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Melanoma is the most common malignant oral tumor in dogs. It frequently presents a diagnostic challenge as many melanomas lack or contain scant melanin and may have a variable microscopic phenotype. Previous studies evaluating immunohistochemical markers for diagnosing melanoma have shown limited sensitivity and/or specificity for S-100, PNL2, melan A, TRP-1, TRP-2, and HMB-45. Sry-related HMG-box gene 10 (SOX-10) is a transcription factor associated with melanocytic, peripheral neural crest, and peripheral nervous system development. In humans, SOX-10 expression has been demonstrated in melanoma, breast carcinoma, glioma, and schwannoma, but has only recently been explored in veterinary species. In this study, 198 tumors comprised of 147 melanocytic neoplasms and 51 non-melanocytic neoplasms were evaluated by immunohistochemistry using a tissue microarray for SOX-10, PNL2, melan A, TRP-1, and TRP-2 expressions. The SOX-10 had the highest diagnostic sensitivity (96.7%) in melanomas. In addition, SOX-10 had the highest percentage (91.5%; 130/142) of melanomas label at least 75% of neoplastic cells. Of the 51 selected non-melanocytic tumors examined, SOX-10 labeling was observed in mammary carcinomas (6/6), gliomas (4/4), and oral soft tissue sarcomas (4/18). Of the 41 non-melanocytic oral neoplasms evaluated, SOX-10 had a specificity of 92.7%. Therefore, SOX-10 represents a useful immunohistochemical screening marker for the diagnosis of canine melanoma given its extremely high sensitivity and robust labeling intensity. The SOX-10 may have utility in diagnosing some non-melanocytic neoplasms in the dog, although this requires further investigation.

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Mucosal melanoma is rare and the occurrence of an invasive malignant melanoma metastasis 11 years post-initial diagnosis is equally uncommon. This is a case of a 66-year-old woman with a history of bilateral vulvar invasive melanoma, who presented with an enlarging inguinal mass with associated tenderness upon palpation. After a right inguinal excisional lymph node biopsy, the pathological findings determined the final diagnosis as metastatic melanoma. To the best of our knowledge, this is the first report of vulvar mucosal melanoma metastasis greater than 10 years after initial diagnosis and treatment in the English language. This case discusses how treatment options for metastatic mucosal melanoma pose a challenge in such cases where follow-up for medical care is lacking. It also highlights the need for further preventative techniques and research directed towards screening techniques, staging guidelines, and treatment options for mucosal melanoma.

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Cutaneous granular cell tumors (GCTs) are rare tumors that typically exhibit benign clinical behavior and are likely of Schwann cell origin. Some histologic and immunohistochemical variants of GCTs may present challenges due to infiltrative growth patterns, perineural invasion, and expression of Melan-A. In this case report, we present a 27-year-old male who had previously been diagnosed with a typical GCT on the back a few years ago. The current biopsy from the proximal palm demonstrated a cytologically similar tumor with extensive perineural spread and notable positivity for Melan-A. Although uncommon, these features are consistent with the histological appearances of GCTs. The current views on the histogenesis of GCTs, clinical associations, differential diagnosis with melanoma, and histological criteria for malignant GCTs are discussed. A panel of immunohistochemical stains, including Inhibin-α and preferentially expressed antigen in melanoma (PRAME), is proposed for use in rare instances of Melan-A-positive GCTs.

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The Melan-A (melanocyte antigen) protein, also termed 'melanoma antigen recognized by T cells 1' (MART-1) is a protein with unknown function whose expression is specific for the melanocyte lineage. Antibodies against Melan-A are thus used for identifying melanocytic tumors, but some Melan-A antibodies show an additional - diagnostically useful - cross-reactivity against an unspecified protein involved in corticosteroid hormone synthesis. To comprehensively compare the staining patterns of a specific and a cross-reactive Melan-A antibody in normal and neoplastic tissues, tissue microarrays containing 15,840 samples from 133 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry. For the Melan-A-specific antibody 'Melan-A specific' (MSVA-900M), Melan-A positivity was seen in 96.0% of 25 benign nevi, 93.0% of 40 primary and 86.7% of 75 metastatic melanomas, 82.4% of 85 renal angiomyolipomas as well as 96.4% of 84 neurofibromas, 2.2% of 46 granular cell tumors, 1.0% of 104 schwannomas, and 1.1% of 87 leiomyosarcomas. The cross-reactive antibody 'Melan-A+' (MSVA-901M+) stained 98.1% of the tumors stained by 'Melan-A specific'. In addition, high positivity rates were seen in sex-cord-stroma tumors of the ovary (35.3%-100%) and the testis (86.7%) as well as for adrenocortical neoplasms (76.3%-83.0%). Only nine further tumor groups showed Melan-A+ staining, including five different categories of urothelial carcinomas. Our data provide a comprehensive overview on the staining patterns of specific and cross-reactive Melan-A antibodies. The data demonstrate that both antibodies are highly useful for their specific purpose. It is important for pathologists to distinguish these two Melan-A antibody subtypes for their daily work.

