The Prognostic Significance of Tumoral Melanosis.

BACKGROUND: Tumoral melanosis (TM) is a histological term to describe a nodular aggregation of macrophages containing melanin pigment (melanophages) that is devoid of viable melanocytes. It is most often identified in skin, where it may be appreciated clinically as a pigmented lesion; however, it can also be found in other organs such as lymph nodes. The presence of TM is usually thought to signify the presence of a regressed melanoma or other pigmented tumor. Until recently, it was a relatively uncommon finding; however, with the use of effective systemic therapies against melanoma, its occurrence in histological specimens is more frequent. METHODS: We identified and reviewed all histopathological diagnoses of TM at any organ site reported at a single institution from 2006 to 2018. TM cases were paired with non-TM cases of cutaneous melanoma through propensity score matching at a 1:2 ratio, and their survival outcomes were compared. The clinical outcomes examined included recurrence-free survival (RFS), distant disease-free survival (DDFS), melanoma-specific survival (MSS), and overall survival (OS). RESULTS: TM was reported in 79 patients. Their median age was 65 years (range 22-88), with a 2:1 male predominance (51 out of 79, 65%). The most common organ involved was the skin (67%), with a third of all cases localized to a lower limb (36%). TM had a strong association with the presence of melanoma (91%) and regression at other sites of melanoma (54%), suggesting that it is part of a systemic immune response against melanoma. Most patients with TM either previously or subsequently developed histologically confirmed melanoma in the same anatomical region as the TM (89%). Thirty-five TM patients were matched with 70 non-TM cases. Patients with melanoma who developed TM without prior regional or systemic therapy showed improved MSS (p = 0.03), whereas no statistically significant differences were observed in terms of RFS, DDFS, and OS. CONCLUSIONS: TM usually occurs in the context of a previous or subsequent cutaneous melanoma and is associated with improved MSS. It is important that TM is recognized by pathologists and documented in pathology reports.

A case of familial progressive hyperpigmentation with or without hypopigmentation presenting with hypopigmented striae along the lines of Blaschko.

Familial progressive hyperpigmentation with or without hypopigmentation (FPHH) is an autosomal dominant disorder characterized by widespread skin hyperpigmentation, café-au-lait spots, and hypopigmented circular macules, resulting from KITLG variants. KITLG, expressed by keratinocytes, binds to KIT on melanocytes, stimulating melanogenesis. Disturbances in the KITLG-KIT interaction result in diffuse hyperpigmentation in FPHH. However, the mechanisms behind hypopigmented macule formation remain unclear. This report presents a unique FPHH case in a patient with a novel KITLG mutation (Ser78Leu). Notably, the patient showed multiple hypopigmented macules and striae along the lines of Blaschko. Digital polymerase chain reaction analysis of the DNA from skin and blood tissues indicated a copy-neutral loss of heterozygosity at the KITLG locus, only in the hypopigmented macule. These findings suggest that the hypopigmented macules might result from revertant mosaicism. Conversely, café-au-lait spots do not follow the lines of Blaschko and can superimpose on the hypopigmented striae, indicating a distinct pathogenesis. This case contributes to the understanding of the genetic mechanisms in FPHH.

Nearly complete hair re-pigmentation in an older patient treated with hydroxyurea for essential thrombocytosis.

INTRODUCTION: Employed in the treatment of malignancies and non-neoplastic conditions, hydroxyurea is associated with integumentary adverse effects, including skin discoloration, xerosis, pruritus, cutaneous atrophy, chronic leg ulcers, oral ulcerations, alopecia, and some nail abnormalities. CASE REPORT: A 77-year-old woman was diagnosed with essential thrombocytosis and started on low dose hydroxyurea. After 20 weeks of treatment, she experienced an unexpected change in hair color from gray to dark brown, without using hair dye or supplements. She later developed bilateral dorsal hand melanoderma, melanonychia, and onychodystrophy. MANAGEMENT AND OUTCOME: It was decided to monitor the patient with no action taken as she was happy with this side effect of hydroxyurea. The platelet count has remained in excellent control. The dark brown hair color persisted over time. DISCUSSION/CONCLUSION: Hair hyperpigmentation likely occurred through melanocyte activation via hydroxyurea. Severe side effects may require dosage adjustments, while milder effects can be monitored closely. The newly observed hair color restoration in this case highlights potential dual (therapeutic and aesthetic) applications of this class of agents.

