Retinal vasculopathy and choroiditis after pegcetacoplan injection: clinicopathologic support for a drug hypersensitivity reaction.

PURPOSE: To report the detailed histopathology of two enucleated eyes from two patients who developed severe visual loss associated with retinal hemorrhages, vessel sheathing and vascular nonperfusion after administration of an initial dose of intravitreal pegcetacoplan, and to propose, with supportive histopathology, the pathogenesis of the clinical syndrome previously termed hemorrhagic occlusive retinal vasculitis (HORV). DESIGN: Case series. SUBJECTS: Two enucleated eyes from two patients treated with intravitreal pegcetacoplan. METHODS: Retrospective, multicenter consecutive clinical-pathologic analysis. MAIN OUTCOME MEASURES: Histopathologic review and immunophenotypic characterization. RESULTS: Both patients presented with inflammation and significant vision loss nine days following the initial injection of pegcetacoplan with no subsequent improvement and underwent enucleation for pain control. Histologic examination of the enucleated eyes (patient one at 4 months post-injection and patient two at 40 days) revealed extensive vascular thrombosis, retinal hemorrhages and necrosis, and a dense inflammatory infiltrate in the uvea and variably the optic nerve, episclera, and muscle tendons composed of predominantly of T-cells, macrophages, and eosinophils. Notably, the inflammatory infiltrate was absent from the retina. In addition, one eye demonstrated multiple foci of glomerular-like vascular proliferations in the uveal tract and thrombosis with focal recanalization of vessels in the optic nerve. CONCLUSION: Drug-induced, immune-mediated, retinal vasculopathy and choroiditis (DIRVAC) is a rare complication following pegcetacoplan injection. Although some limitations arise in interpretation of histopathologic findings due to compensatory changes in the eyes over time (prior to enucleation), the authors propose that the combined clinical, histopathologic, and immunohistochemical findings suggest a mixed-type, delayed hypersensitivity reaction as mechanism of initial injury.

The Histopathology of Chronic "Radiation Conjunctivitis" Shows Diagnostic Features Similar to Those Seen in Radiation Dermatitis, Including Radiation Fibroblasts.

PURPOSE: Radiation therapy is a treatment modality for various ocular and ocular adnexal tumors. The histopathology of chronic radiation dermatitis has been well-described. The authors present two cases demonstrating and characterizing "chronic radiation conjunctivitis" which has not been histopathologically illustrated in detail. METHODS: Retrospective case review of two patients who received proton beam irradiation for an anterior uveal melanoma and external beam radiation for conjunctival lymphoma, and developed leukoplakia and/or thickening of the eyelid margin and symblepharon. Hematoxylin and eosin-stained sections of eyelid margin and conjunctival biopsies as well as clinical histories were reviewed. RESULTS: Conjunctival biopsies in both cases revealed squamous epithelial metaplasia, chronic inflammation and bizarre-appearing stromal cells with hyperchromatic nuclei in a fibrotic/sclerotic stroma, consistent with chronic radiation conjunctivitis. These stromal cells are believed to be the same "radiation fibroblasts" described in chronic radiation dermatitis. CONCLUSION: The radiation fibroblast is characteristic for the diagnosis of chronic radiation conjunctivitis, as it is in radiation dermatitis. Features of squamous metaplasia of conjunctival epithelium, keratinization, subepithelial fibrosis/sclerosis and chronic inflammation are frequently found but not specific. A detailed history and other ancillary tests help differentiate cicatrizing conjunctival conditions, and biopsy should be performed in the setting of suspicion for a secondary malignancy.

Lentigo Maligna Part II: Management.

Lentigo Maligna (LM) arises on chronically-sun damaged skin and can have extensive subclinical spread, often in functionally and cosmetically challenging areas. This two-part continuing medical education (CME) series reviews LM. Part I reviews epidemiology, risk factors, clinical presentation, diagnostic tools, biopsy technique, and histopathology of LM. Part II reviews both surgical and non-surgical treatment options. Surgical approaches - including conventional excision, Mohs micrographic surgery, and staged excision - remain first-line therapy to achieve cure. Some patients may be poor surgical candidates or elect for alternative treatments. Non-surgical modalities, such as topical and radiation therapy, are also reviewed. Finally, surveillance recommendations are discussed.

Lentigo Maligna Part I: Epidemiology, Risk Factors, and Diagnosis.

