DERMATOPATHOLOGY

Neurotrophin receptors and perineural invasion in desmoplastic melanoma Noah Frydenlund, BS,a Dominick A. Leone, MPH,b Brendon Mitchell, MA,e Shi Yang, MD,c April Deng, MD, PhD,f Mai P. Hoang, MD,g and Meera Mahalingam, MD, PhD, FRCPathd Boston and Worcester, Massachusetts; and Gainesville, Florida 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. ( J Am Acad Dermatol 2015;72:851-8.) Key words: desmoplastic melanoma; immunohistochemistry; neurotrophin; p75NGFR; perineural invasion; RET; TrkA.

P

erineural invasion (PNI) refers to the invasion of the perineural sheath by tumor cells, followed by their subsequent proliferation and axial spread within the perineural space.1 In melanoma, PNI is most frequently seen in desmoplastic melanoma, although epithelioid melanomas may, albeit rarely, display PNI.1-3 The clinical relevance of PNI in cutaneous malignancies has been best established in squamous cell carcinoma in which it is considered a high-risk tumor characteristic,4 and in melanoma PNI has been linked From the Division of Graduate Medical Sciences,a School of Public Health,b Department of Pathology,c and Dermatopathology, Section, Department of Dermatology,d Boston University School of Medicine; University of Florida College of Medicinee; Department of Pathology, University of Massachusetts Medical School, Worcesterf; and Department of Pathology, Massachusetts General Hospital, Boston.g Funding sources: None. Conflicts of interest: None declared. Accepted for publication January 16, 2015.

Abbreviations used: IHC: NGF: OR: PNI: RETp:

immunohistochemistry nerve growth factor odds ratio perineural invasion functional RET polymorphism

to increased depth of invasion and greater risk of local recurrence.1,5,6 Reprints not available from the authors. Correspondence to: Meera Mahalingam, MD, PhD, FRCPath, Dermatolopathology Section, Department of Dermatology, Boston University School of Medicine, 609 Albany St, J-401, Boston, MA 02118. E-mail: [email protected]. Published online March 6, 2015. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.01.026

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The biological basis for PNI remains to be Laboratory, Boston University School of Medicine. elucidated. Neurotrophins and their receptors Inclusion criteria were randomly selected cases of have emerged as popular candidates for mediating primary melanoma with adequate tumoral tissue to PNI.5,7-9 Particular attention has been paid to nerve allow for analyses. Histologic sections of all cases growth factor (NGF) and both its high and low were reviewed by 2 board-certified dermatopatholaffinity receptors (TrkA and p75NGFR, respectively). ogists (initial sign-out on all by a dermatopathologist; Expression of TrkA has been linked to PNI in select cases were then re-reviewed, and the diagnoses cutaneous and noncutaconfirmed by the senior neous malignancies.8,10-13 author). All patient data CAPSULE SUMMARY There is at least 1 report of were de-identified. TrkA detected by immuPerineural invasion is frequently nohistochemistry (IHC) in Immunohistochemical observed in desmoplastic melanoma and primary and metastatic analyses of TrkA may be a negative prognostic finding. melanoma,14 and another expression p75NGFR expression in desmoplastic demonstrating TrkA expresFormalin-fixed, paraffinmelanoma is associated with an sion in vitro in melanoma cell embedded tissue of primary increased incidence of perineural lines.15 The use of staining melanomas (n = 43) were invasion beyond its previous affiliation for p75NGFR for distinguishbaked at 758C for 30 minutes. with spindle cell morphology. ing spindled melanomas Sections were deparaffinized from other cutaneous spinwith xylene and rehydrated p75NGFR positivity in desmoplastic dled lesions has been previin a series of decreasing melanoma indicates a locally aggressive ously demonstrated.16-21 In concentrations of ethanol sotumor, and should prompt a high degree 2010, Chan and Tahan5 used lution. Heat-induced antigen of suspicion toward perineural invasion. IHC to show that p75NGFR retrieval was carried out in expression was present in 8 retrieval solution (Dako, of 10 PNI-positive melanomas compared with 1 of 9 Carpinteria, CA) with a pH of 6.1 in a 988C bath for of PNI-negative cases, although the study was not 20 minutes. All immunostained slides were reviewed confined to desmoplastic melanoma and the small and scored by the first author (N. F.) and the senior sample size precluded extensive analysis. Lastly, author (M. M.) in a blinded fashion with respect to the proto-oncogene RET (which encodes the each other’s scores and any disagreements were receptor tyrosine kinase for glial cell lineederived reviewed together to achieve a consensus score. neurotrophic factor) has been suggested to play a The slides were treated with dual endogenous role in mediating PNI in pancreatic cancers.9,22 enzyme block (Dako) then incubated with anti-TrkA Notably, a functional RET polymorphism in exon (14G6) rabbit monoclonal antibody (Cell Signaling 11 (RETp) has been shown to be more frequently Technology, Danvers, MA) at a dilution of 1:200 for 50 expressed in desmoplastic melanoma, suggesting minutes at room temperature, followed by treatment that it contributes to the enhanced propensity of with polymer horseradish peroxidase (Dako) for 20 desmoplastic melanoma for PNI.23 minutes. Color development and contrast were Given the above, aims in the current study were to achieved using DAB and hematoxylin, respectively. evaluate the relationship between TrkA, p75NGFR, Positive TrkA expression was defined as either RETp, and PNI in a cohort of desmoplastic membranous or mixed (membranous and cytomelanomas. In addition, we investigated their plasmic) staining of tumor cells. Those cells displaying relationship to established histopathologic progonly cytoplasmic staining were considered negative. nosticators (Breslow depth, Clark level, pure vs Membranous staining of basal epidermal cells, eccrine mixed subtype, host response, ulceration, and epithelial cells, mature sebocytes, and the outer root regression). sheath of hair follicles served as positive internal controls where they could be visualized. d