Influence of 17α-Methyltestosterone on Morphological Deformities and Pigmentation Development in Juvenile Japanese Eels, Anguilla japonica.

17α-methyltestosterone (MT) is a synthetic steroid used to induce masculinization when administered during the larval stage of fish. However, the side effects of MT on eel are still poorly understood and, in this study, we examined the various effects of MT on juvenile eel A. japonica (100.63 ± 8.56 mm total length (TL)). To further investigate growth and sex differentiation, juvenile eels (n = 1000) were exposed to 25 µg/g MT for 6 months. We analyzed growth-related factors, sex steroid hormones, skin pigmentation, and color-related gene expression. Through this study, we found a 90% sex conversion of juvenile eels to males using MT treatment. In the MT-treated eel group (285.97 ± 26.21 mm TL) where sexual maturity was induced, spermatogonia stages were observed in the gonads. In contrast, the control group (395.97 ± 27.72 mm TL) exhibited an 80% immaturity rate, with only 20% of the subjects that were rapidly developing displaying early oogonia. ELISA analysis results showed that the level of growth hormone, which is known to be secreted from spermatogonia, did not change as a result of MT treatment. We confirmed that MT delayed growth and caused morphological changes, particularly a shortened snout length and pigmentation of the fin. The total length, body weight, and snout length were considerably lower in the experimental group than in the control group. In addition, in histological analysis we also observed that some of the MT-treated group (5 out of 10 fish) showed liver atrophy and inflammation, and physiological analysis showed that the cortisol concentration increased in the MT-treated eels. Interestingly, we found that some pigment color-related genes, such as melanocortin 1 receptor (MC1R), tyrosinase (Tyr), and dopachrome tautomerase (DCT), were significantly overexpressed in the fins of MT-treated eels. These results suggest that the treatment of A. japonica larvae with MT induced masculinization but also causes growth side effects from the use of synthetic hormones.

Overview on tyrosinases: Genetics, molecular biology, phylogenetic relationship.

Tyrosinases (TYRs) are enzymes found in various organisms that are crucial for melanin biosynthesis, coloration, and UV protection. They play vital roles in insect cuticle sclerotization, mollusk shell formation, fungal and bacterial pigmentation, biofilm formation, and virulence. Structurally, TYRs feature copper-binding sites that are essential for catalytic activity, facilitating substrate oxidation via interactions with conserved histidine residues. TYRs exhibit diversity across animals, plants, fungi, mollusks, and bacteria, reflecting their roles and function. Eukaryotic TYRs undergo post-translational modifications, such as glycosylation, which affect protein folding and activity. Bacterial TYRs are categorized into five types based on their structural variation, domain organization and enzymatic properties, showing versatility across bacterial species. Moreover, bacterial TYRs, akin to fungal TYRs, have been implicated in the synthesis of secondary metabolites with antimicrobial properties. TYRs share significant sequence homology with hemocyanins, oxygen-carrier proteins in mollusks and arthropods, highlighting their evolutionary relationships. The evolution of TYRs underscores the dynamic nature of these enzymes and reflects adaptive strategies across diverse taxa.

Structural characterization of tyrosinases and an update on human enzymes.

Tyrosinase, a pivotal enzyme in melanin biosynthesis, orchestrates the pigmentation process in humans, affecting skin, hair, and eye color. This chapter examines the three-dimensional structure and functional aspects of tyrosinases from various sources, highlighting their di-metal ion coordination crucial for catalytic activity. I explore the biochemical pathwayscheme catalyzed by tyrosinase, specifically the oxidation of L-tyrosine to L-dopaquinone, a precursor in melanin synthesis. Detailed structural analyses, including 3D structures obtained from X-ray crystallography and computational modeling, reveal key insights into the enzyme's active site, variations among tyrosinases, and substrate binding mechanisms. Furthermore, the chapter investigates the role of human tyrosinase variants, their inhibitors, essential for developing therapeutic and cosmetic applications targeting hyperpigmentation disorders. Structural characterizations of tyrosinase-inhibitor complexes provide a foundation for designing effective inhibitors, with compounds like kojic acid, L-mimosine, and (S)-3-amino-tyrosine demonstrating significant inhibitory potential. This comprehensive examination of the structure, function, and inhibition mechanisms of tyrosinase offers avenues for innovative treatments in biotechnology, health, and beyond.

