Hidden in the Eyes-Recurrence of Systemic Hemopathies Reportedly "In Remission": Six Cases and Review of Literature.

Background and Objectives: Secondary ocular localizations of hematological malignancies are blinding conditions with a poor prognosis, and often result in a delay in the diagnosis. Materials and Methods: We describe a series of rare cases of ocular involvement in six patients with hematological malignancies, reportedly in remission, who presented secondary ocular localizations, challenging to diagnose. Two patients had an acute lymphoblastic leukemia (ALL) and developed either a posterior scleritis or a pseudo-panuveitis with ciliary process infiltration. One patient had iris plasmacytoma and developed an anterior uveitis as a secondary presentation. Two patients had a current systemic diffuse large B-cell lymphoma (DLBCL) and were referred either for intermediate uveitis or for papilledema and vitritis with secondary retinitis. Finally, one patient with an acute myeloid leukemia (AML) presented a conjunctival localization of a myeloid sarcoma. We herein summarize the current knowledge of ophthalmologic manifestations of extramedullary hematopathies. Results: Inflammatory signs were associated with symptomatic infiltrative lesions well displayed in either the iris, the retina, the choroid, or the cavernous sinus, from the admission of the patients in the ophthalmological department. These findings suggest that patients with ALL, AML, systemic DLBCL, and myeloma can present with ophthalmic involvement, even after having been reported as in remission following an effective systemic treatment and/or allograft. Conclusions: Early detection of hidden recurrence in the eyes may permit effective treatment. Furthermore, oncologists and ophthalmologists should be aware of those rare ocular malignant locations when monitoring patient's progression after initial treatment, and close ophthalmologic examinations should be recommended when detecting patient's ocular symptoms after treatment.

Intravoxel incoherent motion (IVIM) 3 T MRI for orbital lesion characterization.

OBJECTIVES: To determine the diagnostic accuracy of MRI intravoxel incoherent motion (IVIM) when characterizing orbital lesions, which is challenging due to a wide range of locations and histologic types. METHODS: This IRB-approved prospective single-center study enrolled participants presenting with an orbital lesion undergoing a 3-T MRI prior to surgery from December 2015 to July 2019. An IVIM sequence with 15 b values ranging from 0 to 2000 s/mm2 was performed. Two neuroradiologists, blinded to clinical data, individually analyzed morphological MRIs. They drew one region of interest inside each orbital lesion, providing apparent diffusion coefficient (ADC), true diffusion coefficient (D), perfusion fraction (f), and pseudodiffusion coefficient (D*) values. T test, Mann-Whitney U test, and receiver operating characteristic curve analyses were performed to discriminate between orbital lesions and to determine the diagnostic accuracy of the IVIM parameters. RESULTS: One hundred fifty-six participants (84 women and 72 men, mean age 54.4 ± 17.5 years) with 167 orbital lesions (98/167 [59%] benign lesions including 54 orbital inflammations and 69/167 [41%] malignant lesions including 32 lymphomas) were included in the study. ADC and D were significantly lower in malignant than in benign lesions: 0.8 × 10-3 mm2/s [0.45] versus 1.04 × 10-3 mm2/s [0.33], p < 0.001, and 0.75 × 10-3 mm2/s [0.40] versus 0.98 × 10-3 mm2/s [0.42], p < 0.001, respectively. D* was significantly higher in malignant lesions than in benign ones: 12.8 × 10-3 mm2/s [20.17] versus 7.52 × 10-3 mm2/s [7.57], p = 0.005. Area under curve was of 0.73, 0.74, 0.72, and 0.81 for ADC, D, D*, and a combination of D, f, and D*, respectively. CONCLUSIONS: Our study showed that IVIM might help better characterize orbital lesions. KEY POINTS: • Intravoxel incoherent motion (IVIM) helps clinicians to assess patients with orbital lesions. • Intravoxel incoherent motion (IVIM) helps clinicians to characterize orbital lymphoma versus orbital inflammation. • Management of patients becomes more appropriate.

Multimodal imaging of Hurler syndrome-related keratopathy treated with deep anterior lamellar keratoplasty.

