Introduction. Cesinaro A M, Schirosi L, Bettelli S, Migaldi M & Maiorana A (2010) Histopathology 57,
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1 Histopathology 2010, 57, DOI: /j x Alterations of 9p21 analysed by FISH and MLPA distinguish atypical spitzoid melanocytic tumours from conventional Spitz s nevi but do not predict their biological behaviour Anna Maria Cesinaro, Laura Schirosi, Stefania Bettelli, Mario Migaldi & Antonio Maiorana Department of Anatomic Pathology, University of Modena e Reggio Emilia, Modena, Italy Date of submission 19 October 2009 Accepted for publication 10 January 2010 Cesinaro A M, Schirosi L, Bettelli S, Migaldi M & Maiorana A (2010) Histopathology 57, Alterations of 9p21 analysed by FISH and MLPA distinguish atypical spitzoid melanocytic tumours from conventional Spitz s nevi but do not predict their biological behaviour Aim: The aim of this study was to investigate whether 9p21 status influence the prognosis of the spitzoid melanocytic tumours, peculiar lesions whose biological behaviour cannot be predicted by histopathological criteria alone. Methods and results: Twenty-eight atypical spitzoid tumours, 12 conventional Spitz s nevi and one congenital Spitz s nevus were studied by fluorescent in-situ hybridization (FISH) and multiple ligation-dependent probe amplification (MLPA) for the presence of 9p21 deletion. The 28 patients were aged 3 56 years (mean 32, median 35), and follow-up ranged between 4 and 156 months (mean 51, median 48). Eight patients (28.5%) experienced lymph node metastasis (three cases with macrometastasis and five with micrometastasis). Of those with macrometastasis, two are alive after 159 and 26 months, whereas a third developed widespread metastases and died after 26 months. All of the other patients are alive. Statistically, the thickness (P = 0.01) and the diameter (P = 0.009) of the lesions significantly correlated with metastasis. Deletion of 9p21 by FISH analysis was observed in eight spitzoid tumours (28.5%), and MLPA demonstrated alterations of 9p21, particularly deletion of CDKN2A, in the same lesions, whereas all Spitz s nevi, except the congenital one, were of unaltered 9p21 status (P < ). Deletion of 9p21 CDKN2A did not correlate with the presence of metastasis. Conclusion: Alterations at 9p21 locus are significantly more frequent in spitzoid tumours than in Spitz s nevi, but do not predict their biological behaviour. Keywords: spitzoid tumour, Spitz s nevus, 9p21, FISH, MLPA, histopathology, follow-up Abbreviations: anova, analysis of variance; CGH, comparative genomic hybridization; EDTA, ethylenediamine tetraacetic acid; FISH, fluorescence in-situ hybridization; MLPA, multiple ligation-dependent probe amplification; PCR, polymerase chain reaction; SLN, sentinel lymph node Introduction One of the main problems in dermatopathology is the differential diagnosis of tumours belonging to the group Address for correspondence: A M Cesinaro, Department of Anatomic Pathology, Azienda Ospedaliero-Universitaria Policlinico, Via del Pozzo 71, Modena, Italy. cesinaro.annamaria@policlinico.mo.it Preliminary results of the present paper were presented at the 12th Joint Meeting of the International Society of Dermatopathology, San Francisco, CA, USA, 4 5 March [Correction added after online publication 28 September 2010: a typographical error in the abstract was corrected.] of so-called spitzoid lesions. Since the first paper that dealt with the so-called malignant Spitz s nevus, 1 no consensus has emerged to date regarding the classification 2 6 and, consequently, the management of these tumours. 7,8 Stratification of the risk of progression, based upon a series of histopathological parameters, 9,10 has been proposed for these lesions, but the problematic issues are far from being resolved. Sentinel lymph node (SLN) biopsy has also been indicated as a diagnostic tool, although divergent opinions have been expressed in recent years about the real value of the procedure Ó 2010 Blackwell Publishing Limited.
