Adverse mucocutaneous reactions to chemotherapeutic agents - Part I

The local and systemic treatment of tumors can cause changes in the skin, mucous membranes, hair and nails. Accurate diagnosis and appropriate treatment of side effects require knowledge about the patterns of the most common adverse reactions to drugs the patient may be using. The dermatologist must be familiar with the manifestations of certain soft tissue neoplasms, as well as with the adverse mucocutaneous forms of cancer treatment.

Oral lesions in lupus erythematosus-cytokines profiles of inflammatory infiltrate

Background: Lupus erythematosus (LE) is a chronic inflammatory disease. Presence of type 1 cytokines in cutaneous discoid lesions suggests that they may be critical for induction, development and maintenance of these manifestations. Type 2 cytokines in combination with local interferon gamma (INF-gamma) are thought to be related to the physiopathology of cutaneous LE. Cytokines profiles are still unknown in oral LE lesions. Materials and Methods: Expression of Th1 and Th2 cytokines (including IL-4, IL-5, IL-6, IL-10, IL-12, tumor necrosis factor alpha (TNF-alpha) and INF-gamma was investigated and compared in 29 biopsies of intra-oral (sun-protected) and labial lesions (sun-exposed) of LE using immunohistochemistry. Results: Inflammatory infiltrate of LE lesions was strongly positive for IFN-gamma (97%) and TNF-alpha (90%), both Th1 type cytokines. Interleukin-10, a Th2 cytokine was also strongly expressed. Other cytokines were only mildly positive. Cytokines patterns were similar in intra-oral (sun-covered) and labial (sun-exposed) LE lesions. Conclusions: Oral LE lesions are associated with both type 1 and type 2 cytokines, characterized by stronger expression of INF-gamma, TNF-alpha and IL-10. These findings suggest that although ultraviolet (UV) light is involved in the induction of LE lesions, mechanisms of lesions formation may be similar in sun-exposed as well as sun-covered areas.

Lichen planus sialadenitis: a mucosal analog of lichen planopilaris and lichen planoporitis

Lichen planus (LP) is the most prevalent dermatological disorder with oral manifestation. Oral lesions comprise a broad spectrum of clinical presentations. We report the case of a 56-year-old woman who presented erosive LP on the buccal and lower lip mucosae. Besides typical erosions, small white keratotic papules on an erythematosus background on the lower lip mucosa were observed. Biopsy of lower lip lesions showed an unusual histopathological presentation consisting of a lichenoid inflammation targeted to salivary gland ducts. This is probably a salivary gland analog of lichen planopilaris and lichen planoporitis.

Oral manifestations of inflammatory bowel disease: a review based on the observation of six cases

Inflammatory bowel disease (IBD) comprises two chronic, tissue-destructive, clinical entities: Crohn`s disease (CD) and ulcerative colitis (UC), both immunologically based. Bowel symptoms are predominant, but extra-intestinal complications may occur, including involvement of the oral cavity. Oral involvement during IBD includes several types of lesions: the most common are aphthae; uncommon lesions include, among others, pyostomatitis vegetans and granulomatous lesions of CD. Starting with a presentation of six patients with oral manifestations, which were crucial for the final diagnosis of IBD, a review on the subject is presented. Oral involvement in IBD may be previous or simultaneous to the gastrointestinal symptoms. However, in the majority of cases, bowel disease precedes the onset of oral lesions by months or years. In many patients, the intestinal symptoms may be minimal and can go undetected; thus, most authors believe that the bowel must be thoroughly examined in all patients with suspected IBD even in the absence of specific symptoms. Usually, the clinical course of oral lesions is parallel to the activity of IBD; therefore, oral manifestations are a good cutaneous marker of IBD.

Diffuse plane idiopathic normolipemic xanthoma with hiperesplenism

Diffuse plane normolipemic xanthoma is a rare disease, of a group of clinical syndromes called histiocytoses, characterized by the presence of yellowish or yellow-orange plaques, distributed symmetrically on the cutaneous surface and usually accompanied by xanthelasma. It affects mainly adults and it may cause discrete changes in serum lipids. The case of an 85-year-old female patient who has been showing extensive asymptomatic yellow-orange plaques in the trunk and abdomen for a year is reported. Laboratory tests did not show an increase in serum lipids or the occurrence of reticuloendothelial disorders.