Oral administration of cysteine peptides attenuates UV-B-induced skin erythema and pigmentation in humans.

The oral administration of antioxidants may suppress UV-B-induced skin damage. HITHION YH-15, the extract of Torula yeast (Cyberlindnera jadinii), is rich in cysteine-containing peptides such as reduced and oxidized glutathione (GSH and GSSG), γ-glutamylcysteine (γ-Glu-Cys), and cysteinylglycine (Cys-Gly). These four constituents are termed cysteine peptides. In this study, we investigated the protective effects of cysteine peptides against UV-B in a randomized, placebo-controlled, double-blind, parallel-group study. A total of 90 healthy males and females aged 30-59 years were enrolled and randomized into two groups of 45 individuals each (cysteine peptides (48 mg/day) and placebo). Changes in UV-B-induced erythema and pigmentation were compared between groups after 5 weeks of test food intake. The minimal erythema dose (MED) significantly increased (*p = 0.019) in the cysteine peptides group compared to that in the placebo group, indicating suppression of UV-B-induced erythema. ΔL* value significantly increased (***p < 0.0001) in the cysteine peptides group compared to that in the placebo, indicating pigmentation suppression. We demonstrated that oral administration of cysteine peptides suppresses UV-B-induced erythema and pigmentation through multiple mechanisms. Thus, cysteine peptides may find use as nutricosmetics for maintaining skin health and well-being.UMIN Clinical Trials Registry ID: UMIN 000050157.

Anthocyanin modified by chondroitin sulphate and tannic acid improved the quality-indicating properties of gelatin-based intelligent film.

A highly pH-responsive gelatin film incorporating purple cabbage anthocyanin (PCA) and chondroitin sulphate (CS)/tannic acid (TA) was developed. Co-pigmentation of PCA via CS/TA improved its photothermal stability and visibility of color change in gelatin film. The morphological and structural properties of CS-PCA and TA-PCA films revealed that a more stable network was formed as new hydrogen bonds were generated by the co-pigmentation. Meanwhile, the co-pigmentation improved film's mechanical and hydrophobic properties, expressed as higher tensile strength (16.65 and 17.97 Mpa) and lower water vapor permeability (1.45 and 1.41) in CS-PCA and TA-PCA films, compared to PCA film. CS-PCA and TA-PCA films showed distinct color transitions for chilled fish fillets during storage. Total color difference (ΔE) of CS-PCA and TA-PCA films correlated well with the deterioration indexes of total volatile base nitrogen (TVB-N). All the results provided a novel pH-sensitive intelligent packaging strategy by co-pigmenting CS/TA with PCA for freshness monitoring.

Dynamic changes of anthocyanins during 'Ziyan' tea wine processing.

In this study, the dynamic changes of different anthocyanins in the processing of 'Ziyan' tea wine were investigated quantitatively. Results showed that six types of anthocyanins, namely petunidin, malvidin, pelargonidin, delphinidin, cyanidin and peonidin, as well as two co-pigmented substances, procyanidins and flavonoids, were detected in 'Ziyan' tea wine. As fermentation proceeded, the contents of petunidin, pelargonidin, delphinidin, cyanidin and peonidin decreased. Among them, petunidin, peonidin and pelargonidin showed a tendency of decreasing first, then increasing and finally decreasing, whereas delphinidin and cyanidin continued to decrease during fermentation. Variation trend of procyanidins and flavonoids was consistent with those of petunidin. Furthermore, metabolism of delphinidin, cyanidin and pelargonidin were main pathways responsible for the anthocyanin changes during 'Ziyan' tea wine processing. These findings suggested that the color of 'Ziyan' tea wine was achieved by the combination of various anthocyanins in different ratios and the co-pigmentation of procyanidins and flavonoids.