2 516 A M Cesinaro et al. The advent of molecular pathology has widened the scope of investigations and its use has been advocated as a possible solution to the problem. 18,19 Different ancillary techniques, such as comparative genomic hybridization (CGH), loss of heterozygosity, 23,24 microsatellite instability, 23,25 fluorescent in-situ hybridization (FISH) and multiple ligation-dependent probe amplification (MLPA) have been applied over the years in the attempt to differentiate benign from malignant melanocytic lesions, and to characterize more clearly the Spitz s nevus and the family of spitzoid lesions. 21,22,24,25,29,32 35 In recent years, the observation of a high frequency of 9p21 aberrations in melanomas, compared with nevi, 20,24,36,37 has directed researchers towards the study of this chromosome locus in the group of so-called spitzoid lesions. The number of cases analysed so far, however, is small and follow-up is short or incomplete. 25,29 In the present paper, deletion of 9p21 was studied by FISH and MLPA methods in a series of atypical spitzoid melanocytic lesions and in a control group of conventional Spitz s nevi. Complete follow-up was available in all cases. The aims of the study were the following: (i) to compare the 9p21 status in the group of Spitz s nevi with that observed in atypical spitzoid lesions and, parenthetically, to verify the degree of concordance of results between FISH and MLPA analyses; and (ii) to evaluate the impact of 9p21 status on the biological behaviour of these tumours. Materials and methods Twenty-eight atypical spitzoid melanocytic lesions were included in the study, together with 12 conventional Spitz s nevi. Spitz s nevi had been removed from different anatomical sites (nine cases from lower extremities and three from upper extremities) in 10 females and two males (age range years, mean 23.8, median 20). A further case of giant congenital Spitz s nevus from the scalp of a 16-year-old boy was also studied. Criteria for inclusion in the study for atypical spitzoid lesions were a minimum of 1 mm thickness and the occurrence of at least one of the following nine histopathological features, selected from the literature because of their high frequency in atypical spitzoid lesions and melanomas, compared with Spitz s nevi: asymmetry, 10 presence of ulceration, 10 consumption of the epidermis, 38 confluence of nests, 1 solid growth, 2,10 pushing-type growth, 1 lack of maturation, 2,10,39 prominent nucleoli 1 and deep dermal mitoses. 1,2,10,40 At least three haematoxylin and eosin-stained histological sections were scrutinized for each case. The 28 lesions had been removed from 10 males and 18 females (M:F = 1:1.8), ranging in age from 3 to 56 years (mean: 32.1, median 35). Only two patients were younger than 10 years (7.1%), and six younger than 20 years at the time of tumour excision (21.4%). The anatomical sites were the following: head (four cases), trunk (seven cases), upper extremities (three cases) and lower extremities (14 cases, seven of which were from the thigh). The diameter of the lesions ranged from a minimum of 5 mm in a 3-year-old boy to a maximum of 17 mm in a 23-year-old woman (mean 8.6, median 8.0). The profile of the lesions was exophytic in 17 cases, whereas 11 cases presented as a dermal nodule. The thickness ranged from 1 to 15 mm (mean 4.12, median 2.7). Six lesions (21.4%) reached Clark s level III, 21 (75.0%) reached Clark s level IV and one case was at Clark s level V (3.6%). Kamino s bodies were observed in five lesions (17.8%). Focal pagetoid spread, confined to the centre of the lesion, was observed in six cases (21.4%). The latter two features, frequently observed in conventional Spitz s nevi, were not considered among the criteria for atypia. The cytological component was purely epithelioid in 14 cases (50%), purely spindle in three (10.7%) and mixed (epithelioid and spindle) in 11 cases (39.3%). Regarding the inclusion criteria selected for atypical spitzoid lesions, asymmetry was observed in three of 28 cases (10.7%), ulceration in five cases (17.8%), consumption of the epidermis in 18 cases (64.2%), confluence of nests in 27 cases (96.4%), solid growth in 12 cases (42.8%), pushing-type growth in 13 cases (46.4%), lack of maturation in 23 cases (82%), prominent nucleoli in 11 cases (39%) and deep dermal mitoses in 14 cases (50%). Overall, 26 cases (92.4%) showed at least three criteria for inclusion, whereas the remaining two (7.6%) presented two criteria, i.e. the thickness (at least 1 mm) plus the confluence of nests. In eight cases (28.5%), a second opinion of a pathologist dermatopathologist with particular expertise in the field of melanocytic lesions was obtained (see Acknowledgments). The adoption of rigid inclusion criteria in the study avoided the possibly forced classification of the lesions into stereotypical entities, such as atypical Spitz s nevus, spitzoid tumour with uncertain biological behaviour or spitzoid melanoma, as this was not the aim of the study, although this type of classification, the value of which is not under discussion in the present paper, is the one used currently by the authors. fish analyses FISH analyses to target the 9p21 locus were performed using the LSI p16 (9p21) CEP 9 Dual Color probe
