Amelanotic Melanoma Research Articles

GNAQ Q209R Mutations Are Highly Specific for Circumscribed Choroidal Hemangioma.

Several tumors, including uveal melanoma, show somatic mutations of GNAQ/GNA11. Circumscribed choroidal hemangioma is a benign tumor that becomes symptomatic in adulthood. In some patients, morphologic examination of biopsies is required for differential diagnosis between amelanotic choroidal melanoma and circumscribed choroidal hemangioma. Here, we report the results of GNAQ/GNA11 mutation analysis in samples from circumscribed choroidal hemangioma. Deep amplicon sequencing (Illumina MiSeq, San Diego, CA, USA) of positions R183 and Q209 of GNAQ and GNA11 in tissue samples from 33 patients with histologically diagnosed circumscribed choroidal hemangioma. All patients underwent biopsy or enucleation at our clinic between 2008 and 2018. To enable detection of variant alleles at low fractions, read depth exceeded 15,000-fold. DNA for genetic analysis was prepared from either snap-frozen (n = 22) or FFPE (n = 11) tissue samples. Samples from 28/33 patients (85%) showed a somatic missense mutation of GNAQ (c.626 A > G) predicted to result in p.Q209R. Variant allele fraction was variable (range 2.3% to 28%). Variants of GNAQ resulting in p.Q209 are characteristic for circumscribed choroidal hemangiomas. It appears that the GNAQ mutation spectrum in this tumor is narrow, possibly restricted to p.Q209R. Moreover, the spectrum is distinct from that of uveal melanoma, in which alterations resulting in p.Q209R are very rare.

PHOTODYNAMIC THERAPY AS PRIMARY TREATMENT FOR SMALL CHOROIDAL MELANOMA.

To report outcomes of photodynamic therapy (PDT) as primary treatment for small amelanotic choroidal melanoma. Retrospective interventional case series of 12 patients with small choroidal melanoma treated with standard-fluence PDT (83 seconds; 50 J/cm) using verteporfin. Tumor regression, subretinal fluid resolution, best-corrected visual acuity, and PDT complications. There were 12 eyes with melanoma, demonstrating amelanotic (10 [83%]) or lightly pigmented (n = 2, 17%) appearance. The mean tumor thickness was 2.7 mm (median, 2.8; range 1.8-3.7 mm). After PDT, mean follow-up was 56 months (median, 53; range, 14-91). Outcomes revealed complete tumor regression after 1 session (n = 3, 25%), 2 sessions (n = 3, 25%), and 3 sessions (n = 2, 17%) of PDT, reduced to mean thickness of 2.1 mm (median, 2.0; range 1.2-3.4 mm). Tumors that failed to regress (n = 4, 33%) were further controlled with transpupillary thermotherapy (n = 1) or plaque brachytherapy (n = 3). Subretinal fluid, present in six eyes, demonstrated resolution (n = 5) or progression (n = 1), and one tumor developed new subretinal fluid after PDT (n = 1). Visual outcome was stable (n = 11 eyes) or improved (n = 1). Photodynamic therapy complications included local retina pigment epithelium atrophy at the site of treatment in 3 (25%) eyes, with no effect on macular or optic nerve function. Primary PDT resulted in complete tumor regression of small amelanotic choroidal melanoma in 67% at mean 5 years, with no major effect on visual acuity.

Abstract 881: A role for microsomal glutathione transferase 1 in melanin biosynthesis in melanoma

