Blue Nevus Research Articles

Expanding the dermatological acronym from BLEND TAN EGG to PEGG: A rare case of painful palmar neurofibroma

Painful skin tumors present a diagnostic challenge due to their diverse presentations. The acronym blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, tufted angioma, angiolipoma, neurilemmoma, endometrioma, granular cell tumor, and glomus tumor (BLEND TAN EGG) encompasses some of the common causes of painful skin tumors. This case report documents a 24-year-old woman presenting with a painful, solitary palmar nodule confirmed as a neurofibroma after an excisional biopsy. Neurofibromas are frequently asymptomatic, but their location within the tight palmar fascia can lead to significant discomfort. The rarity of this presentation and the difficulty in pre-operative diagnosis highlight the importance of considering palmar neurofibromas as a differential diagnosis for painful skin tumors, particularly in the hand and feet. To enhance the educational value of the existing acronym, we propose its expansion to “BLEND TAN PEGG,” where “P” signifies palmar or plantar neurofibroma.

The role of signaling pathways mediated by the GPCRs CysLTR1/2 in melanocyte proliferation and senescence.

In contrast with sun exposure-induced melanoma, rarer melanocytic tumors and neoplasms with low mutational burden present opportunities to study isolated signaling mechanisms. These include uveal melanoma and blue nevi, which are often driven by mutations within the G protein-coupled signaling cascade downstream of cysteinyl leukotriene receptor 2. Here, we review how the same mutations within this pathway drive the growth of melanocytes in one tissue but can inhibit the growth of those in another, exemplifying the role of the tissue environment in the delicate balance between uncontrolled cell growth and senescence.

Spectrum of blue nevus-like lesions, including blue nevus, pigmented epithelioid melanocytoma & animal-type melanoma

Blue nevus-like lesions constitute a category of melanocytic lesions clinically identified by their blue coloration. Histologically, they exhibit two primary features: a dermal location and intense pigmentation. The latest World Health Organization (WHO) classification categorizes blue melanocytic lesions into benign entities (dermal melanocytoses, blue nevus, and deep penetrating nevus), melanocytic tumors with low to intermediate malignant potential (pigmented epithelioid melanocytoma, PEM), and malignant lesions (blue nevus-like melanoma and melanoma arising in blue nevus).Clinically, blue nevi are enduring and stable lesions, displaying a structureless blue pigmentation both clinically and dermatoscopically, with a straightforward histologic diagnosis. Conversely, lesions with recent onset and/or rapid growth are more commonly associated with diagnoses falling within the intermediate part of the spectrum or with melanoma. These lesions often present with a blue color along with additional features such as black blotches, irregular vessels, and irregular pigmented globules. They typically emerge de novo without recognizable precursors, they pose significant challenges for patient management.Melanoma on a blue nevus is an exceedingly rare entity with only a few cases described to date. Histologically, differentiating between lesions with intermediate malignant potential and melanoma is always challenging, necessitating a comprehensive evaluation of all morphologic findings of the lesion.

Ancillary immunohistochemistry testing for loss of p16 in melanoma: A systematic review and meta-analysis of diagnostic accuracy studies.

Ancillary immunohistochemistry testing for p16 loss has been proposed as a diagnostic tool for melanoma, but its accuracy remains uncertain. A systematic review and meta-analysis were conducted on 26 studies involving 979 melanomas and 974 nevi. Through bivariate analysis of data across all cut-off values, the sensitivity and specificity were calculated to be 0.55 (95% confidence interval [CI]: 0.38, 0.70) and 0.85 (95% CI: 0.70, 0.94), respectively. Summary estimates of diagnostic accuracy fell below recommended thresholds for effective tests, but subgroup analysis suggested that p16 loss could aid in diagnosing ambiguous lesions as melanoma in certain scenarios. However, the presence of p16 expression in these contexts does not definitively rule out melanoma. The findings were limited by underpowered exploratory study designs at risk for bias in patient selection and test interpretation. While the use of p16 immunohistochemistry for detecting melanoma is not universally reliable, it may serve as a confirmatory test in differential diagnoses involving common, congenital, acral, Spitz, and deep penetrating nevi. Nevertheless, further studies are needed to validate its utility. Until then, the application of p16 immunohistochemistry in melanoma diagnosis should be regarded as experimental.

