Angel Fernandez-Flores

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158Acta Dermatovenerol Croat                     2008;16(3):158-163         REVIEWPlasma Cell Infiltrate in Common Acquired 	Melanocytic NevusAngel Fernandez-Flores	  Department of Anatomic Pathology, Hospital El Bierzo, and Department of Cellular Pathology, Clinica Ponferrada, Ponferrada, SpainCorresponding author:Angel Fernandez-Flores, MD, PhDS. Patología Celular, Clinica PonferradaAvenida Galicia 124400 PonferradaSpain gpyauflowerlion@terra.esReceived: June 17, 2008Accepted, July 15, 2008SUMMARY The presence of plasma cells in melanocytic lesions has been considered in literature as a sign of concern, when evaluated in the appropriate context. Plasma cells have been evaluated in halo nevus, but they are not frequently reported in non-halo common acquired nevus. Our claim was to study how common and frequent plasma cells are in the latter type of nevi. Therefore, we examined 280 of these nevi and selected the cases with an inflammatory infiltrate, even if mild. We then looked for plasma cells in the inflammatory infiltrate in the hematoxylin-eosin routine sections and selected 17 cases in which plasma cells (even if only occasional) could be found in the hematoxylin-eosin staining. Out of these 17, plasma cells were easily found in four cases, which were then further studied with immunohistochemistry for epithelial membrane antigen. The percentage of plasma cells varied in these four cases from 0.5% to 7%. No relation between the amount of plasma cells and either the location of the nevus or the location of the inflammatory infiltrate could be established. We conclude that the main point of this study is not to trust the presence of plasma cells as a solid criterion on its own, when evaluating a melanocytic lesion.KeY woRdS: plasma cell, melanocytic nevus, epithelial membrane antigenIntRodUCtIonThe presence of plasma cells in the inflamma-tory infiltrate of a melanocytic lesion is not a trivial finding and, depending on the context, can be quite meaningful. When found in a melanoma, for instance, plasma cells have been demonstrated to have a prognostic value (1-5): an infiltrate rich in plasma cells correlates adversely with the possi-bility of metastasis. Moreover, plasma cells have also been sug-gested as a diagnostic clue in the differential diag-nosis between benign and malignant melanocytic lesions: halo nevus usually shows only a discrete number of plasma cells (6,7). Thus, a melanocytic lesion which looks like a halo-nevus but in which plasma cells are numerous should raise concern for melanoma. On the contrary, a low amount of plasma cells does not necessarily exclude mela-noma: the inflammatory infiltrate that is evidenced in melanoma regression usually has a few plasma cells (8). 159ACTA DERMATOVENEROLOGICA CROATICAPlasma cells can also be of diagnostic value in the differential diagnosis between desmoplastic Spitz nevus and desmoplastic melanoma; the for-mer nearly always lacks plasma cells (9).We wanted to study something which is hardly ever mentioned in the literature: how abundant plasma cells are in the inflammatory infiltrate of innocent-looking acquired non-halo nevi. We also wanted to investigate if plasma cells were distrib-uted according to any preferential pattern (band, perifollicular, etc.).MAteRIAl And MethodSWe examined 280 melanocytic nevi of patients who did not have a clinical halo phenomenon. The nevi were classified according to the eponymic designation that had been previously proposed in the literature (10-12).From these, we selected those with an inflam-matory infiltrate, even if mild. We then looked for plasma cells in the inflammatory infiltrate in the hematoxylin-eosin routine sections and selected those cases in which plasma cells (even if only occasional) could be found in the hematoxylin-eosin staining. The cases in which plasma cells were more easily found, were also studied by immunohistochemistry with epithelial membrane antibody (DakoCytomation, monoclonal mouse antihuman, isotype Ig2a, kappa, immunogen: fat globule