Abstract Higher organisms have multiple defenses against toxic chemical insult, ultraviolet light (UVR) and oxidative stress. These include thioredoxin and glutathione dependent enzymes, some of which are selenium (Se) dependent, including thioredoxin reductases, Se-dependent glutathione peroxidases, Se-independent glutathione transferases and peroxiredoxins. Microsomal glutathione transferase 1 (MGST1) shares an important and unique characteristic with Se-dependent glutathione peroxidase GPX4, namely the ability to reduce lipid hydroperoxides directly in membranes. In contrast to most other glutathione transferases and peroxidases, we previously found that deletion of MGST1 in mice was embryonic lethal, signifying some essential functional importance. We found that MGST1 was crucial for embryonic development through regulating early hematopoiesis in both zebrafish and mouse derived hematopoietic stem cells. Interestingly, after partial knock-down MGST1, the number of melanocytes located at the midline of zebrafish embryos was significantly reduced. Melanocytes are specialized cells that produce melanin, contributing to skin color, but also providing an antioxidant defense system that includes UVR - causative in the initiation of melanoma. Both mRNA and protein levels of MGST1 were markedly decreased in several amelanotic melanoma cell lines and melanogenesis was significantly decreased in B16 melanoma cells when MGST1 expression was knocked down by 60%. This was accompanied by increased UVB-induced cell death in these B16 cells. In contrast, in normal human melanocytes, recombinant adenovirus induced over-expression of MGST1 induced melanogenesis, concomitant with an increase of tyrosinase protein levels. UVB light was used to show that stimulus of melanin biosynthesis occurred in different melanoma cells in quantitative agreement with their levels of MGST1. We conclude that within the melanin synthetic pathway, MGST1 is critical in regulating conversion of dopaquinone to glutathionyl-DOPA, a precursor of pheomelanin. In the absence of MGST1, dopaquinone can cause toxicities and result in reduced or absent levels of melanin, leading to a deficiency in protection against UVR-induced DNA damage. Thus, absence of MGST1 produces embryonic lethality and influences the susceptibility of skin melanocytes to melanoma. Citation Format: Jie Zhang, Zhi-wei Ye, Danyelle M. Townsend, Ralf Morgenstern, Kenneth D. Tew. A role for microsomal glutathione transferase 1 in melanin biosynthesis in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 881.

Astrocytoma of the optic nerve head

In this article, a clinical case of astrocytoma of optic nerve head in patient with neurofibromatosis type 1 is presented. The main feature of this clinical case is a difficulty in differential diagnosis with amelanotic choroidal melanoma.

DISSEMINATED METASTATIC MELANOMA OF UNKNOWN ORIGIN fiRST DIAGNOSED IN THE ORAL CAVITY WITH NEAR RESOLUTION AFTER IMMUNOTHERAPY AND SUBSEQUENT IMMUNE-RELATED SEQUALAE

Herein, we report an atypical clinicopathological presentation of amelanotic melanoma first diagnosed in the oral cavity of a 68-year-old man. The tumor was immunopositive for HMB45 and S-100, and weakly positive to Melan A. PET (positron emission tomography) and CT (computed tomography) scans demonstrated widespread organ and bone metastases, obviating surgical intervention. Standard immunotherapy was instituted with ipilimumab and nivolumab. At 3-weeks, near resolution of the oral lesion was evident and repeat imaging showed resolution of the left lung lesions and marked reductions in size of other affected sites. The patient subsequently experienced and recovered from multiple immune-related adverse events, including autoimmune carditis, which was managed with steroid administration. Following subsequent immunoregimens and 4 months since the initial diagnosis, the patient succumbed to sudden apparent cardiac arrest. Historically, surgery, chemotherapy, and radiotherapy to manage mucosal melanoma have yielded poor long-term outcomes, necessitating alternative efforts to improve patient care. Immunotherapy is an emerging modality for management of late-stage melanoma and has shown promising results to extend overall survival.

Recurrent amelanotic melanoma of nasal cavity: Biological variability and unpredictable behavior of mucosal melanoma. A case report.

The aim of this report is to present a case of a patient with a recurrent nasal cavity amelanotic melanoma (AM), with emphasis on diagnosis and therapy options of this clinical entity. A 65-year-old female patient presented with pain in the right cheek region and nasal obstruction. In 2013, she was diagnosed with mucosal melanoma (MM) of the left nasal cavity. After endoscopic surgery and radiotherapy, the patient was followed by the oncology team. Five years after the initial diagnosis, rhinoscopy showed a tumorous formation in the right nasal cavity. The tumor mass was without black discoloration and was the same color as the surrounding nasal mucosa. Microscopic examination after biopsy of the tumor confirmed amelanotic MM. The patient underwent an additional endoscopic surgery. A complete standard diagnostic workup for MM found metastases in head and neck lymph nodes, on both sides. MMs of head and neck are uncommon malignancies. Unique biology of MM cells causes a high rate of recurrences. This report presents an example of recurrent AM of the nasal cavity, in treatment with checkpoint inhibitor (pembrolizumab), which could provide a good therapy option for patients with MM.

