Publications by authors named "Alison B Durham"

28 Publications

  • Page 1 of 1

Vismodegib for Preservation of Visual Function in Patients with Advanced Periocular Basal Cell Carcinoma: The VISORB Trial.

Oncologist 2021 May 14. Epub 2021 May 14.

Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.

Background: Basal cell carcinoma (BCC) is a common skin cancer often curable by excision; however, for patients with BCC around the eye, excision places visual organs and function at risk. In this article, we test the hypothesis that use of the hedgehog inhibitor vismodegib will improve vision-related outcomes in patients with orbital and extensive periocular BCC (opBCC).

Materials And Methods: In this open-label, nonrandomized phase IV trial, we enrolled patients with globe- and lacrimal drainage system-threatening opBCC. To assess visual function in the context of invasive periorbital and lacrimal disease, we used a novel Visual Assessment Weighted Score (VAWS) in addition to standard ophthalmic exams. Primary endpoint was VAWS with a score of 21/50 (or greater) considered successful, signifying globe preservation. Tumor response was evaluated using RECIST v1.1. Surgical specimens were examined histologically by dermatopathologists.

Results: In 34 patients with opBCC, mean VAWS was 44/50 at baseline, 46/50 at 3 months, and 47/50 at 12 months or postsurgery. In total, 100% of patients maintained successful VAWS outcome at study endpoint. Compared with baseline, 3% (95% confidence interval [CI], 0.1-15.3) experienced major score decline (5+ points), 14.7% (95% CI, 5 to 31.1) experienced a minor decline (2-4 points), and 79.4% experienced a stable or improved score (95% CI, 62.1-91.3). A total of 56% (19) of patients demonstrated complete tumor regression by physical examination, and 47% (16) had complete regression by MRI/CT. A total of 79.4% (27) of patients underwent surgery, of which 67% (18) had no histologic evidence of disease, 22% (6) had residual disease with clear margins, and 11% (3) had residual disease extending to margins.

Conclusion: Vismodegib treatment, primary or neoadjuvant, preserves globe and visual function in patients with opBCC. Clinical trail identification number.NCT02436408.

Implications For Practice: Use of the antihedgehog inhibitor vismodegib resulted in preservation of end-organ function, specifically with regard to preservation of the eye and lacrimal apparatus when treating extensive periocular basal cell carcinoma. Vismodegib as a neoadjuvant also maximized clinical benefit while minimizing toxic side effects. This is the first prospective clinical trial to demonstrate efficacy of neoadjuvant antihedgehog therapy for locally advanced periocular basal cell carcinoma, and the first such trial to demonstrate end-organ preservation.
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http://dx.doi.org/10.1002/onco.13820DOI Listing
May 2021

Unknown primary Merkel cell carcinoma in the immunosuppressed patient: Case series.

JAAD Case Rep 2021 Feb 1;8:19-22. Epub 2020 Dec 1.

Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan.

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http://dx.doi.org/10.1016/j.jdcr.2020.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806541PMC
February 2021

Treatment and Outcomes for Cutaneous Periauricular Basal Cell Carcinoma: A 16-Year Institutional Experience.

OTO Open 2020 Oct-Dec;4(4):2473974X20964735. Epub 2020 Oct 19.

Department of Otolaryngology-Head and Neck Surgery, Michigan Medicine, Ann Arbor, Michigan, USA.

Objective: To report a single institutional experience with the surgical management of cutaneous periauricular basal cell carcinoma.

Study Design: Retrospective chart review.

Setting: Tertiary academic center.

Methods: Retrospective chart review of 71 patients diagnosed with periauricular basal cell carcinoma managed surgically from 2000 to 2016. Data were analyzed with descriptive statistics.

Results: The median age at diagnosis was 73.0 years (interquartile range, 13.0). Of all lesions, 2.8% (n = 2) were preauricular, 80.3% (n = 57) auricular, and 16.9% (n=12) postauricular. Auricular subsites included conchal bowl (36.6%, n = 26), helix (21.1%, n = 15), antihelix (1.4%, n = 1), peritragus (5.6%, n = 4), triangular fossa (1.4%, n = 1), external auditory canal (2.8%, n = 2), and lobule skin (1.4%, n = 1). Surgical approach included wide local excision (80.3%, n = 57), partial auriculectomy (8.5%, n = 6), and total auriculectomy or other combinations of surgical methods (11.3%, n = 8). Due to aggressive pathology, 3 cases required concurrent parotidectomy, neck dissection, ear canal sleeve resection, or mastoidectomy. In sum, 52.1% (n = 37) of cases had clear margins on first pass in the operating room; 25.4% (n = 18) required further resection; and 12.7% (n = 9) demonstrated final positive/overturned margins read as negative from the frozen sections. Reconstruction included full-thickness (25.4%, n = 18) or superficial-thickness (29.6%, n = 21) skin grafts and local flap reconstruction (25.4%, n = 18), while 5.6% (n = 4) required combinations of free flap and/or other reconstruction techniques; 14.1% (n = 10) did not undergo formal reconstruction.

Conclusion: Periauricular basal cell carcinoma occurs in anatomically diverse locations in and around the ear, and multiple surgical methods are required for successful treatment.
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http://dx.doi.org/10.1177/2473974X20964735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580161PMC
October 2020

Management of the positive sentinel lymph node in the post-MSLT-II era.

J Surg Oncol 2020 Dec 6;122(8):1778-1784. Epub 2020 Sep 6.

Department of Surgery, Michigan Medicine, Ann Arbor, Michigan.

