Phyu Phyu Aung

Background: Distinguishing melanoma cells from nevus cells remains a diagnostic challenge, particularly in cases where melanoma exhibits nevoid morphology or nevus cells display atypical or epithelioid features. Accurate identification is essential for proper measurement of Breslow depth in melanomas arising in association with nevi and for margin assessment, both of which are critical for patient prognosis. The dual multiplex immunohistochemical stain utilizing Melan‐A (red chromogen) and Ki67 (brown chromogen) is a valuable tool for assessing the proliferative index of melanocytic populations, with melanoma cells typically showing a higher Ki67 index than nevus cells. Methods: We identified 10 cases with invasive melanoma and associated nevus present on the same scanned histologic section for which the signing pathologist had ordered this dual multiplex immunohistochemical study. We annotated areas of melanoma versus nevus, then quantified the staining intensities. Results: Melanoma cells often demonstrate more intense Melan‐A red chromogen labeling than adjacent nevus cells ( p = 0.008; Wilcoxon signed rank test). Conclusion: This differential labeling provides a helpful visual distinction between melanoma and nevus cells within the same histologic section, enhancing diagnostic confidence beyond the difference in Ki67 proliferation index.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin malignancy characterized by high mortality and a rising incidence. Although immune checkpoint inhibitors have significantly improved patient outcomes, many patients exhibit primary or acquired resistance, frequently in the setting of an immunosuppressive tumor microenvironment (TME) enriched for myeloid populations. This review synthesizes current evidence and proposes a testable model in which nicotinic acetylcholine receptor (nAChR) signaling may intersect with tumor-associated macrophage (TAM) biology to reinforce immune exclusion in MCC. Direct MCC-specific evidence currently supports nAChR-subunit expression in tumor tissues and the association of CD163⁺/CD14⁺/S100A8⁺ myeloid populations with resistance to PD-1 pathway blockade; however, functional nAChR signaling in MCC tumor cells, TAMs, or dendritic cells has not yet been demonstrated. We therefore distinguish established MCC observations from mechanistic hypotheses extrapolated from macrophage biology, cholinergic anti-inflammatory signaling, and other cancer models. Within this framework, α7-nAChR signaling on TAMs may activate the cholinergic anti-inflammatory pathway and favor suppressive myeloid states, whereas α3- and α5-containing receptors detected in MCC tumor cells may represent tumor-cell-associated candidates for future mechanistic testing. By integrating evidence on TAM plasticity, spatial immune exclusion, and cholinergic signaling, we propose that the nAChR–macrophage axis is a rational but unproven therapeutic hypothesis that warrants systematic validation in MCC models.

Angiomatoid fibrous histiocytoma is a rare mesenchymal neoplasm of uncertain cell lineage with indeterminate behavior, hallmarked by EWSR1 translocations. This tumor typically arises in the subcutaneous or deep soft tissues and is composed of bland to mildly atypical histiocytoid cells with frequent intralesional hemorrhagic pseudocystic spaces. It affects both children and adults, without a significant sex predilection. Histologically, the tumor may be mistaken for a lymph node given the apparent predilection for node-bearing sites as well as the brisk lymphoid cuff featuring germinal centers. Surgical excision is often curative, with local recurrence occurring occasionally and metastasis only very rarely. A possible relationship to molecularly related entities arising primarily within the thoracic cavity and intracranial compartment has been proposed, although this association remains incompletely understood.

Cutaneous metastases are an uncommon but clinically significant manifestation of internal malignancy, occurring in approximately 0.7–10.4% of patients with cancer. In some cases, they represent the first clinical manifestation of an otherwise occult malignancy, making accurate diagnosis critical for timely patient management. Distinguishing cutaneous metastases from primary cutaneous neoplasms, particularly malignant adnexal tumors, remains one of the most challenging problems in dermatopathology because of their substantial clinical, histopathologic, and immunophenotypic overlap. This review summarizes the epidemiology and biology of cutaneous metastasis and the clinical presentation of cutaneous metastases and emphasizes the central role of clinicopathologic correlation in diagnosis. Histologic features such as a purely dermal or subcutaneous location, intravascular tumor emboli, and a “bottom-heavy” growth pattern favor metastasis, whereas the presence of an in situ component or transition from a benign precursor lesion strongly supports a primary cutaneous neoplasm. We review the diagnostic utility of optimized immunohistochemical panels, highlighting the complementary roles of p63, cytokeratin 15, calretinin, and D2-40 (podoplanin) in establishing primary adnexal lineage, together with emerging markers including SOX10, androgen receptor, TRPS1, adipophilin, INSM1, SATB2, and BerEP4 for diagnostically challenging cases. We also discuss recent advances in molecular biology and comprehensive genomic profiling, including recurrent gene fusions (e.g., MYB::NFIB, CRTC1::MAML2, and YAP1 fusions) and characteristic mutational signatures that provide increasingly robust diagnostic evidence of tumor lineage. Finally, we provide a comprehensive, practical diagnostic algorithm for differentiating primary cutaneous adnexal carcinomas from cutaneous metastases of adenocarcinomas. By integrating traditional histopathologic techniques with modern immunohistochemical and molecular techniques, pathologists and clinicians can successfully navigate this complex differential diagnosis and thereby facilitate appropriate patient management and therapeutic intervention.

