Fusion-driven cutaneous and superficial mesenchymal and adnexal tumors-A clinicopathologic and molecular study of 15 cases, including a novel case of ACTB::ZMIZ2-rearranged adnexal carcinoma.

BACKGROUND: While the list of fusion-driven soft tissue neoplasms is expanding rapidly, their importance among cutaneous and superficial mesenchymal and adnexal neoplasms remains poorly understood. This challenge is especially evident in cases with ambiguous histopathology that are difficult to classify based on morphology. AIMS: Our goal was to investigate the benefits of next-generation sequencing in diagnosing complex cutaneous neoplasms. MATERIALS & METHODS: Departmental archives were searched for fusion-driven cutaneous neoplasms. Slides were retrieved and clinical information including follow-up was obtained. RESULTS: Fifteen cases occurred in eight female and seven male patients, with a median age of 26 years (range: 1-83) at diagnosis. Tumors involved the extremities (9), scalp (5), and head and neck (1). Predominant features included myoepithelial (5), nested spindled with clear cytoplasm (2), atypical adnexal/squamoid (2), small round blue cell (2), cellular spindled (3), and fibrohistiocytic morphology (1). Most frequently encountered fusions involved EWSR1 (6) fused to ERG (1), FLI1 (1), CREB1 (2), CREM (1), PBX3 (1), followed by PLAG1 (4) with LIFR (2), TRPS1 (1) and CHCHD7. Additional fusions encountered were YAP1::NUTM1, EML4::ALK, SS18::SSX1 (2), and a novel fusion: ACTB::ZMIZ2. Integration of histologic features and molecular findings led to final diagnoses of primary cutaneous Ewing sarcoma (2), soft tissue myoepithelioma (4), cutaneous syncytial myoepithelioma (1), cutaneous adnexal carcinoma (1), porocarcinoma (1), inflammatory myofibroblastic tumor (1), synovial sarcoma (2), clear cell sarcoma (2), and angiomatoid fibrous histiocytoma (1). DISCUSSION AND CONCLUSION: Our results show that fusion testing can be a helpful diagnostic tool, especially in cases with unusual or uncommon morphology in superficial sites. Furthermore, it can allow for the identification of potential therapeutic targets in some instances.

Digital dermatopathology implementation: Experience at a multisite academic institution.

BACKGROUND: Technology has revolutionized not only direct patient care but also diagnostic care processes. This study evaluates the transition from glass-slide microscopy to digital pathology (DP) at a multisite academic institution, using mixed methods to understand user perceptions of digitization and key productivity metrics of practice change. METHODS: Participants included dermatopathologists, pathology reporting specialists, and clinicians. Electronic surveys and individual or group interviews included questions related to technology comfort, trust in DP, and rationale for DP adoption. Case volumes and turnaround times were abstracted from the electronic health record from Qtr 4 2020 to Qtr 1 2023 (inclusive). Data were analyzed descriptively, while interviews were analyzed using methods of content analysis. RESULTS: Thirty-four staff completed surveys and 22 participated in an interview. Case volumes and diagnostic turnaround time did not differ across the institution during or after implementation timelines (p = 0.084; p = 0.133, respectively). 82.5% (28/34) of staff agreed that DP improved the sign-out experience, with accessibility, ergonomics, and annotation features described as key factors. Clinicians reported positive perspectives of DP impact on patient safety and interdisciplinary collaboration. CONCLUSIONS: Our study demonstrates that DP has a high acceptance rate, does not adversely impact productivity, and may improve patient safety and care collaboration.

Idiopathic eruptive macular pigmentation in a pediatric patient and a review of the literature.

Idiopathic eruptive macular pigmentation (IEMP) is a rare, benign, self-resolving melanosis consisting of hyperpigmented macules typically on the face, trunk, and extremities that can occur in children and adolescents and often presents a diagnostic conundrum. We report a case involving an 8-year-old female whose previous clinical presentation was concerning for an atypical presentation of cutaneous mastocytosis or neurofibromatosis. The clinical and histopathologic evaluation was consistent with the diagnosis of IEMP, and no active intervention was pursued. Our accompanying literature review serves to better characterize this condition, highlight key diagnostic features, and emphasize the tendency for spontaneous resolution to avoid unnecessary treatments with limited clinical efficacy.

