Letters to the Editor 91

cycle regulation apparently lead to cutaneous primary and metastatic melanomas. However, uveal or conjunctival cell cycles do not seem to be profoundly affected. To date, several characteristic genetic anomalies for tumor progression and metastasis of cutaneous as well as uveal melanoma have been identified [5]. However, unlike in cutaneous melanoma, B-Raf, Ras, or Kit mutations occur rarely in uveal melanoma, and characteristic mutations differ between uveal and cutaneous melanoma [5]. Although mutations similar to skin melanoma such as B-RAF V600 have been found in conjunctival melanomas [6], our findings underline genetic differences between conjunctival and skin melanomas as well. However, as remarkable changes regarding pigmentation were noted in the cornea and chamber angle in these animals, further investigation of the anterior segment might allow the study of mechanisms of corneal neovascularization and possibly also glaucoma.

Acknowledgements This study was supported by an in-house BONFOR research grant. Conflicts of interest

There are no conflicts of interest.

References 1

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Landsberg J, Gaffal E, Cron M, Kohlmeyer J, Renn M, Tuting T. Autochthonous primary and metastatic melanomas in Hgf-Cdk4 R24C mice evade T-cellmediated immune surveillance. Pigment Cell Melanoma Res 2010; 23:649–660. Mallikarjuna K, Pushparaj V, Biswas J, Krishnakumar S. Expression of epidermal growth factor receptor, ezrin, hepatocyte growth factor, and c-Met in uveal melanoma: an immunohistochemical study. Curr Eye Res 2007; 32:281–290. Landsberg J, Kohlmeyer J, Renn M, Bald T, Rogava M, Cron M, et al. Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature 2012; 490:412–416. Tormo D, Ferrer A, Gaffal E, Wenzel J, Basner-Tschakarjan E, Steitz J, et al. Rapid growth of invasive metastatic melanoma in carcinogen-treated hepatocyte growth factor/scatter factor-transgenic mice carrying an oncogenic CDK4 mutation. Am J Pathol 2006; 169:665–672. Van den Bosch T, Kilic E, Paridaens D, de Klein A. Genetics of uveal melanoma and cutaneous melanoma: two of a kind? Dermatol Res Pract 2010; 2010:360136. Lake SL, Jmor F, Dopierala J, Taktak AF, Coupland SE, Damato BE. Multiplex ligation-dependent probe amplification of conjunctival melanoma reveals common BRAF V600E gene mutation and gene copy number changes. Invest Ophthalmol Vis Sci 2011; 52:5598–5604.

DOI: 10.1097/CMR.0000000000000206

Diagnostic approach to melanocytic lesion of unknown malignant potential Francesco Pisciolia, Teresa Pusiola and Luca Roncatia,b, aProvincial Health Care Services, Santa Maria del Carmine Hospital, Rovereto (TN) and b Department of Diagnostic and Clinical Medicine and of Public Health, Section of Pathology, University of Modena and Reggio Emilia, Modena (MO), Italy Correspondence to Luca Roncati, MD, PhD, Department of Diagnostic and Clinical Medicine and of Public Health, Section of Pathology, University of Modena and Reggio Emilia, Policlinico Hospital, I-41124 Modena (MO), Italy Tel: + 39 059 422 4812; fax: + 39 059 422 4998; e-mail: [email protected] Received 27 June 2015 Accepted 30 September 2015