Antimelanoma activity of perphenazine and prochlorperazine in human COLO829 and C32 cell lines

Cutaneous melanoma is least common (only about 1% of skin cancers) but is the deadliest malignant tumor. Moreover, amelanotic types of melanoma are very difficult for clinical diagnosis. The standard therapy can cause a lot of side effects, e.g., nausea, vomiting, and headaches, which means that novel and effective strategies are required. Interestingly, phenothiazine derivatives possess sedative, antiemetic, and anticancer activity. Our goal was to determine the effect of perphenazine and prochlorperazine on cell viability, motility, microphthalmia-associated transcription factor (MITF) and tyrosinase content in melanotic and amelanotic melanoma cells. The viability of C32 and COLO829 melanoma cells was evaluated by the WST-1 colorimetric assay; impact on motility of human melanoma was performed by wound-healing assay, while tyrosinase and MITF content were determined by Western blot. In the present study, we explore the anticancer effect of perphenazine and prochlorperazine in human melanotic (COLO829) and amelanotic (C32) melanoma cells concluding that prochlorperazine inhibits cell viability in a concentration-dependent manner, impairs motility, and decreases tyrosinase and MITF amounts. Moreover, the analyzed drugs decrease/increase MITF amount depending on the type of melanoma. We demonstrated that the decrease of MITF and tyrosinase protein induces motility inhibition of C32 cells, which suggests the ability of those drugs to restore cancer cell sensitivity to treatment. The ability of prochlorperazine to contain the spread of the amelanotic melanoma in vivo may be helpful in the development of a new and effective antimelanoma therapies.

Amelanotic melanoma.

Cutaneous amelanotic melanoma (AM) is a rare amelanotic or a hypomelanotic subtype of melanoma, comprising only 0.4-27.5% of all melanoma cases. The mean age of the patients is over 50 years, and the male/female ratio varies from 0.5 to 4. Patients with red hair, type I skin, freckles, lack of nevi on the back, a sun-sensitive phenotype, or previous AM history are more likely to develop AMs. As AMs lack pigmentation, their appearances vary and can mimic many benign and malignant conditions, thus presenting a diagnostic challenge. AMs are composed of greater proportions of nodular melanoma, acral lentiginous melanoma, and desmoplastic melanoma than pigmented melanomas. They also present with thicker Breslow thickness, higher mitotic rate, more frequent ulceration, higher tumor stage, and lower survival than pigmented melanomas.

Suspected Iatrogenic Seeding of Oral Melanoma Secondary to Endotracheal Intubation in a Dog

A 10 yr old castrated male pug was presented with a 3 day history of intermittent dyspnea, cough, inappetence, and inability to breathe while sleeping. He had previously received hypofractionated radiation therapy for an amelanotic oral malignant melanoma (OMM) 7 mo prior to presentation. At presentation, the dog was gasping and dyspneic. Oral examination identified the OMM on the right hard palate. Thoracic radiographs revealed an angular soft-tissue opacity within the trachea just distal to the thoracic inlet. No evidence of pulmonary metastatic disease was seen. Tracheoscopy identified a pedunculated, nonpigmented mass within the lumen of the distal trachea near the carina. Treatment options were presented to the owners and included tracheal stenting or tracheal resection and anastomosis. Because of the poor prognosis, the owners elected humane euthanasia. Postmortem examination confirmed the presence of melanoma in the distal trachea; no other sites of OMM metastasis were identified. The cause of OMM development in the distal trachea in this case is suspected to have resulted from mechanical tumor cell seeding during endotracheal tube placement for general anesthesia 7 mo prior to presentation. Despite the reported rarity of mechanical tumor seeding, this potential complication warrants consideration in dogs with OMM.

Choroidal amelanotic tumours: clinical differentiation of benign from malignant lesions in 5586 cases

PurposeTo investigate demographics and clinical features of patients with amelanotic choroidal tumours.DesignRetrospective analysis.MethodsComparison of demographic and clinical features of various amelanotic choroidal tumours based on stratification by patient age, sex...

794 Genetic expression profiling in the diagnosis of amelanotic melanoma: An emerging technology and a caution to potential increased reliance

794 Genetic expression profiling in the diagnosis of amelanotic melanoma: An emerging technology and a caution to potential increased reliance

804 Characterization of amelanotic melanomas from genetically-engineered mouse models

804 Characterization of amelanotic melanomas from genetically-engineered mouse models

187 Characterizing amelanotic melanoma and factors associated with survival

187 Characterizing amelanotic melanoma and factors associated with survival

Metastasis of amelanotic melanoma to the small intestine complicated with bleeding, perforation and intestinal obstruction

The paper presents the clinical observation of a rare case of metastasis of amelanotic melanoma of the small intestine without a clinically determined primary tumor complicated with perforation, bleeding and small intestinal obstruction, successfully treated by surgery, with good immediate and long-term results.

