Squamous cell carcinoma in the anophthalmic socket-a series of 4 cases with HPV-16 profiling

To present the clinical and histological features of squamous cell carcinoma (SCC) in the anophthalmic socket in four adult patients, and to determine the presence of human papillomavirus infection (HPV).Retrospective case series of four adult patients with SCC of the anophthalmic socket. P16 immunohistochemistry and HPV testing was carried out in all cases. The authors report clinical findings, histopathology, management and outcomes for all four\ua0patients with conjunctival SCC. Previously reported cases of conjunctival SCC in anophthalmic sockets were reviewed.Four adult patients presented with eyelid lumps, discharge or change in prosthesis fit. Common examination findings included papillomatous changes, eyelid masses and epithelial changes. Three out of the four cases (75%) were positive for p16 by immunohistochemistry and the same cases positive for HPV-16 DNA. All patients received cryotherapy, topical or intralesional chemotherapy. Two patients proceeded to exenteration for control of invasive disease.To the authors' knowledge, this is the largest series of SCC in the anophthalmic socket with comprehensive annotation of HPV status. Although socket conjunctiva is protected from environmental radiation, there is still a risk of neoplastic transformation in this tissue, thus patient education and regular checking of sockets by ophthalmologists should be undertaken as a preventative measure. The potential role of HPV in these tumours warrants further investigation

Human papillomavirus type 16 causes a defined subset of conjunctival in situ squamous cell carcinomas

Funder: CUH | Addenbrooke's Charitable Trust, Cambridge University Hospitals (Addenbrooke's Charitable Trust, Cambridge University Hospitals NHS Foundation Trust); doi: https://doi.org/10.13039/501100002927Abstract: Squamous cell carcinoma of the conjunctiva is associated with a number of risk factors, including HIV infection, iatrogenic immunosuppression and atopy. In addition, several studies have suggested an involvement of HPV, based on the presence of viral DNA, but did not establish whether there was active infection or evidence of causal disease association. In this manuscript, 31 cases of conjunctival in situ squamous cell carcinoma were classified as HPV DNA-positive or -negative, before being analysed by immunohistochemistry to establish the distribution of viral and cellular biomarkers of HPV gene expression. Our panel included p16INK4a, TP53 and MCM, but also the virally encoded E4 gene product, which is abundantly expressed during productive infection. Subsequent in situ detection of HPV mRNA using an RNAscope approach confirmed that early HPV gene expression was occurring in the majority of cases of HPV DNA-positive conjunctival in situ squamous cell carcinoma, with all of these cases occurring in the atopic group. Viral gene expression correlated with TP53 loss, p16INK4a elevation, and extensive MCM expression, in line with our general understanding of E6 and E7’s role during transforming infection at other epithelial sites. A characteristic E4 expression pattern was detected in only one case. HPV mRNA was not detected in lower grades of dysplasia, and was not observed in cases that were HPV DNA-negative. Our study demonstrates an active involvement of HPV in the development of a subset of conjunctival in situ squamous cell carcinoma. No high-risk HPV types were detected other than HPV16. It appears that the conjunctiva is a vulnerable epithelial site for HPV-associated transformation. These cancers are defined by their pattern of viral gene expression, and by the distribution of surrogate markers of HPV infection

A Multicenter Study Validates the WHO 2022 Classification for Conjunctival Melanocytic Intraepithelial Lesions With Clinical and Prognostic Relevance

Several nomenclature and grading systems have been proposed for conjunctival melanocytic intraepithelial lesions (C-MIL). The fourth "WHO Classification of Eye Tumors" (WHO-EYE04) proposed a C-MIL classification, capturing the progression of noninvasive neoplastic melanocytes from low- to high-grade lesions, onto melanoma in situ (MIS), and then to invasive melanoma. This proposal was revised to the WHO-EYE05 C-MIL system, which simplified the high-grade C-MIL, whereby MIS was subsumed into high-grade C-MIL. Our aim was to validate the WHO-EYE05 C-MIL system using digitized images of C-MIL, stained with hematoxylin and eosin and immunohistochemistry. However, C-MIL cases were retrieved from 3 supraregional ocular pathology centers. Adequate conjunctival biopsies were stained with hematoxylin and eosin, Melan-A, SOX10, and PReferentially expressed Antigen in Melanoma. Digitized slides were uploaded on the SmartZoom platform and independently scored by 4 ocular pathologists to obtain a consensus score, before circulating to 14 expert eye pathologists for independent scoring. In total, 105 cases from 97 patients were evaluated. The initial consensus diagnoses using the WHO-EYE04 C-MIL system were as follows: 28 benign conjunctival melanoses, 13 low-grade C-MIL, 37 high-grade C-MIL, and 27 conjunctival MIS. Using this system resulted in 93% of the pathologists showing only fair-to-moderate agreement (kappa statistic) with the consensus score. The WHO-EYE05 C-MIL system (with high-grade C-MIL and MIS combined) improved consistency between pathologists, with the greatest level of agreement being seen with benign melanosis (74.5%) and high-grade C-MIL (85.4%). Lowest agreements remained between pathologists for low-grade C-MIL (38.7%). Regarding WHO-EYE05 C-MIL scoring and clinical outcomes, local recurrences of noninvasive lesions developed in 8% and 34% of the low- and high-grade cases. Invasive melanoma only occurred in 47% of the cases that were assessed as high-grade C-MIL. This extensive international collaborative study is the first to undertake a comprehensive review of the WHO-EYE05 C-MIL scoring system, which showed good interobserver agreement and reproducibility.</p