Development and multicenter international validation of a diagnostic tool to differentiate between pemphigoid gestationis and polymorphic eruption of pregnancy.

BACKGROUND: Pemphigoid gestationis (PG) and polymorphic eruption of pregnancy (PEP) may be similar morphologically but confer different maternal and fetal risks. Direct immunofluorescence is the gold standard test used to differentiate between the 2 diagnoses but is not always available. OBJECTIVE: To develop and validate a clinical scoring system to differentiate PG from PEP. METHODS: After developing a scoring system based on differentiating clinical factors reported in existing literature, we tested its diagnostic accuracy in a retrospective international multicenter validation study in collaboration with the European Academy of Dermatology and Venereology's Skin Diseases in Pregnancy Taskforce. RESULTS: Nineteen pregnancies (16 patients) affected by PG and 39 pregnancies (39 patients) affected by PEP met inclusion criteria. PG had a mean score of 4.6 (SD, 2.5) and PEP had a mean score of -0.3 (SD, 2.0). The area under the curve was 0.93 (95% CI, 0.86-1.00). Univariate analysis revealed that almost all criteria used in the scoring system were significantly different between the groups (P < .05), except for skip pregnancy and multiple gestations, which were then removed from the final scoring system. LIMITATIONS: Small retrospective study. CONCLUSION: The Pregnancy Dermatoses Clinical Scoring System may be useful to differentiate PG from PEP in resource-limited settings.

Histopathological features of pemphigoid gestationis and polymorphic eruption of pregnancy: A blinded retrospective comparative study of 31 cases.

BACKGROUND: Pemphigoid gestationis (PG) and polymorphic eruption of pregnancy (PEP) are pregnancy-related dermatoses. Definitive diagnosis often relies upon histopathology and direct immunofluorescence (DIF). PG is associated with fetal and neonatal risks, while PEP confers minimal risk. OBJECTIVE: We aimed to compare histopathologic features to determine key differentiators. METHODS: A retrospective cohort study of PG and PEP cases, with accompanying DIF, conducted from 1995 to 2020. Skin biopsies were examined independently in a blinded fashion by two dermatopathologists for a list of histopathological features. RESULTS: Twenty-one cases of PG and 10 cases of PEP were identified. PG had significantly denser eosinophils than PEP (mean 155 vs. 48 cells/5 hpf; p < 0.018). PG was also noted to have eosinophilic spongiosis and eosinophils at the dermal-epidermal junction more frequently compared to PEP (80% PG vs. 10% PEP; p < 0.001). A mean cutoff value of 86 eosinophils and a mean optimal sensitivity and specificity of 81% and 83%, respectively, for eosinophils density's diagnostic power of PEP versus PG were achieved. Subepithelial separation was exclusively seen in PG (40% vs. 0%; p < 0.007). CONCLUSION: Eosinophilic spongiosis, eosinophilic epitheliotropism, and dense superficial dermal eosinophils were diagnostic of PG. Given overlapping clinicopathologic features, however, DIF results with clinicopathologic correlation, remain the gold standard.

Histopathologic features predictive of perivascular deposition of IgA on direct immunofluorescence in cases of leukocytoclastic vasculitis: A retrospective study of 112 specimens.

IgA vasculitis is a small-vessel vasculitis subtype with increased risk of systemic involvement. We aimed to investigate if any light-microscopic features can predict the presence of perivascular granular IgA deposits on direct immunofluorescence (DIF) microscopy. We performed a retrospective search of cutaneous pathology reports from our internal and consultation practice (January 1, 2010-October 5, 2021) with a diagnosis of leukocytoclastic vasculitis and accompanying DIF. A blinded dermatopathologist reviewed standard microscopy slides for predetermined histopathological features. Fifty-six biopsies (48 patients) and 56 biopsies (42 patients) met inclusion criteria for IgA+ and IgA-, respectively. The presence of eosinophils and mid and deep dermal inflammation were statistically more associated with IgA- (41/56 [73.2%] and 31/56 [55.4%], respectively) than IgA+ cases (28/56 [50.0%] and 14/56 [25.0%]; p = 0.049 and 0.006, respectively, chi-squared test). Other microscopic criteria recorded were not significantly different between the two groups (p > 0.05, chi-squared and Fisher's exact tests). In this retrospective study of 112 cases, we found that while the absence of eosinophils and absence of mid- and deep inflammation were correlated with increased likelihood of IgA perivascular deposition on DIF, no other histopathological features on light microscopy tested could reliably predict the presence of IgA perivascular deposition on DIF. Therefore, DIF remains a necessary component for the accurate diagnosis of cutaneous IgA vasculitis.