Primary Oral Mucosal Melanoma: A Series of 35 New Cases From South America

Oral mucosal melanoma is rare and reported to be more aggressive than its cutaneous counterpart. Due to the rarity of this entity, data on epidemiology, tumor behavior, treatment, follow-up, and Survival of patients are mainly based oil single case reports. The few existing series of patients show that oral mucosa melanoma has its peak between 4 1 and 60 years of age, and male to female ratio is 2: 1. Preferred oral sites include hard palate and maxillary alveolar crests. Risk factors have not been clearly identified, and surgical treatment is still the treatment of choice for oral mucosal melanomas. The authors retrospectively studied 35 patients with primary melanoma of the oral cavity to report their clinical and pathological features, Such as age, sex, site of the tumor, metastasis, treatment, response to therapy, and Outcome. We found no significant sex predominance, and the mean age of the patients was 60.6 years, with a range From 9 to 91 years. The majority of the patients (71.42%) had palate commitment, and invasive histopathological aspect was observed in 80% of the specimens (grade 3). Long-distance metastasis was found in 60% of the cases. Fourteen patients were submitted to wide Surgical resections, with local relapse being observed in 11 of them (78.5%). The authors Suggest that improved outcome in oral malignant melanoma requires the development of new therapies and the prevention of distant metastasis.

Interferon and Alternative Activation of Monocyte/Macrophages in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension

Objective. To explore the relationship between biomarkers of pulmonary arterial hypertension (PAH), interferon (IFN)-regulated gene expression, and the alternative activation pathway in systemic sclerosis (SSc). Methods. Peripheral blood mononuclear cells (PBMCs) were purified from healthy controls, patients with idiopathic PAH, and SSc patients (classified as having diffuse cutaneous SSc, limited cutaneous SSc [lcSSc] without PAH, and lcSSc with PAH). IFN-regulated and ""PAH biomarker"" genes were compared after supervised hierarchical clustering. Messenger RNA levels of selected IFN-regulated genes (Siglec1 and MX1), biomarker genes (IL13RA1, CCR1, and JAK2), and the alternative activation marker gene (MRC1) were analyzed on PBMCs and on CD14- and CD14+ cell populations. Interleukin-13 (IL-13) and IL-4 concentrations were measured in plasma by immunoassay. CD14, MRC1, and IL13RA1 surface expression was analyzed by flow cytometry. Results. Increased PBMC expression of both IFN-regulated and biomarker genes distinguished SSc patients from healthy controls. Expression of genes in the biomarker cluster, but not in the IFN-regulated cluster, distinguished lcSSc with PAH from lcSSc without PAH. The genes CCR1 (P < 0.001) and JAK2 (P < 0.001) were expressed more highly in lcSSc patients with PAH compared with controls and mainly by CD14+ cells. MRC1 expression was increased exclusively in lcSSc patients with PAH (P < 0.001) and correlated strongly with pulmonary artery pressure (r = 0.52, P = 0.03) and higher mortality (P = 0.02). MRC1 expression was higher in CD14+ cells and was greatly increased by stimulation with IL-13. IL-13 concentrations in plasma were most highly increased in lcSSc patients with PAH (P < 0.001). Conclusion. IFN-regulated and biomarker genes represent distinct, although related, clusters in lcSSc patients with PAH. MRC1, a marker for the effect of IL-13 on alternative monocyte/macrophage activation, is associated with this severe complication and is related to mortality.