Giant Primary Amelanotic Scalp Melanoma: Report of a Rare Case and Review of the Literature

Giant Primary Amelanotic Scalp Melanoma: Report of a Rare Case and Review of the Literature

Phenotypic and genotypic analysis of amelanotic and hypomelanotic melanoma patients.

Amelanotic/hypomelanotic melanoma is associated with poorer outcomes due to a more advanced disease stage at diagnosis. To determine phenotypic risks and genotypic associations with amelanotic/hypomelanotic melanoma to develop a clinical and genetic profile that could assist in identifying high-risk individuals. The Brisbane Naevus Morphology Study conducted from 2009 to 2016 has recruited a core of 1254 participants. Participants were drawn from a combination of volunteers from dermatology outpatient clinics, private dermatology clinics, the Brisbane Longitudinal Twin Study and QSkin study. Case participants had a personal history of melanoma and control participants no personal history of melanoma. We specifically examined seven known candidate pigmentation and melanoma genes and pigmentary phenotypic characteristics in participants with amelanotic/hypomelanotic melanoma compared to pigmented melanomas. This assayed single nucleotide polymorphisms in MC1R, TYR, HERC/OCA2, IRF4, MTAP, PLA2G6 and MITF. Forty-seven participants had at least one amelanotic/hypomelanotic melanoma, and 389 had pigmented melanomas, with amelanotic/hypomelanotic melanoma patients significantly older than pigmented melanoma participants (63.3±13.0 vs. 54.6±15.3years; P<0.001). Amelanotic/hypomelanotic melanoma patients were more likely than pigmented melanoma patients to have red hair (34% vs. 15%; P=0.01), severe hand freckling (13% vs. 5%; P=0.01) and propensity to sunburn (63% vs. 44%; P=0.01). MC1R R/R genotype was much more frequent in our amelanotic/hypomelanotic melanoma population (31.1% vs. 11%; P<0.001; OR 26.4 vs. 5.9; control 1.0). Amelanotic/hypomelanotic melanoma was associated with TYR rs1126809*A/A [OR (CI 95%) 2.7 (1.1-6.8) vs. 1.2 (0.8-1.9)] and PLA2G6 rs11570734*A/A [OR (CI 95%) 3.7 (1.0-13.6) vs. 1.3 (0.9-2.0)]. The MTAP melanoma risk SNP genotype, associated with darker pigmentation, (rs4636294*A/A) was less common in amelanotic/hypomelanotic melanoma patients [OR (CI 95%) 0.8 (0.3-2.1) vs. 2.0 (1.3-3.1)]. Knowledge of phenotypic and genotypic associations of amelanotic/hypomelanotic melanoma can help predict risks and associations of this difficult to diagnose melanoma, which may ultimately assist clinical management and patient skin self-examination.

Subconjunctival Bevacizumab for Recurrent Conjunctival Pyogenic Granuloma

A 45-year-old male presented with a pyogenic granuloma of the bulbar conjunctiva of the left eye following a stick injury. It was a benign friable, hyperplastic, vascular lesion comprised of inflammatory cells and lobular capillary proliferation. The differential diagnosis includes squamous papillomas, hemangiomas, suture granulomas, and ocular surface tumors, such as squamous cell carcinoma and amelanotic melanoma. Conventional treatment includes topical corticosteroids and surgical excision. Treatment of recurrent lesions with cryotherapy, electrocautery, topical antimetabolites, and plaque irradiation has been described. We present a case of recurrent pyogenic granuloma successfully treated with two subconjunctival bevacizumab injections. The patient developed three recurrences after excision at a peripheral hospital after which he was successfully treated with excision and adjuvant subconjunctival bevacizumab 2.5 mg/0.1 ml injection. This case highlights the novel use of bevacizumab for recurrent pyogenic granuloma.