Background And Objectives: The publication of MSLT-II shifted recommendations for management of sentinel lymph node biopsy positive (SLNB+) melanoma to favor active surveillance. We examined trends in immediate completion lymph node dissection (CLND) following publication of MSLT-II.

Methods: Using a prospective melanoma database at a high-volume center, we identified a cohort of consecutive SLNB+ patients from July 2016 to April 2019. Patient and disease characteristics were analyzed with multivariate logistic regression to examine factors associated with CLND.

Results: Two hundred and thirty-five patients were included for analysis. CLND rates were 67%, 33%, and 26% for the year before, year after, and second-year following MSLT-II. Factors associated with undergoing CLND included primary located in the head and neck (59% vs 33%, P = .003 and odds ratio [OR], 5.22, P = .002) and higher sentinel node tumor burden (43% vs 10% for tumor burden ≥0.1 mm, P < .001 and OR, 8.64, P = .002).

Conclusions: Rates of CLND in SLNB+ melanoma decreased dramatically, albeit not uniformly, following MSLT-II. Factors that increased the likelihood of immediate CLND were primary tumor located in the head and neck and high sentinel node tumor burden. These groups were underrepresented in MSLT-II, suggesting that clinicians are wary of implementing active surveillance recommendations for patients perceived as higher risk.
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http://dx.doi.org/10.1002/jso.26200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752829PMC
December 2020

Lymph protects metastasizing melanoma cells from ferroptosis.

Nature 2020 09 19;585(7823):113-118. Epub 2020 Aug 19.

Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Cancer cells, including melanoma cells, often metastasize regionally through the lymphatic system before metastasizing systemically through the blood; however, the reason for this is unclear. Here we show that melanoma cells in lymph experience less oxidative stress and form more metastases than melanoma cells in blood. Immunocompromised mice with melanomas derived from patients, and immunocompetent mice with mouse melanomas, had more melanoma cells per microlitre in tumour-draining lymph than in tumour-draining blood. Cells that metastasized through blood, but not those that metastasized through lymph, became dependent on the ferroptosis inhibitor GPX4. Cells that were pretreated with chemical ferroptosis inhibitors formed more metastases than untreated cells after intravenous, but not intralymphatic, injection. We observed multiple differences between lymph fluid and blood plasma that may contribute to decreased oxidative stress and ferroptosis in lymph, including higher levels of glutathione and oleic acid and less free iron in lymph. Oleic acid protected melanoma cells from ferroptosis in an Acsl3-dependent manner and increased their capacity to form metastatic tumours. Melanoma cells from lymph nodes were more resistant to ferroptosis and formed more metastases after intravenous injection than did melanoma cells from subcutaneous tumours. Exposure to the lymphatic environment thus protects melanoma cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood.
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http://dx.doi.org/10.1038/s41586-020-2623-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484468PMC
September 2020

DNA copy number changes correlate with clinical behavior in melanocytic neoplasms: proposal of an algorithmic approach.

Mod Pathol 2020 07 17;33(7):1307-1317. Epub 2020 Feb 17.

Department of Pathology, Michigan Medicine, 2800 Plymouth Rd, Ann Arbor, MI, 48109, USA.

Increasingly, molecular methods are being utilized in the workup of melanocytic neoplasms. To this end, we sought to correlate data from a single nucleotide polymorphism (SNP) array platform based on molecular inversion probes with clinical data. Copy number variation (CNV) data were obtained on 95 melanocytic tumors (6 ordinary nevi, 15 atypical nevi, 34 ambiguous neoplasms, and 40 melanomas) from 92 patients. The average number of significant CNVs was 0 for nevi, 0.6 for atypical nevi (range 0-3), 2.8 for ambiguous neoplasms (range 0-17), and 18.1 for melanomas (range 0-69). Clinical follow-up data were available in 57 of 95 lesions (56 of 92 patients). Tumors from patients with adverse events demonstrated an average number of CNVs of 24.5 (range 6-69) as compared with 7.9 (range 0-35) among tumors without an associated adverse event (p ≤ 0.001). No adverse events were observed in nevi including atypical nevi. Adverse events were found in 2 of 19 ambiguous neoplasms and 10 of 32 melanomas with follow up. In these two latter groups of neoplasms, the correlation between adverse events and the average number of CNVs remained statistically significant even when controlled for Breslow depth (21.5 versus 8.7, p value = 0.036). No neoplasm with adverse events had ≤3 CNVs. These results provide further evidence that SNP array testing for CNVs may be helpful in the classification and prognostication of ambiguous neoplasms. Based on these results, an algorithmic approach to challenging melanocytic neoplasms using CNV data is suggested, using as cutoff of >3 CNVs with some caveats, as the threshold for a positive result. Future clinical validation, using a larger cohort of relevant tumors, will be necessary.
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http://dx.doi.org/10.1038/s41379-020-0499-yDOI Listing
July 2020

Sentinel Lymph Node Biopsy in Head and Neck Melanoma: Long-term Outcomes, Prognostic Value, Accuracy, and Safety.

Otolaryngol Head Neck Surg 2020 04 11;162(4):520-529. Epub 2020 Feb 11.

Department of Otolaryngology-Head and Neck Surgery, Michigan Medicine, Ann Arbor, Michigan, USA.

Objective: To evaluate the long-term outcomes of sentinel lymph node biopsy (SLNB) for head and neck cutaneous melanoma (HNCM).

Study Design: Retrospective cohort study.

Setting: Tertiary academic medical center.

Subjects And Methods: Longitudinal review of a 356-patient cohort with HNCM undergoing SLNB from 1997 to 2007.