Impaired IFN-alpha secretion by plasmacytoid dendritic cells induced by TLR9 activation in chronic idiopathic urticaria

P>Background The evolution and therapeutic outcome of American tegumentary leishmaniasis (ATL) depend upon many factors, including the balance between Th1 and Th2 cytokines to control parasite multiplication and lesion extension. Other cytokines known for their role in inflammatory processes such as interleukin IL-17 or IL-18 as well as factors controlling keratinocyte differentiation and the inflammatory process in the skin, like the Notch system, could also be involved in the disease outcome. Notch receptors are a group of transmembrane proteins that regulate cell fate decisions during development and adulthood in many tissues, including keratinocyte differentiation and T-cell lineage commitment, depending on their activation by specific groups of ligands (Delta-like or Jagged). Objectives To compare the in situ expression of Notch system proteins (receptors, ligands and transcriptional factors) and cytokines possibly involved in the disease outcome (IL-17, IL-18, IL-23 and transforming growth factor-beta) in ATL cutaneous and mucosal lesions, according to the response to therapy with N-methyl glucamine. Methods Cutaneous and mucosal biopsies obtained from patients prior to therapy with N-methyl glucamine were analysed by immunohistochemistry and real-time polymerase chain reaction. Results Notch receptors and Delta-like ligands were found increased in patients with ATL, particularly those with poor response to therapy or with mucosal lesions. Conclusions The increase of Notch receptors and Delta-like ligands in patients with a poor response to treatment suggests that these patients would require a more aggressive therapeutic approach or at least a more thorough and rigorous follow-up.

Carcinoid syndrome - Case report

Carcinoid tumors are rare neoplasms with, an estimated incidence of I to 2 cases per 100, 000 inhabitants. The malignant carcinoid syndrome, characterized by flushing, diarrhea, abdominal pain and, less frequently, pellagra, bronchospasm and valvular disease, occurs in less than 10% of patients. Nevertheless, in advanced stages of the disease, the incidence is about 40 to 50%. Retrospective studies and descriptive case series have shown that cutaneous involvement is relatively common but has rarely been reported. We present a case of carcinoid syndrome diagnosed with basis on skin findings on clinical examination.

Human visceral leishmaniasis expresses Th1 pattern in situ liver lesions

The architectural and infiltrate pattern of liver human visceral leishmaniasis (HVL) have been systematically classified as typical, fibrogenic or nodular. Despite this histopathological classification, the immune response based on cytokines and cellular phenotypes have never been performed. The aim of this study was to determine the immunophenotypic pattern and cytokine profile of the nodular involvement of the Liver in HVL. We evaluated nine cases of the nodular form of HVL. In situ immune response was studied through cytokine analysis and immunohistochemical study for phenotype markers: IL-1, IL-4, IL-1 0, TNF-alpha, IFN-gamma, CD4+ T cells, CD8+ T cells, CD20, CD68, CD57 and macrophage activation was determined by evaluation of iNOS activity. HVL seems to be related to a better immune response. Amastigotes were rarely found on liver sections. Leishmania antigen expression was also rare and located in the inflammatory nodules. The lower expression of IL-4 and IL-10, moderate expression of TNF-alpha and IFN-gamma demonstrate a panorama of Th1 phenotype. The increased expression of NK cells could help in sustaining this model of response. This pattern of immune response is probably responsible for improvement in the parasite`s clearance from liver tissue and it is a prognostic marker of human visceral leishmaniasis. (C) 2008 The British Infection Society. Published by Elsevier Ltd. All rights reserved.

Disseminated blue naevus and malignant blue naevus associated with excessive aromatase syndrome

We report a case of a 17-year-old boy who had a giant congenital blue naevus with multiple satellite pigmented lesions. Later the patient developed melanoma arising in the pre-existing lesion. He also had gynaecomastia and was diagnosed as having aromatase excess syndrome. To our knowledge, the association of these two rare conditions has not been previously reported. Further studies should be performed to investigate this unusual combination, which may have a genetic, endocrine or local cutaneous link leading to its occurrence.