Updates and Proposed Diagnostic Approach to Psoriasiform Dermatoses.

Psoriasiform dermatoses represent a wide array of skin diseases commonly encountered by clinicians and pathologists. While they may present a diagnostic challenge, thorough observation coupled with proper interpretation of subtle additional clinical or histopathologic features provide clues to the correct diagnosis. In this review, we provide updates on emerging entities and develop a systemic approach to establish the pathologic diagnosis, with emphasis on the importance of clinicopathologic correlation.

Impact of adding an IgG4 conjugate to routine direct immunofluorescence testing for subepithelial and intraepithelial autoimmune blistering disorders.

BACKGROUND: Certain autoimmune bullous dermatoses are mediated by autoantibodies of the IgG4 subclass. We determined the diagnostic impact of adding IgG4 to our conventional direct immunofluorescence (DIF) panel. METHODS: For all cases submitted to our referral laboratory for DIF over 1 month (n = 630), we performed IgG4 testing and collected consecutive biopsy specimens showing definite or indeterminate linear or cell-surface deposition of IgG, IgG4, and/or C3. On retrospective blinded review, we classified the pattern and whether the findings were definite, indeterminate, or negative. When present, substantial background staining was recorded. RESULTS: Seventy DIF specimens met the inclusion criteria. Of 22 (31.4%) specimens equivocal for linear or cell-surface deposition, 9 (40.9%) had definitive IgG4 findings, either linear (3 of 14 equivocal linear cases; 21.4%) or cell-surface (6 of 8 equivocal cell-surface cases; 75.0%). Background deposition was substantial in 14 cases (20.0%) for IgG but in none for C3 or IgG4. CONCLUSION: IgG4 allowed the classification of over 40% of DIF cases that were otherwise equivocal by IgG and C3. IgG4 staining showed lower levels of non-specific background staining than IgG or C3. IgG4 appears to contribute most value in cases with cell-surface deposition or with equivocal linear IgG deposition and negative C3 results.

Mycosis fungoides with spongiosis: A potential diagnostic pitfall.

BACKGROUND: Mycosis fungoides (MF) is characterized by epidermotropic atypical lymphocytes in the absence of spongiosis. However, we describe an unusual presentation of MF with spongiosis, mimicking benign inflammatory dermatoses and highlight the importance of pathologic interpretation for diagnostic confirmation. METHODS: A cross-sectional study of consecutive patients diagnosed with MF with spongiosis was conducted. The clinical, histopathologic, immunophenotypic, and molecular genetic features of cases were reviewed. RESULTS: We identified nine cases of MF (age range 34-82 years; mean 75 years), with an initial diagnosis of dermatitis (6/9), psoriasis (4/9), or other inflammatory dermatoses (2/9). Pruritus, pain, and blisters were common clinical manifestations. The most common areas of involvement were the extremities (8/9). Epidermotropism with spongiosis was a central histopathological feature in all cases. CONCLUSION: These cases highlight prominent spongiosis in MF and overlap with common benign inflammatory dermatoses. We present these cases to show the diagnostic pitfalls associated with spongiotic presentations of MF. Dermatitis, psoriasis, and other inflammatory skin conditions not responsive to standard therapy warrant further work-up including biopsy to rule out MF. Multiple skin biopsies and review by a dermatopathologist with expertise in the diagnosis of cutaneous lymphoma is highly recommended.

