MALIGNANT HEMANGIOENDOTHELIOMA

Background. The administration of interleukin-2 (il-2 ) has recently been reported to be favorable for treating malignant hemangioendothelioma (mhe ). Methods. Two patients with mhe responded well to intra-lesional injections of recombinant il-2 (ril-2 ) without major side effects. The purpose of this study was to characterize cells infiltrating the regressing tumor following ril-2 treatment. Immunohistochemical studies were performed on biopsy specimens taken from ril-2 -injected lesional skin. Results. It was shown that CD8⁺ lymphocytes and CD56⁺ natural killer (nk ) cells infiltrated at the ril-2 -injection sites, suggesting that these cells contributed to the tumor regression. In addition, MHE cells bore intercellular adhesion mole-cule-1 (icam -1) whose expression was augmented by rn-2 injections. Conclusions. These findings suggested, that ril-2 not only induces lymphokine-activated killer (lak ) cells and nk cells, but also facilitates these cytotoxic cells to adhere to MHE cells by enhancing icam -1 expression of tumor cells.     

Effective induction of melanoma‐antigen‐specific CD8+ T cells via Vγ9γδT cell expansion by CD56high+ Interferon‐α‐induced dendritic cells

Dendritic cells (DCs) can be differentiated from CD14⁺ monocytes in the presence of interferon‐α (IFNα) and granulocyte/macrophage‐colony stimulating factor (GM‐CSF) in vitro and are known as IFN‐DCs. Circulating blood CD56⁺ cells expressing high levels of CD14, HLA‐DR and CD86 have been shown to spontaneously differentiate into DC‐like cells in vitro after their isolation from blood. We show here that IFN‐DCs expressing high levels of CD56 (hereafter, CD56^high+ IFN‐DCs) can be differentiated in vitro from monocytes obtained as adherent cells from healthy donors and patients with metastatic melanoma. These cells expressed high levels of CD14, HLA‐DR and CD86 and possessed many pseudopodia. These CD56^high+ IFN‐DCs may be an in vitro counterpart of the circulating CD56⁺ CD14⁺ CD86⁺ HLA‐DR⁺ cells in blood. Conventional mature DCs differentiated from monocytes as adherent cells in the presence of GM‐CSF, IL‐4 and TNF‐α (hereafter, mIL‐4DCs) did not express CD56 or CD14. In contrast to mIL‐4DCs, the CD56^high+ IFN‐DCs exhibited a stronger capacity to stimulate autologous CD56⁺ Vγ9γδT cells highly producing IFNγ in the presence of zoledronate and IL‐2. The CD56^high+ IFN‐DCs possessing HLA‐A*0201 effectively induced Mart‐1‐modified melanoma peptide (A27L)‐specific CD8⁺ T cells through preferential expansion of CD56⁺ Vγ9γδT cells in the presence of A27L, zoledronate and IL‐2. Vaccination with CD56^high+ IFN‐DCs copulsed with tumor antigens and zoledronate may orchestrate the induction of various CD56⁺ immune cells possessing high effector functions, resulting in strong immunological responses against tumor cells. This study may be relevant to the design of future clinical trials of CD56^high+ IFN‐DCs‐based immunotherapies for patients with melanoma.     

Phenotypic determination of T-lymphocytes responding to chemotactic stimulation from fMLP,IL-8, human IL-10, and epidermal lymphocyte chemotactic factor