There are currently no effective targeted therapies for BRAF-mutant metastatic melanoma patients with acquired resistance to approved BRAF and MEK inhibitors (BRAFi and MEKi), and very few ongoing clinical trials. Anti-apoptotic BCL2 family proteins promote de novo resistance to several therapies, including single-agent BRAFi in BRAF-mutant melanomas. In this study, in vivo testing of a large collection of patient-derived xenograft (PDX) models from melanoma patients with acquired resistance to BRAFi or BRAFi+MEKi shows that combining BCL2 inhibitors (BCL2i; navitoclax or venetoclax) with BRAFi+MEKi induces tumor regressions in a subset of these PDXs. High basal BCL2 predicts response whereas high basal MCL1 predicts resistance to this strategy. MCL1 overexpression studies functionally validate its role in resistance. Further, combining BRAFi+MEKi with an MCL1 inhibitor (MCL1i) counteracts resistance and interestingly decreases MCL1i-associated markers of cardiotoxicity. Together these studies identify potential personalized strategies to improve outcomes in this challenging patient population.

Cutaneous metastases represent a relatively rare but clinically significant manifestation of advanced internal malignant neoplasms, occurring in approximately 0.7% to 10.4% of all cancer patients. Because cutaneous metastases can occasionally serve as the first indication of an occult internal malignant neoplasm, their accurate and timely diagnosis is of paramount importance. However, distinguishing cutaneous metastases from primary cutaneous neoplasms, particularly malignant cutaneous adnexal tumors, poses a diagnostic challenge in dermatopathology due to significant clinical and histomorphologic overlap. Here, we review the current literature on the epidemiology and clinical presentation of cutaneous metastases, emphasizing the importance of clinicopathologic correlation. While histologic features such as a purely dermal/subcutaneous location, intravascular tumor emboli, and a "bottom-heavy" architecture suggest metastasis, the presence of an in situ component or morphologic transition from a benign precursor lesion strongly supports a primary cutaneous origin. Furthermore, we detail the utility of optimized immunohistochemical panels, highlighting the diagnostic value of markers such as p63, cytokeratin 15, calretinin, and D2-40 (podoplanin) in confirming primary adnexal lineage. We also explore recent advances in molecular biology and comprehensive genomic profiling, discussing how the identification of specific gene fusions (e.g., MYB::NFIB, CRTC1::MAML2, YAP1 fusions) and mutational signatures can resolve ambiguous cases and provide critical insights into lineage. Finally, we provide a comprehensive, practical diagnostic algorithm for differentiating primary cutaneous adnexal carcinomas from cutaneous metastases of adenocarcinomas. By integrating traditional histopathologic techniques with modern immunohistochemical and molecular techniques, pathologists and clinicians can successfully navigate this complex differential diagnosis and thereby facilitate appropriate patient management and therapeutic intervention.

Crystal‐storing histiocytosis (CSH) is a rare histopathologic phenomenon characterized by the accumulation of crystalline material within histiocytes, most often associated with lymphoplasmacytic or plasma cell neoplasms. Cutaneous involvement is uncommon and may present diagnostic challenges. We report a 63‐year‐old woman with indurated plaques involving the face, chest, and upper extremities. Skin biopsies revealed aggregates of epithelioid histiocytes containing intracytoplasmic crystalline material, admixed with a lymphoplasmacytic infiltrate. The histiocytic cells were positive for CD68 and CD163. Plasma cells showed IgG kappa light chain restriction, and molecular studies demonstrated a monoclonal immunoglobulin heavy chain gene rearrangement. Serum studies identified an IgG kappa monoclonal gammopathy, supporting a diagnosis of cutaneous involvement by a B‐cell lymphoma with plasmacytic differentiation associated with localized CSH. Weak, nonspecific immunoreactivity with the BRAF V600E antibody was observed; however, next‐generation sequencing did not identify a BRAF V600E mutation, supporting interpretation as antibody cross‐reactivity. A subset of histiocytes showed weak BCL6 expression of uncertain significance. This case highlights the importance of recognizing cutaneous CSH, emphasizes evaluation for an underlying lymphoproliferative disorder, and illustrates immunohistochemical pitfalls that may complicate interpretation.

Background: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy with neuroendocrine differentiation. Several molecular pathways have been implicated in MCC development and multiple cell‐of‐origin candidates have been proposed, including neural crest cells, which express acetylcholine receptors (AChRs). The role of nicotinic acetylcholine receptors (nAChRs) in MCC has not been explored. In this study, we investigated if MCC expresses nAChRs and if nAChR expression correlates with patient characteristics.Methods: The study included 71 MCC cases diagnosed with sufficient tissue available to perform immunohistochemical analysis. The median follow‐up was 29.8 months (range, 2.7–234.1). We performed immunohistochemistry using antibodies against the α3, α5, and α7nAChR subunits.Results: Our results show that the majority of MCC cases expressed α3, α5, and α7‐nAChR subunits. Of the 71 cases, 59 (83%) expressed α3‐nAChR, 71 (100%) expressed α5‐nAChR, and 63 (88%) expressed α7‐nAChR. Location of immunoreactivity differed between cases and included cytoplasmic only and nuclear/peri‐nuclear, with variation in the intensity of staining. There were significant correlations between the intensity or location of immunoreactivity and clinical and histopathologic parameters.Conclusions: These findings seem to support that MCC displays the features of neural crest cells, and suggest the potential for nAChR‐targeted therapy.