Melanocytic lesion of unknown malignant potential (MELTUMP) is a provisional diagnosis, which underlies an indeterminate biological behavior. In fact, a conclusive diagnosis for some melanocytic lesions is not always possible at initial presentation and long-term (or perhaps lifelong) clinical follow-up represents the only evidence to understand their biologic behavior. We have read with great interest the paper of Kaltoft et al. [1]. In a Danish study of 67 consecutive patients with a diagnosis of MELTUMP, four patients (6%) had regional dissemination at the time of the diagnosis. One patient (1%) developed regional spread during follow-up and another patient (1%) died from distant metastases 1 year after the diagnosis. Kaltoft et al. [1] found no predictive factors with respect to histological tumor characteristics and they believe that MELTUMP has a low malignant potential, with a low risk for nodal metastasis and death from distant metastases during follow-up. In this study, all the slides were reviewed by independent dermatopathology experts. The authors recommend that all patients diagnosed with MELTUMP should be managed according to the guidelines for invasive melanoma. We believe that all patients with a diagnosis of MELTUMP should also be treated according to the guidelines for invasive melanoma. However, a histological stratification is necessary to establish the most probable behavior. The following features should be considered and reported in the diagnosis: (1) Histopathological features: In the study of Cerroni et al. [2], 75 cases of MELTUMP were classified within three groups according to their behavior as follows: (a) favorable (no evidence of metastatic disease after a follow-up of 5 years or more); (b) unfavorable (tumor-related death and/or large deposits in the lymphatic nodes and/or visceral metastases; and (c) borderline (small nodal deposits of tumor cells less than or equal to 0.2 mm). The only three histopathologic criteria that were statistically different between the groups of unfavorable and favorable cases were presence of mitoses, mitoses near to the base, and an inflammatory reaction. All these features were found more frequently in cases with unfavorable behavior. (2) Lymphatic invasion is defined as S100 proteinpositive cells within a podoplanin-positive lymphatic space. This dual immunohistochemical staining should be performed in all cases of MELTUMP because it can provide a prognostic adjunct in determining that those lesions are capable of distant metastases and fatal outcomes [3]. The presence of lymphatic invasion correlates with a more aggressive clinical outcome, defined as developing nodal metastases, distant metastases, or melanoma-related death [3]. (3) Fluorescence in-situ hybridization (FISH) can serve as a useful adjunct in the study of MELTUMP to

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92 Melanoma Research 2016, Vol 26 No 1

detect chromosomal abnormalities in chromosomes 6 and 11. In the analysis of 21 melanocytic neoplasms from 21 patients younger than 25 years of age, FISH detected chromosomal aberrations in one of two MELTUMPs, in which the patient developed subsequent lymph node and distant metastases [4]. The value of this research is limited by a small number of examined cases, but FISH should be performed in all cases of MELTUMP for better biological stratification of the lesion. Fig. 1

(4) Second opinion consultation: In the experience by Pusiol et al. [5], the second opinion of Professors Elder and Murphy has enabled a better comprehension of MELTUMP (Fig. 1). In conclusion, in the diagnostic report of MELTUMP, the above-mentioned points and all the specifications for an invasive melanoma, that is, Breslow thickness, Clark level, Elder growth phase, mitotic count, vascular invasion, inflammatory infiltrate, presence of regression, satellitosis and/or ulceration, and state of margins, should be provided.

Acknowledgements Conflicts of interest

There are no conflicts of interest.

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A singular case of MELTUMP submitted for second opinion consultation (hematoxylin and eosin, × 5): incohesive atypical melanocytes and scattered clusters of atypical melanocytes (white circles) are noticeable in the dermis. A deep nest is observable adjacent to eccrine glands (inset, white arrow, hematoxylin and eosin, × 20). The provisional diagnosis of this MELTUMP has been formulated recently; the patient is currently on follow-up and thus it is not yet possible to determine its clinical behavior and to establish its biological aggressiveness. MELTUMP, melanocytic lesion of unknown malignant potential.

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Kaltoft B, Hainau B, Lock-Andersen J. Melanocytic tumour with unknown malignant potential: a Danish study of 67 patients. Melanoma Res 2015; 25:64–67. Cerroni L, Barnhill R, Elder D, Gottlieb G, Heenan P, Kutzner H, et al. Melanocytic tumors of uncertain malignant potential: results of a tutorial held at the XXIX Symposium of the International Society of Dermatopathology in Graz, October 2008. Am J Surg Pathol 2010; 34:314–326. Abraham RM, Karakousis G, Acs G, Ziober AF, Cerroni L, Mihm MC Jr, et al. Lymphatic invasion predicts aggressive behavior in melanocytic tumors of uncertain malignant potential (MELTUMP). Am J Surg Pathol 2013; 37:669–675. DeMarchis EH, Swetter SM, Jennings CD, Kim J. Fluorescence in situ hybridization analysis of atypical melanocytic proliferations and melanoma in young patients. Pediatr Dermatol 2014; 31:561–569. Pusiol T, Morichetti D, Piscioli F, Zorzi MG. Theory and practical application of superficial atypical melanocytic proliferations of uncertain significance (SAMPUS) and melanocytic tumours of uncertain malignant potential (MELTUMP) terminology: experience with second opinion consultation. Pathologica 2012; 104:70–77.

DOI: 10.1097/CMR.0000000000000215

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