Disseminated and penile mpox with histopathologic correlation: Two separate case reports.

The 2022-2023 mpox outbreak is a global worldwide concern, especially since the virus was previously mainly localized regionally in Central and West Africa. The infection is typically self-limiting and transmitted by close contact/exposure with infected material. Recent cases have been known to present atypically without prodromal symptoms and initially with skin lesions. The histopathology of mpox lesions is rarely reported. Here, we present two middle-aged males presenting initially with painless skin lesions confirmed for mpox by nucleic acid amplification assay. Skin biopsies of the lesion were available for clinicopathologic correlation. Histopathology demonstrated ulceration with viral cytopathologic changes.

Absence of Differential Cyclin D1 Immunohistochemical Protein Expression in Nevi and Melanoma Evaluated by Digital Image Analysis.

BACKGROUND: Distinction of superficial spreading melanoma (SSM) from compound nevi (CN) sometimes poses difficult diagnostic challenges. Herein, we studied cyclin D1 protein expression by immunohistochemistry in SSM and CN and evaluated the results by digital image analysis. DESIGN: A total of 13 CN and 12 SSM cases were retrospectively reviewed and cyclin D1 immunohistochemistry was performed. Immunohistochemical stained slides were evaluated by digital imaging analysis that included quantification and staining intensity of the cyclin D1 expressing dermal cells. RESULTS: Cyclin D1 expression was observed in all CN and SSM. CN-positive staining was present in 30% to 93% of the dermal nevocytes, more positive in the upper (mean 85%), than lower half (mean 57%). SSM-positive staining was present in 44% to 96% of the dermal lesion, more positive in the upper (mean 88%) than lower half (mean 49%). When analyzed based on 3+ strong staining intensity, similar regional differences in cyclin D1 expression were observed. CONCLUSIONS: Digital image analysis of Cyclin D1 expression showed no differences between CN and SSM. Quantity and regional distribution of cyclin D1 positivity were found to be similar in both lesions. Our findings argue against the routine use of cyclin D1 immunohistochemistry as a diagnostic tool for differentiating CN from SSM.

PRAME immunohistochemistry of spitzoid neoplasms.

BACKGROUND: Spitzoid melanocytic neoplasms are well known to be diagnostically challenging. Immunohistochemistry (IHC) and molecular approaches have been used as ancillary diagnostic tests. Herein, we investigate the use of PRAME IHC for the assessment of spitzoid melanocytic neoplasms. METHODS: Ten Spitz nevi, 14 atypical Spitz tumors, and 11 spitzoid melanomas were retrieved, and PRAME IHC was scored on a scale of 1-4 (in % quartiles). Intensity of staining was categorized as weak or strong. Cases with no staining received a score of 0. Positive lymph nodes from three spitzoid melanomas were also analyzed. RESULTS: Spitz nevi, atypical Spitz tumors, and spitzoid melanomas had mean PRAME IHC scores of 1.20, 0.93, and 3.36, respectively. The percentage of cases with a score 3 or higher for each category of spitzoid neoplasms are as follows: Spitz nevus (20%), atypical Spitz tumor (0%), and spitzoid melanoma (82%). Among the spitzoid melanomas, three cases had positive sentinel lymph nodes, which showed PRAME score of 2, 4, and 4 in the metastatic deposits. CONCLUSIONS: Previous reports revealed PRAME IHC as useful tool to distinguish benign from malignant melanocytic lesions. The results presented here are concordant with the prior studies, but expand the application of this marker to Spitz nevi/tumors and spitzoid melanomas. The present findings suggest the potential diagnostic utility of PRAME IHC in the assessment of spitzoid melanocytic lesions, particularly in distinguishing spitzoid melanomas from Spitz nevi and atypical Spitz tumors.

Multiple myxoid cellular neurothekeomas in a patient with systemic lupus erythematosus.