Lentigo maligna (LM) is an increasingly common subtype of melanoma, presenting as a slow-growing tan-brown macule or patch with irregular borders arising on chronically solar-damaged skin. This two-part continuing medical education (CME) series provides an overview of LM. Part I reviews LM's epidemiology, risk factors, and clinical presentation. Clinical tools to aid in diagnosis - such as dermoscopy and reflectance confocal microscopy - are discussed, as well as optimal biopsy strategies. Histopathology and current understanding of molecular underpinnings are also reviewed. Management of LM presents unique challenges given a predilection for subclinical spread on functionally and cosmetically sensitive areas such as the face. Part II reviews the two pillars of management including both surgical and non-surgical treatment options and surveillance.

Primary Conjunctival Molluscum Contagiosum in a Patient With Ocular Graft-Versus-Host Disease.

PURPOSE: Primary conjunctival molluscum contagiosum (MC) is rare and usually reported in patients with acquired immunodeficiency syndrome. In this study, we present a case of bilateral primary conjunctival MC in a patient with ocular graft-versus-host disease (oGVHD). METHODS: This is a case report study. Clinical evaluation, in vivo confocal microscopy imaging, and histopathology were used to confirm the diagnosis. RESULTS: A 38-year-old woman with a history of allogeneic bone marrow transplant and secondary chronic oGVHD presented with ocular discomfort, redness, and dryness. On examination, clusters of white gelatinous nodular lesions, stained with fluorescein and Lissamine green, were observed on the bulbar conjunctiva, along with similar solitary nodular lesions in all quadrants of both eyes. In vivo confocal microscopy revealed nests of epithelial cells with bright inclusions measuring approximately 30-35 µm. Excisional biopsy confirmed the diagnosis of MC. A 6-month post-operative follow-up showed healed conjunctiva with no recurrence and improved ocular comfort. CONCLUSIONS: Molluscum contagiosum should be considered in the differential diagnosis of conjunctival lesions in patients with impaired immunity such as oGVHD. In diagnosing MC lesions, in vivo confocal microscopy proves to be valuable. In the absence of topical antiviral treatment, surgical excision is warranted.

"Demodicosis" Mimicking PreSeptal Cellulitis: Severe Periocular and Facial Inflammation Caused by "Normal" Skin Flora.

Due to their relatively high prevalence and commensalism, the pathogenicity of Demodex mites has been debated. Recent data, however, show Demodex to be associated with skin and ocular surface diseases such as rosacea, blepharitis, and keratitis. Here the authors report the first known case, to the best of the their knowledge, of Demodex infestation mimicking preseptal cellulitis in an adult human. A 29-year-old male bilaterally blind from advanced retinopathy of prematurity presented with a 2-month history of right-greater-than-left upper eyelid and periocular/cheek swelling, redness, and ocular discharge that did not resolve with oral antibiotics or oral steroids. Based on MRI findings, biopsies of the right lacrimal gland, right orbital fat, and right upper eyelid preseptal skin were obtained which revealed marked intrafollicular Demodex mite density and budding yeasts in the upper eyelid skin. This case serves to alert clinicians to this entity that may not otherwise be usually considered in ophthalmic clinical practice.

Congenital Corneal Staphyloma: A Comprehensive Histopathologic Assessment Including Associated Anterior Segment Abnormalities.

Congenital corneal staphyloma is a rare congenital malformation with guarded visual potential. The cornea is opaque, markedly ectatic, and lined by uveal tissue with a variety of associated anterior segment abnormalities. In this case report, the detailed histopathology of this condition is highlighted with an unusual finding of the malformed lens. [J Pediatr Ophthalmol Strabismus. 2024;61(3):e28-e32.].

Unusual isolated cytomegalovirus cutaneous infections: A subtle histopathologic diagnosis with review of the literature.

Cytomegalovirus (CMV) infection is common and often self-limited. Reactivation results in a variety of disease presentations, especially in the setting of immunocompromise. While cutaneous manifestations of systemic CMV infection are rare, dermatologic manifestations of CMV are increasingly reported with a wide morphologic spectrum clinically. Three male patients, with untreated human immunodeficiency virus (HIV), penile lichenoid dermatitis treated with long-term topical and intralesional corticosteroids, and metastatic Merkel cell carcinoma on immune checkpoint inhibitor therapy, each presented with isolated cutaneous ulcers. The ulcers were located on the perianal skin, glans of the penis, and distal thumb. In each case, nonspecific histopathologic features were seen. However, very rare dermal cytomegalic cells with nuclear and cytoplasmic inclusions were present and highlighted with an immunohistochemical stain for CMV. Isolated ulcers due to CMV infection may occur in the setting of systemic or localized immunosuppression. A high index of suspicion is needed upon histopathologic evaluation, as few cytomegalic cells may be present and accurate diagnosis is crucial for prompt and appropriate clinical management.

Ocular lichen planus as a cause of recurrent restrictive strabismus.

