Telmisartan/hydrochlorothiazide-induced nevus-associated cutaneous melanoma: first report in the medical literature.

Introduction: The treatment of hypertension with certain groups of drugs may be problematic, particularly because certain drugs are capable of potentiating carcinogenesis. The presence of various receptors or components of the renin - angiotensin system in the skin, and particularly in melanocytes, determines the possible influence on this tissue by the so-called angiotensin receptor blockers or sartans. Thiazide diuretics can further influence the processes of carcinogenesis in all forms of skin cancer - melanocytic and non-melanocytic.Areas covered: We present a 67-year-old patient treated for a period of 3 years with a combined preparation containing Telmisartan/hydrochlorothiazide 80 mg/12.5 mg. Within 2 years, the patient observed the rapid development of a nevus that progressed to melanoma and was subsequently identified histopathologically as nevus-associated cutaneous melanoma with a 0.6 mm thickness, Clark IV. Following surgical treatment, no tumor progression has occurred to date. To our knowledge, this is the first reported case of a patient who developed a nevus-associated cutaneous melanoma after combination therapy with generic sartan and hydrochlorothiazide.Expert opinion: We discuss the diverse but mutually potentiating pro-carcinogenic effects of this class of agents, potentially leading to the development of cutaneous melanoma.

Nevoid melanoma and eruptive nevi from erlotinib.

Cutaneous side effects such as acneiform eruption, xerosis, and paronychia are frequently observed in patients undergoing treatment with epidermal growth factor receptor (EGFR) inhibitors for non-small cell lung cancer and other solid tumors. Interestingly, these side effects appear to positively correlate with length of remission, indicating that disruption of homeostatic EGFR signaling in the skin may serve as a marker of therapeutic EGFR inhibition in tumors. We report the case of a woman with metastatic lung cancer in remission being treated with the EGFR inhibitor, erlotinib, who experienced numerous commonly occurring adverse cutaneous reactions early in her treatment, and after two years of treatment developed eruptive nevi as well as a nevoid melanoma. Changes in pigmented lesions and the development of melanoma have been described during treatment with the BRAF inhibitor, vemurafenib, and are believed to relate to paradoxical activation of BRAF and the MAPK pathway. We speculate that a similar mechanism may occur during treatment with EGFR inhibitors. Therefore, thorough skin examinations are essential for patients undergoing long term treatment with erlotinib.

Leukoderma induced by rhododendrol is different from leukoderma of vitiligo in pathogenesis: A novel comparative morphological study.

BACKGROUND: Rhododendrol (rhododenol), an inhibitor of tyrosinase activity, is used as a skin-whitening component. Many cases of leukoderma after the application have been reported, termed rhododenol-induced leukoderma (RIL). The aim of this study was to clarify the pathogenesis of RIL morphologically through comparison with vitiligo. METHODS: We examined 14 cases of RIL and 15 cases of vitiligo using routine histopathology and immunohistochemistry. Thirteen cases of RIL, six cases of vitiligo and specimens of the RIL mouse model were evaluated by electron microscopy. RESULTS: There were common findings in RIL and vitiligo at the light-microscopic level: (a) vacuolar changes in the dermo-epidermal junction, (b) melanophages in the papillary dermis, (c) perifollicular lymphocyte infiltration, (d) loss or decrease of basal melanin pigment and (e) decrease of melanocytes in the lesions. The ultrastructural observations showed specific findings of RIL: (a) remaining melanocytes in depigmented lesions, (b) inhomogeneous melanization in melanocytes and (c) degenerated melanosomes in melanocytes. Some of the findings were observed in a RIL mouse model. Furthermore, it is notable that cell organelles of melanocytes were intact in our RIL cases. CONCLUSION: Morphological changes of RIL targeting melanosomes in melanocytes without degeneration of organelles reflect the reversible clinical course of most cases.

[Adverse skin reactions induced by BRAF inhibitors: a systematic review]. / Effets indésirables cutanés des inhibiteurs de BRAF: revue systématique.