3 9p21 alterations in spitzoid tumours 517 (Abbott Molecular Inc., Des Plaines, IL, USA). The LSI p16 (9p21) CEP 9 Dual Color Probe is a mixture of the LSI p16 probe labelled with SpectrumOrange and the CEP 9 probe labelled with SpectrumGreen. The LSI p16 SpectrumOrange probe spans approximately 190 kb and contains a number of genetic loci, including D9S1749, D9S1747, p16 (INK4A), p14 (ARF), D9S1748, p15 (INK4B) and D9S1752. The CEP 9 SpectrumGreen probe hybridizes to alpha satellite sequences specific to chromosome 9. Three micra-thick sections, obtained from representative paraffin-embedded blocks, were incubated at 60 C overnight, deparaffinized in xylene washes, then incubated in pretreatment solution 1 saline sodium citrate (SSC) ph 6.3 at 85 C for 35 min. After rinsing in distilled H 2 O, they were digested with protease I (250 mg) in protease buffer II solution at 42 C for 6 min. Slides were counterstained with 4, 6-diamino-2-phenylindole dihydrochloride (DAPI) antifade and subsequently washed in distilled H 2 O and air-dried. The probe was applied to each slide and covered with a glass coverslip. Slides were incubated at 85 C for 3 min for co-denaturation of chromosomal and probe DNA, and hybridized at 37 C for 16 h using the Hybrite system (Vysis, Inc., Downers Grove, IL, USA). Posthybridization washes were performed in 2 SSC 0.3% NP40 for 2 min at 75 C. After air-drying, slides were mounted with DAPI antifade. Locus 9p21 analyses were performed under an Axiophot Zeiss fluorescence microscope (Carl Zeiss MicroImaging GmbH, Jena, Germany) equipped with a specific workstation. After identifying the lesion on the slide, at least 100 nonoverlapping interphase tumour nuclei per case were scored and the number of orange (gene-specific) and green (chromosome-specific) spots were recorded. In a normal sample, the expected pattern for nuclei hybridized with the LSI p16 (9p21) CEP 9 probe is the twoorange, two-green signal pattern. Cases were recorded as FISH-deleted for locus 9p21 when at least 30% of examined nuclei exhibited the one-orange and twogreen signal pattern, or a number of orange spots fewer than half of the green spots. 41 mlpa procedures The SALSA MLPA Kit P024-B 9p21 CDKN2A 2B region (MRC Holland, Amsterdam, the Netherlands) was used to detect the copy number changes of genes located in the 9p21 region (in particular CDKN2A, CDKN2B and MTAP). The probe mix contains 13 different probes for the CDKN2A CDKN2B genes, plus three probes for the MTAP gene and eight probes surrounding these genes in the 9p21 region, as well as 15 reference probes for sequences located in other genes. For each target region, two pairs of probes coding for unique human single-copy DNA sequences were designed and prepared as described previously. 42 The material under examination was microdissected previously in order to avoid contamination from surrounding normal skin. For each MLPA reaction, ng DNA was dissolved in 5 ll H 2 O. DNA was denatured for 5 min at 98 C and subsequently cooled down to 25 C. After addition of 1.5 ll probe mix and 1.5 ll buffer [1.5 KCl, 300 mm Tris HCl ph 8.5, 1 mm ethylenediamine tetraacetic acid (EDTA)], the sample was denatured (1 min at 95 C) and the probes were allowed to hybridize for 16 h at 60 C. Ligation was performed for 15 min at 54 C after the addition of 32 ll Ligase-65 mix (2.6 mm MgCl 2, 5 mm Tris HCl ph 8.5, 0.013% non-ionic detergents, 0.2 mm NAD) containing one U Ligase-65 enzyme. The Ligase-65 was heat-inactivated at 98 C for 5 min. Polymerase chain reaction (PCR) was performed in a 25-ll volume containing 5 ll of the ligation reaction mixture, 1 ll SALSA PCR-primers (one was FAM-labelled) and 1 ll SALSA enzyme dilution buffer. PCR was performed in a T3 Thermocycler (Biometra, Goettingen, Germany) by 37 cycles of denaturation at 95 C for 20 seconds, annealing at 60 C for 30 s and extension at 72 C for 1 min, with a final extension of 20 min at 72 C. Aliquots of 1.5 ll of the PCR reaction were combined with 0.5 ll tetramethyl-6-carboxyrhodamine (TAM- RA)-labelled internal size standard and 24 ll deionized formamide (Applied Biosystems, Foster City, CA, USA). Samples were denatured and separated by electrophoresis on an ABI 310 capillary sequencer (Applied Biosystems) and analysed using the GeneMapper software (version 3.7; Applied Biosystems). Normal DNA obtained from identically treated tissue, a negative control (without DNA) and a positive control (with a gene alteration screened previously and confirmed by FISH) were included in each test. MLPA data processing was performed initially by examination of the capillary electrophoresis peak profiles. The first peaks were represented by the four control fragments that generated amplification products of 64, 70, 76 and 82 base pairs (bp). As a rule, control peaks should be below 20% of the mean peak ratio. When higher, the DNA used for each sample is not sufficient and the sample is discarded. If the ligation reaction is efficient, the control probe generates an amplification product of 94 bp. If the peak is lower than 80% of mean peak ratio, the sample is not analysed. The deletion of one copy of a probe target sequence appears as a reduction of 35 55% in the relative peak area for that probe amplification product.