BACKGROUND: Hurler syndrome-associated keratopathy is an exceedingly rare corneal disorder that requires corneal transplantation in advanced stages. Precise assessment of the corneal condition is necessary for deciding which type of keratoplasty (i.e., deep anterior lamellar or penetrating) should be proposed. We aimed to confront the results of multimodal imaging with those of histology in a case of Hurler syndrome-associated keratopathy. CASE PRESENTATION: A 16-year-old patient with Hurler's syndrome treated with hematopoietic stem cell transplantation was referred for decreased vision related to advanced keratopathy. The patient was treated with deep anterior lamellar keratoplasty (DALK) in both eyes with uncomplicated outcome. Visual acuity improved from 0.1 (20/200) preoperatively to 0.32 (20/63) and 0.63 (20/32) after transplantation. The corneal endothelial cell density was 2400 cells/mm2 in both eyes 3 years after transplantation. In vivo confocal microscopy (IVCM) and spectral domain optical coherence tomography (SD-OCT) were performed preoperatively. The corneal buttons retrieved during keratoplasty were processed for histology. In SD-OCT scans, corneal opacities appeared as diffuse stromal hyperreflectivity associated with increased corneal thickness. IVCM showed diffuse cytoplasmic granular hyperreflectivity and rounded/ellipsoid aspects of keratocytes, presence of small intracellular vacuoles, and hyperreflective epithelial intercellular spaces. Bowman's layer was thin and irregular. The corneal endothelium was poorly visualized but no endothelial damage was observed. Histology showed irregular orientation and organization of stromal lamellae, with the presence of macrophages whose cytoplasm appeared clear and granular. A perinuclear clear halo was visible within the epithelial basal cells. Bowman's layer featured breaks and irregularities. CONCLUSIONS: The observed corneal multimodal imaging features in mucopolysaccharidosis-related keratopathy were concordant with histology. Compared with standard histology, multimodal imaging allowed additional keratocyte features to be observed. It revealed both morphological and structural changes of all corneal layers but the endothelium. This information is essential for therapeutic management which should include DALK as the first-choice treatment in case of impaired visual acuity.

Sostdc1 is expressed in all major compartments of developing and adult mammalian eyes.

PURPOSE: This study was conducted in order to study Sostdc1 expression in rat and human developing and adult eyes. METHODS: Using the yeast signal sequence trap screening method, we identified the Sostdc1 cDNA encoding a protein secreted by the adult rat retinal pigment epithelium. We determined by in situ hybridization, RT-PCR, immunohistochemistry, and western blot analysis Sostdc1 gene and protein expression in developing and postnatal rat ocular tissue sections. We also investigated Sostdc1 immunohistolocalization in developing and adult human ocular tissues. RESULTS: We demonstrated a prominent Sostdc1 gene expression in the developing rat central nervous system (CNS) and eyes at early developmental stages from E10.5 days postconception (dpc) to E13 dpc. Specific Sostdc1 immunostaining was also detected in most adult cells of rat ocular tissue sections. We also identified the rat ocular embryonic compartments characterized by a specific Sostdc1 immunohistostaining and specific Pax6, Sox2, Otx2, and Vsx2 immunohistostaining from embryonic stages E10.5 to E13 dpc. Furthermore, we determined the localization of SOSTDC1 immunoreactivity in ocular tissue sections of developing and adult human eyes. Indeed, we detected SOSTDC1 immunostaining in developing and adult human retinal pigment epithelium (RPE) and neural retina (NR) as well as in several developing and adult human ocular compartments, including the walls of choroidal and scleral vessels. Of utmost importance, we observed a strong SOSTDC1 expression in a pathological ocular specimen of type 2 Peters' anomaly complicated by retinal neovascularization as well in the walls ofother pathological extra-ocular vessels.  CONCLUSION: As rat Sostdc1 and human SOSTDC1 are dual antagonists of the Wnt/ß-catenin and BMP signaling pathways, these results underscore the potential crucial roles of these pathways and their antagonists, such as Sostdc1 and SOSTDC1, in developing and adult mammalian normal eyes as well as in syndromic and nonsyndromic congenital eye diseases.

Evolutionary Routes in Metastatic Uveal Melanomas Depend on MBD4 Alterations.

