Publications by authors named "Victor L Quan"

19 Publications

  • Page 1 of 1

Long-term retinal vasculature abnormalities following intravitreal bevacizumab for retinopathy of prematurity.

Graefes Arch Clin Exp Ophthalmol 2021 Dec 1. Epub 2021 Dec 1.

Division of Ophthalmology, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 E. Chicago, Box 70, Chicago, IL, 60611, USA.

Purpose: To report long-term fluorescein angiography (FA) findings in consecutive patients with type 1 retinopathy of prematurity (ROP) treated with intravitreal bevacizumab (IVB), whose ROP seemed to have resolved clinically.

Methods: Data were retrospectively collected for all patients with IVB-treated type 1 ROP who underwent an exam under anesthesia (EUA) and FA at 60 weeks post-gestational age (PGA) or older at a tertiary medical center between 2011 and 2020. FA results were reviewed for pathological vascular findings.

Results: Twenty-nine eyes of 16 patients were included. Mean gestational age and birth weight were 25.3 ± 1.5 weeks and 762.2 ± 189.8 g, respectively. The mean age at the time of EUA and FA was 23.4 ± 15.8 months. All eyes had a peripheral avascular zone and irregular peripheral branching. Vascular loops were seen in 27 eyes (93.1%) and vascular bulbs and anastomoses in 16 eyes each (55.2%). Additional abnormal findings included leakage (10 eyes, 34.5%), vessels crossing the fovea (5 eyes, 17.2%), tortuous arteries and veins (9 eyes, 31%, and 5 eyes, 17.2%, respectively), and neovascularization (2 eyes, 6.9%). When comparing patients who were less than or greater than 70 weeks PGA at follow-up, FA findings in the group with shorter follow-up were significant for more anastomoses and vascular bulbs (p = 0.002 and p = 0.024, respectively) and trended towards more leakage (45.5% vs. 27.8%, p = 0.331).

Conclusion: The vast majority of IVB-treated type 1 ROP eyes suffered from vascular pathologies long after treatment. There may be long-term progression in the vascularization process of the retina in some cases.
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http://dx.doi.org/10.1007/s00417-021-05499-0DOI Listing
December 2021

Acquired perforating dermatosis in patients with copper deficiency.

JAAD Case Rep 2021 Sep 27;15:110-114. Epub 2021 Jul 27.

Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

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http://dx.doi.org/10.1016/j.jdcr.2021.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387729PMC
September 2021

A Series of RET Fusion Spitz Neoplasms With Plaque-Like Silhouette and Dyscohesive Nesting of Epithelioid Melanocytes.

Am J Dermatopathol 2021 Apr;43(4):243-251

Professor of Dermatology and Pathology, Northwestern University, Department of Dermatology, Chicago, IL; and.

Abstract: Two distinct studies have shown that RET fusions are found in 3%-4% of Spitz neoplasms. RET fusions have been well described in papillary thyroid cancer, non-small-cell lung cancer, breast cancer, and soft-tissue mesenchymal tumors as well as some other neoplasms. However, there are no comprehensive descriptions to date of the characteristic morphologic, clinical, or genomic findings in RET fusion Spitz neoplasms. In this study, we identified 5 cases of RET fusion Spitz neoplasms. These tumors showed characteristic morphologic features which included plaque-like silhouette and monotonous epithelioid cytology with expansile and dyscohesive nesting. Four of 5 patients including 1 diagnosed as Spitz melanoma had clinical follow-up all of which was uneventful. Furthermore, we describe the genomic sequences in 4 of these cases, 2 of which have previously described KIF5B-RET fusion and 2 of which had a novel LMNA-RET fusion. We believe this report significantly contributes to our current knowledge regarding Spitz neoplasms and describes characteristics features which can help with recognition of the RET subgroup of Spitz.
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http://dx.doi.org/10.1097/DAD.0000000000001780DOI Listing
April 2021

Perforating lichen nitidus.