Orbital Pigmented Epithelioid Melanocytoma Tumor Associated With Nevus of Ota (Oculodermal Melanocytosis).

The authors report a patient with nevus of Ota (oculodermal melanocytosis) who presented with pigmented epithelioid melanocytoma in the right orbit. A 36-year-old female patient attended with proptosis OD and diplopia for 3 months. MRI disclosed an expansive lesion adhered to the right inferior rectus muscle, enlargement of the superior orbital fissure, and filling of the right cavernous sinus. Excision of the orbital mass through a transconjunctival inferior fornix access disclosed a heavily pigmented lesion. Anatomopathological study revealed a diagnosis of pigmented epithelioid melanocytoma. A positron emission tomography scan did not show any metastasis. The patient was submitted to radiotherapy, had an improvement of the proptosis and diplopia, and showed no distant metastases for 3 years now. Pigmented epithelioid melanocytoma belongs to the group of heavily pigmented neoplasms, as do atypical blue nevus, which is characterized by prominent melanin production and a low degree of malignancy.

Artificial Intelligence (Neural Network) in the Diagnosis of Benign Skin Tumors in Pediatric Patients

Relevance: ten years ago, artificial intelligence (AI), particularly neural networks (NN), as a diagnostic option in practice seemed a distant prospect. Today, the use of AI is becoming an increasingly popular and daily improving approach in all aspects of clinical and fundamental medicine. Purpose: design and learning of a NN to recognize four types of benign melanocytic skin tumors, integration into a mobile app to apply in practice. Material and methods: сlinical and dermatoscopic analysis of skin tumors was carried out in 600 children. In 65 cases the tumors were removed. Histological types were dermal nevus – 43% (n=28), complex nevus - 33.8% (n=22), pyogenic granuloma - 10.8% (n=7), Spitz-nevus - 6.2% (n=4), blue nevus - 3.1% (n=2), melanoma - 3.1% (n=2). Seven patients with pyogenic granulomas and two patients with melanoma were excluded. The test set included 56 dermatoscopic images. Due to the small number of images augmentation was performed. The database has been increased from 600 images to 1800. NN is written in the machine language Python. The machine learning framework was TensorFlow 2.0. The network architecture is based on the pre-trained model “EfficientNet B7”. This model uses the “supervised learning” paradigm. Each element of the sample had a class affiliation. Results: an accuracy of 83% was achieved after a period of learning on the test set. Mathematical metrics calculated in the Scikit-learn library. Sensitivity was 100% (blue nevus), 73% (complex nevus), 93% (dermal nevus), 75% (Spitz-nevus), and specificity were 98%; 94%; 82%; 98%, respectively. AI was integrated into the mobile app “KIDS NEVI”. Conclusion: AI as an auxiliary method for the skin tumors diagnosis in children and adolescents has demonstrated high potential and great opportunities. Dermatoscopic analysis of a skin tumor and a mobile app are able to provide “double control”, quick and correct clinical diagnosis and determination treatment tactics.

Malignant blue melanoma

Malignant blue melanomas (MBMs) arise from blue nevi and all related intradermal melanocytic proliferations. They harbor specific, mutually exclusive mutations in the G-coupled protein pathway, mainly involving GNAQ or GNA11. Other rare genetic drivers include CYSLTR2 or PCLB4 mutations. PKC and GRM1-gene fusions have been recently added to this list. MBMs have a predilection for the scalp area, presenting as rapidly growing nodules within a pre-existing lesion. Histopathologically, these tumors are located in the dermis and subcutaneous fat and consist of large nodules or expanding dense sheets. Tumor necrosis is commonly seen. Large spindle-shaped and epithelioid melanocytes with high-grade cytological atypia and frequent mitotic figures are at higher magnification. A benign blue nevus or intermediate-grade blue melanocytoma is frequently found on the side of the central mass. Loss of nuclear BAP1 immunoreactivity is a poor prognostic factor.