Vascular Tumors in Infants: Case Report and Review of Clinical, Histopathologic, and Immunohistochemical Characteristics of Infantile Hemangioma, Pyogenic Granuloma, Noninvoluting Congenital Hemangioma, Tufted Angioma, and Kaposiform Hemangioendothelioma.

Vascular tumors in infants present a diagnostic and treatment dilemma for both clinicians and pathologists. Infantile hemangioma, the most common vascular tumor in infants, can be confused for other less common vascular tumors in infants. Correct and timely diagnosis is important, as some vascular tumors can be associated with life-threatening coagulopathy. We present the cases of 5 vascular tumors that have clinical and histologic overlap: infantile hemangioma, pyogenic granuloma, noninvoluting congenital hemangioma, tufted angioma, and kaposiform hemangioendothelioma. Typical clinical and histopathologic features of each lesion are summarized. We review the utility and characteristic immunohistochemistry including CD31, CD34, GLUT-1, D2-40, LYVE-1, Prox-1, and WT-1. Collaboration between the clinician and the dermatopathologist correlating the clinical history and histopathologic features can lead to the correct diagnosis, whereas the utility of immunohistochemistry remains in question.

Recurrent Oral and Genital Ulcers in an Infant: Neonatal Presentation of Pediatric Behçet Disease.

Behçet disease is a complex, multisystem disease characterized by recurrent oral and genital ulcerations. It rarely occurs in infants or children. Neonatal Behçet disease has been reported in infants whose ulcers resolve at or before 9 weeks of age. Few cases of neonatal Behçet disease persisting into childhood have previously been reported. We report the case of a 1-month-old infant who presented with severe recurrent genital ulcerations and at 6 months developed recurrent oral ulcerations. Her orogenital ulcerations continue to recur. Human leukocyte antigen testing revealed HLA-B51 and B44 positivity. This is a case of pediatric Behçet disease in the neonatal period. Behçet disease should be considered in the differential diagnosis of recurrent genital and oral ulcerations in infants and children.

Primary melanoma of the nipple: Report of 10 cases including coexistence with Paget's disease.

Primary melanoma of the nipple (PMN) is exceedingly rare, with only single cases reported to date. We identified 10 patients with PMN: 5 females, 5 males, median age 55.5 years (range 29-66) at diagnosis of melanoma in situ (4 cases) or invasive melanoma (6 cases, Breslow depth 0.2 mm to 3.5 mm). Follow-up was available for all 10 patients (median 19 months, range 1-183). Nine patients had no evidence of disease; one patient died of disease (13.5 months) after presenting with a nodal metastasis. One case was exceptional, because the patient presented with a pigmented lesion that histopathologically exhibited co-existence of melanoma in situ and Paget disease, a challenging differential diagnosis due to immunohistochemical pitfalls in distinction between melanoma in situ and the pigmented variant of mammary Paget disease. Here we report the second largest series of PMN including a case of PMN colliding with mammary Paget disease, to raise awareness of these rare malignancies.

An update on long-term outcomes of pediatric follicular mucinosis over a 20-year period: a retrospective cohort study.

BACKGROUND: Follicular mucinosis (FM) is a rare disease characterized by mucin accumulation in the follicular unit. FM's etiology is still widely debated since its first description in 1957. Follicular mucinosis is usually reported to be benign in children, although reports of malignant transformation, most commonly mycosis fungoides, exist. The present project aims to demonstrate that children with a diagnosis of follicular mucinosis have positive long-term outcomes and do not develop mycosis fungoides. MATERIALS AND METHODS: This is a retrospective cohort study where patients with a diagnosis of follicular mucinosis ages 22 years and below were identified. Data surrounding the patient's diagnosis of FM, differential diagnosis, treatments, and long-term outcomes were collected. Patients who were lost to follow-up were contacted by phone for an update on the status of their skin and overall health. RESULTS: Out of 14 patients with follow-up information, none developed subsequent mycosis fungoides or other hematologic malignancies. CONCLUSION: Pediatric patients with follicular mucinosis will likely present with limited disease and not experience malignant transformation.

Majocchi's granuloma-A multicenter retrospective cohort study.