Cellular neurothekeoma is a cutaneous tumor with a distinctive histopathologic appearance characterized by a dermal-based multinodular proliferation of epithelioid to spindled cells. Although the tumor may show varying amounts of myxoid stroma, extensive myxoid change is uncommon. The tumor typically presents as a solitary nodule with a predilection for the head and neck and upper limbs; examples of multiple cellular neurothekeomas are decidedly rare. The present report describes a unique case of multiple myxoid cellular neurothekeomas arising in a 60-year-old female with systemic lupus erythematosus. Two papular lesions were identified involving the skin inferior to the umbilicus and the left inguinal crease. Both lesions were histopathologically similar, forming a nodular mass composed of epithelioid cells in a prominent myxoid stroma. By immunohistochemistry the lesional cells expressed NKI/C3, microphthalmia transcription factor (MiTF), and CD68, with focal staining for PGP9.5, factor XIIIa, and CD10 also observed. The tumors were negative for S-100, SOX-10, epithelial membrane antigen, desmin, smooth muscle actin, glial fibrillary acid protein, and CD34. The present case confirms that cellular neurothekeoma can present clinically as multiple lesions and can have a predominantly myxoid appearance, potentially mimicking other cutaneous myxoid lesions.

Ossifying Plexiform Tumor: A Case Report.

ABSTRACT: Ossifying plexiform tumor is an exceedingly rare cutaneous neoplasm with distinctive histologic features. The typical microscopic appearance is that of a well-circumscribed dermal lesion composed of spindled and epithelioid cells in a myxoid appearing matrix with a plexiform architecture associated with areas of ossification. The present report details the clinicopathologic features of an ossifying plexiform tumor involving the lower extremity of a 69-year-old man. The cutaneous lesion exhibited characteristic morphologic features of this entity. By immunohistochemistry, the tumor was negative for most markers assessed, but notably exhibited diffuse positivity for SATB2. No lesional recurrence was observed. The present case serves to expand on the limited existing knowledge regarding the clinicopathologic features of this uncommon tumor. The histogenesis of ossifying plexiform tumor remains unclear; however, the demonstration of SATB2 expression in this case suggests osteoblastic differentiation.

Sporadic Neurofibroma of the Tongue Unassociated with Neurofibromatosis Type I: A Clinicopathologic Study of Ten Cases.

Neurofibromas rarely occur within the oral cavity and infrequently involve the tongue. The majority of lingual neurofibromas arise in patients affected by neurofibromatosis type 1 (NF1). Neurofibromas of the tongue unassociated with this disorder are exceedingly uncommon. The clinical and pathologic features of 10 cases of sporadic lingual neurofibromas, unassociated with NF1, were evaluated. The patients included six females and four males ranging in age from 30 to 69 years (mean 59 years; median 63 years). An asymptomatic or slowly enlarging lingual mass was the most common clinical presentation. None of the patients were documented to have NF1. Histologically, the tumors were unencapsulated and situated beneath an intact squamous mucosa. The tumors are comprised of spindle cells with wavy nuclei within a collagenous to myxoid stroma. One tumor was characterized by a plexiform growth pattern. The lesional cells were positive for S-100 protein. Clinical follow up, available for all patients, showed no recurrences and no subsequent development of additional clinical manifestations of NF1. Lingual neurofibromas should be distinguished from other peripheral nerve sheath tumors that can affect this anatomic site. This series of cases confirms that sporadic neurofibromas of the tongue may be rarely encountered in patients having no other features of NF1.

Tongue Schwannoma: A Clinicopathologic Study of 19 Cases.

Schwannomas commonly occur in the head and neck but infrequently involve the oral cavity and rarely affect the tongue. The clinical and pathologic features of 19 cases of schwannoma arising in the tongue were analyzed. There were 13 males and 6 females ranging in age from 12 to 82 years (mean 34 years; median 29 years). The majority of tumors presented as an asymptomatic mass localized to the anterior two-thirds of the tongue. Histologically, 18 schwannomas exhibited characteristic Antoni A and B areas with the former pattern predominating. One tumor was composed exclusively of cellular Antoni A tissue and was classified as a cellular schwannoma. Tumor encapsulation was variable with nearly half of the lesions lacking a well-defined fibrous capsule. All were strongly and diffusely positive for S-100 protein. No recurrences were observed on clinical follow-up. Schwannoma of the tongue, although rare, should be separated from other types of lingual nerve sheath proliferations and tumors.

Immunohistochemistry of p16 in nevi of pregnancy and nevoid melanomas.