Summary Human T lymphocytes were collected after they had migrated towards N-formyl-methionyl-leukyl-phenylalanine (fMLP), rIL-8, human IL-10 (hIL-10), and epidermal lymphocyte chemotactic factor (ELCF). They were stained for determination of their phenotype by FACS analysis using anti-CD4, -CD8, -CD18, -CD45R0 and OPD4 antibodies. Human IL-10 increased the percentage of CD8⁺ T lymphocytes in the migrating cell population by 152% compared with cells migrating towards the medium and decreased the number of CD4⁺ T lymphocytes by 79%. ELCF increased the number of CD4⁺ T lymphocytes by 18%, and the number of CD45R0⁺ T lymphocytes by 52%, while the number of CD8⁺ T lymphocytes was decreased by 20%. rIL-8 increased the number of CD4⁺ T lymphocytes and decreased the CD8⁺ T lymphocytes. The distribution of the different subpopulations of T lymphocytes was not changed significantly by fMLP. The observed changes in the phenotypes did not occur when incubating T lymphocytes with the chemotaxins. Our observations demonstrate that individual chemotactic factors will attract specific subsets of T lymphocytes. They may help to explain the predominance of memory T lymphocytes (CD4R0⁺, CD4⁺) in allergic contact dermatitis and certain other skin diseases. They also confirm the results of a recent study, that showed hIL-10 to be selectively chemotactic for CD8⁺ T lymphocytes.     

Evidence that regression in Keratoacanthoma is immunologically mediated: a comparison with squamous cell carcinoma

Recent research observations suggest that the keratoacanthoma (KA) is a form of resolving squamous cell carcinoma (SCC). The mechanism by which this resolution takes place has not been fully explored, although it may have an immunological basis. To investigate this, we compared 15 clinically and histologically diagnosed KAs and 15 SCCs with regard to cellular infiltrate and keratin expression. We found that KAs have significantly higher numbers of CD3⁺ and CD4⁺ cells invading their epidermal component than SCCs. The lymphocytes infiltrating KAs were more immunologically active, as greater numbers expressed the interleukin-2 receptor (IL-2R) than those in SCCs. It is of interest that CD36 was expressed by a significantly greater proportion of tumour cells within KAs than SCCs. This was also the case for the intercellular adhesion molecule ICAM-1, and the differentiation marker keratin 10. Overall, these findings suggest that KA regression is immunologically mediated, with activated (IL-2R⁺) CD4⁺ T lymphocytes and adhesion molecules playing a pivotal role in the immune response.     

Correlation among metallothionein expression,intratumoural macrophage infiltration and the risk of metastasis in human cutaneous malignant melanoma

Background The formation of metastases and the efficacy of systemic therapies in cutaneous malignant melanoma (CMM) depend on the characteristics of the tumour cells and the host immune response. Aberrant expression of metallothionein (MT) has been observed in several types of cancers with poor prognoses. Objective To perform an immunohistochemical study on primary CMM comparing the MT expression of tumours without metastases (n = 23) to that of samples with haematogenous metastases (n = 23) and to examine the correlation between MT staining and immunological markers relevant in CMM progression. Methods The immunohistochemical labelling of different tumour sections was analysed using tissue microarrays for the evaluation of the suitability of this method in future studies. Results Our results suggest that MT overexpression is significantly more frequent in primary CMM with haematogenous metastases (P = 0.018) and that the overexpression is independent of the Breslow tumour thickness (R = 0.102, P = 0.501). Interestingly, MT overexpression of the tumour cells was correlated with the presence of tumour‐infiltrating CD68⁺ macrophages (P = 0.003), a known predictive factor for melanoma progression, thereby suggesting a role for MT in the development of a defective host immune response. Furthermore, the presence of CD163⁺ macrophages infiltrating the tumours correlated with metastasis formation (P < 0.001), whereas the presence CD1a⁺ dendritic cells surrounding the tumours was associated with a lower risk of haematogenous spread (P = 0.003). Conclusion Our results demonstrate that MT may represent a suitable prognostic factor that can characterize the metastasising ability of CMM and the tumour‐promoting host immune response.     