PURPOSE: Uveal melanomas (UM) are genetically simple tumors carrying few copy number alterations (CNA) and a low mutation burden, except in rare MBD4-deficient, hypermutated cases. The genomics of uveal melanoma metastatic progression has not been described. We assessed the genetic heterogeneity of primary and metastatic MBD4-proficient and -deficient uveal melanomas.Experimental Design: We prospectively collected 75 metastatic and 16 primary samples from 25 consecutive uveal melanoma patients, and performed whole-exome sequencing. RESULTS: MBD4-proficient uveal melanomas contained stable genomes at the nucleotide level, acquiring few new single nucleotide variants (SNVs; 16 vs. 13 in metastases and primary tumors, respectively), and no new driver mutation. Five CNAs were recurrently acquired in metastases (losses of 1p, 6q, gains of 1q, 8q, and isodisomy 3). In contrast, MBD4-deficient uveal melanomas carried more than 266 SNVs per sample, with high genetic heterogeneity and TP53, SMARCA4, and GNAS new driver mutations. SNVs in MBD4-deficient contexts were exploited to unveil the timeline of oncogenic events, revealing that metastatic clones arose early after tumor onset. Surprisingly, metastases were not enriched in monosomy 3, a previously defined metastatic risk genomic feature. Monosomy 3 was associated with shorter metastatic-free interval compared with disomy 3 rather than higher rate of relapse. CONCLUSIONS: MBD4-proficient uveal melanomas are stable at the nucleotide level, without new actionable alterations when metastatic. In contrast, MBD4 deficiency is associated with high genetic heterogeneity and acquisition of new driver mutations. Monosomy 3 is associated with time to relapse rather than rate of relapse, thus opening avenues for a new genetic prognostic classification of uveal melanomas.

Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors.

Metastatic uveal melanoma is a deadly disease with no proven standard of care. Here we present a metastatic uveal melanoma patient with an exceptional high sensitivity to a PD-1 inhibitor associated with outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic MBD4 inactivation in the tumor. We identify additional tumors in The Cancer Genome Atlas (TCGA) cohorts with similar hypermutator profiles in patients carrying germline deleterious MBD4 mutations and somatic loss of heterozygosity. This MBD4-related hypermutator phenotype may explain unexpected responses to immune checkpoint inhibitors.

Recurrent lacrimal gland choristoma of the ciliary body in an infant mimicking a medulloepithelioma.

PURPOSE: Choristoma is a congenital tumor made up of ectopic normal tissue. Different histopathologic subtypes have been described. Among them, lacrimal gland choristoma is found mainly in infants and can affect the iris, the ciliary body, or the choroid and epibulbar region. Our aims were to report a case of lacrimal gland choristoma, review the published cases, and present the main differential diagnoses. METHODS: A local resection of a limited mass of the ciliary body was performed on a 12-month-old girl who had a 6-month history of visual loss, leukocoria, and pupillary deformation. RESULTS: Histopathologically, we observed a well-demarcated lesion involved under the epithelium of the ciliary body. It was composed of acini delineated by a well-differentiated epithelium without atypia and mitotic figures. Immunohistochemical analyses confirmed the lacrimal nature with the expression of epithelial markers (cytokeratin 7 positive and cytokeratin 20 negative) and neuron-specific enolase without immunoreactivity for other neuronal markers. Two years later, a local recurrence appeared and was resected. It showed nearly the same histopathologic features. CONCLUSIONS: Lacrimal gland choristoma is a very rare lesion of the infant. Diagnosis is based on a histopathologic analysis with immunohistochemical studies to exclude other differential diagnoses such as a more common malignant tumor in childhood, medulloepithelioma. This observation shows an atypical clinical presentation of this benign lesion characterized by local recurrences.

High prevalence of IgG4-related lymphoplasmacytic infiltrative disorder in 25 patients with orbital inflammation: a retrospective case series.