JAAD Case Rep 2021 Feb 10;8:4-8. Epub 2020 Dec 10.

Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

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http://dx.doi.org/10.1016/j.jdcr.2020.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797926PMC
February 2021

Clinical, morphologic, and genomic findings in ROS1 fusion Spitz neoplasms.

Mod Pathol 2021 02 29;34(2):348-357. Epub 2020 Aug 29.

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

The presence of a characteristic chimeric fusion as the initiating genomic event is one defining feature of Spitz neoplasms. Characterization of specific subtypes of Spitz neoplasms allows for better recognition facilitating diagnosis. Data on clinical outcomes of the specific tumor types may help in predicting behavior. In this study we present the largest series to date on ROS1 fusion Spitz neoplasms. We present the clinical, morphologic, and genomic features of 17 cases. We compared the morphologic features of these 17 cases to a cohort of 99 other non-ROS1 Spitz neoplasms to assess for features that may have high specificity for ROS1 fusions. These tumors consisted of ten Spitz nevi and seven Spitz tumors. None of the cases met criteria for a diagnosis of Spitz melanoma. Morphologically, the ROS1 fusion tumors of this series were characterized by a plaque-like or nodular silhouette, often densely cellular intraepidermal melanocyte proliferation, frequent pagetosis, tendency toward spindle cell cytomorphology, low grade nuclear atypia, and floating nests with occasional transepidermal elimination. However, there was a significant range in microscopic appearances, including two cases with morphologic features of a desmoplastic Spitz nevus. Different binding partners to ROS1 were identified with PWWP2A and TPM3 being the most common. No case had a recurrence or metastasis. Our findings document that most ROS1 fusion Spitz neoplasms have some typical characteristic microscopic features, while a small proportion will have features overlapping with other genomic subtypes of Spitz neoplasms. Preliminary evidence suggests that they tend to be indolent or low grade neoplasms.
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http://dx.doi.org/10.1038/s41379-020-00658-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855005PMC
February 2021

BRAF fusion Spitz neoplasms; clinical morphological, and genomic findings in six cases.

J Cutan Pathol 2020 Dec 14;47(12):1132-1142. Epub 2020 Sep 14.

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

Background: Fusions involving the BRAF gene are responsible for 5% of Spitz neoplasms. To better characterize them, we report the clinical, morphological, and genomic findings of six BRAF fusion Spitz tumors.

Methods: The morphological, clinical, and molecular findings of six BRAF fusion Spitz neoplasms assessed by next generation sequencing (NGS) were compared to a control set of Spitz without BRAF fusions.

Results: BRAF fusion Spitz tumors had frequent predominance of epithelioid morphology (4/6 cases), frequent high-grade nuclear atypia and pleomorphism (5/6 cases), and a frequent desmoplastic base (3/6 cases). Five of six cases were diagnosed as atypical Spitz tumor and one as Spitz nevus. All cases had uneventful clinical follow-up. There were five different fusion partners, with CLIP2 being the most frequent. Secondary pathogenic mutations were frequent and chromosomal copy number changes were seen in three of six cases by an NGS platform.

Conclusions: BRAF fusions Spitz usually have epithelioid morphology, high-grade nuclear atypia, and desmoplasia. Chromosomal copy number changes are not infrequent. While our cases had uneventful follow-up, a meta-analysis of the literature suggests that among the fusion subtypes associated with Spitz tumors, they are among the subgroups more likely to develop distant metastasis.
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http://dx.doi.org/10.1111/cup.13842DOI Listing
December 2020

A retrospective cohort study of the diagnostic value of different subtypes of atypical pigment network on dermoscopy.

J Am Acad Dermatol 2020 Oct 21;83(4):1028-1034. Epub 2020 May 21.

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Robert H. Lurie Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Electronic address:

Background: Atypical network encompasses several patterns. Few studies assess the sensitivity, specificity, and positive and negative predictive values of network subtypes.