ANTITUMOR ACTIVITY OF ANTI-INTEGRIN PROTEIN SAV-RGD ON XENOGRAFTED HUMAN SKIN MELANOMA WITH INTEGRIN AVG3 EXPRESSION

Anti-integrins are considered as potential anticancer agents capable of inhibiting differentiation and proliferation of various malignant cells, including disseminated melanoma. The possibility of including anti-integrins with different RGD-motives in combined therapy schedules is discussed. We have studied the oridinal recombinant lyophilized protein SAV-RGD (lyo-SAV-RGD), specifically binding to melanoma cells by means of the Tripeptide Arg-Gly-Asp. As models of melanoma of the skin selected amalonaticus MeWo/mel- and pigmented melCher/mel+ with prospectively certain expression of the marker, giving subcutaneous xenograft in mice Balb/c nude. Objective: to evaluate the antitumor activity of lyo-SAV-RGD in vivo on human skin melanoma models melCher and MeWo with different melanogenesis ability and integrin avB3 expression. Both melanomas in vitro were shown to express integrin avB3 detected in melCher/mel+ cells with fluorescent-labeled rat antibodies Luc.H11 according to the expression component integrins avp3, p3-chain (CD61), and MeWo cells/mel- antibodies 23С6. In a high therapeutic total dose of 900 mg/kg, lyo-SAV-RGD inhibited growth of both melanomas in vivo with satisfactory tolerability. Compared to melCher/mel+, MeWo/mel-: T/Cmin=30% (p&lt;0.05) versus T/ Cmin=50% (p=0.001) was more sensitive to treatment. The effect on melCher/mel+ was obtained only in the exponential phase of tumor growth. The results obtained allow us to consider it expedient to conduct an in-depth preclinical study of anti-integrin SAV-RGD, focused on the most aggressive disseminated amelanotic melanoma of the skin, regardless of the nature of blocking receptor expression.

Urogenitalis lokalizációjú mucosamelanoma primer és áttétes esetei klinikánkon

Both primary and metastatic cases of mucosal melanoma in urogenital localization are rare tumors. Only 4-5% of all primary melanomas do not arise from the skin. Extracutaneous melanomas have a complex clinical presentation, but these aggressive tumors have a poor prognosis. In our department, we found 7 patients with malignant melanoma of the genitourinary tract in the past few years. The 7 cases were: primary amelanotic melanoma of the female urethra, a primary melanoma of the bladder, two primary melanomas of the penis, a metastatic melanoma of the urethra and another to the testis and a metastatic melanoma of the bladder with melanuria. We retrospectively analyzed the available data to describe the presentation, management, and clinical outcome of the patients. In the three inoperative cases, palliative, urologic surgical procedures and systemic antitumor therapy were performed. Two of the four primary urogenital tumors were localized to the penis. In one case, local recurrence developed after surgical treatment, but with a radical, repeated surgery, the patient has been asymptomatic for a year and a half. In the other, neglected case, the penis melanoma spread through the urethra and the inguinal lymph nodes two years after radical surgery and inguinal block dissection. In the female primary urethral melanoma case, the first histological study reported a primary mesenchymal tumor, and the recurrent tumor that occurred one and a half years later showed melanoma diagnosis. Radical surgery performed because of urethral involvement resulted in a 5-year asymptomatic state, followed by local recurrence and distant metastasis. In the fourth case of a primary bladder melanoma, the rapid progression of the disease and the BRAF positivity of the tumor suggested that not the firstly diagnosed bladder melanoma was the primary tumor. The occurrence of urinary tract melanoma is very rare and its discovery happens often in a disseminated state, so the expected prognosis of the cases is also poor. The most important factors for increasing therapeutic efficacy are early diagnosis and radical surgical intervention. Tumors appearing in different localizations require different urological surgical approaches. The literature recommendations for treatment are not uniform. Their prognosis is worse compared to the cutaneous melanoma, which may be due to clinical and pathological diagnostic difficulties. The latest targeted and immunotherapeutic agents can significantly improve the survival of metastatic patients. Orv Hetil. 2019; 160(10): 378-385.

The One Step Melanoma Surgery (OSMS): A New Chance for More Adequate Surgical Treatment of Melanoma Patients!?

One step melanoma surgery (OSMS) is applicable to all patients with clear clinical and dermatoscopic criteria for thin cutaneous melanomas or melanoma in situ lesions, even without the need for preoperative tumour thickness measurement. Amelanotic melanomas and melanomas with clinical and dermatoscopical features for regression zones could be problematic when applying the OSMS. The methodology could be also applicable to all groups of patients where the tumour thickness could be measured preoperatively/by ultrasound (while in parallel also determining the status of the locoregional lymph nodes). For tumours with a tumour thickness between 2 and 4 mm, but also over 4mm the OSMS seems to be the correct choice.