BACKGROUND: Hormonal changes in pregnancy are known to alter melanocytic lesions, with some nevi noted to have increased mitotic figures and increased Ki-67 proliferation index. Additionally, cytomorphologic changes have also been noted, referred to as superficial micronodules of pregnancy. These changes may alarm the pathologist for malignancy, particularly nevoid melanoma. Immunohistochemistry for p16 has been recently utilized to distinguish benign nevi from melanoma. We assessed the use of p16 immunohistochemistry for distinguishing melanocytic nevi of pregnant patients from nevoid melanomas. METHODS: Fourteen nevomelanocytic lesions were obtained from pregnant or postpartum patients along with 20 nevoid melanomas for comparison. Immunohistochemistry with p16 was performed on each melanocytic lesion. The percentage of nuclear p16 staining of dermal melanocytes was grouped on a scale of <5%, 5% to 25%, >25% to 50%, and >50%. RESULTS: The majority of nevi from pregnant patients (81%) showed staining of >5% for p16. In contrast, the majority of nevoid melanomas (65%) had staining of <5% for p16. CONCLUSION: The application of p16 as a potential immunohistochemistry diagnostic marker to distinguish nevi from pregnant patients vs nevoid melanomas may be useful.

Immunohistochemical Expression of p16 in Melanocytic Lesions: An Updated Review and Meta-analysis.

CONTEXT: - Making an accurate diagnosis for melanocytic lesions has always been challenging for pathologists, especially when dealing with difficult-to-diagnose cases. Misdiagnosis of melanoma and melanocytic lesions in general has tremendous medical-legal implications, often leading to unnecessary and excessive use of adjunctive tests. Although molecular testing is of much interest and there is great support for its development, currently, for most melanocytic lesions, immunohistochemical studies remain the most practical method for assistance in the routine diagnosis of melanocytic lesions for the average pathologist. OBJECTIVES: - To review the practical use of p16 immunohistochemistry for evaluating melanocytic lesions, particularly for differentiating benign from malignant tumors, and to perform a meta-analysis of primary studies evaluating p16 immunohistochemistry in melanocytic lesions. DATA SOURCES: - A PubMed database search for literature reporting melanocytic lesions and p16 immunohistochemistry was performed. Essential information from each study (number of samples, antibody used, collection dates, overall p16 immunohistochemistry results, and general method of interpretation) was tabulated and analyzed. Examples of representative cases showing p16 immunostaining pattern are also illustrated. CONCLUSIONS: - Incorporation of p16 immunohistochemistry for the diagnosis of melanocytic lesions is of limited use, especially for the purpose of differentiating benign from malignant lesions. Evaluation of multiple studies reveals a wide range of results. However, there appears to be some value for the use of p16 in distinguishing nodal nevi from metastatic melanoma within nodes. The method of interpretation (nuclear versus cytoplasmic staining) also appears to give differing results, as studies considering only nuclear staining appeared to show more consistent results from study to study.

Cutaneous Smooth Muscle Tumors: A Review.

Smooth muscle tumors occur infrequently in the skin. They consist of a diverse group of lesions representing hamartomas as well as benign and malignant neoplasms. They may arise from arrector pili muscle, specialized smooth muscle of the genitalia, or vascular smooth muscle. Although rare, accurate diagnosis and classification of cutaneous smooth muscle proliferations is important as they can exhibit a range of clinical behavior and may be associated with underlying syndromes. This review summarizes the clinicopathologic spectrum of smooth muscle tumors involving the skin.

Leukocytoclastic vasculitis presenting in association with Coxiella burnetii (Q fever): A case report.

Q fever caused by Coxiella burnetii usually presents asymptomatically or as an undifferentiated febrile disease and rarely as rash or other cutaneous manifestations of the disease. Here we present a 41-year-old male complaining of body ache, fever, nausea, malaise, bilateral knee pain and vomiting. Clinical examination revealed a notable erythematous blanching rash all over his body. Workup revealed positive serologic testing for C. burnetii and skin biopsy of the rash revealed leukocytoclastic vasculitis.

Merkel cell carcinoma of unknown primary with lymph node and mesenteric metastasis involving the pancreas and duodenum.