Objective: We assessed the diagnostic value of atypical network subtypes and their histopathologic correlates in cutaneous melanocytic lesions.

Methods: A retrospective search (2014-2018) from a high-risk melanoma clinic for cases scored for atypical network with accompanying dermoscopic photographs yielded 120 lesions (15 melanoma; 30 severely, 38 moderately, and 32 mildly atypical nevi; 4 compound nevi; and 1 junctional nevus). A dermatopathologist blinded to diagnosis assessed dermoscopic and histologic features. Network abnormality correlates with histopathology and clinical diagnoses were assessed with sensitivity, specificity, positive and negative predictive values, and odds ratios.

Results: A multivariable model with shiny white streaks (odds ratio 3.02) and inverse network (OR 4.46) was most predictive of melanoma or severe atypia. Positive predictive value for melanoma or severe atypia in decreasing order was inverse network (73.9%), shiny white streaks (71.4%), loss of network (46%), branched streaks (29.4%), and thick brown lines (28.4%).

Limitations: Cases were retrospectively found from a pigmented lesion clinic and evaluated by a single dermatopathologist.

Conclusion: Shiny white streaks and inverse network are most predictive of melanoma or severe atypia and warrant biopsy if found on dermoscopy.
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http://dx.doi.org/10.1016/j.jaad.2020.05.080DOI Listing
October 2020

Incorporation of dermoscopy improves inter-observer agreement among dermatopathologists in histologic assessment of melanocytic neoplasms.

Arch Dermatol Res 2021 Mar 27;313(2):101-108. Epub 2020 Apr 27.

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Histopathologic assessment of melanocytic neoplasms is the current gold standard of diagnosis. However, there are well recognized limitations including inter-observer diagnostic discordance. This study aimed to determine if integrating dermoscopy with histopathology of melanocytic neoplasms impacts diagnosis and improves inter-observer agreement. We conducted a prospective cohort study in a pigmented lesion clinic. Consecutive melanocytic lesions were identified for biopsy based on atypical gross or dermoscopic features. Standardized immunohistochemistry and levels were ordered on each specimen. The cases were randomized. Three dermatopathologists blinded to the clinical impression assessed each lesion. The cases were then re-randomized and re-assessed with addition of gross clinical and dermoscopic images. Inter-rater reliability (IRR) using Fleiss' kappa statistic revealed an increase from 0.447 without to 0.496 with dermoscopy amongst all dermatopathologists. The kappa increased from 0.495 before to 0.511 with dermoscopy in separating high-grade atypia or melanoma from moderate atypia or less. In 16 of 136 cases, at least 2 of 3 dermatopathologists favored a diagnosis of melanoma only after dermoscopy. In total, the consensus grade of atypia changed in 24.3% (33/ 136) of cases thereby representing changes to excisional margins and patient follow up. This study is limited by the cohort size. Dermoscopy significantly impacts diagnosis and improves identification of early melanomas in high risk populations and improves inter-observer agreement.
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http://dx.doi.org/10.1007/s00403-020-02079-wDOI Listing
March 2021

Integrating Next-Generation Sequencing with Morphology Improves Prognostic and Biologic Classification of Spitz Neoplasms.

J Invest Dermatol 2020 08 29;140(8):1599-1608. Epub 2020 Jan 29.