Results: Descriptive characteristics included the following: age, 53.5 ± 19 years (mean ± SD); sex, 26.8% female; median follow-up, 4.9 years; and Breslow depth, 2.52 ± 1.87 mm. Overall, 75 (21.1%) patients had a positive SLNB. Among patients undergoing completion lymph node dissection following positive SLNB, 20 (27.4%) had at least 1 additional positive nonsentinel lymph node. Eighteen patients with local control and negative SLNB developed regional disease, indicating a false omission rate of 6.4%, including 10 recurrences in previously unsampled basins. Ten-year overall survival (OS) and melanoma-specific survival (MSS) were significantly greater in the negative sentinel lymph node (SLN) cohort (OS, 61% [95% CI, 0.549-0.677]; MSS, 81.9% [95% CI, 0.769-0.873]) than the positive SLN cohort (OS, 31% [95% CI, 0.162-0.677]; MSS, 60.3% [95% CI, 0.464-0.785]) and positive SLN/positive nonsentinel lymph node cohort (OS, 8.4% [95% CI, 0.015-0.474]; MSS, 9.6% [95% CI, 0.017-0.536]). OS was significantly associated with SLN positivity (hazard ratio [HR], 2.39; < .01), immunosuppression (HR, 2.37; < .01), angiolymphatic invasion (HR, 1.91; < .01), and ulceration (HR, 1.86; < .01). SLN positivity (HR, 3.13; < .01), angiolymphatic invasion (HR, 3.19; < .01), and number of mitoses ( = .0002) were significantly associated with MSS. Immunosuppression (HR, 3.01; < .01) and SLN status (HR, 2.84; < .01) were associated with recurrence-free survival, and immunosuppression was the only factor significantly associated with regional recurrence (HR, 6.59; < .01).

Conclusions: Long-term follow up indicates that SLNB showcases durable accuracy, safety, and prognostic importance for cutaneous HNCM.
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http://dx.doi.org/10.1177/0194599819899934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012010PMC
April 2020

Next-generation sequencing implicates oncogenic roles for p53 and JAK/STAT signaling in microcystic adnexal carcinomas.

Mod Pathol 2020 06 19;33(6):1092-1103. Epub 2019 Dec 19.

Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.

Microcystic adnexal carcinoma is a locally aggressive sweat gland carcinoma characterized by its infiltrative growth and histopathologic overlap with benign adnexal tumors, often posing challenges to both diagnosis and management. Understanding the molecular underpinnings of microcystic adnexal carcinoma may allow for more accurate diagnosis and identify potential targetable oncogenic drivers. We characterized 18 microcystic adnexal carcinomas by targeted, multiplexed PCR-based DNA next-generation sequencing of the coding sequence of over 400 cancer-relevant genes. The majority of cases had relatively few (<8) prioritized somatic mutations, and lacked an ultraviolet (UV) signature. The most recurrent mutation was TP53 inactivation in four (22%) tumors. Frame-preserving insertions affecting the kinase domain of JAK1 were detected in three (17%) cases, and were nonoverlapping with TP53 mutations. Seven (39%) cases demonstrated copy number gain of at least one oncogene. By immunohistochemistry, p53 expression was significantly higher in microcystic adnexal carcinomas with TP53 mutations compared with those without such mutations and syringomas. Similarly, phospho-STAT3 expression was significantly higher in microcystic adnexal carcinomas harboring JAK1 kinase insertions compared with those with wild-type JAK1 and syringomas. In conclusion, microcystic adnexal carcinomas are molecularly heterogeneous tumors, with inactivated p53 or activated JAK/STAT signaling in a subset. Unlike most other nonmelanoma skin cancers involving sun-exposed areas, most microcystic adnexal carcinomas lack evidence of UV damage, and hence likely originate from a relatively photo-protected progenitor population in the dermis. These findings have implications for the biology, diagnosis, and treatment of microcystic adnexal carcinomas, including potential for therapeutic targeting of p53 or the JAK/STAT pathway in advanced tumors.
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http://dx.doi.org/10.1038/s41379-019-0424-4DOI Listing
June 2020

Institutional Experience of Treatment and Outcomes for Cutaneous Periauricular Squamous Cell Carcinoma.

OTO Open 2019 Jul-Sep;3(3):2473974X19875077. Epub 2019 Sep 13.

Department of Otolaryngology-Head and Neck Surgery, Michigan Medicine, Ann Arbor, Michigan, USA.

Objectives: To report our institutional experience, management, and outcomes of cutaneous periauricular squamous cell carcinoma (SCC).

Study Design: Retrospective chart review.

Setting: Tertiary academic center.

Subjects: Patients undergoing treatment of cutaneous periauricular SCC from 2000 to 2016.

Results: A total of 112 patients had a median follow-up of 24.5 months, a mean ± SD age of 75.7 ± 10.6 years, and a strong male predominance (93.8%). Site distribution shows 87 (77.7%) auricular, 26 (23.2%) preauricular, and 10 (8.8%) postauricular lesions. Of auricular lesions, tumors involved the tragus (n = 3, 3.4%), helix/antihelix (n = 47, 54.0%), conchal bowl (n = 31, 35.6%), external auditory canal (n = 18, 16.1%), and lobule (n = 3, 3.4%). Most patients presented at stage I (52.7%) versus stages II (28.6%), III (6.3%), and IV (12.5%). Patients were largely treated surgically with primary tumor resection ranging from wide local excision to lateral temporal bone resection (± parotidectomy and neck dissection), with 17.0% and 5.4% receiving adjuvant radiation and chemoradiation, respectively. Metastatic spread was seen to the parotid (25.9%) and neck (26.8%), with most common cervical spread to level II. Overall survival, disease-specific survival, and disease-free survival at 3 years were 62%, 89%, and 56%, respectively. Nodal disease was associated with worse disease-specific survival ( < .001) and disease-free survival ( = .042). Pre- and postauricular sites were associated with worse overall survival ( = .007) relative to auricular sites.