Merkel cell carcinoma (MCC) of skin is a rare, aggressive cutaneous malignancy of neuroendocrine origin. MCC predominantly affects elderly Caucasians and has high predilection for sun exposed areas. Histologic exam and immunohistochemical profile is required to establish the diagnosis. It has high propensity for local recurrence and metastasis, and carries poor prognosis. However, metastasis to mesentery involving the duodenum is very uncommon and rarely reported in literature. We hereby describe a patient with lymph node and mesenteric metastasis invading duodenum and pancreas with unknown primary origin of MCC.

Differential gene expression profiling of primary cutaneous melanoma and sentinel lymph node metastases.

Limited understanding of molecular mechanisms of metastasis in melanoma contributes to the absence of effective treatments. Increased knowledge of alterations in genes that underpin critical molecular events that lead to metastasis is essential. We have investigated the gene expression profiles of primary melanomas and melanoma metastases in sentinel lymph nodes. A total of 19 samples (10 primary melanomas and 9 sentinel lymph node metastases) were evaluated. Melanoma cells were dissected from tissue blocks. Total mRNA was isolated, amplified, and labeled using an Ambion Recover All Total Nucleic Acid Isolation kit, Nu-GEN WT-Ovation formalin-fixed, paraffin-embedded RNA Amplification System, and FL-Ovation cDNA Biotin Module V2, respectively. Samples were hybridized to the Affymetrix Gene Chip Human U133 Plus 2.0 Array. Data were analyzed using Partek Genomics Suite Version 6.4. Genes selected showed ≥2-fold difference in expression and P<5.00E-2. Validation studies used standard immunohistochemical assays. Hierarchical clustering disclosed two distinct groups: 10 primary melanomas and 9 sentinel lymph node metastases. Gene expression analysis identified 576 genes that showed significant differential expression. Most differences reflected decreased gene expression in metastases relative to primaries. Reduced gene expression in primaries was less frequent and less dramatic. Genes significantly increased or decreased in sentinel lymph node metastases were active in cell adhesion/structural integrity, tumor suppression, cell cycle regulation, and apoptosis. Validation studies indicate that MAGEC1 (melanoma antigen family C1) and FCRL1 (Fc receptor-like 1) are involved in melanoma progression. There are striking differential gene expression patterns between primary and nodally metastatic melanomas. Similar findings were seen with autologous paired primary melanomas and sentinel lymph node metastases, supporting involvement of these gene alterations in evolution of metastases. With further study, it may be possible to determine the exact sequence of molecular events that underlie melanoma metastases.

Molecular classification of melanomas and nevi using gene expression microarray signatures and formalin-fixed and paraffin-embedded tissue.

Melanoma may be difficult to identify histologically and relatively high rates of misdiagnosis leads to many malpractice claims. Currently separation of melanomas from nevi is based primarily on light microscopic interpretation of hematoxylin and eosin stained sections with limited assistance from immunohistology. To increase the accuracy of discrimination of benign and malignant melanocytic lesions we identified DNA microarray-derived gene expression profiles of different melanocytic lesions and evaluated the performance of these gene signatures as molecular diagnostic tools in the molecular classification and separation of melanomas and nevi. Melanocyte-derived cells were isolated by laser capture microdissection from 165 formalin-fixed and paraffin-embedded melanocytic nevi and melanoma tissue sections. RNA was isolated, amplified, labeled, and hybridized to a custom DNA microarray. In all 120 samples were used to identify differentially expressed genes and generate a gene expression classifier capable of distinguishing between melanomas and nevi. These classifiers were tested by the leave-one-out method and in a blinded study. RT-PCR verified the results. Unsupervised hierarchical clustering identified two distinct lesional groups that closely correlated with the histopathologically identified melanomas and nevi. Analysis of gene expression levels identified 36 significant differentially expressed genes. In comparison with nevi, melanomas expressed higher levels of genes promoting signal transduction, transcription, and cell growth. In contrast, expression of L1CAM (homolog) was reduced in melanomas relative to nevi. Genes differentially expressed in melanomas and nevi, on the basis of molecular signal, sub classified a group of unknown melanocytic lesions as melanomas or nevi and had high concordance rates with histopathology. Gene signatures established using DNA microarray gene expression profiling can distinguish melanomas from nevi, indicating the feasibility of using molecular classification as a supplement to standard histology. Our successful use of a standard formalin-fixed and paraffin-embedded tissue further supports the practicability of combining molecular diagnostic testing with histopathology in evaluation of difficult melanocytic lesions.

