Publications by authors named "Noah Frydenlund"

9 Publications

  • Page 1 of 1

Non-Muscle Invasive Papillary Urothelial Carcinoma Metastatic to the Mandible.

J Investig Med High Impact Case Rep 2018 Jan-Dec;6:2324709618806332. Epub 2018 Oct 16.

University of Iowa Hospitals and Clinics, Iowa City, IA, USA.

Urothelial carcinoma, the most common histologic subtype of bladder cancer in the United States, most frequently presents as non-muscle invasive disease. Initially, therapy involves transurethral endoscopic resection and subsequent intravesical therapies with extended surveillance for high-risk disease. Even with the best treatments, recurrence and progression can occur. However, metastasis of non-muscle invasive bladder cancer to distant sites without evidence of progression or regional metastasis is rare. In this article, we present the case of a patient with high-grade papillary urothelial carcinoma who developed an unusual metastasis to the mandible, confirmed by GATA-3 immunostaining, over 4 years after initial transurethral resection. Prior to the development of metastatic disease, this patient had no evidence of local recurrence during maintenance Bacillus Calmette-Guerin intravesical therapy and concurrent surveillance. Positron emission tomography-computed tomography taken after presentation with mandibular metastasis did not show any evidence of regional metastasis. This case highlights an unusual location for distant metastasis of urothelial carcinoma occurring in a patient without evidence of muscle invasive disease or regional metastasis. We additionally highlight the utility of GATA-3 immunostaining in identifying urothelial carcinoma histologically.
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http://dx.doi.org/10.1177/2324709618806332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194919PMC
October 2018

Targeting epigenetics for treatment of BRAF mutated metastatic melanoma with decitabine in combination with vemurafenib: A phase lb study.

Oncotarget 2017 Oct 26;8(51):89182-89193. Epub 2017 Sep 26.

Department of Hematology, Oncology and Blood and Marrow Transplantation and the Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA.

Introduction: Epigenetic modifications play an important role in progression and development of resistance in BRAF positive metastatic melanoma. Therefore, we hypothesized that the action of vemurafenib (BRAF inhibitor) can be made more effective by combining with low dose decitabine (a DNA methyltransferase inhibitor). The primary objective of this phase lb study was to determine the dose limiting toxicity and maximum tolerated dose of combination of subcutaneous decitabine with oral vemurafenib in patients with BRAF positive metastatic melanoma with or without any prior treatment.

Experimental Design: The study employed 3+3 dose escalation combining subcutaneous decitabine at different doses and schedules (4 cohorts) with the standard oral dose of vemurafenib 960 mg twice daily. Preclinical assessment and further analysis were also performed in A375 melanoma cell line.

Results: Fourteen patients received study treatment. No dose limiting toxicity was encountered and maximum tolerated dose was not reached. Important toxicities included fatigue, increased creatinine, neutropenia, leucopenia, hypophosphatemia, rash and hyperuricemia. Three patients achieved complete response, three had partial response and five had stable disease. Preclinical assessment demonstrated action of the combination which delayed the development of acquired resistance and improved duration of treatment sensitivity.

Conclusions: The combination of oral vemurafenib with subcutaneous decitabine is safe and showed activity in BRAF positive metastatic melanoma. Since most responses were seen in cohort 1, which utilized low-dose, long-term decitabine, future studies of this combination treatment should utilize longer duration of decitabine, at the lowest dose of 0.1 mg/kg.
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http://dx.doi.org/10.18632/oncotarget.21269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687680PMC
October 2017

PD-L1 and immune escape: insights from melanoma and other lineage-unrelated malignancies.

Hum Pathol 2017 08 8;66:13-33. Epub 2017 Jul 8.

Dermatopathology Section, Department of Pathology and Laboratory Medicine (113), VA Integrated Systems Network (VISN1), West Roxbury, 02132, MA. Electronic address:

One of the major breakthroughs in oncology in the past decade has been the research and development of immune checkpoint inhibitors. Since the discovery of the PD-1/PD-L1 axis as a key mediator in peripheral self-tolerance and the subsequent discovery of its role promoting immune escape in cancers, the PD-1/PD-L1 pathway has produced considerable excitement from both a scientific and therapeutic standpoint. The past decade has seen an explosion in the number of clinical trials utilizing anti-PD-1/PD-L1 therapy. Notably, pathologists have played a critical role in the development of these trials, and in guiding the use of anti-PD-1/PD-L1 therapies in FDA-approved clinical settings. Analysis of tissue biopsies has been increasingly used to predict patients with which cancers are most likely to benefit from these new therapies. However, many open questions remain in a rapidly changing therapeutic and scientific landscape. In this review, we describe the basic functioning of the PD-1/PD-L1 axis in normal biology, how it is coopted by cancers to promote immune escape, and then review the literature regarding the prognostic value of tumoral PD-L1 expression on its own before discussing recent therapeutic advances, and the emerging role for pathologists in predicting response to anti-PD-1/PD-L1 therapies. Special attention is given to melanoma and non-small cell lung cancer, malignancies that have seen the broadest applications of anti-PD-L1/PD-1 therapies.
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http://dx.doi.org/10.1016/j.humpath.2017.06.012DOI Listing
August 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

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

Perineural invasion in cutaneous squamous cell carcinoma: role of immunohistochemistry, anatomical site, and the high-affinity nerve growth factor receptor TrkA.