d

d

METHODS Sample selection This study was approved by the institutional review board of Boston University School of Medicine (docket numbers H-32816, H-32952). Archival annotated tissue samples with a diagnosis of desmoplastic melanoma (n = 43) were retrieved from the pathology files of the Skin Pathology

p75NGFR and RET polymorphism Sections from the same formalin-fixed paraffinembedded tissue blocks of desmoplastic melanoma cases used in the current study were analyzed previously for p75NGFR expression and RET G619S polymorphism.24 Briefly, p75NGFR expression was determined via IHC analysis using an anti-p75NGFR

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antibody (1:100 Biocare Medical LLC, Concord, CA). Slides were scored using cut-offs based on the methodology reported by Iwamoto et al.17 For statistical purposes cases with 11% or more of tumor cells staining were considered positive. RET polymorphisms were detected by direct DNA sequencing in the RET coding region on exon 11 with the forwarding primer. More detailed methodology can be found in Miller et al.24 Statistical analyses The associations between PNI and p75NGFR with potential confounding factors were separately assessed using univariate analysis. A x2 test of independence was used for categorical demographics (gender) and the following histopathologic prognosticators: Breslow depth; Clark level; pure vs mixed subtype; host response; ulceration; and regression. Fisher exact test was used if the expected frequencies were less than 5, and a Student t test was used to examine the association of age with PNI and p75NGFR. Factors associated with both PNI and p75NGFR, but not believed to be on the causal pathway, were controlled for in a multivariable logistic regression model. Although underpowered, additional logistic models were examined using factors associated with either PNI or p75NGFR (but not both), and a stratified analysis of mixed versus pure type desmoplastic melanoma.

RESULTS Clinical data Of the 43 cases of desmoplastic melanoma studied, 24 were male and 19 were female. The median age at the time of diagnosis was 72 years (range: 16-92), and tumors presented in predominantly sun-exposed sites. A total of 21 of 43 were located on the head and neck, 14 of 43 on the extremities, and 7 of 43 on the trunk. Clinically apparent pigmentation was reported in 18 of 41 cases (data not available for 2 cases). PNI is associated with greater Clark level and increasing Breslow depth but not other histopathologic variables PNI was observed in 29 of 43 (67%) cases of desmoplastic melanoma. Of histopathologic variables analyzed, both greater Clark level and increased Breslow depth were significantly associated with PNI (P = .002 and P = .01, respectively). Notably, 31% of PNI-positive cases exhibited Clark level V invasion compared with 7% of PNI-negative cases. Presence of mitosis, host response, ulceration, and regression were not significantly associated with PNI. No difference was

Table I. Perineural invasion and histopathologic variables in desmoplastic melanoma

Variable

Sex Male Female Breslow depth, mm 0.01-1.00 1.01-2.00 2.01-4.00 [4.00 Clark level I II III IV V Desmoplastic varianty Pure Mixed Mitosis Present Absent Host response Present Absent Ulceration Present Absent Regression Present Absent

PNI-negative PNI-positive P cases, No. (%) cases, No. (%) n = 14 values* n = 29

16 (57.1) 12 (42.9)