Relationship of adhesion molecules expression with epithelial differentiation markers during fetal skin development

Background: Cadherins and integrins are important for maintenance of tissue integrity and in signal transduction during skin development. Distribution of these molecules in human skin development was investigated and associated with markers of differentiation, cytokeratins (CK) and involucrin (INV). Methods: Using immunohistochemistry expression of E- and P-cadherins, integrins beta-1 and -4, CK10, CK14 and INV was assessed in skin fragments of 10 human fetuses (gestational weeks ranged from 4 to 24, all weighing up to 500 g). Results: At initial phases of development, integrins beta-1 and -4 and E- and P-cadherins were present on epithelial cell membranes in all layers. CK14 and CK10 were expressed in all epithelial layers and INV weakly detected in the superficial layer. In more advanced stages, integrins were detected in all layers, but a marked polarized expression was seen in basal layer. E-cadherin was detected in all layers, but the cornified stratum and P-cadherin were observed in the lower layers. CK14 was expressed in basal layer, CK10 in suprabasal stratum and INV was observed in cornified layer. Conclusions: Cadherins and integrins are essential for skin development, being spatially and temporally regulated. Their expression is related with the expression of maturation markers of the epidermis.

Skin cancer in Taubate (SP) - Brazil, from 2001 to 2005: a prevalence study

BACKGROUND - Cancer represents the third principal cause of death in Brazil. Skin is the most frequent location and about 50% of caucasian patients older than sixty years will develop some type of cutaneous cancer OBJECTIVE - To describe the profile of the individuals with skin cancer assisted at the University Hospital of Taubate in the period between 2001 and 2005. METHODS - A hospital-based cross-sectional study involving individuals assisted at the Dermatology Department at the University Hospital of Taubate in the period between January 2001 to December 2005 was performed. Study variables were gender, age, skin color, location and clinical type of the tumor basal cell carcinoma, squamous cell carcinoma, combined and melanoma. Statistical analyses were performed using qui-square, Student`s t-test and ANOVA. RESULTS - A total of 639 individuals were included in the study. Prevalence was 50 cases/100.000 inhabitants. The most prevalent age group was that of individuals older than sixty years of age, gender distribution was higher among females than males (57.2% / 42.8%) and the proportion of white to non-white was of 4:1. CONCLUSION - This study fills a gap that was due to the inexistence of studies in the region and also to the small number of studies in the state of Sao Paulo, and its results are in accordance with, those in the literature.

Cutaneuos cryoglobulinemic vasculitis induced by chronic hepatitis C virus infection

Cutaneous vasculitis may represent a great clinical challenge, even after careful dermatological examination and laboratory assessment. The authors present a case of cutaneous cryoglobulinemic vasculitis associated to chronic hepatitis C virus infection, pointing out the importance of the dermatological examination for diagnostic investigation. They discuss about the importance of defining the etiology and making correct classification for appropriate prognosis and treatment of cutaneous vasculitis.

High numbers of human skin cancers express MMP2 and several integrin genes

Background: Basal cell carcinomas (BCC), squamous cell carcinomas (SCC) and cutaneous malignant melanoma (MM) are solid skin cancers derived from different cell types, with different ability to metastasize. Several subtypes of integrins and matrix metalloproteinases (MMP) have been related to malignization and metastasis processes. This work aimed at a quantitative evaluation of skin cancers expressing eight integrins and MMP2 genes. Methods: Expression of integrins and MMP2 genes was evaluated on fresh tumor biopsies from BCC, SCC and MM, and respective controls, by the reverse transcriptase polychain reaction (RT-PCR) technique. Results: More than 90% tumors expressed alpha 6a, beta 1, beta 3 and beta 6 (non-melanoma), and alpha 5a, alpha 6a and MMP2 (MM). Up to 100% controls also expressed beta 1 and beta 3. The results were significant for alpha 6a in BCC (p = 0.026), alpha 6b in SCC (p = 0.035), alpha 2a in BCC (p = 0.003), beta 5 and beta 6 in BCC (p = 0.005). MMP2 was expressed in 100% MM (p = 0.0004). Conclusion: Integrin subunits alpha 2a and alpha 6a would be interesting targets for BCC anti-tumor therapy, as well as alpha 6b in case of SCC. The elevated number of BCC expressing alpha 2 and alpha 6, and of MM expressing alpha v and MMP2, corroborate literature data.