S100 protein expression in PKC-fused blue naevi, cellular blue naevi and PRKAR1A-inactivated pigmented epithelioid melanocytomas

Recent data have redefined the genetic spectrum of pigmented epithelioid melanocytomas (PEMs). PEM is now defined by a secondary genetic event, a protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) inactivation, that confers the specific cytomorphology of the entity, but this event can arise within a naevus with a genetic background of common, blue or Spitz type. PKC-fused melanocytic proliferations, although they can exhibit PEM-like morphological features, have now been regrouped within the blue group of tumours. Past studies have shown that the latter group tends to lose S100 expression. Herein, we studied the nuclear expression of S100 by immunohistochemistry in 73 PKC-fused benign blue naevi. Histologically, the most frequent pattern found in PKC-fused blue naevi (51%) was a dermal biphasic architecture associated with a horizontal band of medium-sized bland melanocytes in the upper papillary dermis, with a deeper dermal expansion combining spindled and dendritic melanocytes with occasional small nests of bland melanocytes within a fibrous background. A PEM-like hyperpigmented hyperplasia of the epidermis was seen in 32% of cases. The immunohistochemical study found in 31 of the 37 (84%) dermal biphasic PKC-fused melanocytic tumour cases a significant loss of nuclear expression of S100 (in more than 50% of cells) in the superficial horizontal dermal band area and in 68% of the biphasic dermal component. However, the hyperpigmented PEM-like junctional components were not assessable by immunohistochemistry. An exploratory analysis of S100 expression in 21 blue naevi and in 25 PEM with confirmed PRKAR1A inactivation was also performed. In blue naevi, a loss of nuclear S100 expression in more than 50% of melanocytes was found in over 70% of these lesions both in the dendritic and epithelioid dermal components. By contrast, nuclear expression of S100 was most often preserved in PEM with PRKAR1A inactivation (85% preservation in the epithelioid component). These results suggest that searching for S100 expression loss by immunohistochemistry may be helpful in the diagnosis of PKC-fused blue naevus similarly as in dendritic and cellular blue naevi. This simple test, especially if a band-like structure is present in the upper dermis, can effectively support this diagnosis, as a genetic confirmation of these benign tumours is not warranted.

Plaque-Type Blue Nevus on the Forehead Extending Into the Muscular Layer During Early Childhood.

Plaque-Type Blue Nevus on the Forehead Extending Into the Muscular Layer During Early Childhood.

Blue Rubber Bleb Nevus Syndrome and Retinal Cavernous Hemangioma

Blue Rubber Bleb Nevus Syndrome and Retinal Cavernous Hemangioma

PA23 Glomuvenous malformation or blue rubber bleb naevus syndrome: a case highlighting how a genetic diagnosis can avoid invasive testing and the need for long-term follow-up

PA23 Glomuvenous malformation or blue rubber bleb naevus syndrome: a case highlighting how a genetic diagnosis can avoid invasive testing and the need for long-term follow-up

Diagnostic approach to hepatic vascular lesions: a paediatric perspective.

The pathological evaluation of hepatic vascular lesions in children requires special consideration. Inconsistent terminology, rarity of pathology specimens and overlapping pathological features between various lesions may pose a serious diagnostic challenge. In this review, we highlight the importance of using the International Society for the Study of Vascular Anomalies (ISSVA) classification scheme to characterise these lesions. Selected entities are discussed, including hepatic vascular tumours exclusively seen in the paediatric age group, hepatic infantile haemangioma and hepatic congenital haemangioma. Vascular malformations, with emphasis on their syndromic associations (venous malformation in blue rubber bleb naevus syndrome) and complications (hepatocellular nodules in Abernethy malformation) are also covered.

PRKC Fusion Melanocytic Tumors, a Subgroup of Melanocytic Tumors More Closely Aligned to Blue Nevi Than to PRKAR1A-inactivated Pigmented Epithelioid Melanocytomas.