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. Electronic address:

The newest World Health Organization classification of skin tumors suggests the elimination of cases with BRAF and NRAS mutations from the categories of Spitz tumors (ST) and Spitz melanoma (SM). The objective of this study is to better characterize the genomics of Spitz neoplasms and assess whether the integration of genomic data with morphologic diagnosis improves classification and prognostication. We performed DNA and RNA sequencing on 80 STs, 26 SMs, and 22 melanomas with Spitzoid features (MSF). Next-generation sequencing data were used to reclassify tumors by moving BRAF and/or NRAS mutated cases to MSF. In total, 81% of STs harbored kinase fusions and/or truncations. Of SMs, 77% had fusions and/or truncations with eight involving MAP3K8. Previously unreported fusions identified were MYO5A-FGFR1, MYO5A-ERBB4, and PRKDC-CTNNB1. The majority of MSFs (84%) had BRAF, NRAS, or NF1 mutations, and 62% had TERT promoter mutations. Only after reclassification, the following was observed: (i) mRNA expression showed distinct clustering of MSF, (ii) six of seven cases with recurrence and all distant metastases were of MSFs, (iii) recurrence-free survival was worse in MSF than in the ST and SM groups (P = 0.0073); and (iv) classification incorporating genomic data was highly predictive of recurrence (OR 13.20, P = 0.0197). The majority of STs and SMs have kinase fusions as primary initiating genomic events. The elimination of BRAF and/or NRAS mutated neoplasms from these categories results in the improved classification and prognostication of melanocytic neoplasms with Spitzoid cytomorphology.
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http://dx.doi.org/10.1016/j.jid.2019.12.031DOI Listing
August 2020

Retrospective Cohort: Genomic Differences Between Pigmented Spindle Cell Nevi of Reed and Reed-Like Melanomas.

Am J Dermatopathol 2020 Sep;42(9):641-647

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL.

Background: Some melanomas closely resemble pigmented spindle cell nevi (PSCN) of Reed histologically. The distinction of these entities is important for clinical management. A recent study showed most PSCN (78%) are fusion-driven, commonly involving NTRK3 (57%). Conversely, BRAF V600E mutations are not characteristic of PSCN but are frequent in melanoma.

Objective: In this study, we assessed clinical, histologic and genomic differences between PSCN of Reed and Reed-like melanomas (RLMs).

Methods: We performed BRAF V600E immunohistochemistry (IHC) for 18 PSCN and 20 RLM cases. All 23 benign PSCN cases previously underwent whole transcriptome and targeted DNA sequencing with a 1711 gene panel.

Results: We previously demonstrated the majority of PSCN (18 of 23) has chimeric fusions. Among PSCN without a chimeric fusion, BRAF mutations were common. Noncanonical BRAF mutations were identified in 2 of 5 nonfusion cases, and 1 case had a canonical BRAF mutation. Alternatively, 70% of RLM demonstrated a BRAF V600E mutation. RLM also occurred more frequently in older patients.

Limitations: The overall sample size was small.

Conclusions: In diagnostically challenging cases, ancillary IHC studies can assist in distinguishing PSCN from RLM. Our study suggests positive staining by IHC for BRAF V600E and older age strongly favors a diagnosis of RLM.
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http://dx.doi.org/10.1097/DAD.0000000000001603DOI Listing
September 2020

Distinct Genomic Features in a Retrospective Cohort of Mucosal, Acral and Vulvovaginal Melanomas.

J Am Acad Dermatol 2019 Jul 12. Epub 2019 Jul 12.

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL; Robert H. Lurie Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL. Electronic address:

Background: Compared to sun-exposed melanomas, less is known regarding the pathogenesis of sun-protected melanomas. Sun-protected melanomas share many epidemiologic factors but their genetic heterogeneity is not well studied.

Objective: We investigated the genomic profile of acral, mucosal and vulvovaginal melanomas. We hypothesize that mucosal melanomas, recognized for their uniquely aggressive clinical behavior, have distinct genomic features.

Methods: We performed whole transcriptome mRNA and DNA (1711 genes) sequencing, mRNA expression profiling, TMB, UV signature and CNV analysis on 29 volar/digital acral, 7 mucosal and 6 vulvovaginal melanomas.