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Introduction: Lentigo maligna (LM) and lentigo maligna melanoma (LMM) predominantly affect the head and neck areas in elderly patients, presenting as challenging ill-defined pigmented lesions with indistinct borders. Surgical margin determination for complete removal remains intricate due to these characteristics. Morphological examination of surgical margins is the key form of determining successful treatment in LM/LMM and underpin the greater margin control provided through the Slow Mohs micrographic surgery (SMMS) approach. Recent assessments have explored the use of immunohistochemistry (IHC) markers, such as Preferentially Expressed Antigen in Melanoma (PRAME), to aid in LM/LMM and margin evaluation, leveraging the selectivity of PRAME labelling in malignant melanocytic neoplasms. Methods: A Novel double-labelling (DL) method incorporating both PRAME and MelanA IHC was employed to further maximise the clinical applicability of PRAME in the assessment of LM/LMM in SMMS biopsies. The evaluation involved 51 samples, comparing the results of the novel DL with respective single-labelling (SL) IHC slides. Results: The findings demonstrated a significant agreement of 96.1% between the DL method and SL slides across the tested samples. The benchmark PRAME SL exhibited a sensitivity of 91.3% in the SMMS specimens and 67.9% in histologically confirmed positive margins. Discussion: This study highlights the utility of PRAME IHC and by extension PRAME DL as an adjunctive tool in the assessment of melanocytic tumours within staged excision margins in SMMS samples.

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Histologic diagnosis of less well-differentiated cases of canine extramedullary plasmacytomas (CEMPs) may require immunohistochemical confirmation to discriminate these tumors from other round cells tumors including lymphoma, cutaneous histiocytoma, and amelanotic melanomas. CEMPs are characterized by widespread immunoreactivity for multiple myeloma 1 (MUM1) antigen and λ light chains, while the melanocytic marker melan-A has been reported to yield negative results. Here, 33 randomly selected CEMPs, 20 melanocytomas, and 20 malignant melanomas were immunohistochemically tested for MUM1, melan-A, and PNL2. In addition, CEMPs were examined for PAX5, E-cadherin, CD3, CD18, CD20, S100, as well as λ and κ light chain immunoreactivity. All CEMPs were characterized by labeling for MUM1 and λ light chain, as well as variable immunopositivity for the remaining antibodies. Notably, 13 cases of CEMPs (39.4%) exhibited immunolabeling for melan-A. Melanocytic tumors immunolabeled for melan-A (40/40; 100%) and PNL2 (34/40; 85%). An unexpected cytoplasmic immunoreactivity for MUM1 was observed in 2 melanocytic tumors. Summarized, MUM1 or melan-A immunomarkers alone are not sufficient to differentiate between CEMPs and amelanotic melanomas and should be part of a larger immunopanel including λ light chain, CD20, and PNL2.

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BACKGROUND: PEComa is a mesenchymal tumor that can occur in various organs including the uterus and soft tissues. PEComas are composed of perivascular epithelioid cells, and angiomyolipoma (AML), clear cell sugar tumor (CCST), and lymphangiomyomatosis (LAM) are considered lesions of the same lineage as tumors of the PEComa family. Histologically, a common PEComa shows solid or sheet-like proliferation of epithelioid cells. This is accompanied by an increase in the number of dilated blood vessels. Here, we report a case of pancreatic PEComa with marked inflammatory cell infiltration. CASE PRESENTATION: A 74-year-old male patient underwent an appendectomy for acute appendicitis. Postoperative computed tomography and magnetic resonance imaging revealed a 30 × 25 mm non-contrast-enhanced circular lesion in the tail of the pancreas. The imaging findings were consistent with a malignant tumor, and distal pancreatectomy was performed. Histologically, most area of the lesion was infiltrated with inflammatory cells. A few epithelioid cells with large, round nuclei, distinct nucleoli, and eosinophilic granular cytoplasm were observed. Spindle-shaped tumor cells were observed. Delicate and dilated blood vessels were observed around the tumor cells. Immunohistochemically, the atypical cells were positive for αSMA, Melan A, HMB-45, and TFE3. The cytological characteristics of the tumor cells and the results of immunohistochemical staining led to a diagnosis of pancreatic PEComa. CONCLUSIONS: A histological variant known as the inflammatory subtype has been defined for hepatic AML. A small number of tumor cells present with marked inflammatory cell infiltration, accounting for more than half of the lesions, and an inflammatory myofibroblastic tumor-like appearance. To our knowledge, this is the first report of pancreatic PEComa with severe inflammation. PEComa is also a generic term for tumors derived from perivascular epithelioid cells, such as AML, CCST, and LAM. Thus, this case is considered an inflammatory subtype of PEComa. It has a distinctive morphology that is not typical of PEComa. This histological phenotype should be widely recognized.