We report the case of an 80-year-old man with restrictive strabismus in lateral gaze following multiple oculoplastic procedures for idiopathic epiphora. Despite excellent initial response to nasal conjunctival recession with lysis of adhesions and a miminal recession of the medial rectus muscle, the patient suffered recurrence of diplopia associated with limitation of abduction due to aggressive, deep, subconjunctival scarring. Given the history of oral lichen planus (LP), the patient was diagnosed with ocular involvement of LP. He underwent a second conjunctival recession, this time accompanied by an intensive LP treatment regimen. Nine months after surgery, he remained diplopia free and orthophoric in primary gaze. Surgeons treating restrictive strabismus in patients with LP should consider implementing systemic and topical immunosuppressive treatment simultaneously with surgical management.

Distinguishing spheno-orbital metastatic prostate cancer mimicking a meningioma using novel 18F-PSMA PET/CT imaging.

A 78-year-old man presented with acute-onset left temporal pain, eyelid swelling, and double vision. Computed tomography (CT) demonstrated a left sphenoid wing mass with extra-osseous intra-orbital and intracranial extension, thought to be a typical sphenoid wing meningioma by the primary team. The patient was admitted for an urgent craniotomy, which was planned for the following day. However, upon consultation with ophthalmic plastic surgery, concern was raised for an alternative diagnosis given the atypical timeline, inflammatory changes, and uncharacteristic imaging findings of mixed lytic and sclerotic bony changes without hyperostosis on CT and extensive peri-lesional dural thickening and enhancement on magnetic resonance imaging. A serum prostate-specific antigen was elevated to 206 ng/mL. Subsequent positron emission tomography (PET)/CT using 18F-fluorodeoxyglucose radiotracer was negative for metastatic disease. A prostate-specific membrane antigen (PSMA) PET/CT was then obtained and demonstrated extensive metastases. An orbital biopsy revealed poorly differentiated prostatic adenocarcinoma. The significant incongruence between the standard PET/CT and PSMA PET/CT highlights the value of this novel advanced radiographic modality in narrowing the differential diagnosis and determining the extent of disease. Findings of widespread metastasis on the PSMA PET/CT ultimately helped to avoid a large, morbid neurosurgical intervention in this patient, allowing for a minimally invasive orbital biopsy to characterize the tumor for therapeutic targeting.

Periorbital necrotizing sweet syndrome: A report of two cases mimicking necrotizing soft tissue infections.

Purpose: Two cases are described of necrotizing Sweet syndrome (nSS), a rare variant of acute febrile neutrophilic dermatosis that mimics necrotizing soft tissue infections. Observation: A 74-year-old female with myelodysplastic syndrome (MDS) presented with isolated periorbital nSS that closely mimicked necrotizing fasciitis (NF); she displayed pathergy to debridement, was exquisitely responsive to corticosteroids, and underwent successful first-stage reconstruction of the eyelid with full-thickness skin grafting. A second 40-year-old female patient with relapsed acute myelogenous leukemia (AML) presented with multifocal nSS most prominently involving the eyelid. Positive herpes zoster virus (HSV) PCR and bacterial superinfection complicated the diagnosis. She improved with chemotherapy for AML and corticosteroid therapy. Conclusion: nSS is rare and a high level of clinical suspicion as well as an understanding of its distinguishing features is necessary to avoid undue morbidity. Identification of pathergy, histopathology, microbiology, and clinical context are critical to avoid misdiagnosis of infection.

Melanoma Arising Beneath the Lateral Rectus Muscle in a Teenager With Ocular Melanocytosis: Possible Origin From Intrascleral Melanocytes.

Ocular melanocytosis is a well-established risk factor for choroidal melanomas but, despite its reported associations in the literature, it is infrequently discussed in relation to orbital melanomas. The authors describe a teenage patient with ocular melanocytosis who presented with an asymptomatic ipsilateral right orbital mass associated with the lateral rectus muscle. An exploratory orbitotomy revealed a lesion lightly adherent to the underlying sclera. Histopathology demonstrated a markedly atypical epithelioid melanocytic proliferation, bound by a thin rim of superficial sclera, implying an origin from intrascleral melanocytes, likely within an emissary canal. Next-generation sequencing identified GNAQ and NF1 mutations. The histopathology and molecular genetics designated the lesion as having a uveal melanoma-like profile, suggesting that it may behave as a choroidal melanoma. This case underscores the importance of the association between ocular melanocytosis and orbital melanoma and provides additional evidence for primary orbital melanoma etiopathogenesis.

Histopathologic clues to the etiopathogenesis of orbital inflammatory disease: Idiopathic, IgG4-related, neoplastic, autoimmune and beyond.