A case of malignant haemangioendothelioma treated with recombinant interleukin-2

A case of malignant haemangioendothelioma of the scalp in an 82-year-old female treated with intralesional, intra-arterial and intravenous recombinant interleukin-2 (rIL-2) is reported. The scalp lesions disappeared after injection of 35 350 000 Japan reference units of rIL-2 and excision of the residual tumour. Immunohistochemical characterization of the cells infiltrating the lesion after rIL-2 administration revealed 30–40% CD4⁺ and CD8⁺ T lymphocytes, 20–30% macrophages and 5–10% natural killer cells. These findings are similar to those in other human cancers. Almost all of the cells in the intersticies of the lesion after rIL-2 injection expressed leucocyte function-associated antigen-1, and some of the tumour cells and the infiltrating cells around them expressed intercellular adhesion molecule-1. HLA-DR-positive cells markedly increased in number after rIL-2 administration. This report suggests that rIL-2 administration is the most effective therapy for malignant haemangioendothelioma.     

Activation of human vascular endothelium in melanoma metastases induces ICAM‐1 and E‐selectin expression and results in increased infiltration with effector lymphocytes

Lymphocytic infiltration into melanoma tissue is an important prerequisite for effective antitumoral immunity. However, analysis of human metastatic melanoma has shown that leucocyte adhesion receptor expression on melanoma blood vessels is very low or absent, thereby impairing the entry of cytotoxic lymphocytes into tumor tissue. We hypothesized that adhesion molecules can be induced on melanoma vasculature allowing better infiltration of cytotoxic lymphocytes. Quantitative real‐time PCR and immunofluorescence staining indicated that the adhesion molecules ICAM‐1 (CD54) and E‐selectin (CD62E) can be significantly induced by intralesional application of TNF alpha in tissue from human melanoma metastases either in vitro or in vivo when grafted onto immunodeficient NSG (NOD.Cg‐PrkdcscidIl2rgtm1Wjl/SzJ) mice that preserved human vessels. Furthermore, activated human autologous CD3⁺ lymphocytes were injected intravenously into mice bearing melanoma xenografts treated with TNF‐α or PBS in addition to the leucocyte chemoattractant TARC (CCL17). Significantly increased numbers of CD8⁺ cells were detected in TNF‐α–treated melanoma metastases compared with PBS‐treated controls. In addition, tumor cell apoptosis was enhanced and melanoma cell proliferation reduced as shown by TUNEL assay and KI‐67 staining. We conclude that adhesion molecules can be induced on human melanoma vasculature resulting in significantly improved homing of activated autologous cytotoxic T cells to melanoma tissue and inhibition of melanoma cell proliferation. These observations should be considered when designing protocols for immunotherapy of malignant melanoma.     

Possible role of superantigens in inducing autoimmunity in pemphigus patients

The diagnostic and pathological relevance of anti‐desmoglein autoantibodies in common forms of pemphigus has been well established, and T cells have been shown to play a role in the onset and progression of these diseases. The role of superantigens in provoking polyclonal activation of T cells with many different fine specificities, possibly including autoreactive T cells and T‐cell mediated autoantibody response, is unknown. Further, abnormal T‐cell function may lead to opportunistic infections particularly with Candida. The response of T cells of pemphigus patients to recall antigens of these opportunists is not clear. The aim of this study was to investigate the in vitro response of T lymphocytes from pemphigus patients to common bacterial superantigens such as streptococcal pyrogenic exotoxin A and staphylococcal enterotoxin B, and recall antigens such as Candida antigen. Changes in CD3⁺CD4⁺ and CD3⁺CD8⁺ T‐cell sub‐populations and expression of naive/memory markers (CD45RA⁺/RO⁺) on different T cells were analyzed by flow cytometry. Significant elevation in CD3⁺CD4⁺ and expression of the memory (CD45RO⁺) markers on these cells was observed both in pemphigus vulgaris and pemphigus foliaceus patients, as compared to healthy controls, upon stimulation with streptococcal pyrogenic exotoxin A and staphylococcal enterotoxin B. However, only memory T cells (CD45RO⁺) were significantly increased upon Candida antigen stimulation. Our study suggests that CD4⁺ memory T lymphocytes may modulate the pathogenic autoantibody response in pemphigus patients, and also emphasizes the possibility that the superantigen‐reactive T cells participate in the triggering of autoimmunity in pemphigus.     