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A 7-year-old Lhasa Apso presented with a history of left thoracic limb lameness and neck pain. Magnetic resonance imaging revealed a well-defined, extradural lesion that was hyperintense on T1-weighted (T1W) images and isointense on T2-weighted (T2W) images and T2* images located at the left lamina of the C4 vertebra. Computed tomography showed an isoattenuating and contrast-enhancing mass centered on the left C4 vertebral lamina with associated osteolysis. The mass was surgically debulked, and histopathology revealed a malignant melanocytic tumour. The patient recovered completely and received radiotherapy and three doses of the melanoma vaccine as adjunctive treatment. Eighteen months following treatment, the patient presented with neck pain again, but further investigations were declined at this stage, and the patient was euthanised. To the author's knowledge, this is the first case report describing the imaging characteristics of a cervical extradural melanocytic tumour in a dog. This case illustrates the MRI and CT imaging features and treatment of a canine melanocytic tumour of the cervical vertebrae.

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Granular cell tumors (GCTs) are rare, indolent neoplasms classically characterized by eosinophilic granular cytoplasm, infiltrations of polygonal cells in the collagenous stroma, and pustulo-ovoid bodies of Milian. We describe a case of a 10-year-old female presenting with a GCT of the upper arm, remarkable for positive Melan-A expression without additional melanocytic features. The differentiation between granular cells versus melanocytic neoplasms carries significant implications for clinical management, and such diagnoses should be considered carefully in the setting of unusual immunophenotypes.

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Desmoplastic melanoma (DM), a type of spindle cell melanoma separated into pure desmoplastic melanoma (PDM) and mixed desmoplastic melanoma (MDM) subtypes, can be a diagnostic challenge and easily confused for dermal scar, especially PDM. We report a 65-year-old white man who received a left thumb amputation after an initial biopsy for melanoma, an unclassified type with epithelioid morphology. The amputation and sentinel lymph node specimens were significant for residual melanoma with epithelioid morphology, dermal scar, and a slightly expanded "scar-like" capsular area in one of seven lymph nodes, which was diffusely positive for SOX10 on reflex sentinel lymph node immunohistochemical protocol. On re-review of the amputation "scar" like area, a subsequent SOX10 stain confirmed the diagnosis of MDM in this area with epithelioid and spindle cell morphology, significantly upgrading the tumor stage. We share this case to highlight: (i) MDM, although exceptionally uncommon, can result in a pure spindle cell lymph node metastasis, (ii) to encourage increased utilization of SOX10 to assess sentinel lymph node biopsies, especially in the context of melanomas with a spindle cell component, and (iii) share an example of inattentional blindness which was fortunately identified by reflex sentinel lymph node immunohistochemical protocols.

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Morphological overlap exists between cutaneous granular cell tumours (GCT) and malignant melanoma, with the melanocyte-specific markers HMB45 and Melan-A commonly used to support the diagnosis of melanoma. We recently encountered several cases of GCT in our practice showing strong expression of Melan-A. The aim of this study was to establish the prevalence of positive immunohistochemical staining for Melan-A and HMB45 in a series of unequivocal GCTs. We also aimed to assess the prevalence of staining for PRAME (PReferentially expressed Antigen in MElanoma), a marker expressed in >80% of primary melanomas as well as many non-melanocytic tumours. A total of 20 cutaneous/subcutaneous GCTs were evaluated using Melan-A, HMB45 and PRAME immunohistochemistry. Staining for Melan-A and HMB45 was scored using a semiquantitative scale from 0 (absent) to 3+ (staining present in >50% of tumour cells). PRAME expression was recorded as either positive (>75% of cell nuclei staining) or negative. Melan-A expression was observed in four GCTs (20%), with strong and diffuse (3+) staining seen in two cases (10%), both from anogenital areas. Weak patchy nuclear PRAME expression was seen in every case, interpreted to be negative. HMB45 was also negative in all cases (100%). Our study demonstrates that Melan-A expression can be strong and diffuse in a subset of otherwise unequivocal cutaneous GCTs, which may cause diagnostic confusion with malignant melanoma. HMB45 and PRAME did not stain any of the GCTs in our series.

