as well as Fisher exact test. Neurofibromin loss was more common in DM than non-DM (69% versus 54%; P=.02). In DM, significant differences in neurofibromin loss were noted in the following: non-head and neck versus head and neck biopsy site (88% versus 55%) and PDM versus MDM variants (80% versus 56%). No significant associations were noted with sex, presence of a junctional component, Breslow depth, ulceration, mitoses, host response, RETp, BRAF status, or PNI. RETp was marginally associated with PNI-positive DM versus PNI-negative DM (36 versus 18%; P=.08). Our findings, the largest to date investigating neurofibromin in DM, validate the incidence of NF1 mutations/allelic loss in DM and suggest that the DM subtypes have distinct genetic drivers.
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http://dx.doi.org/10.1016/j.humpath.2016.02.012DOI Listing
July 2016
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