We report the first autopsy-proven case of colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy harboring the CSF1R mutation c.2320T>C (p.Cys774Arg). The patient, a man in his 40s, exhibited progressive neuropsychiatric symptoms with predominant frontal white matter lesions and corpus callosum atrophy. Neuropathological examination revealed frontal-predominant demyelination with a relatively low number of axonal spheroids compared with typical cases, as well as the absence of intracranial calcifications. In addition, prominent cerebral amyloid angiopathy was observed despite an APOE ε3/ε3 genotype. These findings expand the clinicopathological spectrum of CSF1R-related leukoencephalopathy and highlight variability in pathological features associated with different CSF1R mutations.

Pigmented oral lichen planus (OLP) is a chronic, immune-mediated mucosal disorder associated with dark black or brown discoloration secondary to the excess melanin deposition. This medical condition is often accompanied by the typical white (reticular) or red (erosive) OLP features and is refractory to conventional therapy. We report a case of OLP which was successfully managed with oral mycophenolate mofetil (MMF), resulting in significant symptomatic relief and reduction of hyperpigmentation. MMF offers a safe and effective systemic option for persistent pigmented OLP.

Oral malignant melanoma (OMM) is a rare but highly aggressive malignancy that develops in the mucosal lining of the oral cavity. Of all primary melanoma cases, those arising from the oral cavity are extremely uncommon, and among these, involvement of the mandible as the primary site is even rarer. A 42-year-old woman presented with a bluish pigmented lesion over the left mandibular gingiva, associated with mild pain and intermittent bleeding from the lesion. Clinical examination revealed a melanocytic lesion involving the gingiva. Imaging studies, including contrast-enhanced computed tomography (CECT) and positron emission tomography (PET), revealed a metabolically active lesion with bone involvement. A biopsy confirmed the diagnosis of oral malignant melanoma. The patient underwent wide local excision with segmental mandibulectomy and elective neck dissection with pectoralis major myocutaneous flap reconstruction and adjuvant radiotherapy. The postoperative period was satisfactory. The patient remains disease-free at 18-month follow-up, with no signs of recurrence. OMM, though rare, requires high clinical suspicion due to its resemblance to other benign lesions. Early detection and aggressive surgical resection remain the key to a favorable outcome. Due to its rarity, it is not uncommon to mistake this oral melanotic lesion for other benign oral lesions such as dental amalgam, drug-induced pigmentation, Peutz-Jeghers syndrome, and even Addison's disease. The prognosis remains poor due to its aggressive nature and tendency for early metastasis. This case emphasizes the importance of timely diagnosis and multidisciplinary treatment for this rare malignancy.

In recent years, dermatoscopy has emerged as a valuable adjunctive tool for the diagnosis of various cutaneous disorders. Initially developed for the evaluation of melanocytic lesions, this non-invasive technique has since demonstrated significant utility in the assessment of non-melanocytic hyperpigmented dermatoses. This review provides an up-to-date and practical overview of the dermatoscopic manifestations of common non-melanocytic hyperpigmented conditions, including melasma, nevus of Ota, freckles, lentigines, solar lentigines, seborrheic keratosis, porokeratosis, acquired dermal macular hyperpigmentation, lichen planus-like keratosis, pigmented actinic keratosis, pigmented Bowen's disease, basal cell carcinoma, and acanthosis nigricans. Many of these hyperpigmented disorders exhibit distinct and characteristic dermatoscopic features. Given the clinical diagnostic challenges posed by these conditions and their significant psychological impact on patients, dermatoscopy offers a complementary approach to enhance the accuracy of evaluation and differential diagnosis.