Evaluation of activatory and inhibitory natural killer cell receptors in non-segmental vitiligo: a flow cytometric study

Background Recent observations established the role of altered cellular immunity and autoimmune hypothesis in the pathogenesis of vitiligo. There have been several reports discussing T‐cell and natural killer (NK) cell populations, but NK cell receptors were not evaluated in vitiligo. Objective The purpose of this investigation was to assess the role of T and NK cells as well as activatory and inhibitory NK cell receptor alterations in the pathogenesis of vitiligo and whether any aberrations were correlated with clinical findings of the disease. Patients/methods Fifty‐three patients with non‐segmental vitiligo and 45 age‐ and sex‐matched healthy controls were enrolled in the study. The percentages of lymphocytes, granulocytes, monocytes and CD3, CD4, CD8, CD14, CD16, CD56, CD45, CD45RA, CD54RO, CD28, CD80, CD94, CD158a, KIR3DL‐1 receptors as well as CD94, CD158a, KIR3DL‐1 receptors on CD16⁺ cells were detected by using flow cytometry. The patient and control groups were compared in terms of the results of flow cytometric analysis, and the results were assessed regarding the type and activity of vitiligo. Results The percentages of CD16⁺CD56⁺, CD3⁺CD16⁺CD56⁺, CD8⁺ and CD45RO⁺ cells were significantly increased in vitiligo group compared with the controls. No difference was detected between the patients and control groups in percentages of CD3⁺, CD4⁺, CD3^?CD16⁺CD56⁺, CD28⁺, CD45⁺, CD45RA⁺, CD94⁺, CD158a⁺ and KIR3DL‐1⁺ cells. The percentage of CD16⁺CD158a⁺ cells was significantly decreased in a randomized selected group of vitiligo patients. There were no differences in percentage expression of studied cell surface antigens between patients in the active or stable period. CD3⁺ cells were significantly increased in generalized form, and CD45RO⁺ cells were significantly increased in acral/acrofacial form when compared with the other types of vitiligo. Conclusions These results indicate further evidence for T and NK cell abnormalities in non‐segmental vitiligo. The present data show that NK cell activation may be responsible in the pathogenesis of vitiligo in conformity with decreased inhibitory and increased activatory NK cell receptors.     

The roles of P- and E-selectins and P-selectin glycoprotein ligand-1 in primary and metastatic mouse melanomas

Background

Malignant melanoma is often accompanied by a host response of inflammatory cell infiltration that is highly regulated by multiple adhesion molecules.

Objective

To evaluate the role of adhesion molecules, including P-selectin glycoprotein ligand-1 (PSGL-1), P-selectin, and E-selectin.

Methods

Subcutaneous primary growth and metastasis to the lung of B16 melanoma cells were examined in mice lacking PSGL-1, P-selectin, or E-selectin.

Results

Primary subcutaneous growth of B16 melanoma was augmented by loss of PSGL-1, P-selectin, or E-selectin, while pulmonary metastasis was reduced by the loss of E-selectin. The enhancement of subcutaneous tumor growth was associated with a reduced accumulation of natural killer cells, CD4⁺ T cells and CD8⁺ T cells, while the attenuation of pulmonary metastasis was related to the numbers of CD8⁺ T cells. The expressions of transforming growth factor (TGF)-β and interleukin (IL)-6 were correlated with primary subcutaneous growth; TGF-β, IL-6, and interferon-γ were related to number of metastatic lung nodules. Cytotoxicity against melanoma cells in splenocytes and in tumor-draining lymph node cells were not defective by the absence of adhesion molecules, suggesting that the enhancement of tumor growth and metastasis caused by the loss of selectins results from an impaired migration of effector cells into the tissue.

Conclusions

The results indicate the complexity of anti-tumor responses mediated by adhesion molecules in primary subcutaneous tumors and pulmonary metastasis of murine experimental melanoma.     