4 518 A M Cesinaro et al. To calculate the probe ratio and evaluate the presence of possible gene deletion, peak area values were exported from the capillary sequencer in txt files and then analysed by Coffalyser software (version 8; MRC Holland) which includes four wild-type normal controls, according to the manufacturer s instructions. statistical analyses Statistical analyses were performed using Fisher s exact test to analyse the frequencies of all dichotomic variables of the spitzoid lesions, both clinical and histopathological, in relation to the follow-up (metastatic versus non-metastatic tumours). The continuous variables, such as age of the patients, diameter and thickness of the lesions, were analysed and compared with follow-up using the analysis of variance (anova) test. The chi squared test was used to compare molecular results between the group of atypical spitzoid lesions and the group of Spitz s nevi, and to analyse the molecular features of atypical spitzoid lesions related to follow-up. The results were considered statistically significant for P values <0.05. Results clinicopathological correlations Clinical and histopathological data of the 28 patients with atypical spitzoid lesions are shown in Table 1. In 19 of 28 patients sentinel lymph node (SLN) biopsy was performed and, in a further case (case 1), a palpable lymph node was biopsied, synchronously to tumour excision. In eight of 20 (40%) cases that underwent lymphadenectomy, metastatic deposits were found in regional lymph nodes. In particular, three patients had macrometastases (cases 1, 15 and 21); the remaining five had micrometastases (cases 2, 6, 8, 24 and 27). Follow-up ranged from 4 to 159 months (mean = 54, median = 46). All patients except one (case 15) are alive. This latter patient had a metastatic SLN and underwent regional lymph node dissection that was negative for metastases. After 1 year, the patient developed widespread lymph node, visceral and cutaneous metastases, and died from the disease 26 months after the initial diagnosis. Another patient (case 1) had a palpable metastatic lymph node at the time of tumour excision and four positive lymph nodes in the complete regional lymph node dissection. She developed a local recurrence 12 months later, but is still alive with no evidence of disease 159 months after the initial diagnosis. A third patient (case 21), who had a SLN macrometastasis and a micrometastasis in a further lymph node at regional lymph node dissection, is alive and well after 26 months of follow-up. No further metastases or recurrences developed in other patients. At statistical analysis, the mean diameters of the metastasized spitzoid lesions were significantly greater than those of lesions that did not metastasize (12.12 ± 4.9 versus 8.35 ± 2.13; P = 0.009). The mean thickness of the metastasized lesions was also significantly greater than that of lesions that did not metastasize (6.49 ± 5.51 versus 2.75 ± 1.72; P = 0.01). No significant differences regarding other clinical and histopathological criteria were found between the groups of lesions that metastasized and those that did not, although a higher frequency of metastases was found in male compared with female patients (P = 0.07). Tumour examples without LN involvement are shown in Figure 1. Metastasized tumours are shown in Figures 2 and 3. molecular analyses related to the follow-up of atypical spitzoid lesions Results obtained from FISH and MLPA analyses, together with follow-up and details of CDKN2A gene status, are shown in Table 2. MLPA and FISH were performed successfully in all cases (28 atypical spitzoid lesions, 12 conventional Spitz s nevi and a case of congenital Spitz s nevus). In atypical spitzoid lesions, both FISH and MLPA showed alterations of the 9p21 locus in eight of 28 cases (28.5%). In particular, MLPA detected loss of the CDKN2A CDKN2B MTAP genes in two cases, whereas CDKN2A CDKN2B gene loss was observed in two cases and CDKN2A MTAP gene loss was found in two other cases, the remaining two cases showing loss of the CDKN2A gene only. The eight cases with loss of the CDKN2A gene at MLPA showed deletion of the 9p21 locus at FISH analysis. In 17 cases, FISH and MLPA analyses showed no alterations in the 9p21 locus. Three further cases showed MTAP gene loss only, as shown by MLPA, but no alterations were found with FISH analysis. In 12 conventional Spitz s nevi, FISH and MLPA detected no alterations of the 9p21 locus (Figure 4), whereas in the case of congenital Spitz s nevus, deletion of p16 exon 1 in the CDKN2A region was observed by MLPA. This last case was a giant nevus that showed foci of confluence of melanocytic nests. Three of eight cases of atypical spitzoid lesions that showed CDKN2A gene deletion, either with or without codeletion of CDKN2B and MTAP genes, had lymph node involvement (cases 2, 15 and 27), including the case with fatal outcome (case 15), but four cases with