Objective: To investigate the diagnostic value of PRAME immunohistochemistry in the differential diagnosis between clear cell sarcoma (CCS) of soft tissue and melanoma, and its utility in routine diagnostic practice. Methods: A retrospective analysis was conducted on 25 CCS and 25 site-matched melanoma cases diagnosed at the Fudan University Shanghai Cancer Center from 2021 to 2025. Clinicopathologic data were collected, histologic features were assessed, and PRAME immunohistochemistry was performed. Clinicopathologic differences between the two groups were compared. The sensitivity and specificity of PRAME for differential diagnosis were evaluated. Results: Twenty-five patients with CCS were included, aged 38.0 (31.5, 56.0) years old. Another 25 patients with melanoma were included, aged 61.0 (54.0, 72.0) years old. In each group, 11 male and 14 female patients were included. Tumors were predominantly located in the extremities and trunks in both groups. In primary or recurrent melanomas, epidermal involvement with pagetoid proliferation at the dermoepidermal junction was frequently observed, whereas epidermal involvement was usually absent in CCS. Epithelioid morphology with prominent tumor-infiltrating lymphocytes and scant fibrous collagen septa were more often observed in metastatic melanomas, whereas a mixed epithelioid-spindle pattern, paucity of tumor-infiltrating lymphocytes, and frequent fibrous collagen septa were more commonly observed in CCS. PRAME negativity was observed in 96.0% (24/25) of the CCS cases, with only one case showing 5% nuclear positivity. By contrast, PRAME positivity was observed in 88.0% (22/25) of the melanoma cases, including diffuse nuclear positivity in>50% of tumor cells in 80.0% (20/25) of cases (P<0.001). With the cut-off of >50% positive cells, the sensitivity and specificity of PRAME for the diagnosis of melanoma were 80.0% and 100.0%, respectively. BRAF V600E immunohistochemistry was positive only in melanoma (56.0%, 14/25). All CCS cases were molecularly confirmed to harbor EWSR1 rearrangement.No co-occurrence of EWSR1 rearrangement and BRAF V600E immunohistochemistry positivity was observed in this cohort. Conclusions: Diffuse PRAME nuclear positivity is highly specific for diagnosing melanoma. It is particularly useful in biopsy specimens from recurrent lesions, needle biopsy specimens from metastatic lesions with inconspicuous pigmentation, biopsies of small primary lesions, and ulcerated specimens lacking an epidermal component. Therefore, PRAME immunohistochemistry is especially practical for community-hospital laboratories and interpreting biopsy specimens with limited tissue.

Endocrine signaling relies heavily on the second messenger cAMP to influence different functional outcomes including hormone secretion, steroidogenesis, ion channel regulation, and cell growth. Selectivity of cAMP action is often achieved through compartmentalized activation of protein kinase A (PKA). Local PKA action is organized by A-kinase anchoring proteins. These organellar enzyme scaffolds not only define where and when PKA phosphorylation occurs but also influence which substrates are accessible. A substantial literature suggests that endocrine disease can arise from lesions that promote dysfunctional PKA signaling. Recent studies suggests that common PKA mutations disrupt localization, causing the mutant catalytic subunits to escape A-kinase anchoring protein complexes. Such pathological events are evident in endocrine disorders such as Carney complex, sporadic primary pigmented nodular adrenocortical disease, and adrenal Cushing syndrome where somatic mutations in PKA subunits uncouple normal spatial control of the kinase. We postulate that future therapies should aim to restore the fidelity of local PKA signaling. SIGNIFICANCE STATEMENT: Compartmentalized cAMP signaling, organized by A-kinase anchoring protein scaffolds, is essential for ensuring precise spatial and functional control of endocrine processes. Disruption of this localization by disease-associated protein kinase A mutations uncouples signaling fidelity and drives endocrine pathologies, highlighting restoration of localized protein kinase A activity as a promising therapeutic strategy.

Primary extramammary Paget disease (PEMPD) is a rare adenocarcinoma, and is histopathologically characterised by intraepithelial proliferation of carcinoma cells with abundant amphophilic cytoplasm. Minor histopathological findings in PEMPD, including syringomatous structures and syringocystadenocarcinoma papilliferum (SCACP) in situ-like changes, have rarely been reported. The present study aimed to analyse histopathological changes in PEMPD. Consecutive patients with PEMPD who underwent surgical resection were included. Melanin within carcinoma cell cytoplasm, syringomatous structures and SCACP in situ-like changes were assessed on haematoxylin and eosin-stained slides. Overall, 55 patients (16 female and 39 male patients) were included; 23 patients (41.8%) had an invasive carcinoma component and the remainder had only in situ lesions. Melanin pigment within carcinoma cell cytoplasm was observed in 85.5% of patients, while 17.4% of patients with invasive PEMPD exhibited melanin pigment in invasive carcinoma cells. Syringomatous structures, characterised by ductal, tadpole-like or small cystic structures composed of bland epithelial cells, were observed in 9.1% of patients (31.3% of all female patients), including in areas outside the PEMPD lesions. SCACP in situ-like changes, characterised by papillary epidermal hyperplasia with replacement of carcinoma cells, were also observed in 9.1% of PEMPD cases. These findings demonstrated that a high frequency of the presence of melanin pigment within carcinoma cell cytoplasm, including in invasive carcinoma cells, could lead to misdiagnosis as malignant melanoma. Additionally, syringomatous structures (especially in female patients) and SCACP in situ-like changes may lead to the misdiagnosis of syringoma and SCACP in situ, respectively. Therefore, recognition of these histopathological changes in PEMPD is required for accurate diagnosis.