Skewed distribution of natural killer cells in psoriasis skin lesions

Psoriasis is a hyper‐proliferative disease of the skin in which immunological mechanisms play a direct pathogenetic role. There have been limited studies of natural killer (NK) cells in psoriasis. The aim of this study was to examine the phenotype of NK cells in skin biopsies and peripheral blood mononuclear cells from patients with psoriasis and healthy controls. CD56⁺CD16^? and CD56⁺CD16⁺ NK cells were isolated from lesional skin, unaffected skin and PBMC of psoriasis patients, and normal skin and PBMC from healthy controls. The expression of CD57, NKG2A and NKG2C was assessed by flow cytometry. NK cells in psoriasis skin lesions were skewed in their expression of CD57, a marker of NK cell maturity, with CD57 expression significantly reduced and NKG2A expression increased on NK cells in lesional and unaffected skin compared to controls. These data suggest that in this patient cohort, NK cells could be isolated from psoriasis lesions and exhibit an immature phenotype.     

Two Cases of Metastatic Malignant Melanoma of the Lower Limb Treated with Hyperthermic Isolated Limb Perfusion and Concomitant Infusion of Either Carboplatin or β-Interferon

Two cases of metastatic malignant melanoma of the lower limb who were treated successfully with hyperthermic isolated limb perfusion are reported. One patient was infused with cis-diammine (1.1-cyclobutanedicarboxylate) platinum (II) (carboplatin, Paraplatin®, Bristol-Myers Squibb Company, New Jersey, USA), and the other was infused with human natural β-interferon (Feron®, Toray, Tokyo, Japan), via the external iliac artery. The first case showed a remarkable suppression of the growth of multiple metastatic melanoma nodules associated with numerous melanophage infiltrations, as shown histopathologically after the operation. The patient's serum level of 5-S-cysteinyl dopa decreased for the two months following the treatment In the second case, new formation of metastatic melanoma nodules was completely suppressed for up to 12 months following the operation. Analysis of immunological parameters showed that the number of peripheral CD8⁺ lymphocytes gradually and constantly increased after the operation, while that of CD4⁺ lymphocytes transiently increased and then returned to the pre-operative level. Natural killer activity transiently decreased to a slight degree 4 days after the operation and then returned to the pre-operative level 21 days after the operation. Side effects, such as nausea, vomiting and leg discomfort, were seen in the patient (Case 1) treated with carboplatin, but were completely reversible. These results suggest that hyperthermic isolated limb perfusion with concomitant infusion of carboplatin or β-interferon is effective in suppressing the growth of metastatic malignant melanomas of the lower limb.     

Immunohistological analysis of anti-melanoma host responses

Various clinical and experimental observations point to the existence of an immunological host defense in cutaneous malignant melanoma. To identify the major effector mechanisms mediating the specific anti-tumor immune response, we examined 23 benign and neoplastic melanocytic lesions (3 nevi, 14 primary melanomas, and 3 cutaneous and 3 systemic metastases) by quantitative immunohistology, and correlated these results with the histopathological and clinical subtypes of malignant melanoma. Our analyses indicate that CD3⁺ T-cell receptor /-expressing lymphocytes are the prevailing leukocyte subset in primary as well as secondary malignant melanoma. We further observed that in early lesions (<0.75 mm) of superficial spreading melanoma the vast majority of tumor-infiltrating lymphocytes (TIL) belong to the CD4⁺ subset and frequently express CD45RA antigens. In more advanced tumors, the contribution of CD8⁺ TIL gradually increases, indicating that the quality of the anti-tumor immune response changes during the course of the disease. Finally, we found that a varying percentage of cutaneous TIL express the cutaneous leukocyte antigen which is defined by the monoclonal antibody HECA 452 and preferentially expressed by skin-seeking memory T cells. In contrast, extracutaneous melanoma metastases (liver, brain, ovary) were completely devoid of HECA 452-reactive lymphocytes. These findings suggest that lymphocytes infiltrating cutaneous melanomas belong to a memory/effector T-cell subset functionally associated with the skin.     