Background: Majocchi's granuloma (MG) is an uncommon deep fungal folliculitis predominantly caused by dermatophytes. Given the rarity of this condition, available data regarding predisposing comorbidities/risk factors, clinical characteristics, offending microbiologic pathogens, diagnostics, pathologic findings, and treatment approaches has been inferred from historical cases. Objectives: To review our institutional experience with MG. Methods: We retrospectively analyzed a multicenter cohort of adult patients diagnosed with MG between 1992 and 2022. Results: We analyzed 147 patients with MG, 105 of which were male with a median age of 55.6 years. Immunosuppressant and topical corticosteroid use were common prior to development of MG. Dermatologic lesions and their sites of involvement did not differ based on the immune status of patients. Trichophyton rubrum was the most common causative pathogen of MG, in addition to other dermatophytes. Treatment duration for all prescribed agents was median 31.5 days with oral terbinafine being the most frequently utilized agent. Clinical resolution was achieved in 96.6% of cases. Limitations: Retrospective, nonrandomized study. Conclusions: Although rare and clinically variable in presentation, diagnosis of MG often requires histopathologic confirmation to subsequently direct prolonged treatment with systemic antifungal therapy for mycological cure.

Updates on the dermatopathology of pregnancy-associated skin conditions.

Pathologists provide valuable input in the dermatological care of pregnant patients in various contexts. This article provides dermatopathology updates on cutaneous changes associated with pregnancy, organized based on the following classification system: physiological skin changes in pregnancy, specific dermatoses of pregnancy, dermatoses modified in pregnancy, and skin neoplasms in pregnancy. Awareness of the impact of pregnancy on the skin by pathologists is important, as this is an opportunity to contribute to diagnostic precision in this patient population.

Spatiotemporal regulation of GIPR signaling impacts glucose homeostasis as revealed in studies of a common GIPR variant.

OBJECTIVE: Glucose-dependent insulinotropic polypeptide (GIP) has a role in controlling postprandial metabolic tone. In humans, a GIP receptor (GIPR) variant (Q354, rs1800437) is associated with a lower body mass index (BMI) and increased risk for Type 2 Diabetes. To better understand the impacts of GIPR-Q354 on metabolism, it is necessary to study it in an isogeneic background to the predominant GIPR isoform, E354. To accomplish this objective, we used CRISPR-CAS9 editing to generate mouse models of GIPR-Q354 and GIPR-E354. Here we characterize the metabolic effects of GIPR-Q354 variant in a mouse model (GIPR-Q350). METHODS: We generated the GIPR-Q350 mice for in vivo studies of metabolic impact of the variant. We isolated pancreatic islets from GIPR-Q350 mice to study insulin secretion ex vivo. We used a ß-cell cell line to understand the impact of the GIPR-Q354 variant on the receptor traffic. RESULTS: We found that female GIPR-Q350 mice are leaner than littermate controls, and male GIPR-Q350 mice are resistant to diet-induced obesity, in line with the association of the variant with reduced BMI in humans. GIPR-Q350 mice of both sexes are more glucose tolerant and exhibit an increased sensitivity to GIP. Postprandial GIP levels are reduced in GIPR-Q350 mice, revealing feedback regulation that balances the increased sensitivity of GIP target tissues to secretion of GIP from intestinal endocrine cells. The increased GIP sensitivity is recapitulated ex vivo during glucose stimulated insulin secretion assays in islets. Generation of cAMP in islets downstream of GIPR activation is not affected by the Q354 substitution. However, post-activation traffic of GIPR-Q354 variant in ß-cells is altered, characterized by enhanced intracellular dwell time and increased localization to the Trans-Golgi Network (TGN). CONCLUSIONS: Our data link altered intracellular traffic of the GIPR-Q354 variant with GIP control of metabolism. We propose that this change in spatiotemporal signaling underlies the physiologic effects of GIPR-Q350/4 and GIPR-E350/4 in mice and humans. These findings contribute to a more complete understanding of the impact of GIPR-Q354 variant on glucose homeostasis that could perhaps be leveraged to enhance pharmacologic targeting of GIPR for the treatment of metabolic disease.