Tumors morphologically classified as pigmented epithelioid melanocytomas (PEMs) are genomically diverse, with the 2 most common genomic subtypes being PRKC fusions or PRKAR1A inactivating mutations. PRKC fusions activate the Gαq/11 pathway similar to blue nevi. Conversely, inactivating mutations in PRKAR1A activate the Gαs pathway. We hypothesize that PRKC fusions have greater genomic overlap with blue nevi compared with PRKAR1A-inactivated PEMs. We characterized the clinical and morphologic features of 21 PRKC and PRKACB fusion melanocytic tumors and compared this to PRKAR1A mutated PEMs. To test our hypothesis regarding greater genomic overlap between PRKC fusions and blue nevi relative to PRKAR1A mutated PEMs, we performed a principal component analysis (PCA) using mRNA expression data. Lastly, we performed a meta-analysis focusing on the outcome data of PRKC fusions. PRKC fusions occur at a younger median age than PRKAR1A mutated PEMs (16 vs. 27). Histologically, PRKC fusions have solid aggregates of epithelioid melanocytes not typical of PRKAR1A mutated PEMs. The PCA plot showed no overlap between the PRKC fusion group and the PRKAR1A-mutated PEMs. There was a significant overlap between PRKC fusions and blue nevi. A meta-analysis of PRKC fusion cases in the literature suggests melanoma is uncommon, but the loss of BAP-1 nuclear expression may be associated with an adverse prognosis as in tumors from the blue nevus family. PRKC fusion melanocytic tumors have greater genomic overlap with blue nevi compared with PRKAR1A mutated PEMs. We recommend categorizing benign PRKC fusion melanocytic tumors as blue fusion nevi/tumors.

Co-occurrence of posterior chest wall pilonidal sinus with melanocytic nevus: a challenging presentation: a case report

IntroductionTo date, only a limited number of case reports have documented the co-occurrence of PNS and melanocytic nevus in the medical literature. This study aims to report an exceptionally rare case of posterior chest wall PNS in conjunction with a melanocytic nevus.Case presentationA 46-year-old female presented with a long-standing black lesion on her left upper posterior chest wall, that had become painful in the two months prior to presentation. There was a painful, dark blue, non-erythematous, and non-tender nodule on the left upper posterior chest wall. Based on the patient’s desire for cosmetic purposes, the lesion was excised totally with primary closure under local anaesthesia. Histopathological examination revealed intradermal melanocytic nevus with inflamed pilonidal sinus.DiscussionThe rarity of posterior chest wall PNS associated with nevi poses unique diagnostic and therapeutic challenges for clinicians. The distinct anatomical location, different from the conventional region, and the rare association between the two conditions may delay accurate diagnosis and result in mismanagement or inappropriate interventions.ConclusionThe posterior chest wall PNS is another type of atypical PNS that is extremely rare. The association between PNS and blue nevus is a fascinating medical finding that deserves further investigation.

PRAME expression in genital melanocytic lesions – Potential diagnostic pitfall of intermediate expression in atypical genital nevi

IntroductionThe Preferentially Expressed Antigen in Melanoma (PRAME) immunostain has seen significant diagnostic use in confirming malignancy for melanocytic lesions. However, the expression of PRAME in genital melanocytic lesions have not been reported. In this study, PRAME staining was performed on a cohort of genital melanocytic lesions, aiming to investigate the diagnostic role of PRAME in genital melanocytic lesions and its expression in atypical genital nevi. MethodologyA cohort including genital invasive melanoma, melanoma-in-situ, atypical genital nevus (AGN), compound nevus, intradermal nevus, blue nevus, lentigo and melanosis was retrieved with histology reviewed and PRAME immunostaining performed. ResultsA total of 66 cases were reviewed. The average proportion expression of PRAME were 56.75 % and 57.43 % for invasive melanoma and melanoma-in-situ, with average H-scores of 153.5/300 and 163.14/300 respectively, which were greater than AGN (3.25 %, 7.75/300, p<0.001), compound/intradermal nevi, lentigo/melanosis, and background junctional melanocytes (<1 %, <1/300, p<0.001). The different cutoffs of PRAME expression, the sensitivity and specificity were 65.22 % and 100 % (>100/300); 69.57 % and 95.83 % (>10/300); and 82.61 % and 93.75 % (≥1/300) respectively. Low level PRAME expression was seen in half of the cases of AGN (n=2/4, 50 %), and at low cutoffs (>10/300 and ≥1/300) unable to differentiate invasive melanoma from AGN (p>0.05). ConclusionsFor genital melanocytic lesions, PRAME immunostain shows high specificity at strong and diffuse staining. AGN not uncommonly display low level expression. Focal and/or weak PRAME expression should not be considered as an absolute indication of malignancy, and comprehensive histological assessment remains the key to accurate diagnosis of melanocytic lesions.