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Melanomas are tumors arising from externally uncontrolled melanocytes that produce varying amounts of melanin. In this study, we report a case of melanoma with neurological impairment without evidence of cutaneous neoplastic lesions in an adult buffalo in the state of Pará, Brazil. Clinically, the buffalo exhibited apathy, decreased mandibular tone, and occasionally an open mouth with motor incoordination, and eventually succumbed to the condition. Necropsy revealed multifocal tumor masses in the brain, pituitary gland, trigeminal ganglion, and spinal cord. The neoplastic cells showed strong positive signals for vimentin, Melan-A, PNL-2, and SOX10. The diagnosis was made via necropsy, histopathology, and positive immunostaining for Melan-A and PNL-2, which are specific markers for melanocyte identification.

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The visual appearance of humans is derived significantly from our skin and hair color. While melanin from epidermal melanocytes protects our skin from the damaging effects of ultraviolet radiation, the biological value of pigmentation in the hair follicle, particularly on the scalp, is less clear. In this study, we explore the heterogeneity of pigment cells in the human scalp anagen hair follicle bulb, a site conventionally viewed to be focused solely on pigment production for transfer to the hair shaft. Using c-KIT/CD117 microbeads, we isolated bulbar c-KIT-positive and c-KIT-negative melanocytes. While both subpopulations expressed MITF, only the c-KIT-positive fraction expressed SOX10. We further localized bulbar melanocyte subpopulations (expressing c-KIT, SOX10, MITF, and DCT) that exhibited distinct/variable expression of downstream differentiation-associated melanosome markers (e.g., gp100 and Melan-A). The localization of a second 'immature' SOX10 negative melanocyte population, which was c-KIT/MITF double-positive, was identified outside of the melanogenic zone in the most peripheral/proximal matrix. This study describes an approach to purifying human scalp anagen hair bulb melanocytes, allowing us to identify unexpected levels of melanocyte heterogeneity. The function of the more immature melanocytes in this part of the hair follicle remains to be elucidated. Could they be in-transit migratory cells ultimately destined to synthesize melanin, or could they contribute to the hair follicle in non-melanogenic ways?

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Melanocytic skin tumours have been rarely described in pet rabbits, and exposure to UV light in sparsely haired areas has been hypothesised to play a cancerogenic role. Here, we describe a case of cutaneous malignant melanoma arising from the skin of the scrotum in an 8-year-old male wild rabbit, with testicular metastases as an unusual metastatic site for melanoma reported in humans to date. The tumour was nearly 5 cm in size, firm, and highly pigmented, with multifocal superficial ulcerations and large areas of intratumoural necrosis. The adjacent testis was 1.5 cm, multinodular, and black, obscuring tissue morphology. Histologically, the dermis was expanded by an infiltrative, densely cellular neoplasm composed of nests and sheets of polygonal to spindle neoplastic melanocytes, supported by scant fibrovascular stroma. Neoplastic cells showed intermediate N/C ratio, moderate basophilic cytoplasm, often obscured by abundant brownish granular pigment, and eccentric nuclei with prominent nucleoli. Cellular pleomorphism and nuclear atypia were severe, and high mitotic activity was observed. Diffuse dermal lymphovascular invasion was also observed. The testis was delimited by a thin tunica albuginea, and the parenchyma was largely obscured in its morphology by densely packed neoplastic cells. Seminiferous tubules, lined with a thin basement membrane and containing neoplastic and scattered spermatogenic cells, were occasionally observed. Neoplastic cells within the skin and the testis were positive for HMB-45, Melan-A, and S-100. The growing popularity of rabbits as pets allows for a greater ability to accumulate data on the spontaneous occurrence of tumours in these animals. Furthermore, descriptions of the biological aspects of spontaneously occurring tumours may serve to improve current knowledge in animal species and humans in which the same neoplasm may occur.

