Myelodysplasia cutis and VEXAS syndrome initially diagnosed as histiocytoid Sweet syndrome: A diagnostic pitfall.

Histiocytoid Sweet syndrome (H-SS) is a histopathological variant of Sweet syndrome (SS) defined by cutaneous infiltration of immature myeloid cells morphologically resembling histiocytes. The association of H-SS with underlying malignancy, particularly myelodysplastic syndromes, is well-established. Myelodysplasia cutis (MDS-cutis) has been proposed to describe cases historically diagnosed as H-SS but characterized by shared clonality of the myeloid infiltrate in skin and bone marrow. Therefore, identifying patients who might have MDS-cutis is critical for the management of the associated hematologic malignancy. VEXAS syndrome, an adult-onset autoinflammatory disease, should also be included in the histopathologic differential diagnosis of H-SS, as it shares clinical and pathologic features with MDS-cutis. Through the presentation of two cases, we aim to highlight the defining features and key clinical implications of MDS-cutis and VEXAS syndrome.

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.

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.

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.

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.

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.

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.

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.

Suggestions for a New Clinical Classification Approach to Panniculitis Based on a Mayo Clinic Experience of 207 Cases.

BACKGROUND: Panniculitis, or inflammation of adipose tissue, includes a heterogeneous group of disorders with similar morphologic presentations. Currently, panniculitides are classified based on histopathologic findings only. OBJECTIVE: In this retrospective study of 207 cases of biopsy-proven panniculitis over 20 years at Mayo Clinic, we aimed to propose a new classification that integrates the clinical morphologic features with the histopathology of panniculitis. METHODS: We collected patient demographic and lesion morphologic characteristics using lesion photographs and physician notes for each of our 207 cases, including location, ulceration, scale, pattern (unilateral versus circumferential), atrophy/sclerosis (cicatricial), redness, and swelling. RESULTS: The panniculitides most likely to ulcerate were calciphylaxis (85.7% ulcerating), pancreatic panniculitis (66.6%), and α1-antitrypsin deficiency-associated panniculitis (100%). The panniculitides least likely to ulcerate were erythema nodosum and medication-induced and granulomatous panniculitis. This retrospective study used only descriptions in clinical notes and available medical photographs. CONCLUSION: We present an updated classification schema of panniculitides based on clinical findings. The primary distinctions are based on ulceration, location, and number of lesions. Although complete distinction of all panniculitides based on clinical examination alone is not possible, we hope the proposed schema allows clinicians to tailor differential diagnoses.

Intravascular histiocytosis: mimicker of cellulitis, angiosarcoma, inflammatory breast cancer, and others.

BACKGROUND: Intravascular histiocytosis is an underrecognized reactive skin condition characterized by the clinical finding of poorly demarcated erythematous to violaceous patches and plaques. The diagnosis is confirmed by the histologic findings of intraluminal histiocytes on skin biopsy and exclusion of an alternative diagnosis. METHODS: A review of patients with a histologic diagnosis of intravascular or intralymphatic histiocytosis and seen at Mayo Clinic, Rochester, Minnesota, from January 1, 2010, to October 10, 2020, was performed. Histologic and clinical information was collected from the medical records. RESULTS: Nine patients were identified. Clinical impressions prior to biopsy varied widely, and no clinician included intravascular histiocytosis in the initial clinical differential diagnosis. Eight patients had preceding trauma to the affected area. CONCLUSION: Intravascular histiocytosis remains a rare skin condition. Clinical identification remains low. Our cases add support to the hypothesis that intravascular histiocytosis is a reactive condition often preceded by trauma and/or surgery.

Teledentistry in the management of a non-Hodgkin's lymphoma manifesting as a gingival swelling: A case report.

Oral cavity lymphomas constitute only 3% of all lymphomas in the general population but are the third most common oral malignancy. A 67-year-old female with a history of osteoporosis, Graves' disease and non-Hodgkin's lymphoma was referred to the Department of Dental Specialties with a chief complaint of persistent soft tissue swelling facial to the maxillary incisors of possible non-odontogenic origin. To expedite care, the patient was first seen via teledentistry and subsequently appointed for an in-person evaluation and treatment. Examination revealed 1-3 mm probing depths and a firm, non-tender, non-fluctuant mass in the facial soft tissues approximating teeth nos. 7-10. Biopsy of the affected area was performed. A diagnosis of recurrent follicle center cell lymphoma, a form of non-Hodgkin's lymphoma, was rendered. The patient was subsequently referred to the Oncology and Hematology team, followed for 6 weeks and remained symptom-free. This case underlies the importance of teledentistry to expedite care and manage patient expectations. Additionally, it also underscores the importance of microscopic examination of tissue samples from oral lesions that appear non-odontogenic in nature and reinforces the role of dentistry in uncovering the oral-systemic link.

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.

Cutaneous eccrine inflammation and necrosis: review of inflammatory disorders affecting the eccrine apparatus including new associations.

Despite being frequently overlooked during the examination of histopathological sections, eccrine sweat glands can offer clues for diagnosing various skin conditions. They provide important functions and can lead to several diseases when inflamed or injured. This review article provides information regarding eccrine physiology as well as well-established and novel entities that occur in association with eccrine gland pathology.