5 9p21 alterations in spitzoid tumours 519 Table 1. Clinical data and histopathological criteria of inclusion of 28 atypical spitzoid lesions Case no. Age Sex Anatomical site Diameter (mm) Thickness (mm) Asymmetry Ulceration COE* Type of growth Confluence of nests Solid growth Maturation Prominent nucleoli Deep mitoses 1 18 F Auricolar lobe No Yes Yes Pushing Yes Yes No No Yes 2 23 F Auricolar lobe No No Yes Pushing Yes No No No Yes 3 13 F Light breast No No No Pushing Yes Yes No Yes No 4 45 F Left ankle 9 4 No No No Infiltrating Yes No No Yes Yes 5 35 F Right calf No No No Infiltrating Yes No No Yes Yes 6 56 M Right flank 16 4 No No No Infiltrating Yes No No No No 7 19 F Right thigh 10 3 No Yes Yes Pushing Yes Yes No Yes No 8 20 M Upper arm No Yes Yes Infiltrating Yes No No Yes Yes 9 36 F Left thigh 8 2 No No Yes Infiltrating Yes No No No No F Perineum 8 1 Yes No No Infiltrating Yes No Yes No No F Left leg No No No Pushing Yes Yes Yes Yes Yes M Right leg No No Yes Pushing Yes Yes No No No F Right thigh No No Yes Pushing Yes Yes No No Yes M Right flank No No Yes Pushing Yes Yes No No No M Right forearm No Yes Yes Pushing Yes Yes No No Yes 16 7 M Right cheek Yes No Yes Pushing Yes Yes Yes No No F Right knee No No Yes Infiltrating Yes No No No Yes F Back No No Yes Infiltrating Yes No No Yes No F Back No No No Infiltrating Yes No Yes No No 20 3 M Left cheek No No Yes Pushing Yes Yes No Yes Yes M Right knee 18 8 No No No Infiltrating Yes No No Yes No F Dorsum of foot 8 5 No No No Infiltrating No No No Yes Yes F Thigh 6 8 No No Yes Pushing Yes No No No No
6 520 A M Cesinaro et al. Table 1. (Continued) Deep mitoses Prominent nucleoli Solid growth Maturation Confluence of nests Type of growth Thickness (mm) Asymmetry Ulceration COE* Diameter (mm) Anatomical site Case no. Age Sex F Right thigh 6 1 Yes No No Infiltrating Yes No No No No F Left arm No No No Infiltrating Yes No Yes No No F Leg 13 4 No Yes Yes Pushing Yes Yes No Yes Yes M Back 6 2 No No Yes Infiltrating Yes Yes No No Yes M Left thigh 10 3 No No Yes Infiltrating Yes No No Yes Yes *COE, Consumption of epidermis. lymph node metastatic deposits (cases 1, 6, 8 and 21), one of which had also a local recurrence (case 1), showed no CDKN2A deletion. In addition to skin tumours, lymph node metastases and or local recurrences were also studied by FISH and MLPA, detecting a full concordance of the 9p21 status in primary and secondary lesions, i.e. CDKN2A gene loss both in the primary tumour and lymph node metastasis in case 15 (Figure 5), but no alterations of the 9p21 locus in primary tumours and metastases (or local recurrence) in cases 1 (Figure 6) and 21. Case 24, in which the lymph node was involved, had MTAP gene deletion only. MTAP deletion was also found in another case with negative SLN (case 5), whereas in a third case, with MTAP deletion, no SLN had been performed (case 9). At statistical analysis, the atypical spitzoid lesions showed a significantly higher incidence of deletion in the 9p21 locus when compared with the group of conventional Spitz s nevi (P < ), but no significant relationship between the 9p21 status and metastatic potential was observed. molecular analyses related to histopathological features of atypical spitzoid lesions No relationship was found between the 9p21 status, as analysed by FISH or MLPA, and the occurrence of any of the histopathological parameters evaluated in 28 atypical spitzoid lesions. When the 9p21 status was compared with the number of histopathological parameters observed in each case, it turned out that the eight cases that showed CDKN2A gene loss (either with or without CDKN2B and MTAP codeletion) featured a number of parameters, ranging from five to eight. Cases with MTAP gene loss featured only four to five parameters and those with no gene loss at 9p21 were characterized by two to eight parameters. Alterations of the 9p21 locus, in particular CDKN2A gene loss, were not found to be significantly related to the number of histopathological parameters that characterized the atypical spitzoid lesions. Of interest, however, CDKN2A gene loss was never observed in cases that showed a low number (two to four) of histopathological criteria. Moreover, only 15.3% of cases showing two to five criteria of atypia presented CDKN2A gene loss, compared with 40.0% of cases that showed six to eight histopathological parameters. No significant data were observed when molecular results and histopathological features were compared with follow-up in the atypical spitzoid lesions. Interestingly, however, metastases were observed in three of six cases that showed six to eight parameters plus deletion of CDKN2A, including the case with fatal outcome, but