membranes from human milk; clone E29, code N1504) in order to quantify better the amount of plasma cells. The percentage of plasma cells in relation to the rest of the inflammatory cells was evaluated in all cases in which immunostaining was performed.ReSUltSFrom the 280 nevi examined, we found some inflammatory infiltrate (even if mild) in 41 (14.64%) cases. Of these, plasma cells were occasional in 17 cases in the hematoxylin-eosin slides. Table 1 shows clinical details of these 17 cases, with the location and histologic type of the nevi. In these 17 cases, the distribution of the infiltrate was mainly perivascular superficial in 11 cases, perivascular superficial and deep in 1 case, perifollicular in 3 cases, peri-infundibular in 1 case, and peri-infun-dibular plus perifollicular in 1 case. In four cases (cases 1, 2, 3 and 5), plasma cells were found more easily with the hematoxylin-eosin staining (Fig. 2). In these latter four cases, the im-munohistochemical study was useful in standing out the plasma cells (Fig. 2). In the total amount of inflammatory cells, plasma cells accounted for a percentage that varied between 0.5% (case 3) and 7% (case 5) (Table 1, Fig. 3).table 1. Clinical and morphological details of cases presenting plasma cells in inflammatory infiltrateCase No.Sex Age (yrs)Location Type of nevusInflammatory infiltrate distributionPercentage of plasma cells in the infiltrate1 Female 70 Nose Miescher Perifollicular & peri-infundibular12 Female 68 Neck Unna Perifollicular 53 Female 35 Right leg Clark Perivascular superficial 0.54 Female 46 Back Clark Perivascular superficial NS5 Female 46 Nose Miescher Perivascular superficial 76 Female 25 Back Miescher Perivascular superficial NS7 Male 32 Back Clark Perivascular superficial NS8 Female 24 Back Clark Perivascular superficial NS9 Female 48 Neck Unna Perifollicular NS10 Male 72 Face Unna Perifollicular NS11 Male 59 Back Clark Perivascular superficial NS12 Female 29 Abdomen Clark Perivascular superficial NS13 Female 33 Retroauricular area Unna Perivascular superficial NS14 Female 51 Face Unna Perivascular superficial & deepNS15 Female 49 Face Miescher Periinfundibular NS16 Female 59 Face Miescher Perivascular superficial NS17 Male 26 Scalp Miescher Perivascular superficial NSNS=not studiedFernandez-Flores	      Acta Dermatovenerol CroatPlasma cell infiltrate in melanocytic nevus   2008;16(3):158-163160dISCUSSIonThe presence of plasma cells in melanocytic lesions has been considered as a useful criterion in the differential diagnosis between malignancy and benignancy in the appropriate context. For instance, their presence in what looks like a des-moplastic Spitz nevus should alert the possibility of a desmoplastic melanoma (9).Figure 1. Case 2 in which a mild inflammatory infiltrate was seen in a perifollicular location (top, arrow), but mixed with nevus cells in the deep re-ticular dermis (middle). When examined at high magnification, plasma cells were easily identified with routine hematoxylin-eosin staining.It has also been mentioned how plasma cells are only occasionally found in the inflammatory infiltrate of a halo nevus (6). This was later con-firmed at the ultrastructural level (7). Even when halo nevi are studied in their several evolutional stages, neither plasma cells nor B-cells in gen-eral seem to be a main component of the infiltrate (13).On the other hand, plasma cells can be numer-ous in the inflammatory infiltrate accompanying melanoma and this fact has been found to have an adverse prognostic value (1-5): whenever a heavy infiltrate of plasma cells is present in a melanoma, Figure 2. Immunostaining for epithelial membrane antigen in case 2 showing a perifollicular distribu-tion of the inflammatory infiltrate (F, follicle). The technique was useful in standing out numerous plasma cells in the infiltrate, in the proximity of ne-vus cells (N).Figure 3. Immunostaining for epithelial membrane antigen in case 5 showing a focus rich in plasma cells close to nevus cells (N).Fernandez-Flores	      Acta Dermatovenerol CroatPlasma cell infiltrate in melanocytic nevus   