Conclusion: Among cutaneous SCC, periauricular subsites pose treatment challenges related to surrounding anatomy and represent a unique tumor population. The reported propensity toward recurrence and patterns of metastasis may better guide treatment of aggressive tumors to include regional nodal dissection.
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http://dx.doi.org/10.1177/2473974X19875077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791998PMC
September 2019

Cranial nerve outcomes in regionally recurrent head & neck melanoma after sentinel lymph node biopsy.

Laryngoscope 2020 07 23;130(7):1707-1714. Epub 2019 Aug 23.

Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, U.S.A.

Objective: Characterize long-term cranial nerve (CN) outcomes following sentinel lymph node biopsy (SLNB) based management for head and neck cutaneous melanoma (HNCM).

Methods: Longitudinal review of HNCM patients undergoing SLNB from 1997-2007.

Results: Three hundred fifty-six patients were identified, with mean age 53.5 ± 19.0 years, mean Breslow depth 2.52 ± 1.87 mm, and 4.9 years median follow-up. One hundred five (29.4%) patients had SLNB mapping to the parotid basin. Eighteen patients had positive parotid SLNs and underwent immediate parotidectomy / immediate completion lymph node dissection (iCLND), with six possessing positive parotid non-sentinel lymph nodes (NSLNs). Fifty-two of 356 (14.6%) patients developed delayed regional recurrences, including 20 total intraparotid recurrences: five following false negative (FN) parotid SLNB, three following prior immediate superficial parotidectomy, two following iCLND without parotidectomy, and the remaining 12 parotid recurrences had negative extraparotid SLNBs. Parotid recurrences were multiple (4.9 mean recurrent nodes) and advanced (n = 4 extracapsular extension), and all required salvage dissection including parotidectomy. Immediate parotidectomy/iCLND led to no permanent CN injuries. Delayed regional HNCM macrometastasis precipitated 16 total permanent CN injuries in 13 patients: 10 CN VII, five CN XI, and one CN XII deficits. Fifty percent (n = 10) of parotid recurrences caused ≥1 permanent CN deficits.

Conclusions: Regional HNCM macrometastases and salvage dissection confer marked CN injury risk, whereas early surgical intervention via SLNB ± iCLND ± immediate parotidectomy yielded no CN injuries. Further, superficial parotidectomy performed in parotid-mapping HNCM does not obviate delayed intraparotid recurrences, which increase risk of CN VII injury. Despite lack of a published disease-specific survival advantage in melanoma, early disease control in cervical and parotid basins is paramount to minimize CN complications.

Level Of Evidence: 4 (retrospective case series) Laryngoscope, 130:1707-1714, 2020.
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http://dx.doi.org/10.1002/lary.28243DOI Listing
July 2020

Association of the POT1 Germline Missense Variant p.I78T With Familial Melanoma.

JAMA Dermatol 2019 05;155(5):604-609

Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, England.

Importance: The protection of telomeres 1 protein (POT1) is a critical component of the shelterin complex, a multiple-protein machine that regulates telomere length and protects telomere ends. Germline variants in POT1 have been linked to familial melanoma, and somatic mutations are associated with a range of cancers including cutaneous T-cell lymphoma (CTCL).

Objective: To characterize pathogenic variation in POT1 in families with melanoma to inform clinical management.

Design, Setting, And Participants: In this case study and pedigree evaluation, analysis of the pedigree of 1 patient with melanoma revealed a novel germline POT1 variant (p.I78T, c.233T>C, chromosome 7, g.124870933A>G, GRCh38) that was subsequently found in 2 other pedigrees obtained from the GenoMEL Consortium.

Main Outcomes And Measures: (1) Identification of the POT1 p.I78T variant; (2) evaluation of the clinical features and characteristics of patients with this variant; (3) analysis of 3 pedigrees; (4) genomewide single-nucleotide polymorphism genotyping of germline DNA; and (5) a somatic genetic analysis of available nevi and 1 melanoma lesion.

Results: The POT1 p.I78T variant was found in 3 melanoma pedigrees, all of persons who self-reported as being of Jewish descent, and was shown to disrupt POT1-telomere binding. A UV mutation signature was associated with nevus and melanoma formation in POT1 variant carriers, and somatic mutations in driver genes such as BRAF, NRAS, and KIT were associated with lesion development in these patients.

Conclusions And Relevance: POT1 p.I78T is a newly identified, likely pathogenic, variant meriting screening for in families with melanoma after more common predisposition genes such as CDKN2A have been excluded. It could also be included as part of gene panel testing.
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http://dx.doi.org/10.1001/jamadermatol.2018.3662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506889PMC
May 2019

Molecular testing of borderline cutaneous melanocytic lesions: SNP array is more sensitive and specific than FISH.

Hum Pathol 2019 04 18;86:115-123. Epub 2018 Dec 18.

Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA 48109-5602; Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA 48109-5602. Electronic address:

Melanocytic lesions with borderline features are diagnostically challenging. Single-nucleotide polymorphism (SNP) arrays, which detect genomic copy number alterations (CNAs), can be helpful in distinguishing between nevi and melanoma. Fluorescence in situ hybridization (FISH) has been used as a more rapid, less expensive alternative to SNP array, using a panel of probes that are often gained or lost in melanoma. We used SNP array data from 63 borderline cutaneous melanocytic lesions and 44 definitive melanomas to predict the performance of FISH testing. Lesions were considered positive by "virtual FISH" if 1 or more of the 5 FISH-probed loci demonstrated appropriate CNAs by SNP array. Cases were classified as positive by SNP array if ≥3 CNAs were present, based on internal validation studies, or if FISH criteria were met. Conventional FISH was performed in 33 cases (17 borderline lesions, 16 melanomas). Of the 63 borderline cases, 44 (70%) were positive by SNP array and 30 (48%) were positive by virtual FISH. A higher proportion of melanomas were positive by SNP array (41/44, 93% sensitivity) and virtual FISH (36/44, 82% sensitivity). Virtual FISH had 61% sensitivity in the borderline group using SNP array as the gold standard, whereas specificity was 84%. There was good correlation between conventional and virtual FISH, with agreement in 30 of 33 (91%) cases. Although FISH is highly effective in distinguishing between nevi and melanoma in cases where the histological diagnosis is straightforward, it is not nearly as sensitive or specific as SNP array when applied to borderline lesions.
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http://dx.doi.org/10.1016/j.humpath.2018.12.002DOI Listing
April 2019

Completion Lymph Node Dissection or Radiation Therapy for Sentinel Node Metastasis in Merkel Cell Carcinoma.

Ann Surg Oncol 2019 Feb 17;26(2):386-394. Epub 2018 Dec 17.

Division of Surgical Oncology, Department of Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI, 48109-5932, USA.

Background: For sentinel lymph node (SLN) metastasis from Merkel cell carcinoma (MCC), the benefit of completion lymph node dissection (CLND) versus radiation therapy (RT) is unclear. This study compares outcomes for patients with SLN metastasis undergoing CLND or RT. We also evaluated positive non-SLNs as a prognostic factor.

Methods: Using a prospective database, we identified MCC patients with SLN metastasis who underwent CLND or RT. At our institution, CLND was recommended for patients with acceptable perioperative risk, while therapeutic RT was offered to those with high perioperative risk. Primary outcomes were MCC-specific survival (MCCSS), disease-free survival (DFS), nodal recurrence-free survival (NRFS), and distant recurrence-free survival (DRFS).

Results: From 2006 to 2017, 163 patients underwent CLND (n = 137) or RT (n = 26). Median follow-up was 1.9 years. CLND had no significant differences for MCCSS (5-year survival 71% vs. 64%, p = 1.0), DFS (52% vs. 61%, p = 0.8), NRFS (76% vs. 91%, p = 0.3), or DRFS (65% vs. 75%, p = 0.3) compared with RT. Patients with positive non-SLNs (n = 44) had significantly worse MCCSS (5-year survival 39% vs. 87%, p < 0.001), DFS (35% vs. 60%, p = 0.005), and DRFS (54% vs. 71%, p = 0.03) compared with negative non-SLNs (n = 93). Multivariate analysis showed positive non-SLNs were independently associated with MCCSS, DFS, and DRFS.

Conclusions: CLND and RT may have similar outcomes for MCC patients with SLN metastasis when treatment aligns with our institutional practices. For patients undergoing CLND, positive non-SLNs is an important prognostic factor associated with poor survival and distant recurrence. This high-risk group should be considered for adjuvant systemic therapy trials.
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http://dx.doi.org/10.1245/s10434-018-7072-7DOI Listing
February 2019

Pediatric melanoma and aggressive Spitz tumors: a retrospective diagnostic, exposure and outcome analysis.

Transl Pediatr 2018 Jul;7(3):203-210

Department of Pediatrics, The University of Michigan, Ann Arbor, MI, USA.

Background: The diagnosis and management of pediatric melanomas is challenging given the presence of both melanomas and histologically aggressive Spitz tumors of undetermined biological significance (S-UBS) in this age group. Study objectives were to examine: factors leading to diagnostic delays, therapy side effects and patient outcomes in these diagnostic groups.

Methods: A retrospective case review was performed using The University of Michigan's pediatric oncology database over a 13-year timespan. Patients referred to our clinic for consideration of interferon therapy due to a diagnosis of a stage III melanoma or aggressive appearing S-UBS with significant lymph node involvement were included.

Results: We found two major causes of diagnosis delay: patients with amelanotic lesions misdiagnosed as having a wart and cases reviewed by non-expert pathologists upfront. The side effects from interferon therapy requiring dose adjustments included neutropenia, thrombocytopenia and mood disturbances. There was wide variability in surveillance scan utilization, therefore leading to variability in patient radiation exposure. Unlike melanoma patients, none of the S-UBS patients experienced disease progression or death.

Conclusions: This study highlights the challenges with the initial clinical diagnosis and pathological sub-categorization of the pediatric S-UBS/melanoma spectrum of skin lesions and emphasizes the role of expert pathology review upfront. Further, education at the primary care level could improve accurate and timely diagnoses. Earlier diagnosis could spare patients from more extensive interventions, metastatic spread or adverse outcomes in this patient population. This study is limited due to its retrospective, single-institution perspective.
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http://dx.doi.org/10.21037/tp.2018.01.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087836PMC
July 2018

Metastatic melanoma with diffuse melanosis histologically after stable response to talimogene laherparepvec therapy.

JAAD Case Rep 2018 May 4;4(4):379-381. Epub 2018 Apr 4.

Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan.

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http://dx.doi.org/10.1016/j.jdcr.2018.01.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911974PMC
May 2018

Subungual atypical lentiginous melanocytic proliferations in children and adolescents: A clinicopathologic study.