8 (57.1) 6 (35.3)

2 6 14 7

(6.9) (20.7) (48.3) (24.1)

7 3 3 1

(50.0) (21.4) (21.4) (7.1)

0 0 0 20 9

(0.0) (0.0) (0.0) (69.0) (31.0)

0 0 5 8 1

(0.0) (0.0) (35.7) (57.1) (7.1)

.68

.01

.002

15 (51.7) 14 (48.3)

9 (64.3) 5 (35.7)

.44

26 (89.7) 3 (10.3)

10 (71.4) 4 (28.6)

.19

13 (44.8) 16 (55.2)

4 (28.6) 10 (71.4)

.34

2 (6.9) 27 (93.1)

1 (7.1) 13 (92.9)

1.00z

1 (3.4) 28 (96.6)

2 (14.3) 12 (85.7)

.24

One case missing gender data. PNI, Perineural invasion. *Unadjusted P values were calculated using x 2 test of independence or Fisher test when expected frequencies were \5; unadjusted P values were considered significant when \.05 indicated by boldface values. y Tumors were classified as mixed desmoplastic melanoma per previously established criteria24 if 2 morphologically distinct cell populations were present; with at least 10% of cells representing conventional melanoma; pure desmoplastic melanomas were defined as those with [90% of cells displaying typical desmoplastic melanoma morphology. z There was insufficient power to resolve an approximate P value using Fisher method.

noted in the propensity of the pure and mixed variants of desmoplastic melanoma for PNI (Table I). p75NGFR expression is associated with PNI, increasing Breslow depth, and greater Clark level Overall, p75NGFR expression was detected in 28 of 43 (65%) desmoplastic melanomas (17 with #10%, 1 with 11%-50%, 7 with 51%-75%, and 20 with [75% staining of cells). Staining intensity was uniformly

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Table II. p75NGFR expression and histopathologic variables

Variable

Sex Male Female Depth, mm 0.01-1.00 1.01-2.00 2.01-4.00 [4.00 Clark level I II III IV V Desmoplastic variant Pure Mixed Mitosis Present Absent Host response Present Absent Ulceration Present Absent Regression Present Absent

p75NGFR-positive cases, No. (%) n = 28

p75NGFR-negative cases, No. (%) n = 15

Table III. Neurotrophin receptors and perineural invasion in desmoplastic melanomaeunivariate analysis

P values*

15 (55.6) 12 (44.4)

9 (60.0) 6 (40.0)

.78

2 6 12 8

(7.1) (21.4) (42.9) (28.6)

7 3 5 0

(46.7) (20.0) (33.3) (0.0)

.007

0 0 2 16 10

(0.0) (0.0) (7.1) (57.1) (35.7)

0 0 3 12 0

(0.0) (0.0) (20.0) (80.0) (0.0)

.01

15 (53.6) 13 (46.4)

9 (60.0) 6 (40.0)

.69

25 (89.3) 3 (10.7)

11 (73.3) 4 (26.7)

.22

12 (42.9) 16 (57.1)

5 (33.3) 10 (66.7)

.54

2 (7.1) 26 (92.9)

1 (6.7) 14 (93.3)

1.00y

2 (7.1) 26 (92.9)

1 (6.7) 14 (93.3)

1.00y

One case missing gender data. *Unadjusted P values were calculated using x 2 test of independence or Fisher test when expected frequencies were \5; unadjusted P values were considered significant when \.05 indicated by boldface values. y There was insufficient power to resolve an approximate P value using Fisher method.

strong wherever present. On univariate statistical analysis (Table II), p75NGFR expression was significantly associated with increasing Breslow depth and greater Clark level (P = .007 and P = .01, respectively). p75NGFR was significantly associated with PNI (Table III, and Fig 1, A and B), with expression noted in 79% of PNI-positive cases and 36% of PNI-negative cases (P = .005). p75NGFR expression is independently associated with PNI controlling for increasing depth After examining potential confounders using univariate analysis, only depth was associated with both PNI and p75NGFR. Although both Breslow

Positive for Positive for Positive TrkA p75NGFR for RET expression, expression, polymorphism,y No. (%) No. (%) No. (%)

PNI-positive cases, n = 29 PNI-negative cases, n = 14 P values*

0 (0.0)

23 (79.3)

10 (38.5)

0 (0.0)

5 (35.7)

2 (12.5)

1.00

.005

.27

PNI, Perineural invasion. *Unadjusted P values were calculated using x 2 test of independence or Fisher test when expected frequencies were \5; unadjusted P values were considered significant when \.05 indicated by boldface values. y One case was not analyzed for RET polymorphism (case 42).