7 9p21 alterations in spitzoid tumours 521 A B C D Figure 1. Non-metastasized spitzoid tumours: case 14, sentinel lymph node (SLN) not performed, alive after 64 months: A, panoramic view; B, confluence of nests; case 20, SLN not performed, alive after 28 months: C, tumour showing solid growth; D, cells with prominent nucleoli. in only three of 11 cases featuring two to five inclusion criteria and normal 9p21 status. Discussion Several investigations have been performed in an attempt to characterize more clearly the group of so-called spitzoid melanocytic lesions. After an initial approach based on the analysis of a series of histopathological parameters, 1,9,10 the lack of consensus on the classification and prediction of the biological potential of these tumours 2 4 led us to consider the application of novel molecular techniques as a possible aid to resolve the problem. 18 The short arm of chromosome 9 is commonly altered in cutaneous melanoma 43 and has been indicated as a candidate region in its pathogenesis. 41 Two tumour suppressor genes, CDKN2A and CDKN2B, reside in the 9p21 locus, the first encoding for two cell cycle regulatory proteins, p16ink4a and p14arf. 44 Using immunohistochemistry, loss of expression of p16 has been found in a high percentage of invasive melanomas, in contrast with normal expression detected in atypical and common nevi. Spitz s nevi were not evaluated in this study. 37 Loss of heterozygosity (LOH) of chromosome 9p was found in 46% of primary melanomas and in a minority (two of 27) of Spitz s nevi. 24 The finding of LOH at chromosome 9p21 was also reported by Bogdan et al. 33 in a small series of Spitz s nevi. Loss of chromosome 9, particularly the short arm, was observed in 81% of primary cutaneous melanomas by comparative genomic hybridization (CGH), 20 but it was not detected in Spitz s nevi. 21 Allelic imbalance of the microsatellite marker D9S171, located on 9p21, was found in one of 10 Spitz s nevi, in two of five atypical Spitz s tumours, in five of 15 suspected spitzoid melanomas and in eight of 12 primary spitzoid melanomas. 25 FISH detected a 9p21
8 522 A M Cesinaro et al. A B C D Figure 2. Metastasized spitzoid tumours: case 1, five LN metastases + local recurrence, alive after 159 months: A, primary tumour; B, lymph node effaced by metastasis; case 2, sentinel lymph node (SLN) micrometastasis, alive after 135 months: C, primary tumour; D, SLN micrometastasis. deletion in 10% of common nevi, 55% of dysplastic nevi, 59% of primary melanomas and in 62% of melanoma metastases, whereas the specific CDKN locus was found to be deleted in 9% of dysplastic nevi, in 19% of primary melanomas and in 37% of metastases, being always preserved in common nevi. 27 Again, this study did not consider the category of Spitz s nevi. A series of benign and malignant melanocytic lesions, including 14 Spitz s nevi, was analysed by MLPA for a large number of genes, and copy number loss of either CDKN2A or CDKN2B was observed in 70.8% of melanomas, but in none of either the common or Spitz s nevi. 30 MLPA was also performed in a series of melanocytic lesions, including a case of Spitz s nevus, and alterations of the CDKN probe at the 9p21 locus were not observed in the nevi category, in contrast with changes detected in malignant melanocytic lesions. 31 In another recent paper, CDKN2A loss was found in 55% of 22 melanomas, in three of 14 cases of ambiguous Spitz s tumours, and in none of eight Spitz s nevi. 29 All these studies have led to the belief that there are molecular differences between conventional Spitz s nevi and conventional melanomas, but this is not completely true for the intermediate category of so-called spitzoid tumours. Unfortunately, the few investigations that have focused on molecular alterations in spitzoid tumours appear deficient in follow-up data. 25,29 In the present work, histopathological criteria of atypia, proposed by the international literature, were applied to select a series of 28 atypical spitzoid lesions. Follow-up was available in all cases, 28.5% of which showed progression, as proved by the occurrence of SLN micro- or macrometastasis, local recurrence or the development of widespread metastases and death. It is noteworthy that only one case of eight with lymph
9 9p21 alterations in spitzoid tumours 523 A B C D Figure 3. Metastasized spitzoid tumours: case 15, sentinel lymph node (SLN) macrometastasis, died of disease after 26 months: A, ulcerated tumour; B, confluence of nests; case 21, SLN macrometastasis, alive after 26 months: C, tumour mass; D, lack of maturation in the deep portion of the lesion. node involvement had a fatal outcome. The lesion featured histopathological parameters similar to those observed in other lesions that behaved in a less aggressive manner. In a recent study of 67 cases of atypical Spitz s tumours, 45 lymph node involvement was found in 47% of patients investigated for SLN status, a percentage similar to that observed in our series (40%), and all patients with SLN metastases were also alive at follow-up, with the