Malignant blue nevus: Epidemiology, socioeconomic factors, and disease presentation.

e21565 Background: Malignant blue nevus (MBN) is a rare and aggressive melanoma that arises in a blue nevus and tends to metastasize to the lymph nodes. Metastasis has been described in up to 55% of cases, and the 10-year survival rate is 51%. Current literature on MBN is limited. Data from the National Cancer Database (NCDB) on the demographic and socioeconomic characteristics of patients with MBN could provide insightful information regarding the epidemiology of this rare disease. Methods: The 2004-2020 NCDB was used to perform a retrospective cohort analysis of patients diagnosed with malignant blue nevus (N = 118) using ICD-O-3 code 8780/3. This study used descriptive statistics to analyze factors such as age, sex, income status, insurance status, Charlson-Deyo score, treatments, and survival rates. Results: A total of 118 patients diagnosed with MBN were recorded in the NCDB with an average age at diagnosis of 56.7 ± 17.2 years with a female preponderance (59%). Nearly all patients were insured (99%), mostly by private insurance (59%) or Medicare (27%). Over half of patients (54%) were enrolled in research programs, and 62% of patients comprised the top two income quartiles based on median household income. The vast majority of patients (81%) had no major comorbidities (Charlson-Deyo = 0). The top primary sites were the skin of the scalp and neck (36%) and the trunk (21%). The average tumor size was 21.2 ± 30.3 mm ranging from 2 mm-120 mm. The most frequent treatment performed was surgery, with 92% of patients undergoing surgical procedures of the primary site. Among these, the most common procedures were wide excision or re-excision (52%), excisional biopsy (14%), and shave biopsy followed by gross excision (10%). After resection, 77% of patients showed no residual tumor. In place of surgery, a smaller number of patients received alternate treatments as their main therapy, such as radiation therapy (11%), chemotherapy (6%), or immunotherapy (12%). The 2-year and 5-year survival rates were 88% and 68% respectively. Conclusions: Based on our literature review, this study is the first NCDB analysis on MBN and presents data from the largest cohort of patients to date. Patients with MBN are more likely to be female, and most lack major comorbidities. The most common sites are the scalp, neck, or trunk, in line with current literature. Review of socioeconomic factors revealed that an overwhelming majority of patients are likely to be insured and in the top two income quartiles. These findings could implicate that those who are more socioeconomically advantaged may have more resources for recognition of disease and proper diagnosis, especially considering the challenges of diagnosing MBN due to poorly defined histological criteria. Further research efforts should investigate the impacts of socioeconomic factors on diagnosis, treatments, and prognosis.

Atypical Histologic Features Associated with Metastasis in Blue Naevi

Atypical Histologic Features Associated with Metastasis in Blue Naevi

Evaluation of tubulin β-3 and 5 hydroxy-methyl cytosine as diagnostic and prognostic markers in malignant melanoma