J Am Acad Dermatol 2018 Aug 27;79(2):327-336.e2. Epub 2018 Mar 27.

Department of Pathology, University of Michigan, Ann Arbor, Michigan; Department of Dermatology, University of Michigan, Ann Arbor, Michigan. Electronic address:

Background: Most subungual melanocytic lesions in children are benign, but some are difficult to classify due to prominent lentiginous growth and high-grade cytologic atypia.

Objective: To characterize the clinicopathologic features of these rare lesions.

Methods: Subungual atypical lentiginous melanocytic proliferations from patients <20 years of age were collected for clinical and histopathologic review. Fluorescence in situ hybridization (FISH) was performed when possible.

Results: Eleven patients aged 2-19 years had expanding or darkening longitudinal pigmented streak(s) with or without Hutchinson sign. Microscopically, all revealed predominantly single-cell growth, pagetoid scatter, and poor circumscription. Eight (73%) cases showed focal or poor nesting, and 3 (27%) demonstrated confluence. Nuclear enlargement, hyperchromasia, and angulation were present in 8 (73%) cases, 7 (64%) cases, and 6 (55%) cases, respectively. One of 4 cases tested by FISH was positive. Three lesions recurred locally without other adverse outcome.

Limitations: Small sample size and short clinical follow-up. Two cases were examined in partial biopsies only.

Conclusion: Some subungual melanocytic lesions in children and adolescents are histologically indistinguishable from adult subungual melanoma in situ. While the biologic potential remains elusive, FISH might aid in risk stratification. Awareness of this rare group of lesions is crucial for facilitating future investigation into its biologic behavior.
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http://dx.doi.org/10.1016/j.jaad.2018.03.030DOI Listing
August 2018

In reply: Management of thin melanoma.

J Surg Oncol 2018 03 11;117(3):536. Epub 2017 Nov 11.

Department of Surgery, Dartmouth-Hitchcock Medical Center and Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.

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http://dx.doi.org/10.1002/jso.24858DOI Listing
March 2018

The natural history of thin melanoma and the utility of sentinel lymph node biopsy.

J Surg Oncol 2017 Dec 17;116(8):1185-1192. Epub 2017 Jul 17.

Department of Surgery, Dartmouth-Hitchcock Medical Center and Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.

Background And Objectives: Current literature may overestimate the risk of nodal metastasis from thin melanoma due to reporting of data only from lesions treated with SLNB. Our objective was to define the natural history of thin melanoma, assessing the likelihood of nodal disease, in order to guide selection for SLNB.

Methods: Retrospective review. The primary outcome was the rate of nodal disease. Clinicopathologic factors were evaluated to find associations with nodal disease.

Results: Five hundred and twelve lesions, follow up available for 488 (median: 48 months). Lesions treated with WLE/SLNB compared to WLE alone were more likely to have high-risk features. The rate of nodal disease was higher in the WLE/SLNB group (24 positive SLNB, five false-negative SLNB with nodal recurrence: 10.2%) compared to WLE alone (four nodal recurrences: 2.0%). Univariate analysis showed age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm , and ulceration were associated with nodal disease. Multivariate analysis confirmed the association of age ≤45 and ulceration.

Conclusions: SLNB for melanoma 0.75-0.99 mm should be considered in patients age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm , and/or with ulceration. Thin melanoma <0.85 mm without high-risk features may be treated with WLE alone.
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http://dx.doi.org/10.1002/jso.24765DOI Listing
December 2017

Age and Gender Associations of Virus Positivity in Merkel Cell Carcinoma Characterized Using a Novel RNA Hybridization Assay.

Clin Cancer Res 2017 Sep 12;23(18):5622-5630. Epub 2017 Jun 12.

Michigan Center for Translational Pathology, University of Michigan Health System, Ann Arbor, Michigan.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine tumor of the skin. Merkel cell polyomavirus (MCPyV) plays an oncogenic role in the majority of MCCs. Detection of MCPyV in MCCs has diagnostic utility and prognostic potential. We investigated whether RNAscope, an RNA hybridization (ISH) assay for detection of RNA transcripts in tissues, is useful for MCPyV detection. We applied an RNAscope probe targeting MCPyV T antigen transcripts on tissue microarrays (TMA) and whole-tissue sections encompassing 87 MCCs from 75 patients, 14 carcinomas of other types, and benign tissues. For comparison, qPCR was performed on 57 cases of MCC from 52 patients. RNA-ISH demonstrated the presence of MCPyV in 37 of 75 cases (49.3%). Notably, tumors from younger patients (<73 years) had a significantly higher virus positivity than those from elderly patients (≥73 years; 64.9% vs. 34.2%, = 0.011). Female patients had a higher positive rate of MCPyV than male patients (66.7% vs. 39.6%, = 0.032). Data from both RNA-ISH and qPCR were available for 57 samples. Considering MCPyV qPCR as the gold standard for determining MCPyV status, RNAscope had 100% sensitivity and 100% specificity. There was a strong correlation between qPCR copy number and RNA-ISH product score (Spearman correlation coefficient = 0.932, < 0.0001). RNA-ISH is comparably sensitive to qPCR for detection of MCPyV and allows for correlation with tissue morphology. This study also reveals a significant association between age, gender, and MCPyV positivity. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600832PMC
September 2017

Total versus superficial parotidectomy for stage III melanoma.

Head Neck 2017 08 8;39(8):1665-1670. Epub 2017 May 8.

Department of Otolaryngology - Head and Neck Surgery, University of Michigan Health System, Ann Arbor, Michigan.