A Multicenter Study Validates the WHO 2022 Classification for Conjunctival Melanocytic Intraepithelial Lesions With Clinical and Prognostic Relevance

Several nomenclature and grading systems have been proposed for conjunctival melanocytic intraepithelial lesions (C-MIL). The fourth WHO Classification of Eye Tumors (WHO-EYE04) proposed a C-MIL classification, capturing the progression of noninvasive neoplastic melanocytes from low- to high-grade lesions, onto melanoma in situ (MIS), and then to invasive melanoma. This proposal was revised to the WHO-EYE05 C-MIL system, which simplified the high-grade C-MIL, whereby MIS was subsumed into high-grade C-MIL. Our aim was to validate the WHO-EYE05 C-MIL system using digitized images of C-MIL, stained with hematoxylin and eosin and immunohistochemistry. However, C-MIL cases were retrieved from 3 supraregional ocular pathology centers. Adequate conjunctival biopsies were stained with hematoxylin and eosin, Melan-A, SOX10, and PReferentially expressed Antigen in Melanoma. Digitized slides were uploaded on the SmartZoom platform and independently scored by 4 ocular pathologists to obtain a consensus score, before circulating to 14 expert eye pathologists for independent scoring. In total, 105 cases from 97 patients were evaluated. The initial consensus diagnoses using the WHO-EYE04 C-MIL system were as follows: 28 benign conjunctival melanoses, 13 low-grade C-MIL, 37 high-grade C-MIL, and 27 conjunctival MIS. Using this system resulted in 93% of the pathologists showing only fair-to-moderate agreement (kappa statistic) with the consensus score. The WHO-EYE05 C-MIL system (with high-grade C-MIL and MIS combined) improved consistency between pathologists, with the greatest level of agreement being seen with benign melanosis (74.5%) and high-grade C-MIL (85.4%). Lowest agreements remained between pathologists for low-grade C-MIL (38.7%). Regarding WHO-EYE05 C-MIL scoring and clinical outcomes, local recurrences of noninvasive lesions developed in 8% and 34% of the low- and high-grade cases. Invasive melanoma only occurred in 47% of the cases that were assessed as high-grade C-MIL. This extensive international collaborative study is the first to undertake a comprehensive review of the WHO-EYE05 C-MIL scoring system, which showed good interobserver agreement and reproducibility

International consensus guidelines for scoring the histopathological growth patterns of liver metastasis

BACKGROUND: Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs. METHODS: Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined. RESULTS: Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006). CONCLUSIONS: The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies

Platelet-derived growth factor and its receptors in retinal development

Many polypeptide growth factors are expressed in the mammalian central nervous system (CNS) during development and in the adult. In order to understand the functions of these factors we need to identify their cellular sources and targets. I have concentrated on the peripheral visual system, the optic nerve and retina, which is one of the simplest and best-characterized regions of the CNS. Platelet-derived growth factor (PDGF) and its receptors are expressed in the developing and mature CNS. PDGF is a disulphide-linked dimer of A and B chains, with the structure AA, BB or AB. There are also two types of PDGF receptor with different ligand specificities. PDGF-A only activates the alpha receptor whereas PDGF-B activates both alpha and beta receptors. We have used in situ hybridization to visualize cells in the developing rat retina and optic nerve that express mRNAs encoding the A and B chains of PDGF, and the alpha and beta subunits of the receptors. We have also visualized PDGF-A protein in these tissues by immunohistochemistry. In the retina, PDGF-A mRNA is present in retinal ganglion cells (RGCs) and a subset of amacrine neurons. Transcripts accumulate in RGCs during target innervation and in amacrine neurons around the time of eye opening, suggesting that PDGF-A expression in these cells may be regulated by target derived signals or electrical activity. In the mouse retina, PDGF-A immunoreactivity is present in the cell bodies, dendrites and proximal axons of RGCs, and throughout the inner nuclear layer (INL). PDGF-alpha receptor mRNA is expressed in the retina by astrocytes in the optic fibre layer and by a subset of cells in the INL. Taken together, our data suggest short-range paracrine interactions between PDGF-A and PDGF-alpha receptor, the ligand and its receptor expressed in neighbouring layers of cells in the retina. What is the biological significance of these local interactions. There are never any retinal neuroepithelial cell divisions in the INL, so PDGF-A cannot be a mitogen for retinal cells. We tested the possibility that PDGF-A may act as a survival factor, by injecting recombinant PDGF-AA into P-7 rat eyes and counting the pyknotic cell nuclei at P-10, which is the time of maximal naturally-occurring cell death in the INL, during normal development. PDGF- AA reduced the number of pyknotic cell nuclei by approximately 50[percent] as compared to controls. This implies that PDGF-A may be a survival factor in the retina and furthermore that PDGF-A may be present in limiting amounts in the developing inner nuclear layer (INL). Secondly, what is the role of PDGF in astrocyte development. This question was addressed by neutralizing endogenous retinal PDGF, by using a soluble extracellular portion of the rat PDGF- receptor. Cos cells transfected with expression vector pR[alpha]17, encoding the mutant receptor were injected into the vitreous, behind the lens. As compared to controls, the presence of the soluble extracellular alpha receptor significantly reduced the migration of the astrocytes across the retina and caused their processes to fasiculate. In the optic nerve, PDGF-A immunoreactivity is present in astrocytes but apparently not in the retinal ganglion cell axons. PDGF-alpha receptor cells in the optic nerve first appear near the optic chiasm and subsequently spread to the retinal end of the nerve: these PDGF-alpha receptor positive cells are probably oligodendrocyte precursors. RNA transcripts encoding the PDGF-B and PDGF-beta receptor are expressed by cells of the hyaloid and mature vascular systems in the eye and optic nerve

Hemangioblastoma of the optic nerve

Optic nerve hemangioblastoma is a rare tumor that is usually unilateral and most commonly occurs in the context of von Hippel-Lindau disease. Differential diagnosis is based on clinical history and imaging. Magnetic resonance imaging with gadolinium enhancement is the most useful imaging modality as it can reveal flow voids and an absence of dural attachment, differentiating optic nerve hemangioblastoma from other more commonly encountered optic nerve tumors. Optic nerve hemangioblastoma are usually well-circumscribed vascular lesions composed of stromal cells and vascular endothelial cells. These lesions are diagnosed at a mean age of 37 years and can be asymptomatic, but over time, patients may develop reduction in vision, proptosis, and pain. Surgical excision is well described via orbital, transsphenoidal, or transcranial approaches. Given the risks associated with surgery, a stepwise conservative approach is advocated by most clinicians in the absence of severe symptoms. Although uncommon, this optic nerve tumor should be considered in young patients presenting with pain, proptosis, and optic nerve pallor, with or without a history of von Hippel-Lindau disease

Optic nerve haemangioblastoma: signs of chronicity

Optic nerve haemangioblastomas remain exceedingly rare extrinsic tumours of the optic nerve, often associated with von Hippel-Lindau disease. The authors report a 25-year-old female with a slowly progressive unilateral optic nerve lesion, causing reduced vision and bilateral optic tract oedema. A diagnosis of optic nerve haemangioblastoma with piloid gliosis was made histologically after surgical resection. This is the first reported case of such dual pathology occurring in the optic nerve. The patient has been monitored without further adjuvant treatment, and has not had a recurrence to date, at 6 years of follow-up

Chronic Macular Oedema as a Late MIRAgel-Related Complication

Background: MIRAgel® (MIRA, Waltham, MA, USA) is a hydrogel scleral buckle introduced in 1979 to treat rhegmatogenous retinal detachments. Its use was discontinued because late complications that require surgical removal were reported. Methods: Case report. Results: We report a case of left eye MIRAgel® buckle surgery 28 years ago presenting with a tender palpable erythematous swelling at the lower lid, with marked conjunctival chemosis and progressive ophthalmoplegia. Imaging revealed a large, well-defined, horseshoe-shaped lesion in the extraconal space of the left orbit with globe distortion, with histological confirmation of an expanded hydrogel buckle. He recovered well following removal of the explant but developed chronic macular oedema a year later, which persisted despite sub-Tenon’s triamcinolone injections. Repeat imaging demonstrated remaining hydrogel explant. Macular oedema settled well upon successful surgical removal with no recurrence to date. Conclusion: Our case is the first to describe macular oedema as a late MIRAgel-related complication, with complete removal of the explant being the definitive treatment. Macular oedema indicates postoperative inflammation secondary to the remaining explant fragments. Given the friability of hydrolysed MIRAgel®, we recommend ophthalmologists to warn patients regarding the possibility of further inflammation in the globe or the orbit in case of incomplete removal