Melanoma Developing from an Intradermal Nevus: Report on Two Patients.

Dear Editor, Approximately 25-33% of cutaneous melanomas arise from nevi (1). Shitara et al. suggested that junctional and compound nevi are more likely give rise to melanoma than intradermal nevi, but this has not been definitively confirmed (2). Based on these results and our own clinical observation on rare malignant transformation in intradermal nevi, we present two patients with melanoma developing from an intradermal nevus. The first patient, a 63-year-old woman, presented with a suspicious lesion in 2017 on the upper back in the form of a dark brown macula juxtapositioned next to the dermal nevus (Figure 1, a). Dermoscopy of a flat part showed a dark-brown reticular, slightly structureless pattern (Figure 1, b). The patient was therefore referred to surgical excision. Histopathology of the elevated part showed aggregates of intradermal nevus cells of normal morphological characteristics. Atypical and irregularly sized melanocytes were observed in the flat part, infiltrating the entire depth of the epidermis and the upper parts of the papillary dermis. The diagnosis of malignant melanoma developing from a dermal nevus was established (Breslow 0.4 mm, pT1A) (Figure 1, c). The second patient, a 71-year-old man, presented in 2018 with a pendular non pigmented intradermal nevus on middle part of the back. The left-hand lateral side of the intradermal nevus showed a brown to dark-brown spot which measured 12 mm (Figure 2, a). A central blue white veil, atypical pigment network, and dots and globules of various sizes and shapes were observed on dermoscopy (Figure 2, b). The base of the nevus showed an asymmetric pigmentation. Because the lesion was highly suspicious of melanoma, an urgent excision was indicated. The histopathology of the elevated part (dermal nevus) showed a regular maturation of the nest of nevus cells in the dermis. The histopathology of the dark-brown macule showed proliferation of atypical melanocytes with well-marked nucleoli throughout the epidermis with the infiltration of the suprabasal epidermal layers and papillary dermis. The lesion was classified as melanoma with a partial regression (Breslow 1.3 mm, pT2A), arising in association with an acquired intradermal nevus (Figure 2, c). Case reports with melanoma developed from a small congenital or acquired dermal nevus are extremely rare in the literature. In all published cases, histopathology revealed a melanoma component situated below or laterally, next to the merging dermal nevus (3) and in one case next to and above the dermal component (4), which is very similar to our cases. In both of our cases, melanoma presented an epidermal component with atypical, large melanocytes next to or above the typical and small intradermal melanocytes of the Unna nevus. Despite the fact that the reported statistical occurrence of malignant transformation of every individual nevus is very low in the elderly population (>60 years of age), 1 in 33,000 (5), we believe our two presented cases show a striking similarity in the melanoma manifesting in the vicinity of a previously existing lesion, indicating nevus-associated melanoma (NAM). This letter presents an interesting finding of two cases, with a form of melanoma (NAM) that is statistically very rare in older patients but occurred twice within the span of a year within the same town and was diagnosed in the same hospital. Intradermal nevi are most commonly considered to be benign skin lesions. However, previous research and our two cases shows that intradermal nevi are not immune to malignant alteration. Based on these results, we suggest a detailed clinical and dermoscopic evaluation of each skin lesion, including intradermal nevi. Flat melanocytic parts in the vicinity of intradermal nevi should always raise suspicion and warrant excision with histopathological evaluation of the lesion so as to allow timely response to any malignant alteration.

Post-mortem Findings of Inflammatory Cells and the Association of 4-Hydroxynonenal with Systemic Vascular and Oxidative Stress in Lethal COVID-19.

A recent comparison of clinical and inflammatory parameters, together with biomarkers of oxidative stress, in patients who died from aggressive COVID-19 and survivors suggested that the lipid peroxidation product 4-hydroxynonenal (4-HNE) might be detrimental in lethal SARS-CoV-2 infection. The current study further explores the involvement of inflammatory cells, systemic vascular stress, and 4-HNE in lethal COVID-19 using specific immunohistochemical analyses of the inflammatory cells within the vital organs obtained by autopsy of nine patients who died from aggressive SAR-CoV-2 infection. Besides 4-HNE, myeloperoxidase (MPO) and mitochondrial superoxide dismutase (SOD2) were analyzed alongside standard leukocyte biomarkers (CDs). All the immunohistochemical slides were simultaneously prepared for each analyzed biomarker. The results revealed abundant 4-HNE in the vital organs, but the primary origin of 4-HNE was sepsis-like vascular stress, not an oxidative burst of the inflammatory cells. In particular, inflammatory cells were often negative for 4-HNE, while blood vessels were always very strongly immunopositive, as was edematous tissue even in the absence of inflammatory cells. The most affected organs were the lungs with diffuse alveolar damage and the brain with edema and reactive astrocytes, whereas despite acute tubular necrosis, 4-HNE was not abundant in the kidneys, which had prominent SOD2. Although SOD2 in most cases gave strong immunohistochemical positivity similar to 4-HNE, unlike 4-HNE, it was always limited to the cells, as was MPO. Due to their differential expressions in blood vessels, inflammatory cells, and the kidneys, we think that SOD2 could, together with 4-HNE, be a potential link between a malfunctioning immune system, oxidative stress, and vascular stress in lethal COVID-19.