Results: There was significant genetic heterogeneity, particularly in acral melanomas with 36% having BRAF alterations while other melanomas had none (p = 0.0159). Nonzero UV signatures were more frequent in acral melanomas, suggesting greater UV involvement. Mucosal melanomas formed a distinct group with increased expression of cell cycle and proliferation genes. Various targetable aberrations were identified such as AURKA and ERBB2 in mucosal and acral melanomas, respectively.

Limitations: There was a small sample size.

Conclusion: There is significant genetic heterogeneity among sun-protected melanomas. Mucosal melanomas have upregulation in cell cycle and proliferation genes, which may explain their aggressive behavior. Ultraviolet radiation plays some role in a subset of acral but not other melanomas.
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http://dx.doi.org/10.1016/j.jaad.2019.07.017DOI Listing
July 2019

The role of gene fusions in melanocytic neoplasms.

J Cutan Pathol 2019 Nov 20;46(11):878-887. Epub 2019 Jun 20.

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Recent advances in next generation sequencing (NGS) have allowed for efficient whole transcriptome sequencing, leading to the identification of important kinase fusions as the primary driver in some melanocytic neoplasms. These fusions typically occur mutually exclusively of one another and other well-known initiating mutations such as BRAF, NRAS, NF1, KIT, and GNAQ. Fusions are found in over 50% of Spitz neoplasms, including ALK, BRAF, NTRK1, NTRK3, ROS1, MET, MAP3K8, and RET. Familiarity with the typical morphologic features of certain fusion-driven melanocytic neoplasms can help with classification, diagnosis, and identification of targeted molecular therapies in malignant cases. Spitz tumors with ALK, NTRK1, and NTRK3 fusions have characteristic morphologic features. BRAF and MAP3K8 fusions, in particular, tend to be epithelioid, high grade, and more frequent in Spitz melanoma than other fusion subtypes. Sporadic cases of pigmented epithelioid melanocytoma may have PRKCA fusions and sheets of monomorphic epithelioid melanocytes. Fusion events are also enriched among melanomas without the key mutations BRAF, NRAS, or NF1. Although NGS is the most reliable method to detect fusions, immunohistochemistry and fluorescence in situ hybridization are cost-effective alternatives in some cases. We describe recent discoveries regarding the role of kinase fusions in melanocytic neoplasms and their associated morphologies.
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http://dx.doi.org/10.1111/cup.13521DOI Listing
November 2019

Activating Structural Alterations in MAPK Genes Are Distinct Genetic Drivers in a Unique Subgroup Of Spitzoid Neoplasms.

Am J Surg Pathol 2019 04;43(4):538-548

Departments of Dermatology.

Recent studies have described kinase fusions as the most common initiating genomic events in Spitzoid neoplasms. Each rearrangement generates a chimeric protein with constitutive activation of the tyrosine kinase domain, resulting in the development of a Spitzoid neoplasm. Identifying key initiating genomic events and drivers may assist in diagnosis, prognostication, and management. Retrospective, consecutive search of our database between 2009 and 2018 for Spitzoid neoplasms identified 86 cases. Whole transcriptome mRNA and DNA sequencing (1714 genes) detected 9% of cases (8/86) with structural rearrangements in MAPK genes other than BRAF and 47% (40/86) with kinase fusions previously described in Spitzoid neoplasms. We identified in-frame fusions of MAP3K8-DIPC2, MAP3K8-PCDH7, MAP3K8-UBL3, MAP3K8-SVIL (n=6), and ATP2A2-MAP3K3 (n=1) as well as a p.I103_K104 in-frame deletion of MAP2K1 (n=1), in the absence of well-recognized drivers of melanocytic neoplasia. Fluorescence in situ hybridization validated all cases (n=7) with available tissue. Cases occurred in younger patients (median age 18 y). Morphologically, cases were predominantly epithelioid (P=0.0032), often with some melanin pigment (P=0.0047), and high-grade nuclear atypia (P=0.012). A significant proportion were thought to be Spitzoid melanomas (3/8). Average follow-up time was 11 months. One MAP3K8-DIP2C Spitzoid melanoma involved 4/5 sentinel lymph nodes and led to a complete lymph node dissection with unremarkable follow-up at 9 months. One MAP3K8-DIPC2 atypical Spitz tumor raised concern for recurrence at 10 months and was reexcised. We present a distinct subtype of Spitzoid neoplasm characterized by structural alterations in MAPK genes, which are important to recognize given the potential for treatment with MAPK inhibitors in metastatic cases.
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http://dx.doi.org/10.1097/PAS.0000000000001213DOI Listing
April 2019