Background: The primary purpose of this study was to describe the parotid recurrence rates after superficial and total parotidectomy.

Methods: A retrospective cohort study was performed on patients with cutaneous melanoma metastatic to the parotid gland who underwent parotidectomy from 1998 through 2014. Primary outcome was parotid bed recurrence. Secondary outcomes were facial nerve function postoperatively and at last follow-up.

Results: One hundred twenty-nine patients were included in the study. Thirty-four patients (26%) underwent a total parotidectomy and 95 patients underwent superficial parotidectomy. Twelve patients (13%) developed parotid bed recurrence after superficial parotidectomy alone versus zero after total parotidectomy (P = .035). Facial nerve function, clinically detected disease, stage, and adjuvant treatment were not statistically different between the groups (P = .32, .32, .13, and 0.99, respectively).

Conclusion: Parotid bed melanoma recurrence was more common after superficial parotidectomy compared to total parotidectomy, and recurrence resulted in significant facial nerve functional deficit. Our results support total parotidectomy when metastatic melanoma involves the parotid nodal basin.
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http://dx.doi.org/10.1002/hed.24810DOI Listing
August 2017

Efficacy of Staged Excision With Permanent Section Margin Control for Cutaneous Head and Neck Melanoma.

JAMA Dermatol 2017 03;153(3):282-288

Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical School, Ann Arbor3Department of Dermatology, University of Michigan Medical School, Ann Arbor5Division of Plastic Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor.

Importance: Melanoma arising in chronically photodamaged skin, especially on the head and neck, is often characterized by poorly defined clinical margins and unpredictable occult extension. Staged excision techniques have been described to treat these challenging melanomas.

Objective: To investigate the local recurrence rates and margin to clearance end points using staged excision with comprehensive hematoxylin-eosin-stained permanent section margin control.

Design, Setting, And Participants: In this observational cohort study performed from October 8, 1997, to December 31, 2006, with a median follow-up of 9.3 years, 806 patients with melanoma on the head and neck, where clinical occult extension is common, were studied at an academic medical center.

Interventions: Staged excision with comprehensive hematoxylin-eosin-stained permanent section margin control commonly known as the square technique.

Main Outcomes And Measures: Local recurrence rates and margin to clearance end points.

Results: A total of 806 patients (276 women [34.2%]; 805 white [99.9%]) with a median age at the time of first staged excision procedure of 65 years (range, 20-94 years) participated in the study. The estimated local recurrence rates were 1.4% at 5 years, 1.8% at 7.5 years, and 2.2% at 10 years. For each 50-mm2 increase in the size of the clinical lesion, there was a 9% increase in the rate of local recurrence (hazard ratio, 1.09; 95% CI, 1.02-1.15; P = .02). The mean (SD) margin from lesion to clearance for melanoma in situ was 9.3 (5.1) mm compared with 13.7 (5.9) mm for invasive melanoma. For melanoma in situ, margins were clear after 5 mm or less in 232 excisions (41.1%) and after 10 mm or less in 420 excisions (74.5%). For invasive melanoma, margins were clear after 5 mm or less in 8 excisions (3.0%) and after 10 mm or less in 141 excisions (52.2%).

Conclusions And Relevance: Staged excision with comprehensive permanent section margin control of melanomas arising in chronically sun-damaged skin on the head and neck has favorable recurrence rates when melanoma margins are difficult to assess, and recurrence rates are high with traditional techniques.
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http://dx.doi.org/10.1001/jamadermatol.2016.4603DOI Listing
March 2017

Sentinel Lymph Node Biopsy for Cutaneous Squamous Cell Carcinoma on the Head and Neck.

JAMA Otolaryngol Head Neck Surg 2016 12;142(12):1171-1176

Department of Otolaryngology, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor.

Importance: Metastasis of cutaneous squamous cell carcinoma (SCC) to the nodal basin is associated with a poor prognosis. The role of sentinel lymph node biopsy (SLNB) for regional staging in patients diagnosed with SCC is unclear.

Objective: To evaluate a single institution's experience with use of SLNB for regional staging of SCC on the head and neck.

Design, Setting, And Participants: A retrospective review of 53 patients who were diagnosed with SCC on the head and neck, at high risk for nodal metastasis based on National Comprehensive Cancer Network (NCCN) risk factors, and treated with wide local excision (WLE) and SLNB from December 1, 2010, through January 30, 2015, in a single academic referral center was performed. The follow-up period ended November 5, 2015. Sentinel lymph node biopsy paraffin blocks were retrieved and processed retrospectively with serial sectioning and immunohistochemical analysis (IHC) in cases with nodal recurrence following a negative SLNB.

Main Outcomes And Measures: Sentinel node (SN) identification rate, SLNB positivity rate, local recurrence, regional nodal recurrence, and distant recurrence.

Results: In 53 patients with 54 tumors the SN identification rate was 94%. The SLNB positivity rate was 11.3%. On more thorough tissue processing and IHC, metastatic SCC was identified in 2 of 5 (40%) cases previously deemed negative. After reclassification of these cases, the adjusted SLNB positivity rate was 15.1%. The adjusted rate of false omission was 7.1% (95% CI, 2%-19%). Nodal disease developed in 20.8% overall. Angiolymphatic invasion (Cohen d, 3.52; 95% CI, 1.83-5.21), perineural invasion (Cohen d, 0.81; 95% CI, 0.09-1.52), and clinical size (Cohen d, 0.83; 95% CI, 0.05-1.63) were associated with the presence of nodal disease.