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Perivascular epithelioid cell tumors (PEComas), rare mesenchymal tumors with myomelanocytic differentiation, can be a diagnostic challenge, often requiring a panel of immunohistochemical markers. Preferentially expressed antigen in melanoma (PRAME) is a relatively new antigen with utility in diagnosing melanomas. This study aimed to survey PRAME expression patterns in the PEComa family of tumors and morphologic mimics. Twenty cases of PEComas and 27 non-PEComas (10 leiomyosarcomas, 3 smooth muscle tumors of uncertain malignant potential [STUMPs], 11 leiomyomas, 1 uterine inflammatory myofibroblastic tumor [IMT], and 2 low-grade endometrial stromal sarcomas [LGESSs]) were stained with PRAME and compared to previously performed HMB45 and Melan-A stains, when available. Tumors showing no or barely perceptible PRAME staining at 10× were considered negative. Tumors were considered positive if there was full nuclear staining evident at 10× in at least one 10× field. Diffuse staining was defined as positivity in at least 80% of tumor nuclei. Overall, PRAME was expressed in 70% of PEComas, with diffuse positivity in 60%. However, PRAME was not specific for PEComas, with immunopositivity in the majority (70%) of uterine leiomyosarcoma cases, though negative in STUMP, leiomyoma, IMT, and LGESS cases. PRAME sensitivity was 70% and specificity was 74%, while HMB45 was more sensitive (90%) and specific (100%), but only 15% of PEComas showed diffuse staining. Melan-A staining was less common than HMB45 or PRAME, with only 18.8% sensitivity but 100% specificity. Among gynecologic PEComas, PRAME was expressed in 75% overall and enriched among malignant cases (85.7% positive). As part of an immunohistochemical panel, PRAME could be useful in the workup of PEComa cases. In the future, PRAME-specific immunotherapies may be beneficial in treating patients with malignant PEComas.

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[This corrects the article DOI: 10.3389/fimmu.2022.973986.].

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BACKGROUND: Melanoblasts originate in the neural crest from where they migrate to peripheral tissues and differentiate into melanocytes. Alteration during melanocyte development and life can cause different diseases, ranging from pigmentary disorders and decreased visual and auditory functions, to tumours such as melanoma. Location and phenotypical features of melanocytes have been characterised in different species, yet data on dogs are lacking. OBJECTIVE: This study investigates the expression of melanocytic markers Melan A, PNL2, TRP1, TRP2, SOX-10 and MITF in melanocytes of selected cutaneous and mucosal surfaces of dogs. ANIMALS: At necropsy, samples from five dogs were harvested from oral mucosa, mucocutaneous junction, eyelid, nose and haired skin (abdomen, back, pinna, head). MATERIALS AND METHODS: Immunohistochemical and immunofluorescence analyses were performed to assess marker expression. RESULTS: Results showed variable expression of melanocytic markers in different anatomical sites, particularly within epidermis of haired skin and dermal melanocytes. Melan A and SOX-10 were the most specific and sensitive melanocytic markers. PNL2 was less sensitive, while TRP1 and TRP2 were seldomly expressed by intraepidermal melanocytes in haired skin. MITF had a good sensitivity, yet the expression often was weak. CONCLUSIONS AND CLINICAL RELEVANCE: Our results indicate a variable expression of melanocytic markers in different sites, suggesting the presence of subpopulations of melanocytes. These preliminary results pave the way to understanding the pathogenetic mechanisms involved in degenerative melanocytic disorders and melanoma. Furthermore, the possible different expression of melanocyte markers in different anatomical sites could influence their sensitivity and specificity when used for diagnostic purposes.

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BACKGROUND: Benign lichenoid keratosis (BLK) is a cutaneous lesion that can clinically mimic malignancy and may represent regression of a pre-existing lesion. BLK may show epidermal pseudo-nests prompting evaluation for a melanocytic lesion. False positivity of MART-1/Melan-A immunostaining in pseudonests has been showed; however, the value of SRY-related HMG-box 10 (SOX10) staining in BLK with features suspicious for a melanocytic proliferation has not been previously reported. METHODS: Twenty-one cases of BLK from 2015 to 2020 were identified. Slides were reviewed and SOX10 immunohistochemistry was performed on each case. Subsequently, Melan-A immunohistochemical staining was performed on all cases. RESULTS: In 10 cases (47.6%), unexpected SOX10 staining was seen in rare to numerous small, single cells in the epidermis above the basal cell layer. No malignancy was identified. Of the 10 cases, 8 (80%) showed suprabasal SOX10 staining did not show similar suprabasal Melan-A staining; 2 (20%) cases showed scattered suprabasal cells positive for Melan-A. CONCLUSION: SOX10 immunostaining in BLK can highlight scattered cells in the epidermis (not easily noticeable on routine stain). Performing SOX10 immunostain alone on BLK can prompt a misdiagnosis of a melanocytic lesion and should be done with caution.

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