Interleukin-7. Biology and implications for dermatology

Abstract In recent years, it has become apparent that IL-7, originally characterized as a growth factor for pre-B lymphocytes. also has important implications for the skin. Keratinocytes have been shown to produce IL-7, which in turn can elicit a variety of biological responses on several cell types residing in the skin. IL-7 has been demonstrated to augment the cytolytic activity of cytotoxic T cells (CTL) and natural killer (NK) cells against various neoplastic targets indcluding melanoma cells. Proliferation and long-term survival of murine dendritic epidermal T lymphocytes (DETC) in vitro is supported by IL-7. IL-7 also induces secretion of inflammatory cytokines by monocytes/macrophages and renders these cells to become tumoricidal against melanoma cells. Normal and malignant melanocytes respond to IL-7 with increased expression of intercellular adhesion molecule (ICAM-I). In addition, IL-7 has been shown to act as growth factor for Sczary cells, suggesting a röle of keratinocyte-derived IL-7 in the pathogenesis of cutaneous T cell lymphoma. Because of the potent in vitro immunomodulatory effects of IL-7 which have been confirmed in mouse tumor models, IL-7 may become a valuable additional agent to immunotherapeutical regimens currently studied in patients with advanced melanoma. This review summarizes our present knowledge about the molecular and immunological properties of IL7 with emphasis on the effects of that cytokine within the cutaneous compartment and the potentical clinical utility in dermatology.     

Decrease in circulating Th17 cells correlates with increased levels of CCL17, IgE and eosinophils in atopic dermatitis

Background

Clinical significance of circulating CD4⁺ T cell subsets, including T-helper (Th)1, Th2, Th17 and regulatory T (Treg) cells, in patients with atopic dermatitis (AD) remains unclear. No previous studies have simultaneously evaluated the four T cell subset profiles in AD.

Objective

The aim of the present study was to explore whether the percentage of these four subsets of CD4⁺ T cells correlate to the severity parameters of AD patients.

Methods

Intracellular expression of interferon (IFN)-γ, interleukin (IL)-4, IL-17 and forkhead box P3 (Foxp3) in CD4⁺ T cells was evaluated in peripheral blood mononuclear cells from normal controls and patient with AD as well as with chronic eczema using a flow cytometer. Serum CCL17 levels were measured as an objective severity parameter of AD together with percentage of eosinophils and serum IgE levels.

Results

In AD patients, the number of Th1 (IFN-γ⁺) and Th17 (IL-17⁺) subsets was significantly decreased, but that of Th2 (IL-4⁺) and Treg (Foxp3⁺) subsets was similar to that of normal controls. The T cell subset profiles of patients with chronic eczema were not different with those of normal controls. The frequency of Th17cells, particularly that of the IFN-γ^negaIL-17⁺ subset, showed a significant negative correlation with CCL17, IgE and eosinophil levels in AD patients. This was, however, not the case in Th1, Th2 and Treg cells.

Conclusion

Decreased circulating Th17 cells might contribute to activity of AD.     

Nasal‐type extranodal natural killer/T‐cell lymphoma presenting with extensive leg ulcers

Primary cutaneous T‐cell lymphomas are rare and can be difficult to classify precisely. We present a case of extranodal natural killer (NK)/T‐cell lymphoma in a previously healthy, immunocompetent man who presented with extensive necrotic leg ulcers and disseminated skin nodules. Immunohistochemical studies revealed that the tumour cells were positive for CD3, CD30, granzyme B and T‐cell intracellular antigen‐1, and negative for CD5 and CD56, with positive staining for Epstein–Barr virus (EBV) RNA on in situ hybridization. A diagnosis of extranodal NK/T‐cell lymphoma was made, based on the presence of cytotoxic granules and positive EBV RNA staining. The patient was treated with a regimen of chemotherapy comprising corticosteroids, intravenous methotrexate, ifosphamide, L‐asparginase and etoposide with initial response.     