exception of one case. Our results further corroborate the already mentioned concept 6,14 that these lesions, despite their metastatic potential, tend to have a more favourable prognosis when compared with conventional melanomas. As previously reported, 1,11 we observed metastases in lesions characterized by a significantly higher diameter and thickness, allowing speculation that the metastatic potential in atypical spitzoid lesions is mainly a matter of tumour bulk. FISH and MLPA were applied to verify the presence of deletions of the 9p21 locus and or loss of the CDKN2A, CDKN2B and MTAP genes. Full concordance was found between results obtained by the two techniques, because cases that showed deletion of the 9p21 locus, as evidenced by FISH, exhibited loss of the CDKN2A gene, as detected by MLPA. Contemporary loss of the CDKN2B and MTAP genes was also present in about 50% of cases. A high concordance rate between FISH and MLPA has already been demonstrated in the detection of HER2 amplification in breast carcinomas. 46 Conversely, three cases showing only loss of the MTAP gene by MLPA did not show 9p21 deletion at FISH analysis. This finding can be explained by either the higher sensitivity of MLPA in detecting alterations in small chromosomal loci or the possibility of false-positive MLPA results. 31 In agreement with Takata et al., 29 a statistically significant increase in the
10 524 A M Cesinaro et al. Table 2. Results of fluorescence in-situ hybridization (FISH) and multiple ligation-dependent probe amplification (MLPA) analysis and follow-up of 28 atypical spitzoid lesions Case no. FISH (9p21 status) MLPA (9p21 status) CDKN2A deletion Positive SLN Follow-up (months) 1* Non-deleted Non-deleted Yes A&W (159) 2 Deleted CDKN2B CDKN2A MTAP Entire region Yes A&W (135) 3 Non-deleted Non-deleted ND A&W (133) 4 Deleted CDKN2A MTAP Intron between p16 exon 1 and p14 exon 1 (1b) No A&W (120) 5 Non-deleted MTAP No A&W (102) 6 Non-deleted Non-deleted Yes A&W (100) 7 Non-deleted Non-deleted No A&W (82) 8 Non-deleted Non-deleted Yes A&W (74) 9 Non-deleted MTAP ND A&W (72) 10 Non-deleted Non-deleted No A&W (58) 11 Deleted CDKN2B CDKN2A MTAP Entire region No A&W (55) 12 Deleted CDKN2A MTAP p16 exon 2-p16 exon 3 ND A&W (64) 13 Non-deleted Non-deleted No A&W (50) 14 Non-deleted Non-deleted No A&W (48) 15 Deleted CDKN2A p16 exon 1-p16 exon 2 Yes DOD (26) 16 Non-deleted Non-deleted ND A&W (38) 17 Deleted CDKN2A p14 exon 1 (1b)-p16 exon 1-p16 exon 2 No A&W (34) 18 Non-deleted Non-deleted ND A&W (34) 19 Non-deleted Non-deleted ND A&W (30) 20 Non- deleted Non-deleted ND A&W (28) 21 Non-deleted Non-deleted Yes A&W (26) 22 Non-deleted Non-deleted No A&W (20) 23 Non-deleted Non-deleted ND A&W (16) 24 Non-deleted MTAP Yes A&W (15) 25 Non-deleted Non-deleted No A&W (8) 26 Deleted CDKN2B CDKN2A Entire region No A&W (8) 27 Deleted CDKN2B CDKN2A p14 exon 1 (1b)-p16 exon 1 Yes A&W (6) 28 Non-deleted Non-deleted No A&W (4) SLN, Sentinel lymph node; ND, Not done; A&W, Alive and well; DOD, Died of disease. *Case 1: lymph node (LN) metastasis and recurrence also non-deleted. Case 15: LN metastasis also deleted. Case 21: LN metastasis also non-deleted.
11 9p21 alterations in spitzoid tumours Control Spitz s nevus Spitzoid tumour (case 2) Deletion of CDKN2A Deletion of CDKN2B Deletion of MTAP Figure 4. Multiple ligation-dependent probe amplification (MLPA) results in a negative control, a conventional Spitz s nevus (non-deleted) and a spitzoid tumour [case 2, sentinel lymph node (SLN) micrometastasis, alive after 135 months] showing deletion of CDKN2A CKKN2B MTAP genes Spitzoid tumour (case 15) Deletion of CDKN2A LN metastasis (case 15) Deletion of CDKN2A, CDKN2B and MTAP Figure 5. Multiple ligation-dependent probe amplification (MLPA) results in a spitzoid tumour [case 15, sentinel lymph node (SLN) macrometastasis, died of disease after 26 months] and the corresponding LN metastasis, both of them showing deletion at the 9p21 locus. percentage of CDKN2A gene loss was found in atypical spitzoid lesions when compared with Spitz s nevi (P < ), thus underlining the biological difference between the two groups of lesions. Among the specific probes of CDKN2A, p16 exon 1 and exon 2, related to p16ink4, and p14 exon 1 (1b) related to p14arf, were the most involved. In contrast to melanomas, 36 alterations of p14 alone were not observed in atypical spitzoid lesions. At variance with the study of Takata et al., 29 in which CDKN2B gene loss was not reported in the series of ambiguous spitzoid lesions, a few cases in the present series also showed deletion of this gene. The MTAP gene was found to be codeleted in almost half of the cases that showed alterations of the 9p21 locus, in agreement with previous observations. 47,48 The presence of CDKN2A deletion together with a higher number of criteria of atypia appeared slightly more frequently in metastatic