2008;16(3):158-163161ACTA DERMATOVENEROLOGICA CROATICAthe possibility of lymph node metastasis should be considered. Therefore, if a large amount of plasma cells are seen in a lesion that looks like a halo ne-vus, the possibility of melanoma should be consid-ered. This is especially important in cases of halo Spitz nevus, where epitheloid melanocytes can al-ready be a concern for malignancy. Nevertheless, plasma cells are absent in a halo Spitz nevus, un-less there is a traumatic epidermal defect (9). In spite of this diagnostic use of plasma cells, studies investigating them in the inflammatory in-filtrate of halo nevus are not so frequent (6,7), and the ones investigating these cells in common ac-quired nevus are even rarer (14). Our results indicated that on some occasions plasma cells could be present and easily found in common, innocent-looking nevi. A similar result was reported in conjunctival nevi, although mainly in patients who presented a history of allergic dis-ease (14). We found no explanation for the conspicuous plasma cells in these four cases, since the fea-tures of the four were not peculiar: the location of the lesion, the histological type of nevus or the lo-cation of the infiltrate were not different in these four cases from some other examples in the rest of the cases in our series. The location of the lesion could suggest the possibility of trauma in some cases (the neck or nose), but not easily in others (back). Again, among our cases, there were many examples of nevi on the face and nose with only very few and occasional plasma cells. Therefore, in our opinion, the main point of our findings is that the presence of plasma cells should not necessarily make one think of malig-nancy, even if the other morphological features of the melanocytic lesion evaluated point towards benignancy.The reason why plasma cells seem to be more common in melanoma than in nevi has not yet been elucidated. Nevertheless, it might have something to do with the fact that the inflamma-tory infiltrate, according to some, could be just an epiphenomenon in halo nevus (i.e. not necessar-ily for the nevus clearance) (15). It would, on the contrary, represent an immune response against melanoma cells. Nevertheless, this interpretation is not a consensus (13). For some, the inflamma-tory infiltrate plays a crucial role in the regression of the halo nevus (16,17), but it should be noted that such a role is mainly played by T-cells and not by B-cells (13,18,19). In melanoma, on the contrary, it is mostly agreed that the presence of a B-cell infiltrate would be the result of sensitiza-tion of the lymphocytes which have travelled to the skin from the lymph nodes, where they had been in contact with the metastatic melanocytes (15). This explains the observations reported in the past on the predictability of nodal metastasis, based on the presence of plasma cells in the inflammatory infiltrate of melanoma (4,5). It would also explain the paradox on how a prominent inflammatory in-filtrate in a melanoma is not correlated with a bet-ter prognosis (20), opposite to what happens in many other tumors (21,22). A therapeutic proof of this sensitization has been obtained in patients with metastatic mela-noma who were vaccinated with autologous mela-noma cells. Although the resected metastatic nod-ules, previous to vaccination, presented a minimal inflammatory infiltrate, a dense inflammatory infil-trate with plasma cells was found in metastatic le-sions resected after the vaccination (23).This sensitization has nothing to do with the re-ported presence of “plasmacytoid cells” in some inflammatory infiltrates induced by topical treat-ments of melanocytic lesions (24): plasmacytoid cells are not related to plasma cells; the former are CD4+ cells (17,24) which are able to produce large amounts of type 1-interferons (25-30). References1.   Käresen R. The immune reaction against malignant melanoma studied in a biopsy material. Acta Pathol Microbiol Scand Sec A 1974;82:116-26.2.   Roubin R, Cesarini JP, Fridman WH, Pavie-Fischer J, Peter HH. Characterization of the mononuclear cell infiltrate in human malignant melanoma. Int J Cancer 1975;16:61-73.3.   