Recent developments and therapeutic use of selective BRAF inhibitors (e.g. dabrafenib and vemurafenib) have significantly improved overall survival and disease-free survival of patients with BRAF V600 mutation-positive metastatic melanoma. Despite their survival benefits, small-molecule inhibitors of BRAF are associated with significant and sometimes severe treatment-related dermatological toxicity. The most common adverse skin reactions include photosensitivity, induced malignant lesions of the skin such as keratoacanthomas, squamous cell carcinoma and new primary melanomas, as well as keratinocyte proliferation and differentiation dysfunctions that can manifest as skin papillomas, hand-foot skin reaction, keratosis pilaris-like rash, acantholytic dyskeratosis and cysts of the milia type. In this article, we describe the clinical and histological features of the cutaneous manifestations induced by vemurafenib and dabrafenib on the basis of our clinical experience and a literature review. The crucial role of dermatologists in patient management is also highlighted.

[Melanotan-induced lentigines and nevi]. / Melanotan inducerer lentigines og naevi.

A 25-year-old man had self-injected more than 150 doses of melanotan to increase his skin pigmentation, which had increased significantly. At the same time, his nevi had become darker and new nevi and lentigines developed; they also occurred on his genitals causing his referral. Two nevi were excised, but showed no signs of malignant transformation.

[Eruptive nevi associated with sorafenib treatment]. / Naevus éruptifs sous sorafénib.

BACKGROUND: Sorafenib is a new multikinase inhibitor recently approved for renal cell carcinoma and hepatocarcinoma. Among other targets, it blocks the kinase function of the RAF gene products including V600E mutant BRAF, which is frequently found in both melanoma and naevi. Cutaneous side effects are frequent with sorafenib, but no naevus modification has been reported until now. PATIENTS AND METHODS: Five cases of eruptive naevi in patients treated with sorafenib are reported. The mean duration of sorafenib treatment was 9.2 months when naevi eruption was noticed. The patients presented with about 100 to more than 200 small, homogenous, dark-brown naevi located mainly on the trunk and upper limbs. DISCUSSION: Eruptive melanocytic naevi have been reported in association with blistering diseases, and more generally in a setting of immunosuppression. We hypothesize that naevi appearance could be linked to an anti-senescence effect of sorafenib via its action on the MAP kinase pathway. Further prospective studies are needed to explore the relationship between sorafenib and the biology of naevi.

Early exposure to yellow fever vaccine during pregnancy.

OBJECTIVE: To investigate the association of Yellow Fever Vaccination (YFV) during pregnancy with the presence of structural defect in exposed babies. METHODS: An observed/expected frequencies study, before and after the vaccination campaign against YF was designed. 304 babies exposed to YFV during the prenatal period underwent dysmorphological examinations. The expected frequencies of malformations were obtained from a reference population of 10,691 births occurred in the period immediately prior to the vaccination campaign and born in the same region. These frequencies were evaluated using Poisson distribution model. RESULTS: The major malformation rate found in this study was 3.3% (CI 1.7-6.3%). Minor dysmorphisms, especially naevus, were significantly more frequent (P<0.001) than in the reference population. CONCLUSIONS: The data here presented provide no indication that immunization with YFV early in pregnancy increases the risk of major malformations. However, the association found between YFV during pregnancy and minor dysmorphisms, especially pigmented naevus, seems to be a bias of evaluation. We suggest, nevertheless, that a reproductive risk hypothesis regarding minor dysmorphisms should be considered in future studies involving YFV.

[Acral eruptive nevi after chemotherapy in children with acute lymphoblastic leukemia]. / Nevos acrales eruptivos tras quimioterapia en niños afectados de leucemia linfoblástica aguda.

Eruptive melanocytic nevi have mainly been associated with blistering cutaneous diseases and with immunosuppression, particularly after renal allograft transplantation, hematological neoplasms, or HIV infection. Thus, immunosuppression has been suggested to increase the possibility of melanocyte proliferation. We report two cases of children with acute lymphoblastic leukemia who, after receiving chemotherapy, developed severe motor polyneuropathy, and sudden onset of multiple melanocytic nevi on the soles.

Sutton's nevus and growth hormone therapy.