Preliminary Findings on the Association of the Lipid Peroxidation Product 4-Hydroxynonenal with the Lethal Outcome of Aggressive COVID-19.

Major findings of the pilot study involving 21 critically ill patients during the week after admission to the critical care unit specialized for COVID-19 are presented. Fourteen patients have recovered, while seven passed away. There were no differences between them in respect to clinical or laboratory parameters monitored. However, protein adducts of the lipid peroxidation product 4-hydroxynonenal (HNE) were higher in the plasma of the deceased patients, while total antioxidant capacity was below the detection limit for the majority of sera samples in both groups. Moreover, levels of the HNE-protein adducts were constant in the plasma of the deceased patients, while in survivors, they have shown prominent and dynamic variations, suggesting that survivors had active oxidative stress response mechanisms reacting to COVID-19 aggression, which were not efficient in patients who died. Immunohistochemistry revealed the abundant presence of HNE-protein adducts in the lungs of deceased patients indicating that HNE is associated with the lethal outcome. It seems that HNE was spreading from the blood vessels more than being a consequence of pneumonia. Due to the limitations of the relatively small number of patients involved in this study, further research on HNE and antioxidants is needed. This might allow a better understanding of COVID-19 and options for utilizing antioxidants by personalized, integrative biomedicine approach to prevent the onset of HNE-mediated vitious circle of lipid peroxidation in patients with aggressive inflammatory diseases.

Anterior and Posterior Arthroscopic Treatment of Primary Synovial Chondromatosis of the Ankle.

BACKGROUND: Primary synovial chondromatosis (PSC) is a progressive disorder of unknown etiology resulting in formation of multiple loose bodies. If left untreated, it may lead to degenerative changes or malignant transformation to chondrosarcoma. METHODS: Seventeen patients who underwent combined posterior and anterior ankle arthroscopy within the same operative session and had histologically confirmed PSC were included in this retrospective study. American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot score was used to evaluate ankle function preoperatively and at a final follow-up. A 3-question survey was used to evaluate patient's satisfaction at the final follow-up. RESULTS: In 14 patients, loose bodies were found in both compartments of the ankle, in 2 only in the anterior compartment, and in 1 only in the posterior compartment. All patients had evident signs of synovial inflammation in both compartments. The AOFAS Ankle-Hindfoot score increased from the preoperative median score of 65 (range, 29-90) to 95 (range, 65-100) at the final follow-up. Fourteen patients reported they were extremely satisfied with the outcome, 1 was moderately satisfied, and 2 were dissatisfied. No cases of recurrence of synovitis or loose body formation were noted, nor any signs of malignant transformation during the follow-up period. CONCLUSION: We believe the risk of recurrence of PSC, which is in close relation to malignant transformation, can be minimized by performing a complete synovectomy of the ankle. Our experience and review of literature makes us believe that ankle PSC should be regarded as a whole joint disorder. Performing a combined posterior and anterior arthroscopic procedure within the same operative session should always be considered in patients with ankle PSC. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Peritumoral Clefting and Expression of MMP-2 and MMP-9 in Basal Cell Carcinoma of the Skin.

BACKGROUND/AIM: Peritumoral clefting is one of the main histologic features of basal cell carcinoma of the skin (BCC). The aim of the study was to analyze the expression of MMP-2 and MMP-9 both in cells of basal cell carcinoma and in the adjacent stroma and to correlate the findings of immunohistochemical analysis with the presence of peritumoral clefting. PATIENTS AND METHODS: The study was made on archival material comprising 48 cases of BCC. These were scanned for the presence of peritumoral clefts. The results of immunohistochemical staining for MMP-2 and MMP-9 were determined semiquantitatively using immunohistochemical staining index (ISI). RESULTS: Peritumoral retractions were found in 40 BCC cases. Positive immunohistochemical reaction for MMP-2 in tumor cells was found in 47 cases and in all cases in the adjacent stroma. Positive immunostaining for MMP-9 in BCC tumor cells was observed in 37 cases and in all cases in the adjacent stroma. There was no statistically significant association between peritumoral retractions and expression of MMPs. A statistically significant correlation was found in the expression of both MMP-2 and MMP-9 between the tumor and the stroma. CONCLUSION: Tumor cells elaborate MMP-2 and -9, but they also produce some other factors that may induce production of MMPs in adjacent stromal cells. The role of MMPs in the development of peritumoral clefts could not be confirmed.