12 526 A M Cesinaro et al Spitzoid tumour (case 1) Non deleted LN metastasis (case 1) Non deleted Figure 6. Multiple ligation-dependent probe amplification (MLPA) results in a spitzoid tumour (case 1, five metastatic lymph nodes (LN) + local recurrence, alive after 159 months) and the corresponding LN metastasis, both of them non-deleted. than in non-metastatic lesions. Interestingly, the study of metastases and recurrence, in the three cases in which material was available, showed full concordance in molecular status between primary tumour and metastasis recurrence. The only case with a fatal outcome presented deletion of CDKN2A both in the primary tumour and in the SLN macrometastasis, whereas the two patients who are alive, despite the development of SLN macrometastasis, showed no deletion in either the primary lesions or in the metastases. Together, these results indicate that the study of 9p21 by FISH and MLPA can be useful to differentiate so-called atypical spitzoid lesions from conventional Spitz s nevi, so that the patient can be offered the best treatment and management. Unfortunately, our study failed to find significant correlations with biological behaviour, the only exception being the case with a poor outcome which showed deletion in both the primary tumour and metastasis, in contrast to the two cases alive and well with non-deleted primary tumour and metastasis. To establish whether or not this was simply a fortuitous finding, further studies should be carried out on more cases with metastases and longterm follow-up, showing either a favourable or unfavourable prognosis. Acknowledgements The authors would like to thank Drs Bernard A Ackerman (New York, USA), Lorenzo Cerroni (Graz, Austria), Claudio Clemente (Milan, Italy), Martin G Cook (Guildford, UK), Thomas Krausz (Boston, USA) and Guido Massi (Rome, Italy) for consultations. The authors also thank Dr Marzia Gozzoli and Ms Marisa Di Giovanni for technical assistance. References 1. Smith KJ, Barrett TL, Skelton HG III et al. Spindle and epithelioid cell nevi with atypia and metastasis (malignant Spitz nevus). Am. J. Surg. Pathol. 1989; 13; Barnhill RL, Argenyi ZB, From L et al. Atypical Spitz nevi tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. Hum. Pathol. 1996; 27; Cerroni L, Kerl H. Tutorial on melanocytic lesions. Am. J. Dermatopathol. 2001; 23; Farmer ER, Gonin R, Hanna MP. Discordance in the histopathologic diagnosis of melanoma and melanocytic nevi between expert pathologists. Hum. Pathol. 1996; 27; Mones JM, Ackerman AB. Atypical Spitz s nevus, malignant Spitz s nevus, and metastasizing Spitz s nevus : a critique in historical perspective of three concepts flawed fatally. Am. J. Dermatopathol. 2004; 26; Mooi WJ, Krausz T. Spitz nevus versus spitzoid melanoma. Diagnostic difficulties, conceptual controversies. Adv. Anat. Pathol. 2006; 13; Gelbard SN, Tripp JM, Marghoob AA et al. Management of Spitz nevi: a survey of dermatologists in the United States. J. Am. Acad. Dermatol. 2002; 47; LeBoit PE. Safe Spitz and its alternatives. Pediatr. Dermatol. 2002; 19; Barnhill RL, Flotte TH, Fleischli M et al. Cutaneous melanoma and atypical Spitz tumors in children. Cancer 1995; 76; Spatz A, Calonje E, Handfield-Jones S et al. Spitz tumors in children: a grading system for risk stratification. Arch. Dermatol. 1999; 135; Lohmann CM, Coit DG, Brady MS et al. Sentinel lymph node biopsy in patients with diagnostically controversial Spitzoid melanocytic tumors. Am. J. Surg. Pathol. 2002; 26; Murali R, Sharma RN, Thompson JF et al. Sentinel lymph node biopsy in histologically ambiguous melanocytic tumors with Spitzoid features (so-called atypical Spitzoid tumors). Ann. Surg. Oncol. 2008; 15; Su LD, Fullen DR, Sondak VK et al. Sentinel node biopsy for patients with problematic Spitzoid melanocytic lesions: a report on 18 patients. Cancer 2003; 97;
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Spitz nevi display allelic deletions. Arch. Dermatol. 2001; 137; Da Forno PD, Pringle JH, Fletcher A et al. BRAF, NRAS and HRAS mutations in spitzoid tumors and their possible pathogenetic significance. Br. J. Dermatol. 2009; 161; Fullen DR, Poynter JN, Lowe L et al. BRAF and NRAS mutations in spitzoid melanocytic lesions. Mod. Pathol. 2006; 19; Freedberg DE, Rigas SH, Russak J et al. Frequent p16-independent inactivation of p14arf in human melanoma. J. Natl Cancer Inst. 2008; 100; Reed JA, Loganzo F Jr, Shea CR et al. Loss of expression of the p16 Cyclin-dependent kinase inhibitor 2 tumor suppressor gene in melanocytic lesions correlates with invasive stage of tumor progression. Cancer Res. 1995; 55; Hantschke M, Bastian BC, LeBoit PE. Consumption of epidermis: a diagnostic criterion for the differential diagnosis of melanoma and Spitz nevus. Am. J. Surg. Pathol. 2004; 28; LeBoit PE. Spitz nevus: a look back and a look ahead. Adv. 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