Growth hormone (GH) has been suggested to increase the growth of melanocytic nevi and the risk for melanoma in short children treated with substitutive therapy. On the contrary, in GH deficient patients the influence of GH treatment on the appearance and the long-term evolution of Sutton's nevus, a pigmented melanocytic lesion surrounded by a ring (halo) of depigmentation, that usually and progressively involves the nevus, is debated. The aim of this study was to investigate whether GH therapy causes an accelerated growth of Sutton's nevus. In our study, we evaluated 3 children with GH deficiency sharing Sutton's nevus to investigate the relationship between these melanocytic lesions and growth hormone. In case 1 the appearance of the nevus could be induced by hGH therapy. However, the lesion did not change in shape, colour and size even if he entered puberty during substitutive treatment. Moreover, Sutton's nevus is present in case 2, who is prepuberal and not yet treated with hGH. In case 3 Sutton's nevi occurred during GH treatment and after the onset of puberty, but didn't show any long-term change in both the number and size. No clear influence of both GH therapy and sexual steroids on Sutton's nevi was observed.

A two-tier polymerase chain reaction direct sequencing method for detecting and typing human papillomaviruses in pathological specimens.

An in-house polymerase chain reaction direct sequencing (PCR-DS) approach for HPV detection and typing was developed, taking advantage of two widely used pairs of human papillomavirus (HPV)-specific PCR primers, MY09/MY11 and GP5/GP6, and 33P-labeled dideoxynucleotides. In this study, 105 pathological specimens were examined: 89% were diagnosed as cervical intraepithelial neoplasia (CIN) grade I-III, 76.2% were HPV-positive by PCR-DS. The PCR using GP5/GP6 (first tier) and MY09/MY11 primers (second tier for the GP5/GP6-negative samples) detected additional 15%-25% HPV-positive samples compared with each pair used separately. Direct sequencing was then used to type the HPV. A readout of a sequence as short as 34 nucleotides within a specific region in the L1 gene is sufficient to type known or novel sequences. Because of its high sensitivity and cost-effectiveness, the two-tier PCR-DS was adopted by the authors as the current method of choice for HPV diagnosis with ultimate sequence precision.

Complications of growth hormone therapy in children.

The introduction of human growth hormone (GH) prepared by recombinant DNA technology has resulted in increased numbers of children and adults receiving treatment. This trend has led to questions concerning the safety of GH, particularly when used for indications other than GH deficiency. This review discusses the effects of GH on fluid, lipid, and carbohydrate metabolism; the risk of intracranial hypertension or pseudotumor cerebri; the effects on the skeletal system; the risk of malignancy; and the effects on the immune system. At present, GH treatment appears to be safe, although long-term follow-up of GH-treated patients is necessary.

Role of ultraviolet radiation in the induction of melanocytic tumors in hairless mice following 7,12-dimethylbenz(a)anthracene application and ultraviolet irradiation.

We examined the role of UVR (UV radiation) (UVA, 320-400 nm; UVB, 290-320 nm; and the combination of UVA and UVB) as a promoter in the induction of cutaneous melanoma. One hundred and seventy hairless mice (Skh-hr2), 6-8 weeks old, were treated in 8 groups: group I, DMBA [7,12-dimethylbenz(a)anthracene] plus UVA; group II, DMBA plus UVA plus UVB; group III, DMBA plus UVB; group IV, DMBA; group V, UVA; group VI, UVA plus UVB; group VII, UVB; group VIII, control. DMBA (0.5% solution) was applied once to promote the formation of dermal melanocytic nevus-like lesions while UVR treatments were conducted 3 times/week for 30 weeks. The mice were examined periodically for the development of multiple pigmented lesions, papillomas, squamous cell carcinomas, melanomas, and lymphomas. Treatment with DMBA plus UVA, DMBA plus UVB, and DMBA plus UVA plus UVB stimulated the development of multiple pigmented nevus-like lesions (85-100%) in mice of groups I, II, III, and IV. Upon necroscopy, 27-33% of animals in groups I, II, and III receiving UVR treatments developed clinically and histologically characterized melanomas. Treatment with DMBA alone did not produce melanomas. DMBA-treated animals in groups I, II, and III which received UVR treatments also developed lymphomas (21-50%). Animals treated with DMBA alone or those that received UVB or the combination of UVB plus UVA (without DMBA) developed only papillomas and squamous cell carcinomas (25-47%). Skin tumors were analyzed for the presence of point mutations in the ras gene. Polymerase chain reaction amplification of DNA and selective oligonucleotide hybridization revealed mutations in the 61st codon of the N-ras gene in the precursor nevus-like lesions and melanoma samples studied. This study suggests that UVR (both UVA and UVB) plays a role as a promoter in the stimulation of melanoma and lymphoma development in hairless mice.