Distinct Genomic Patterns in Pigmented Epithelioid Melanocytoma: A Molecular and Histologic Analysis of 16 Cases.

Am J Surg Pathol 2019 04;43(4):480-488

Dermatology, Feinberg School of Medicine, Northwestern University.

Pigmented epithelioid melanocytoma (PEM) is considered an intermediate grade melanocytic lesion that is histologically indistinguishable from epithelioid blue nevi associated with Carney complex. PEM are characterized by an intradermal population of heavily pigmented epithelioid-shaped melanocytes along with some spindled and dendritic melanocytes with frequent melanophages. These melanocytic tumors occasionally involve regional lymph nodes but only rarely result in distant metastases. Recent studies have demonstrated a variable but limited number of specific genomic aberrations including protein kinase A regulatory subunit alpha (PRKAR1A), BRAF, GNAQ, and MAP2K1 mutations as well as protein kinase C alpha isoform (PRKCA) fusions. We performed an 8-year retrospective review of our database and identified 16 cases of PEM. Using targeted DNA sequencing and RNA-seq to assess 1714 cancer-related genes, we detected gene fusions involving PRKCA in 31% of cases (5/16) with 5' partners SCARB1(12q24) in 2 cases, CD63 (12q13) in 1 case, ATP2B4 (1q32) in 1 case, and MAP3K3 (17q23) in 1 case. Additional fusions were identified in TPR-NTRK1 (1/16), ALK (1/16), and MYO5A-NTRK3 (1/16). PRKCA fusion lesions tended to occur in younger-aged patients and histologic examination demonstrated sheets of monomorphic epithelioid-shaped melanocytes, moderate to high-grade nuclear atypia, and higher mitotic activity (P=0.037). Our gene panel also identified previously described mutations in PRKAR1A, GNAQ, MAP2K1, BRAF, NF1. To our knowledge, this is the largest and most comprehensive study of PEM integrating molecular data with histologic features that can be utilized in future studies for improved subclassification and prognostication of heavily pigmented melanocytic neoplasms.
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http://dx.doi.org/10.1097/PAS.0000000000001195DOI Listing
April 2019

The role of TERT promoter mutations in differentiating recurrent nevi from recurrent melanomas: A retrospective, case-control study.

J Am Acad Dermatol 2019 Mar 1;80(3):685-693. Epub 2018 Oct 1.

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Electronic address:

Background: Repigmentation at previous biopsy sites pose a significant diagnostic dilemma given clinical and histologic similarities between recurrent nevi and locally recurrent melanoma. Though common in melanoma, the role of TERT promoter mutations (TPMs) in recurrent nevi is unknown.

Objective: We investigated the role of TPMs in recurrent nevi and whether the presence of hotspot TPM distinguishes recurrent nevi from locally recurrent melanoma. We also characterized clinical and histologic features differentiating these lesions.

Methods: We analyzed 11 locally recurrent melanomas, 17 recurrent nevi, and melanoma and nevus controls to determine TPM status. We also assessed clinical and histologic features of the recurrent groups.

Results: Hotspot TPMs were more common in recurrent melanomas than recurrent nevi (P = .008). Recurrent melanomas were more likely to have solar elastosis (P = .0047), multilayering of melanocytes in the epidermis (P = .0221), adnexal involvement (P = .0069), and epidermal consumption (P = .0204). Recurrent nevi had intra-epidermal atypia limited to the area above the scar (P < .0001) and occurred earlier after the original biopsy (P < .0008). Solar elastosis, months to recurrence, and hotspot TPMs were independently associated with recurrent melanoma in multivariate analysis.