Orbital inflammatory diseases represent a heterogenous group of idiopathic, autoimmune-related, and sometimes neoplastic conditions with overlapping clinical and histopathologic features, as well as variable levels of IgG4-positive plasma cells detected within tissue biopsies. Some histopathologic features, especially in an appropriate clinical context, may point to a specific diagnosis in a given patient. Diagnoses of non-specific orbital inflammation, orbital inflammation related to autoimmune diseases such as granulomatosis with polyangiitis and IgG4-related disease, lymphoma, and xanthogranulomatous diseases are discussed, contrasted and illustrated.

A Rapidly Expanding Hemorrhagic BRAF-Mutant Orbital Atypical Glomus Tumor.

A healthy 32-year-old woman presented with the acute onset of left sided eye pain, upper eyelid fullness, and binocular diplopia during light weightlifting. Examination elevated intraocular pressure, proptosis, upper eyelid ptosis, and motility deficits. CT demonstrated a well-circumscribed, homogeneous-appearing extraconal mass in the superior left orbit. The patient underwent an urgent orbitotomy with the excision of a hemorrhagic mass. Histopathology showed a glomus tumor with atypical features and hemorrhagic infarction, best classified as having uncertain malignant potential. A B-Raf proto-oncogene V600E mutation was detected with immunohistochemistry, which suggests a more aggressive tumor behavior yet presents an opportunity for targeted primary or adjunctive therapy. This is the first reported case of a B-Raf proto-oncogene-mutant atypical glomus tumor arising in the orbit.

Development and validation of time-to-event models to predict metastatic recurrence of localized cutaneous melanoma.

BACKGROUND: The recent expansion of immunotherapy for stage IIB/IIC melanoma highlights a growing clinical need to identify patients at high risk of metastatic recurrence and, therefore, most likely to benefit from this therapeutic modality. OBJECTIVE: To develop time-to-event risk prediction models for melanoma metastatic recurrence. METHODS: Patients diagnosed with stage I/II primary cutaneous melanoma between 2000 and 2020 at Mass General Brigham and Dana-Farber Cancer Institute were included. Melanoma recurrence date and type were determined by chart review. Thirty clinicopathologic factors were extracted from electronic health records. Three types of time-to-event machine-learning models were evaluated internally and externally in the distant versus locoregional/nonrecurrence prediction. RESULTS: This study included 954 melanomas (155 distant, 163 locoregional, and 636 1:2 matched nonrecurrences). Distant recurrences were associated with worse survival compared to locoregional/nonrecurrences (HR: 6.21, P < .001) and to locoregional recurrences only (HR: 5.79, P < .001). The Gradient Boosting Survival model achieved the best performance (concordance index: 0.816; time-dependent AUC: 0.842; Brier score: 0.103) in the external validation. LIMITATIONS: Retrospective nature and cohort from one geography. CONCLUSIONS: These results suggest that time-to-event machine-learning models can reliably predict the metastatic recurrence from localized melanoma and help identify high-risk patients who are most likely to benefit from immunotherapy.

Eosinophilic Angiocentric Fibrosis of the Orbit: A Clinicopathologic Review of 6 Novel Cases With Review of the Literature.

PURPOSE: To describe 6 cases and review the current state of knowledge of eosinophilic angiocentric fibrosis (EAF) involving the orbit. DESIGN: Retrospective clinicopathologic case series and review of the current literature METHODS: Clinical records and histopathologic data of orbit-involving EAF were gathered between 2004 and 2022 from a single academic institution. The patients' presenting clinical symptoms and signs, laboratory data, radiographic studies, and management documentation were collected. RESULTS: Retrospective review identified 6 novel cases, totaling 31 cases of EAF involving the orbit described as of this writing. Fourteen patients were male, and the average age of presentation was 49.8 years (range 25-78 years). Eighteen patients had concurrent sinonasal involvement, whereas 13 had primary orbital involvement. The median duration of symptoms prior to evaluation was 24 months, with nasal symptoms, proptosis, periorbital swelling, and pain being the most common presenting symptoms. The majority of patients underwent surgical debulking, as well as treatment with glucocorticoids and steroid-sparing agents, such as rituximab, with varied results. CONCLUSION: EAF involving the orbit is uncommon. The histopathologic findings include a perivascular, eosinophil-rich infiltrate and a pauci-inflammatory storiform type of fibrosis concentrated around small vessels. Orbital involvement usually results from local extension from adjacent sinuses, but primary orbital involvement has been described. Surgical debulking and immunosuppressive agents such as rituximab have been shown to stabilize disease.