depth and Clark level provided information on the associations of depth with PNI and p75NGFR, we chose to dichotomize the depth as less than 2 mm and greater than or equal to 2 mm to increase statistical power in the multivariable logistic model. Adjusting for the potential confounding effects of depth, we observed that expression of p75NGFR was associated with a significant increase in the odds of displaying PNI (adjusted odds ratio [OR] 4.68, 95% confidence interval 1.03-21.17, P = .04). Additional multivariable logistic models were then created using histopathologic factors that were marginally associated with PNI or p75NGFR. After stepwise inclusion of additional confounding factors in the multivariate analyses, the magnitude of the association between PNI and p75NGFR, as measured by the OR, remained relatively stable (Table IV). Although not reaching the .05 significance level, the pure variant showed a greater association between PNI and p75NGFR (OR 6.57, 95% confidence interval 0.84-51.04, P = .07) compared with mixed desmoplastic melanoma (OR 4.50, 95% confidence interval 0.25-80.56, P = .31). RET functional polymorphism is not associated with PNI or any of the histopathologic variables RETp was detected in 12 of 42 (29%) desmoplastic melanomas (1 case [case 42] had insufficient tissue for analysis) (Fig 1, C). Although a greater percentage of PNI-positive cases exhibited RETp (39% in PNI-positive vs 13% in PNI-negative cases) this difference was not significant on univariate analysis (P = .27) (Table III). RETp was not associated with any histopathologic variables on univariate analysis (Table V). Multivariate analysis controlling for the

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Fig 1. Desmoplastic melanoma; representative examples of neurotrophin receptors analyzed in current study. A, Perineural invasion (PNI), case 43, hematoxylin-eosin stain. B, Corresponding section demonstrating PNI with p75NGFR immunohistochemical staining (case 43). C, GGT/AGT functional RET polymorphism (RETp) at codon 691 of exon 11 (case 18). D to F, Immunohistochemical staining with TrkA demonstrating positive staining of only internal controls. D, Positive staining of basal epidermal keratinocytes; negative staining of atypical lentiginous melanocytic proliferation (case 35). E, Positive staining of eccrine glands; negative staining of adjacent desmoplastic melanoma cells (case 24). F, Positive staining of follicular keratinocytes; negative staining of atypical lentiginous melanocytic proliferation extending along follicular epithelium (case 2). (Original magnifications: A, B, D, F, 320; E, 340.)

presence of p75NGFR expression did not show a significant association with PNI. TrkA is not expressed in desmoplastic melanomas TrkA expression was negative in all cases of desmoplastic melanoma. Negative expression was confirmed by validation of positive staining of internal controls (Fig 1, D to F ).

DISCUSSION A conclusive understanding of PNI’s prognostic relevance in melanoma has yet to be ascertained. In our analysis of PNI as a distinct histopathologic entity in desmoplastic melanoma, we observed a significant correlation between PNI and both greater Clark level and increased Breslow depth. Our observation that 90% of Clark level V desmoplastic melanomas display PNI may be explained by

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Table IV. Multivariate analysis of p75NGFR expression and propensity for perineural invasion controlling for potential confounding variables Model

OR*

95% CI

P values

p75NGFR 1 depth p75NGFR 1 depth 1 host response p75NGFR 1 depth 1 mitosis p75NGFR 1 depth 1 host response 1 mitosis

4.68 4.26

1.03-21.17 0.90-20.09

.04 .07

4.26 3.74

0.92-19.78 0.76-18.42

.06 .10

Boldface indicates statistical significance (P \ .05). CI, Confidence interval; OR, odds ratio. *OR for perineural invasion in p75NGFR-positive vs p75NGFRnegative cases, controlling for the other factors in the model.