Limitations: This was a retrospective study.

Conclusion: Hotspot TPMs are significantly more frequent in recurrent melanomas and could serve as a diagnostic clue in histologically ambiguous cases.
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http://dx.doi.org/10.1016/j.jaad.2018.09.030DOI Listing
March 2019

Genomic Fusions in Pigmented Spindle Cell Nevus of Reed.

Am J Surg Pathol 2018 08;42(8):1042-1051

Department of Dermatology, Feinberg School of Medicine, Northwestern University.

Recent molecular studies of spitzoid neoplasms have identified mutually exclusive kinase fusions involving ROS1, ALK, RET, BRAF, NTRK1, MET, and NTRK3 as early initiating genomic events. Pigmented spindle cell nevus (PSCN) of Reed is a morphologic variant of Spitz and may be very diagnostically challenging, having histologic features concerning for melanoma. Their occurrence in younger patients, lack of association to sun exposure, and rapid early growth phase similar to Spitz nevi suggest fusions may also play a significant role in these lesions. However, to date, there is little data in the literature focused on the molecular characterization of PSCN of Reed with next-generation sequencing. We analyzed a total of 129 melanocytic neoplasms with RNA sequencing including 67 spitzoid neoplasms (10 Spitz nevi, 44 atypical Spitz tumors, 13 spitzoid melanomas) and 23 PSCN of Reed. Although only 2 of 67 (3.0%) of spitzoid lesions had NTRK3 fusions, 13 of 23 (57%) of PSCN of Reed harbored NTRK3 fusions with 5' partners ETV6 (12p13) in 2 cases and MYO5A (15q21) in 11 cases. NTRK3 fusions were confirmed with a fluorescent in situ hybridization break-apart probe. The presence of a NTRK3 fusion correlated with younger age (P=0.021) and adnexal extension (P=0.001). Other minor fusions identified in PSCN of Reed included MYO5A-MERTK (2), MYO5A-ROS1, MYO5A-RET, and ETV6-PITX3 leading to a total of 78% with fusions. Our study suggests that the majority of PSCN of Reed are the result of genomic fusions, and the most frequent and characteristic genomic aberration is an NTRK3 fusion.
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http://dx.doi.org/10.1097/PAS.0000000000001074DOI Listing
August 2018

Histomorphologic spectrum of germline-related and sporadic BAP1-inactivated melanocytic tumors.

J Am Acad Dermatol 2018 Sep 10;79(3):525-534. Epub 2018 May 10.

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Electronic address:

Background: BRCA1-associated protein 1 (BAP1)-inactivated melanocytic tumors (BIMTs) are often the earliest sign of the BAP1 tumor predisposition syndrome. Identification of BIMTs and selection of patients for germline testing affect the lives of patients with germline BAP1 mutations.

Objective: To describe the spectrum of histomorphologic findings in BAP1-inactivated melanocytic lesions to improve their recognition. We determined the frequency of sporadic versus germline cases in our cohort, assessing whether any features were statistically linked to germline status.

Methods: Histomorphologic features of BAP1-inactivated melanocytic lesions were analyzed by comparing cases with germline mutations with those with unknown or negative status. Available clinical follow-up data were reported.

Results: The histomorphologic spectrum of BAP1-inactivated melanocytic lesions is broad; it includes cases with spitzoid cytomorphology (69%), smaller epithelioid cells without spitzoid features (31%), and rhabdoid cytologic features (58%). BIMTs from patients with germline mutations were statistically more likely to have an extensive junctional component of BAP1-inactivated melanocytes (P = .0177). All 11 patients with suspected or confirmed germline mutations had a history of cutaneous melanoma or multiple BIMTs.