Hum Pathol 2015 Aug 22;46(8):1209-16. Epub 2015 May 22.

Department of Pathology and Laboratory Medicine (113), VA Medical Center, 1400 VFW PKWY, MA 02132 USA, USA. Electronic address:

Perineural invasion (PNI) has been recently added to the American Joint Committee on Cancer cutaneous squamous cell carcinoma (cSCC) staging criteria as a high-risk tumor characteristic and is purportedly more common in cSCCs of the head and neck (H&N). Expression of the high-affinity nerve growth factor receptor TrkA has been shown to be associated with PNI in noncutaneous neoplasms. Given this, we sought to ascertain the incidence of PNI in cSCCs using double immunostaining (DIS) and to investigate PNI's relationship with TrkA and established histopathologic prognosticators. Fifty-seven cSCCs from the H&N and 53 from non-H&N areas were immunohistochemically analyzed for PNI (DIS with S-100 and p63) and TrkA expression. Comparing H&N versus non-H&N areas, using hematoxylin and eosin, PNI was detected in 11% versus 6% cases, respectively, and, using DIS, in 23% versus 15%, respectively, with significant disagreement between both methods (κ = 0.47; P = .002). There was a 2.33-fold increase in PNI detection with DIS compared to hematoxylin and eosin (95% confidence interval, 1.12-4.87; P = .02). TrkA expression was 1.96 times more frequently observed in cSCCs from the H&N compared to those from non-H&N areas (P = .01). Regardless of site, TrkA expression was associated with decreased degree of differentiation (odds ratio, 6.46; P = .0006) and high-risk morphologic variants (odds ratio, 6.53; P = .002) but not significantly associated with PNI (P = .33). Increased PNI detection with DIS underscores the adjunctive utility of immunohistochemistry in microstaging. Significantly more common TrkA expression in cSCCs of the H&N argues in favor of heterogeneity among SCCs from different anatomical sites.
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http://dx.doi.org/10.1016/j.humpath.2015.05.003DOI Listing
August 2015

Desmoplastic melanoma, neurotropism, and neurotrophin receptors--what we know and what we do not.

Adv Anat Pathol 2015 Jul;22(4):227-41

*Division of Graduate Medical Sciences, Boston University School of Medicine, Boston, MA †Department of Pathology and Laboratory Medicine, VA Medical Center, West Roxbury, MA.

Desmoplastic melanoma (DM) is a relatively rare cytomorphologic variant of melanoma with a marked propensity for perineural invasion (PNI). Historically, DMs that display PNI have been grouped under the umbrella term of neurotropic melanoma (NM). However, definitions for NM and desmoplastic NM are not consistent in the literature, presenting a barrier to a comprehensive understanding of these lesions. In this review, we parse the literature on DM, NM, and desmoplastic NM, to clarify definitions and ascertain the incidence of PNI, with a view toward understanding its prognostic relevance. Neurotrophins, which represent a family of signaling peptides important to the development and maintenance of the peripheral nervous system, have been implicated in the pathogenesis of PNI in select lineage-unrelated malignancies. Given this, we also detail evidence linking neurotrophins and their receptors (TrkA, RET, p75NGFR, and NCAM) to the pathogenesis of PNI in melanoma.
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http://dx.doi.org/10.1097/PAP.0000000000000076DOI Listing
July 2015

Neurotrophin receptors and perineural invasion in desmoplastic melanoma.

J Am Acad Dermatol 2015 May 7;72(5):851-8. Epub 2015 Mar 7.

Dermatopathology, Section, Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts. Electronic address:

Background: Perineural invasion (PNI) in desmoplastic melanoma is associated with increased local recurrence and reduced disease-free survival. The biological mechanisms underlying PNI remain unclear although several lines of evidence implicate neurotrophins and their receptors.

Objectives: We investigated the expression of p75NGFR and TrkA, and the presence of functional RET polymorphism (RETp) as they relate to PNI in desmoplastic melanoma.

Methods: In all, 43 cases of desmoplastic melanoma were immunohistochemically evaluated for TrkA and p75NGFR expression and RETp was detected by direct DNA sequencing.

Results: PNI was present in 67% of cases. On univariate analysis, p75NGFR was associated with PNI (expression detected in 79% of PNI-positive cases compared with 36% of PNI-negative cases, P = .005), increased Breslow depth (P = .007), and greater Clark level (P = .01). RETp was noted in 28% of cases but was not significantly associated with PNI (P = .27) or other histopathologic variables. TrkA expression was absent in all cases. PNI was associated with increased Breslow depth and Clark level (P = .01 and P = .009, respectively). Controlling for the association between p75NGFR and depth, p75NGFR remained associated with an increased propensity for PNI (odds ratio 4.68, P = .04).

Limitations: The sample size was limited.

Conclusion: In desmoplastic melanoma, p75NGFR expression is significantly associated with PNI and a more locally aggressive phenotype.
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http://dx.doi.org/10.1016/j.jaad.2015.01.026DOI Listing
May 2015
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