Lang JR, Davidorf FH, Baba N. The prog-nostic significance of lymphocytic infiltration in malignant melanoma of the choroid. Cancer 1977;40:2388-94.4.   Weissmann A, Roses DF, Harris MN, Dubin N. Prediction of lymph node metastases from the histologic features of primary cutaneous malignant melanomas. Am J Dermatopathol 1984;6 Suppl:35-41.5.   Mascaro JM, Molgo M, Castel T, Castro J. Plasma cells within the infiltrate of primary cutaneous malignant melanoma of the skin. A confirmation of its histoprognostic value. Am J Dermatopathol 1987;9:497-9.6.   Wayte DM, Helwig E. Halo nevi. Cancer 1968;22:69-90.Fernandez-Flores	      Acta Dermatovenerol CroatPlasma cell infiltrate in melanocytic nevus   2008;16(3):158-163162 ACTA DERMATOVENEROLOGICA CROATICA7.   Jacobs JB, Edelstein LM, Snyder LM, Fortier N. Ultrastructural evidence for destruction in the halo nevus. Cancer Res 1975;35:352-7.8.   Dunn GP, Lewis JS, Sunwoo JB, Uppaluri R. Spontaneous regression of cutaneous head and neck melanoma: implications for the im-munologic control of neoplasia. Head Neck 2008;30:267-72.9.   Mooi WJ. Spitz nevus and its histologic simu-lators. Adv Anat Pathol 2002;9:209-21.10. Ackerman AB, Magana-Garcia M. Naming ac-quired melanocytic nevi. Unna’s, Miescher’s, Spitz’s, Clark’s. Am J Dermatopathol 1990;12:193-209.11. Ackerman AB, Milde P. Naming acquired mela-nocytic nevi. Common and dysplastic, normal and atypical, or Unna, Miescher, Spitz, and Clark? Am J Dermatopathol 1992;14:447-53.12. Sánchez Yus E, del Cerro M, Simón RS, Her-rera M, Rueda M. Unna’s and Miescher’s nevi: two different types of intradermal nevus: hy-pothesis concerning their histogenesis. Am J Dermatopathol 2007;29:141-51.13. Bayer-Garner I, Ivan D, Schwartz MR, Tschen JA. The immunopathology of regression in benign lichenoid keratosis, keratoacanthoma and halo nevus. Clin Med Res 2004;2:89-97.14. Zamir E, Mechoulam H, Micera A, Levi-Schaf-fer, Pe´er J. 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Am J Clin Pathol 2005;124:37-48.20. Davidorf FH, Lang JR. Lymphocytic infiltra-tion in choroidal melanoma and its prognostic significance. Trans Ophthalmol Soc U K 1977;97:394-401.21. Nagtegaal ID, Marijnen CA, Kranenbarg EK, Mulder-Stapel A, Hermans J, van de Velde CJ, et al. Local and distant recurrences in rectal cancer patients are predicted by the nonspe-cific immune response; specific immune re-sponse has only a systemic effect – a histo-pathological and immunohistochemical study. BMC Cancer 2001;1:7. 22. Cai T, Nesi G, Boddi V, Mazzoli S, Dal Canto M, Bartoletti R. Prognostic role of the tumor-associated tissue inflammatory reaction in transitional bladder cell carcinoma. Oncol Rep 2006;16:329-34.23. Soiffer R, Hodi FS, Haluska F, Jung K, Gilles-sen S, Singer S, et al. Vaccination with irradia-ted, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-sti-mulating factor by adenoviral-mediated gene transfer augments antitumor immunity in pa-tients with metastatic melanoma. J Clin Oncol 2003;21:3343-50.24. Wolf IH, Kodama K, Cerroni L, Kerl H. Nature of inflammatory infiltrate in superficial cuta-neous malignancies during topical imiquimod treatment. Am J Dermatopathol 2007;29:237-41.25. Gibson SJ, Lindh JM, Riter TR, Gleason RM, Rogers LM, Fuller AE, et al. Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod. Cell Immunol 2002;218:74-86.26. Hartmann E, Wollenberg B, Rothenfusser S, Wagner M, Wellisch D, Mack B et al. Identifi-cation and functional analysis of tumor-infiltra-ting plasmacytoid dendritic cells in head and neck cancer. Cancer Res 2003;63:6478-87.27. Vermi W, Bonecchi R, Facchetti F, Bianchi D, Sozzani S, Festa S, et al. 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J Im-munol 2004;173:3051-61.Fernandez-Flores	      Acta Dermatovenerol CroatPlasma cell infiltrate in melanocytic nevus   2008;16(3):158-163Veramon - against pain; year 1936.(from the collection of Mr. Zlatko Puntijar)

Plasma Cell Infiltrate in Common Acquired Melanocytic Nevus

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