increased density of nerves in the deeper layers of the skin or equally, that melanomas displaying PNI have an enhanced invasive capacity and hence present with deeper margins. Although expression of p75NGFR has long been associated with the spindled cytomorphology in melanomas, much of the previous research has focused on the use of staining for p75NGFR as an adjunct to help identify S100-negative spindle cell melanomas and to differentiate spindle cell melanomas from other lineage-unrelated spindle cell lesions of the skin.19-21 Although some have demonstrated staining for p75NGFR in 100% of cases of desmoplastic melanoma,17,19,21 we observed positive staining in 65% of our cases. Select studies have also noted variable expression of p75NGFR in desmoplastic melanoma, corroborating our findings.5,25 These discrepancies do not appear to be simply the result of variable scoring rubrics as, using similar cut-offs, studies reporting 100% of desmoplastic melanomas staining for p75NGFR did not observe any cases with 10% or less tumoral staining.17,19,21 Hence, we hypothesize that these differences may be the result of differing antibodies used and the relatively small sample sizes (\15) of previous studies.17,19,21 The fact that p75NGFR expression is found more often in desmoplastic melanoma than in other subtypes, when taken together with desmoplastic melanoma’s significant propensity for PNI, has led some to hypothesize that p75NGFR may play a functional role in PNI.5,17 Our findings show that beyond p75NGFR’s previously known association with this variant, it is further associated with PNI, even after controlling for depth. In vitro studies on melanoma cell lines have shown that p75NGFR mediates the induction of protease expression in response to NGF treatment, resulting in an enhanced invasive capacity.26 Furthermore, NGF has been shown to exert chemotactic effects on melanoma cell cultures, with p75NGFR mediating

Table V. RET polymorphism and histopathologic variables

Variable

Sex Male Female Depth, mm 0.01-1.00 1.01-2.00 2.01-4.00 [4.00 Clark level I II III IV V Desmoplastic variant Pure Mixed Mitosis Present Absent Host response Present Absent Ulceration Present Absent Regression Present Absent

RET polymorphism, No. (%) n = 12

RET wild type, No. (%) n = 30

P values*

9 (75.0) 3 (25.0)

14 (48.3) 15 (51.7)

.17

1 4 3 4

(8.3) (33.3) (25.0) (33.3)

8 5 13 4

(26.7) (16.7) (43.3) (13.3)

.20

0 0 1 8 3

(0.0) (0.0) (8.3) (66.7) (25.0)

0 0 4 19 7

(0.0) (0.0) (13.3) (63.3) (23.3)

1.00y

7 (58.3) 5 (41.7)

16 (53.3) 14 (46.7)

.77

8 (66.7) 4 (33.3)

27 (90.0) 3 (10.0)

.09

6 (50.0) 6 (50.0)

11 (36.7) 19 (63.3)

.43

1 (8.3) 11 (91.7)

2 (6.7) 28 (93.3)

1.00y

1 (8.3) 11 (91.7)

2 (6.7) 28 (93.3)

1.00y

One case missing gender data. *Unadjusted P values were calculated using x 2 test of independence or Fisher test when expected frequencies were \5; unadjusted P values were considered significant when \.05. y There was insufficient power to resolve an approximate P value using Fisher method.

the response.27 Taken together, from a scientific perspective it is reasonable to hypothesize that p75NGFR is associated with a greater propensity for PNI by allowing for both an enhanced invasiveness in response to NGF (permitting proteolytic digestion of the perineurium), and a chemotactic attraction to the NGF-rich microenvironment of nerve as NGF is known to be secreted by Schwann cells.28 Lastly, p75NGFR is a promiscuous receptor, and binds other neurotrophins besides NGF (eg, neurotrophin-3 and brain-derived neurotrophic factor) each of which may have an additional role to play in affecting the behavior of melanomas expressing p75NGFR.27 RETp has been shown to be more common in desmoplastic melanomas as compared with

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conventional melanomas,24 and in vitro studies of melanoma cell lines have shown that RETp results in enhanced proliferation, migration, and invasion upon treatment with glial cell lineederived neurotrophic factor compared to cells with wild-type RET.23 In pancreatic cancers, RET-glial cell lineederived neurotrophic factor signaling has emerged as a potential mediator of PNI, with paracrine signaling between nerve and tumor cells believed to occur.9,22 Given this, we hypothesized that RETp would be observed in a greater proportion of PNI-positive cases. However, we observed a nonsignificant 3-fold increase in the proportion of RETp among PNI-positive samples compared with PNI-negative samples (39% vs 13%) (Table III). Although not significant, our findings suggest an association between RETp and PNI, a larger study may be better powered to detect a significant correlation. In addition, for cases in which RETp data were available, 5 (cases 2, 7, 15, 16, and 36) displayed PNI but were p75NGFR negative. Of these, 3 (60%) had RETp, suggesting that in the absence of p75NGFR expression RETp may be of relevance in PNI. Our observation that only 7% of PNI-positive cases lacked both RETp and p75NGFR, as compared with 57% of PNI-negative cases (P = .0008), underscores the potential role played by each. Expression of TrkA has been suggested to play a role in the development of PNI in numerous noncutaneous malignancies and cutaneous squamous cell carcinoma.8,10-13 Although some in vitro studies have reported that TrkA is not expressed in melanomas or melanocytes,26,29,30 in 1 study by Flørenes et al14 using IHC to investigate expression of activated phospho-TrkA (p-TrkA), positive expression was noted in 55% of primary melanomas (none of which were desmoplastic melanomas or of spindled morphologies) and 30% of metastases. Flørenes et al14 also noted that membranous p-TrkA expression was associated with decreased overall survival, and elevated markers of proliferation (cyclin A and Ki-67). Our finding that TrkA was not expressed in any cases of desmoplastic melanoma indicates that TrkA is unlikely to play a role in the pathogenesis of desmoplastic melanoma. Likely explanations for the discordancy between our findings and those of Flørenes et al14 include differential TrkA expression in nondesmoplastic melanoma variants and/or the use of antibodies targeting different epitopes (eg, phosphorylated vs the nonphosphorylated form of the TrkA receptor). Arguing against the former is our own experience using the current antibody in over 40 nondesmoplastic melanomas that consistently