AIMS: To evaluate retrospectively the prevalence of positive IgG4-immunostaining in orbital tissue of patients with idiopathic orbital inflammation and to compare the clinical, radiographic and pathologic features among patients with and without IgG4-positive cells. PATIENTS AND METHODS: 25 patients with biopsy-proven idiopathic orbital inflammation examined from January 2006 through December 2011 were included. Immunohistochemistry with IgG and IgG4 immunostaining from biopsy specimens of all patients was performed. Tissue with more than 10 IgG4-positive plasma cells per high-power field and with a ratio of IgG4+/IgG+ plasma cells of more than 40% was scored as positive. Histopathologic features, demographic and clinical data, radiologic findings, treatment and follow-up information for each patient were analysed. RESULTS: Immunohistochemical staining showed 10 cases (40%) were IgG4 positive. The symptoms and signs included eyelid or periocular swelling/mass in all, pain (3/10), extraocular muscle restriction (3/10), proptosis (5/10) and/or decreased vision (4/10). Demographic and clinical findings of these patients did not differ from those with IgG4-negative cells. The presence of positive IgG4-immunostaining in orbital tissue was significantly associated with characteristic pathological features (more background fibrosis, lymphoid hyperplasia, plasma cells and phlebitis). CONCLUSIONS: Finally, 40% of patients with biopsy-proven orbital inflammation were classified as IgG4-RD, with typical histological features, but without specific clinical or radiological findings.

Superficial punctate keratitis and conjunctival erosions associated with congenital tufting enteropathy.

PURPOSE: To study the value of conjunctival biopsy in congenital tufting enteropathy diagnosis. DESIGN: Case-comparative study. METHODS: Between January 2000 and June 2007, all children seeking treatment with an early onset of intractable diarrhea were examined in the ophthalmology department of Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, France. Children underwent complete ophthalmologic examination with concurrent conjunctival and intestinal biopsies. Main outcome measures were age at diagnosis, associated disorders, parenteral nutrition, and ophthalmologic symptoms. Conjunctival biopsies support diagnosis in the presence of specific alteration. RESULTS: Twenty patients were included. The mean age of the population was 30.2 months. Congenital tufting enteropathy was diagnosed in 15 cases. In the congenital tufting enteropathy group, 10 children exhibited ophthalmic functional disorders since the first months of life, with superficial punctate keratitis and conjunctivitis and in addition alacrima and cataract in 1 case, respectively, whereas 5 children had asymptomatic conjunctival hyperemia at presentation. Conjunctival biopsies showed epithelial parakeratosis, hyperplasia, basal cells hyperplasia, and tufts. In some cases, the lamina propria contained inflammatory cells or fibrosis, and the density of goblet cells then was abnormal. In the comparison group of 5 children with early-onset intractable diarrhea but without congenital tufting enteropathy diagnosis, no tuft occurrence was observed. CONCLUSIONS: In cases of intractable diarrhea in infancy, even without ocular symptoms, a systematic ophthalmologic examination should be performed. It also should be associated with the pathologic examination of both the conjunctival and the intestine mucosae, which helps to diagnose congenital tufting enteropathy (adhesion molecules disease). Specific conjunctival findings allow affirmation of congenital tufting enteropathy before the genetic confirmation of an EpCAM gene mutation.

Eosinophilic angiocentric fibrosis of the sinonasal tract in a male patient with chronic bowel inflammation.

BACKGROUND: Eosinophilic angiocentric fibrosis (EAF) is an uncommon inflammatory fibrosing lesion involving the upper respiratory mucosa, occurring mainly in young to middle aged women (female/male ratio = 2:1). The etiology is unknown; however, severalfactors might play a role in the development of EAF. Among them are prior nasal trauma (in most of the reported cases nasal surgery had been performed afew years prior to diagnosis) and inflammatory or autoimmune etiology (suggested by the ratio and the fact that in many of the reported cases a history of nonspecific allergy was found). METHODS: We report the first case of EAF affecting a male patient who also suffered from chronic inflammatory bowel disease and rheumatic fever. RESULTS: The patient underwent a diagnostic biopsy of his nasal lesion via an open rhinoplasty approach, with the resulting diagnosis of EAF. Despite the fact that the literature does not show advantages to any specific therapy, the patient elected to remain under observation. During a two-year follow-up period, there is no evidence of progression of disease. CONCLUSION: The presence of concomitant rheumatoid arthritis and chronic inflammatory bowel disease in our patient, as well as the fact that nine previously reported cases of EAF had allergic/immune symptoms, raise the possibility that inflammatory or autoimmune factors may have a role in the development of this unusual pathological entity.