Impact of Tumor Pigmentation in 6934 Patients with Uveal Melanoma at a Single Center.

Purpose: To evaluate clinical features and outcomes associated with degree of tumor pigmentation in patients with uveal melanoma (UM) of the choroid and ciliary body. Design: Retrospective observational study. Subjects: Six thousand nine hundred thirty-four consecutive patients with choroidal or ciliary body melanoma between 1971 and 2007 from a single ocular oncology center. Methods: Data on patient demographics, tumor characteristics, treatment approach, and clinical outcomes were collected. Comparisons between pigmented (>80% pigmentation by surface area), partially pigmented (20%-80%), and nonpigmented tumors (<20%) were performed using relevant hypothesis testing. Survival analyses for metastasis and melanoma-related death were conducted using the Kaplan-Meier method with log-rank tests for univariate comparisons. A multivariate Cox regression analysis was performed to assess the independent effects of multiple covariates on time-to-metastasis. Main Outcome Measures: Extraocular extension, ocular melanocytosis, time to tumor recurrence, tumor location, and melanoma-related metastasis and death. Results: There were 6934 eyes with UM and the degree of tumor pigmentation was classified as pigmented (n = 3762; 54%), partially pigmented (n = 2115; 31%), or nonpigmented (n = 1057; 15%). Pigmented UM was associated with extraocular extension (P < 0.001), ocular melanocytosis (P = 0.003), earlier tumor recurrence (P < 0.001), and more anterior tumor epicenter location (ciliary body, and equator to ora serrata) (P < 0.001). Pigmented UMs also exhibited the highest 10-year metastasis rate at 26%, compared with 19% for partially pigmented UMs and 16% for nonpigmented UMs (P < 0.001). Kaplan-Meier survival curves demonstrated differences among the tumor pigmentation groups for melanoma-related metastasis (P < 0.001) and melanoma-related death (P < 0.001). Multivariate Cox regression analysis for melanoma-related metastasis showed that pigmented UMs had a 29% higher relative risk of developing metastasis compared with partially pigmented UMs (P = 0.002) and a 54% higher relative risk of developing metastasis compared with nonpigmented UMs (P < 0.001). Conclusions: Pigmented choroidal and ciliary body melanoma is more often associated with ocular melanocytosis, extraocular extension, anterior tumor epicenter, and earlier tumor recurrence. We also revealed that patients with pigmented UMs demonstrate a higher 10-year rate of metastatic disease and have decreased metastatic survival relative to partially pigmented and nonpigmented UMs. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Tranquilizing and hepatoprotective effects of red-eye tetra (Moenkhausia Forestii) diet fed with Erythrina crista-galli.

This study aimed to assess the leaf aqueous extract composition of Erythrina crista-galli and the effects of its inclusion on the diet of red-eye tetra (Moenkhausia forestii), concerning enzyme content of digestive, hepatic, and oxidation metabolism and pigmentation. Fish (1.78 ± 0.54 g) were divided into groups: fasting (without feeding), control (commercial feed), and treatment (commercial feed with leaf aqueous extract of E. crista-galli) and feeding apparent satiety for 21 days, in the extracted analysis by mass spectrometry, phenolic compost, and flavonoids. The agitation degree and number of dashes, in all supplemented treatments, were lower than those in the control diet when fed for 7 or 15 days. In the digestive enzymatic activity did not differ (p > 0.05). The hepatoprotective treatment group showed lower alanine aminotransferase (ALT) and higher levels of antioxidant catalase (CAT). The results indicated that the aqueous leaf extract of Erythrina crista-galli assists in function maintenance of the liver; and stimulates CAT in red-eye tetra, suggesting that the identified compounds act on the liver and skin, showing hepatoprotective effects and stimulating tranquility.

Pigmentary Changes in Systemic Sclerosis are Associated with More Severe Cutaneous Sclerosis and Severity of Other Systems: A Cross-sectional Study from India.