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demonstrated negative staining in all cases (data not included). Our findings indicate that in desmoplastic melanomas, p75NGFR expression is associated with a greater propensity for PNI. Although we did not observe a significant correlation between RETp and PNI, the 3-fold increase in RETp incidence observed in samples displaying PNI suggests that a larger study may be better powered to detect an association. Lastly, our observation that of cases that displayed PNI, only a limited number (2/28, 7%) were negative for both RETp and p75NGFR highlights the potential role played by each. REFERENCES 1. Scanlon P, Tian J, Zhong J, et al. Enhanced immunohistochemical detection of neural infiltration in primary melanoma: is there a clinical value? Hum Pathol 2014;45:1656-1663. 2. Feasel AM, Brown TJ, Bogle MA, Tschen JA, Nelson BR. Perineural invasion of cutaneous malignancies. Dermatol Surg. 2001;27:531-542. 3. Croker J, Burmeister B, Foote M. Neurotropic melanoma: the management of localized disease. J Skin Cancer. 2012;2012: e706452. 4. Farasat S, Yu SS, Neel VA, et al. A new American Joint Committee on Cancer staging system for cutaneous squamous cell carcinoma: creation and rationale for inclusion of tumor (T) characteristics. J Am Acad Dermatol. 2011;64: 1051-1059. 5. Chan MM, Tahan SR. Low-affinity nerve growth factor receptor (P75 NGFR) as a marker of perineural invasion in malignant melanomas. J Cutan Pathol. 2010;37:336-343. 6. Quinn MJ, Crotty KA, Thompson JF, Coates AS, O’Brien CJ, McCarthy WH. Desmoplastic and desmoplastic neurotropic melanoma. Cancer. 1998;83:1128-1135. 7. Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer. Cancer. 2009;115:3379-3391. 8. Chen-Tsai CP, Colome-Grimmer M, Wagner RF. Correlations among neural cell adhesion molecule, nerve growth factor, and its receptors, TrkA, TrkB, TrkC, and p75NGFR, in perineural invasion by basal cell and cutaneous squamous cell carcinomas. Dermatol Surg. 2004;30:1009-1016. 9. He S, Chen CH, Chernichenko N, et al. GFRa1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling. Proc Natl Acad Sci U S A. 2014;111: E2008-E2017. 10. Ma J, Jiang Y, Jiang Y, Sun Y, Zhao X. Expression of nerve growth factor and tyrosine kinase receptor A and correlation with perineural invasion in pancreatic cancer. J Gastroenterol Hepatol. 2008;23:1852-1859. 11. Zhu Z, Friess H, diMola FF, et al. Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer. J Clin Oncol. 1999;17: 2419-2428. 12. Satoh F, Mimata H, Nomura T, et al. Autocrine expression of neurotrophins and their receptors in prostate cancer. Int J Urol. 2001;8:S28-S34. 13. Kolokythas A, Cox DP, Dekker N, Schmidt BL. Nerve growth factor and tyrosine kinase A receptor in oral squamous cell carcinoma: is there an association with perineural invasion? J Oral Maxillofac Surg 2010;68:1290-1295. 14. Flørenes VA, Mælandsmo GM, Holm R, Reich R, Lazarovici P, Davidson B. Expression of activated TrkA protein in

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Neurotrophin receptors and perineural invasion in desmoplastic melanoma.

Perineural invasion (PNI) in desmoplastic melanoma is associated with increased local recurrence and reduced disease-free survival. The biological mec...
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