Synergistic effects of coactivators GRIP1 and beta-catenin on gene activation: cross-talk between androgen receptor and Wnt signaling pathways.

The p160 coactivators, such as GRIP1, bind nuclear receptors and help to mediate transcriptional activation. beta-Catenin binds to and serves as a coactivator for the nuclear receptor, androgen receptor (AR), and the Lymphoid Enhancer Factor/T Cell Factor family member, Lef1. Here we report that GRIP1 and beta-catenin can bind strongly to each other through the AD2 domain of GRIP1. Furthermore, GRIP1 and beta-catenin can synergistically enhance the activity of both AR and Lef1, and both coactivators are recruited specifically to AR-driven and Lef1-driven promoters. However, the mechanism of beta-catenin-GRIP1 coactivator function and synergy is different with AR and Lef1. While beta-catenin can bind directly to both AR and Lef1, GRIP1 can only bind directly to AR; the ability of GRIP1 to associate with and function as a coactivator for Lef1 is entirely dependent on the presence of beta-catenin. Thus, whereas GRIP1 coactivator function involves direct binding to nuclear receptors and most other classes of DNA-binding transcriptional activator proteins, the coactivator function of GRIP1 with Lef1 follows a novel paradigm where GRIP1 is recruited indirectly to Lef1 through their mutual association with beta-catenin. The beta-catenin-GRIP1 interaction represents another potential point of cross-talk between the AR and Wnt signaling pathways.

Synergistic coactivator function by coactivator-associated arginine methyltransferase (CARM) 1 and beta-catenin with two different classes of DNA-binding transcriptional activators.

The androgen receptor (AR) binds to and activates transcription of specific genes in response to its cognate steroid hormone, dihydrotestosterone. Transcriptional activation by the DNA-bound AR is accomplished with the help of a variety of coactivator proteins. For example, the p160 coactivators bind directly to AR and recruit additional coactivators such as the histone acetyltransferase p300 and the histone methyltransferase CARM1. The current study tested whether CARM1 can cooperate with other types of coactivator proteins. Recently it was shown that beta-catenin can also bind directly to and serve as a coactivator for AR. Here it is shown that CARM1 binds to beta-catenin and can function in synergy with beta-catenin and p300 as coactivators for AR. The methyltransferase activity of CARM1 is important for its synergistic coactivator function with beta-catenin. The synergistic coactivator function of beta-catenin and CARM1 is not restricted to steroid receptors because these two coactivators can also act synergistically with another type of DNA binding transcriptional activator, LEF-1/TCF-4.

Synergy among nuclear receptor coactivators: selective requirement for protein methyltransferase and acetyltransferase activities.

Hormone-activated nuclear receptors (NR) bind to specific regulatory DNA elements associated with their target genes and recruit coactivator proteins to remodel chromatin structure, recruit RNA polymerase, and activate transcription. The p160 coactivators (e.g., SRC-1, GRIP1, and ACTR) bind directly to activated NR and can recruit a variety of secondary coactivators. We have established a transient-transfection assay system under which the activity of various NR is highly or completely dependent on synergistic cooperation among three classes of coactivators: a p160 coactivator, the protein methyltransferase CARM1, and any of the three protein acetyltransferases, p300, CBP, or p/CAF. The three-coactivator functional synergy was only observed when low levels of NR were expressed and was highly or completely dependent on the methyltransferase activity of CARM1 and the acetyltransferase activity of p/CAF, but not the acetyltransferase activity of p300. Other members of the protein arginine methyltransferase family, which methylate different protein substrates than CARM1, could not substitute for CARM1 to act synergistically with p300 or p/CAF. A ternary complex of GRIP1, CARM1, and p300 or CBP was demonstrated in cultured mammalian cells, supporting a physiological role for the observed synergy. The transfection assay described here is a valuable new tool for investigating the mechanism of coactivator function and demonstrates the importance of multiple coactivators, including CARM1 and its specific protein methyltransferase activity, in transcriptional activation.