Background: Pigmentary changes of the skin in systemic sclerosis in the form of diffuse hyperpigmentation and salt-and-pepper pigmentation are well documented in the literature; however, its association with disease severity and extent of underlying internal organ involvement has not been well studied. Aims: To assess the correlation between morphology and extent of pigmentary changes with the degree of cutaneous sclerosis and frequency and degree of major organ involvement. Methods: This was a cross-sectional descriptive study conducted in a tertiary care teaching hospital from December 2014 to November 2016. Consecutive patients of systemic sclerosis attending the outpatient department were screened, and patients satisfying the diagnosis as per the American Rheumatism Association criteria were recruited. Skin sclerosis was quantified using modified Rodnan skin score (MRSS), whereas pigmentary changes were calculated in terms of percentage of body surface area involved by rule-of-nine method. Investigations were carried out depending on organ involvement and as per respective specialty consultations with focus on pulmonary, cardiac, and gastrointestinal systems. Results: Of the 50 patients recruited, all had cutaneous involvement in the form of binding down of skin, followed by pigmentary changes. MRSS was significantly higher in patients with any pigmentary alteration (P = 0.03) compared to those without any pigmentary changes. There was a rising trend in between the MRSS severity and the proportion of patients with hyperpigmentation, and it was statistically significant (P = 0.04). Among systemic involvement, lung was involved in the form of interstitial lung disease in 94% patients (n = 47). However, skin pigmentation of any type was associated with lower high-resolution computed tomography scores (P = 0.02). Conclusion: This study shows that in systemic sclerosis patients presenting with pigmentary skin manifestations, cutaneous sclerosis is significantly higher.

A Case Report of a Young Adult With Peutz-Jeghers Syndrome Presenting With Acute Small Bowel Obstruction: A Common Complication of an Uncommon Disease.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by hamartomatous polyposis of the gastrointestinal tract, melanin pigmentation of the skin and mucous membranes, and an increased risk for cancer. Radiological imaging, contrast studies, and scopy-directed biopsies confirm the diagnosis and help in surveillance. Hamartomatous mucosal polyps, which are characterized by a central core of branching smooth muscle connected to a mucosa unique to the site of origin, are pathognomonic for PJS. We present the case of a young male with a history of pain in the abdomen and vomiting. The patient had mucocutaneous pigmentations on the buccal mucosa. CT scan revealed jejuno-jejunal intussusception with multiple small and large bowel polyps causing acute intestinal obstruction. Intraoperatively, jejunal polyps were found to be the cause of jejuno-jejunal intussusception. Histopathology revealed hamartomatous polyps of PJS. Our interest in this case is due to the uncommon case of intussusception in an adult where radiological imaging played an important role in diagnosis.

Dangerous liaisons: Loss of keratinocyte control over melanocytes in melanomagenesis.

Melanomas arise from transformed melanocytes, positioned at the dermal-epidermal junction in the basal layer of the epidermis. Melanocytes are completely surrounded by keratinocyte neighbors, with which they communicate through direct contact and paracrine signaling to maintain normal growth control and homeostasis. UV radiation from sunlight reshapes this communication network to drive a protective tanning response. However, repeated rounds of sun exposure result in accumulation of mutations in melanocytes that have been considered as primary drivers of melanoma initiation and progression. It is now clear that mutations in melanocytes are not sufficient to drive tumor formation-the tumor environment plays a critical role. This review focuses on changes in melanocyte-keratinocyte communication that contribute to melanoma initiation and progression, with a particular focus on recent mechanistic insights that lay a foundation for developing new ways to intercept melanoma development.

How many is too many? A review of the significant numbers in pediatric skin lesions and their recommended evaluation.

Pediatric dermatologists are frequently consulted to evaluate children for cutaneous signs of systemic disorders. Numerical thresholds of significance have been described in the dermatologic literature for various skin findings where the likelihood of an associated extracutaneous abnormality or known genetic syndrome increases significantly. Knowledge of these numerical thresholds facilitates diagnosis and management, which improves clinical outcomes and avoids severe complications. This review highlights the clinical presentation, complications, evaluation, and numerical significance, when applicable, for the following skin findings: infantile hemangiomas, capillary malformations, café-au-lait macules, hypopigmented macules, juvenile xanthogranulomas, pilomatricomas, and angiofibromas.