Conclusions And Relevance: Rigorous study of SLNB for cutaneous SCC incorporating prospectively-collected comprehensive data sets based on standardized treatment algorithms is justified with potential to modify clinical practice. Our study demonstrates the critical importance of serial sectioning and IHC of the SLNB specimen for accurate diagnosis. Use of the NCCN guidelines may facilitate identification of patients with SCC at high risk for nodal metastasis.
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http://dx.doi.org/10.1001/jamaoto.2016.1927DOI Listing
December 2016

Genomic copy number analysis of a spectrum of blue nevi identifies recurrent aberrations of entire chromosomal arms in melanoma ex blue nevus.

Mod Pathol 2016 Mar 8;29(3):227-39. Epub 2016 Jan 8.

Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

Blue nevi may display significant atypia or undergo malignant transformation. Morphologic diagnosis of this spectrum of lesions is notoriously difficult, and molecular tools are increasingly used to improve diagnostic accuracy. We studied copy number aberrations in a cohort of cellular blue nevi, atypical cellular blue nevi, and melanomas ex blue nevi using Affymetrix's OncoScan platform. Cases with sufficient DNA were analyzed for GNAQ, GNA11, and HRAS mutations. Copy number aberrations were detected in 0 of 5 (0%) cellular blue nevi, 3 of 12 (25%) atypical cellular blue nevi, and 6 of 9 (67%) melanomas ex blue nevi. None of the atypical cellular blue nevi displayed more than one aberration, whereas complex aberrations involving four or more regions were seen exclusively in melanomas ex blue nevi. Gains and losses of entire chromosomal arms were identified in four of five melanomas ex blue nevi with copy number aberrations. In particular, gains of 1q, 4p, 6p, and 8q, and losses of 1p and 4q were each found in at least two melanomas. Whole chromosome aberrations were also common, and represented the sole finding in one atypical cellular blue nevus. When seen in melanomas, however, whole chromosome aberrations were invariably accompanied by partial aberrations of other chromosomes. Three melanomas ex blue nevi harbored aberrations, which were absent or negligible in their precursor components, suggesting progression in tumor biology. Gene mutations involving GNAQ and GNA11 were each detected in two of eight melanomas ex blue nevi. In conclusion, copy number aberrations are more common and often complex in melanomas ex blue nevi compared with cellular and atypical cellular blue nevi. Identification of recurrent gains and losses of entire chromosomal arms in melanomas ex blue nevi suggests that development of new probes targeting these regions may improve detection and risk stratification of these lesions.
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http://dx.doi.org/10.1038/modpathol.2015.153DOI Listing
March 2016

Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma.

Cancer Cell 2015 Mar;27(3):327-41

Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080, USA. Electronic address:

Smoothened (SMO) inhibitors are under clinical investigation for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). Most BCC patients experience significant clinical benefit on vismodegib, but some develop resistance. Genomic analysis of tumor biopsies revealed that vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels. Furthermore, we found evidence for intra-tumor heterogeneity, suggesting that a combination of therapies targeting components at multiple levels of the Hh pathway is required to overcome resistance.
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http://dx.doi.org/10.1016/j.ccell.2015.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675004PMC
March 2015

Sentinel lymph node biopsy in melanoma: final results of MSLT-I.

Future Oncol 2014 May;10(7):1121-3

Department of Dermatology, Ann Arbor, MI, USA.

In 1994 an international randomized controlled clinical trial, MSLT-I, opened to study the utility of sentinel lymph node biopsy (SLNB) for patients with clinically localized melanoma. This trial compared outcomes of patients treated with wide local excision (WLE) and SLNB (followed by immediate completion lymph node dissection [CLND] for those with a positive sentinel node [SN]) with outcomes of patients treated with WLE alone and CLND upon the development of clinically apparent disease. In February 2014 the final analysis of long-term outcomes data was published. Importantly, these data showed that the rates of nodal positivity were the same between the two arms of the trial. Although no difference in 10-year melanoma-specific survival was noted between the two arms, this was not entirely surprising as the overall rate of nodal disease within the trial was 20.8%, meaning that 79.2% of patients could not derive a benefit from SLNB. Subset analysis was performed to determine the impact of early intervention for those patients most likely to have a benefit from early detection. This analysis showed that for patients with nodal disease and intermediate-thickness melanoma (defined as 1.2-3.5-mm Breslow depth), early treatment following positive SLNB was associated with improved 10-year distant disease-free survival and improved 10-year melanoma-specific survival.
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http://dx.doi.org/10.2217/fon.14.67DOI Listing
May 2014

Sentinel lymph node biopsy in melanoma: controversies and current guidelines.

Future Oncol 2014 Feb;10(3):429-42

Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA.

Melanoma is a global health problem and the incidence of this disease is rising. While localized melanoma has an excellent prognosis, regional and distant disease is associated with much poorer outcomes. Optimal treatment for clinically localized melanoma requires surgical control of the primary site and accurate staging of the regional nodal basin with sentinel lymph node biopsy (SLNB). While further data are required to determine if SLNB is associated with a survival advantage, currently available data supports the use of SLNB for staging of appropriate patients and the procedure may offer benefits beyond staging. This article reviews current data that shapes guidelines regarding patient selection for SLNB in melanoma and highlights areas where performing this procedure remains controversial.
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http://dx.doi.org/10.2217/fon.13.245DOI Listing
February 2014

Q-switched laser therapy for recalcitrant and recurrent pigmentation after chemical depigmentation for extensive vitiligo.

Dermatol Surg 2012 Sep 23;38(9):1563-5. Epub 2012 May 23.

Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA.

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http://dx.doi.org/10.1111/j.1524-4725.2012.02447.xDOI Listing
September 2012