Tubulin β-3 staining pattern and staining intensity of 5-hydroxymethyl cytosine (5-hmC) are potential diagnostic and prognostic markers in melanocytic lesions that need further evaluation. Melanocytic nevi and primary cutaneous melanomas were immunohistochemically stained for tubulin-β-3 and 5-hmC. Immunoreactivity and staining patterns were correlated with Breslow-thickness, clinical and pathological characteristics, and progression-free survival. Melanocytes showed positive tubulin β-3 staining. However, in most nevi, tubulin β-3 staining appeared as a gradient with intense cytoplasmic staining in cells of the superficial part of the lesion that faded to weak staining in the deep dermal part, while no gradient was found in deep penetrating nevi and melanomas. In 53 % of the melanomas, areas with loss of tubulin β-3 staining were found. 5-hmC staining intensity was significantly higher in melanocytic nevi compared to melanomas. Breslow thickness in combination with low 5-hmC score and loss of tubulin-β-3 staining was predictive for poor prognosis. As single markers, tubulin-β-3 and 5-hmC can be useful to distinguish between melanocytic nevi and melanoma, but staining variability limits the use of 5-hmC. In melanomas measuring >1.5 mm, combination of low 5-hmC score and loss of tubulin-β-3 staining may have prognostic value.

Smooth muscle hyperplasia in protein kinase C-fused blue naevi: Report of 12 cases.

PKC-fused blue naevi are a recently described group of melanocytic tumours that have distinctive morphological features, including a pigmented epithelioid melanocytoma-like junctional component or a dermal biphasic architecture associating with naevocytoid nests surrounded by dendritic and spindled pigmented melanocytes (so-called 'combined common and blue naevus'). There have been reports of smooth muscle hyperplasia in a hamartoma-like pattern in cases of combined blue naevi without genetic exploration. Herein, we describe 12 cases of protein kinase C (PKC)-fused blue tumours associated with a co-existing smooth muscle hyperplasia, identified from a total of 98 PKC-fused melanocytic tumours. Archived slides of PKC-fused blue naevi with haematoxylin, eosin and phloxin staining, immunohistochemistry and molecular confirmation of a PKC-fusion by fluorescence in-situ hybridisation (FISH) or RNAseq were re-evaluated for identification of notable smooth muscle hyperplasia. Fifty-one of these slides had already been studied in a previous publication from our group. The hyperplasia ranged from hypertrophic arrector pili muscles to extensive horizontal bundles of disorganised fibres constantly associated and limited within a biphasic dermal melanocytic component. At least one arrector pili muscle was always visible within the tumour, with occasionally direct extension of the hyperplastic fibres from the main muscle body. These muscle fibres were devoid of a PKC-fusion signal by FISH. PKC molecules are involved in the regulation of smooth muscle function, offering an explanatory framework. These data suggest incorporating smooth muscle hyperplasia as a diagnostic morphological feature of PKC-fused blue melanocytic tumours.

Navigating a complex case of Mycobacterium xenopi in a patient with blue rubber bleb nevus syndrome

Introduction: Blue rubber bleb nevus syndrome is a rare disorder of venous malformations, with around 200 cases reported. We present a case of Mycobacterium xenopi infection in a patient with blue rubber bleb nevus syndrome. Case Description: A 40-year-old female with blue rubber bleb nevus syndrome, asthma, and bronchiectasis came to the pulmonology clinic with shortness of breath and a cough. She was recently admitted for a bronchiectasis exacerbation but continued to have a worsening productive cough and fevers. The most recent CT scan of the chest showed interval stable right upper lobe fibrocavitary disease, demonstrating gradual progression over two years. She had occasional positive cultures for Mycobacterium Avium Complex and M. xenopi one year previously, assumed to be a colonizer and not treated. Most recent hospital cultures were negative for bacteria and an acid-fast bacilli smear. She was sent to the emergency department for bronchiectasis exacerbation and returned to the clinic six weeks later with two sputum cultures growing M. xenopi. It was decided to treat M. xenopi as this was likely the cause of her cavitary lung lesion and frequent infections. Azithromycin, rifampin, and sulfamethoxazole/trimethoprim were initiated. Intravenous amikacin was added later on. She finally had a right partial lung resection done after one year at an outside hospital. She was on and off antibiotics for M. xenopi for approximately three years with negative repeat cultures for non-tuberculous mycobacteria. Conclusion: Due to the high mortality of M. xenopi infections (which can be as high as 69%), treatment of at least twelve months is recommended. To our knowledge, this is the first reported case of M. xenopi in a patient with blue rubber bleb nevus syndrome.