Complete Response to Immunotherapy Using Pembrolizumab in a Patient With Conjunctival Squamous Cell Carcinoma With Nodal Metastasis.

A 92-year-old woman presented with a large bulbar conjunctival mass in the OD. She also had a palpable parotid mass which on fine needle aspiration biopsy confirmed to be metastatic squamous cell carcinoma. The conjunctival mass was biopsied to confirm the diagnosis of squamous cell carcinoma with positive programmed cell death ligand 1 expression and a high tumor mutation burden. She was treated with pembrolizumab and had complete resolution of the conjunctival mass and the associated parotid metastasis after just 2 cycles of treatment. This case underscores the promising role of immune checkpoint inhibitors in the treatment of conjunctival squamous cell carcinoma, especially when surgery is associated with significant ocular morbidity, in patients who may not be good surgical candidates, or in patients with metastasis.

Histologic and Genomic Analysis of Conjunctival SCC in African and American Cohorts Reveal UV Light and HPV Signatures and High Tumor Mutation Burden.

Purpose: Conjunctival squamous cell carcinoma (conjSCC) is more prevalent and aggressive in sub-Saharan African countries compared with the rest of the world. This study aims to compare the genomic, immunophenotypic, and histologic features between patients from the United States and Ethiopia, to identify etiopathogenic mechanisms and unveil potential treatment strategies. Methods: We compared histologic features and mutational profiles using whole exome sequencing, high-risk human papillomavirus (HPV) status, PD-L1 expression, and tumor-infiltrating lymphocytes in conjSCC tumors of patients from Ethiopia (ETH; n = 25) and the United States (from MD Anderson [the MDA cohort]; n = 29). Genomic alterations were compared with SCCs from other anatomic sites using data from The Cancer Genome Atlas. Results: Solar elastosis was seen in 78% of ETH and 10% of MDA samples. Thicker tumors had higher density of CD8+ and CD3+ cells. HPV status was similar between the cohorts (ETH = 21% and MDA = 28%). The mean tumor mutation burden (TMB) was significantly higher in conjSCC (3.01/Mb, log10) and cutaneous SCC compared other SCC subtypes. ETH samples had higher TMB compared to the MDA cohort (3.34 vs. 2.73). Mutations in genes associated with ultraviolet light (UV) signature were most frequently encountered (SBS7b = 74% and SBS7a = 72%), with higher prevalence in the ETH cohort, whereas SBS2 and SBS13 signatures were more common among MDA HPV+ conjSCCs. Conclusions: Our findings suggest that UV exposure may play a major role in conjSCC, with a higher prevalence in the ETH cohort compared with the MDA cohort, where HPV also contributes.

Neoadjuvant Chemotherapy Alone or Combined with EGFR-Directed Targeted Therapy or Anti-PD-1 Immunotherapy for Locally Advanced Lacrimal Sac and Nasolacrimal Duct Carcinomas.

BACKGROUND/AIMS: We describe our findings in patients with locally advanced lacrimal sac and nasolacrimal duct (NLD) carcinoma who received neoadjuvant systemic therapy. METHODS: We identified patients with locally advanced primary lacrimal sac/NLD carcinoma treated with neoadjuvant systemic intravenous therapy at our institution during 2017-2019. RESULTS: The study included seven patients, four men and three women; the mean age was 60.4 years (range: 43-76). All patients had locally advanced disease with significant orbital soft tissue invasion with or without skull base invasion making eye-sparing surgery not feasible as an initial step. Three patients had poorly differentiated squamous cell carcinoma; two, invasive carcinoma with basaloid and squamous features; one, high-grade carcinoma with features suggestive of sebaceous differentiation; and one, undifferentiated carcinoma. The neoadjuvant regimens were cisplatin and docetaxel (n = 1); carboplatin and docetaxel (n = 1); paclitaxel and cetuximab (n = 1); carboplatin, paclitaxel, and cetuximab (EGFR inhibitor) (n = 2); cisplatin, docetaxel, and pembrolizumab (anti-PD-1 immunotherapy) (n = 1); and carboplatin, paclitaxel, and pembrolizumab (n = 1). All patients had radiologic disease regression, and one patient had radiologic near-complete response. After neoadjuvant therapy, all patients underwent wide local excision and adjuvant concurrent chemoradiation. Two patients had a complete pathologic response. At a median follow-up period of 13 months after chemoradiation (range, 8-54 months), all patients were alive without evidence of disease. One patient had nodal metastasis treated with lymph node dissection and adjuvant chemoradiation. CONCLUSIONS: Neoadjuvant systemic therapy can shrink tumors in patients with locally advanced primary lacrimal sac/NLD carcinoma with orbital or skull base invasion.

Lacrimal Gland Adenocarcinoma Clinicopathologic Features and Outcomes Compared With Those of Lacrimal Gland Adenoid Cystic Carcinoma.