Expression of stress-induced MHC class I related chain molecules on human melanoma

Cellular immune responses to melanoma are tightly regulated and include specific T cell responses to self antigens such as Mart-1 and gp100. Thus, additional signals apart from those mediated by the T cell receptor are needed to ensure T cell activation. Recently, the stress inducible major histocompatibility complex molecules, MHC class I related chain, were identified as an activator of both natural killer and T cells via interaction with their receptor NKG2D. Herein, we report the expression of MIC in 31 of 40 primary cutaneous melanomas and in 13 of 20 metastatic lesions. Moreover, lymphocytes infiltrating the tumor were found to express NKG2D. Detailed analysis identified both CD3+ T cells as well as CD56+ natural killer cells contributing to this NKG2D+ tumor infiltrating lymphocyte population present.     

Evaluation of tumour-infiltrating CD4+CD25+FOXP3+ regulatory T cells in human cutaneous benign and atypical naevi, melanomas and melanoma metastases

BACKGROUND: CD4+CD25+FOXP3+ regulatory T cells (Tregs) are thought to induce immunotolerance in melanoma. They have not yet been investigated in the entire spectrum of melanocytic cutaneous lesions within a tumour site. OBJECTIVES: To evaluate CD4+CD25+FOXP3+ Tregs among tumour-infiltrating lymphocytes in cutaneous melanocytic lesions. METHODS: We analysed 128 lesions (10 benign junctional common naevi, 10 benign compound common naevi, 10 compound Spitz naevi, 10 junctional atypical naevi, 20 compound atypical naevi, 20 radial growth phase melanomas, 30 vertical growth phase melanomas and 18 melanoma metastases). Tregs were identified by CD25-FOXP3 double immunostains. RESULTS: This study indicates that CD4+/CD25+FOXP3+ Tregs are present in all groups of lesions. Junctional atypical naevi, compound atypical naevi and radial growth phase melanomas showed the highest percentages of CD4+CD25+FOXP3+ Tregs (junctional atypical naevi vs. junctional common naevi, compound common naevi, compound Spitz naevi, melanoma metastases: P < 0.0001; junctional atypical naevi vs. vertical growth phase melanomas: P = 0.001; compound atypical naevi vs. junctional common naevi, compound common naevi: P < 0.0001; compound atypical naevi vs. compound Spitz naevi, melanoma metastases: P = 0.002; compound atypical naevi vs. vertical growth phase melanomas: P = 0.02; radial growth phase melanomas vs. junctional common naevi, compound common naevi, compound Spitz naevi, melanoma metastases: P < 0.0001; radial growth phase melanomas vs. vertical growth phase melanomas: P = 0.008). CONCLUSIONS: The strong prevalence of CD25+FOXP3+ Tregs both in junctional and compound atypical naevi and radial growth phase melanomas, suggests that they induce immunotolerance early during melanoma genesis, favouring melanoma growth. Their evaluation within a tumour site could be useful for prognostic and therapeutic purposes.     

Melkersson Rosenthal syndrome: a histopathologic mystery and dermatologic challenge

Melkersson Rosenthal syndrome (MRS) is rare disease of unknown etiology characterized by orofacial edema, facial nerve palsy and fissured tongue. Microscopically, it shows epithelioid non‐caseous granulomas; however, edema and perivascular lymphocytic infiltrates have been described. Two different clinical forms of MRS are presented in this report. In the complete form (Case 1), the main histopathologic finding was a non‐necrotizing granulomatous inflammation with 56% of the total number of cells composed of B cells (CD 20⁺) principally located in the granuloma's center and 33% being T cells predominating in the surrounding area, of which 48% were CD 4⁺ and 16% were CD 8⁺ lymphocytes. In the monosymptomatic form (Case 2), the inflammatory cells were dispersed into the connective tissue without granulomatous formation. B cells were scanty, and 78% of the cells were CD 45⁺ T cells, with 46% and 34%, CD 8⁺ and CD 4⁺ phenotype, respectively. These cases showed different clinical, histopathological and immunohistochemical forms of MRS, suggesting different host immune responses. Kaminagakura E, Jorge J Jr. Melkersson Rosenthal syndrome: a histopathologic mystery and dermatologic challenge.