Limitations: The unknown germline status of 77 patients.

Conclusion: Approximately 12% of patients with BIMTs have germline mutations. Extensive junctional involvement in a BIMT and a personal history of melanoma or previous BIMT may be additional indications for germline testing.
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http://dx.doi.org/10.1016/j.jaad.2018.05.005DOI Listing
September 2018

The diagnostic value and histologic correlate of distinct patterns of shiny white streaks for the diagnosis of melanoma: A retrospective, case-control study.

J Am Acad Dermatol 2018 05 11;78(5):913-919. Epub 2017 Nov 11.

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Electronic address:

Background: Shiny white streaks (SWSs) are best visualized with polarized dermoscopy and correlate with dermal fibroplasia histopathologically. SWSs have been described at higher frequencies in melanomas than in benign nevi.

Objective: We assessed the diagnostic value of different patterns of SWSs and their histologic correlate in melanocytic lesions.

Methods: Polarized dermoscopic images of 1507 histopathologically diagnosed melanocytic neoplasms were analyzed for presence and pattern of SWSs. Histology was also reviewed for correlation.

Results: Among 1507 melanocytic neoplasms, SWSs were observed in 31 of 144 melanomas (22%) and 22 of 1363 benign neoplasms (1.6%) (P < .001). The sensitivity and specificity of SWSs for melanoma were 22% and 98%, respectively. Diffuse SWSs exhibited the greatest diagnostic value for melanoma, with sensitivity of 11.8% and specificity of 99.5%. Focal central and peripheral SWSs were comparable in diagnostic significance. The presence of SWSs was highly uncommon in dysplastic nevi, whereas in certain benign subgroups of nevi such as Spitz nevi and atypical genital special site nevi, SWSs were not uncommon. Diffuse SWSs correlated with greater breadth of deep fibroplasia than focal SWSs (P = .009), and SWSs correlated with greater Breslow depth among melanomas (P = .007).

Limitations: This study was retrospective.

Conclusion: Polarized dermoscopy is a valuable diagnostic tool in the identification of SWSs, a feature that is highly specific for melanoma.
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http://dx.doi.org/10.1016/j.jaad.2017.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480004PMC
May 2018

Distinct Patterns of Acral Melanoma Based on Site and Relative Sun Exposure.

J Invest Dermatol 2018 02 1;138(2):384-393. Epub 2017 Sep 1.

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA; Robert H. Lurie Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. Electronic address:

Acral melanoma is distinct from melanoma of other cutaneous sites, yet there is considerable variation within this category. To better define this variation, we assessed melanomas occurring on dorsal (n = 21), volar (n = 9), and subungual/interdigital (n = 13) acral skin as well as acral nevi (n = 24) for clinical, histologic, and molecular features. Melanomas on dorsal acral surfaces demonstrated clear differences compared with volar and subungual/interdigital melanomas. The latter two groups exhibited significantly less frequent BRAF mutations (P = 0.01), were significantly less likely to have the superficial spreading histologic subtype (P = 0.01), occurred in older patients (P = 0.05), and had more frequent involvement in non-Caucasians (P = 0.01). These differences can be explained by differing levels of UV exposure. Subungual/interdigital melanomas had the most diverse group of oncogenic mutations including PIK3CA (2/13), STK11 (2/13), EGFR (1/13), FGFR3 (1/13), and PTPN11 (1/13). In addition, subungual/interdigital melanomas had a significantly higher frequency of copy number aberrations (67%) than other subgroups (P = 0.02), particularly in CDK4 and cyclin D1, and were less likely to have BRAF mutations or a superficial spreading histologic subtype (P = 0.05) compared with volar acral melanomas. Although based on a limited sample size, differences between volar and subungual/interdigital melanomas in our study may be the result of differing levels of UV exposure.
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http://dx.doi.org/10.1016/j.jid.2017.08.022DOI Listing
February 2018
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