PURPOSE: Lacrimal gland (LG) adenocarcinomas (ACs) are rare, with limited data. We compared clinicopathologic features and local recurrence, distant metastasis, and survival rates between LG AC and LG adenoid cystic carcinoma (ACC). METHODS: The records of LG AC patients treated from 2008 to 2022 and LG ACC patients treated from 1998 to 2022 at the same center were retrospectively reviewed. RESULTS: The study included 20 patients with AC; 10 de-novo AC, 10 ex-pleomorphic AC; and 51 ACC patients. The median age at diagnosis was 61 years for de-novo AC, 54 years for ex-pleomorphic AC, and 45 years for ACC. All groups had male predominance. The initial T category was T2 in 50% (5/10) of de-novo ACs; 60% (6/10) of ex-pleomorphic ACs; and 59% (30/51) of ACCs. Perineural invasion was present in 33% (5/15) of ACs and 90% (45/50) of ACCs (p < 0.001). Of the 20 AC patients, 14 had eye-sparing surgery; 4 had orbital exenteration; and 2 had unresectable disease. All AC patients received postoperative radiotherapy and 15 (75%) received concurrent chemotherapy. Fourteen AC patients were tested for human growth factor receptor 2 expression, and 10 (71%) were human growth factor receptor 2 positive; 5 received human growth factor receptor 2-targeted therapy. AC and ACC had similar 5-year recurrence rates (20% and 33%, respectively, p = 0.31) and metastasis rates (20% and 34%, respectively, p = 0.30). de-novo AC, ex-pleomorphic AC, and ACC had similar 5-year disease-specific survival rates (80%, 79%, and 81%, respectively, p > 0.99). CONCLUSIONS: LG AC and ACC have similar baseline clinicopathologic features, except that perineural invasion is more common in ACC, and similar recurrence, metastasis, and survival rates. Human growth factor receptor 2-targeted therapy may be appropriate in some patients with LG AC.

Nectin-4 expression in a subset of cutaneous adnexal carcinomas: A potential target for therapy with enfortumab vedotin.

BACKGROUND: Enfortumab vedotin (EV) is an antibody-drug conjugate directed against Nectin-4 that is used to treat urothelial carcinoma. Nectin-4 is inherently expressed in the skin and adnexal structures. Since therapeutic options for cutaneous adnexal carcinomas are limited, we sought to evaluate Nectin-4 expression in adnexal carcinomas and benign adnexal neoplasms to identify tumors that are potentially targetable with EV. METHODS: Eight sebaceous carcinomas (seven periocular and one lymph node metastasis), eight digital papillary adenocarcinomas, seven squamoid eccrine ductal carcinomas, eight poromas, eight trichilemmomas, and seven sebaceous adenomas were subjected to immunohistochemical staining for anti-Nectin-4 antibody. H-scores for Nectin-4 expression were calculated. RESULTS: Benign adnexal neoplasms had a significantly lower mean (±SD) Nectin-4 H-score (142.6 ± 39.1) than did the adnexal carcinomas (198 ± 90.8; p = 0.006). Nectin-4 was expressed in 91% (21/23) of adnexal carcinomas. Sebaceous carcinomas frequently exhibited high expression of Nectin-4 (88% [7/8]), with a mean (±SD) H-score (258.1 ± 58.4) significantly higher than those for digital papillary adenocarcinomas (197.5 ± 52.5; p = 0.035) and squamoid eccrine ductal carcinomas (131.4 ± 114.1; p = 0.031). Sebaceous carcinomas also had significantly higher H-scores than did sebaceous adenomas (186.4 ± 25.0; p = 0.013). CONCLUSIONS: Increased Nectin-4 expression in a subset of cutaneous adnexal carcinomas, particularly sebaceous carcinomas, reveals that EV is a potential therapeutic option for these tumors.

Orbital and periocular complications in patients with sinonasal tumours with orbital invasion.

AIMS: The purpose of this study was to determine the frequency and associated risk factors of orbital/periocular complications in patients with sinonasal tumour with orbital invasion managed with eye-sparing treatments. METHODS: A retrospective case series of patients with primary sinonasal tumour with orbital invasion from January 2008 to December 2018. Patient factors were compared between the following groups: (1)patients with orbital/periocular complications versus those who did not and (2) patients who needed secondary oculoplastic surgical procedures versus those who did not. RESULTS: Out of 80 patients, 48 had eye-sparing surgery, 8 had orbital exenteration and 24 were managed non-surgically. The most common histology was squamous cell carcinoma (n=28, 35%). Among the eye-sparing treatment group, 51/72 patients experienced one or more orbital/periocular complication(s), with motility deficit (N=26, 36%) being the most frequent. Factors associated with higher risk of complications included tumour involving the orbital floor (p=0.019), clinical disease stage III/IV (p=0.038), maxillectomy (p=0.004), resection of the orbital floor (p=0.027) and cigarette smoking (p=0.041). Tumour involving the orbital floor had an OR of 3.9 (95% CI 1.3 to 11.6, p=0.016) in predicting orbital/periocular complication. In the eye-sparing surgery group, the most frequent secondary oculoplastic procedures was dacryocystorhinostomy (n=6, 13%). The use of a free flap in reconstruction had an OR of 8.2 (95% CI 2.1 to 31.8, p=0.002) in predicting need for secondary oculoplastic surgery. CONCLUSION: Majority of patients with sinonasal tumours and secondary orbital invasion were managed with eye-sparing multidisciplinary treatments. Preservation of the eye can lead to reasonably good functional outcome despite expected orbital and periocular complications.

Immune Checkpoint Inhibitor Therapy for Orbital and Ocular Adnexal Squamous Cell Carcinomas: International Society of Ocular Oncology President's Lecture, 2022.

To summarize an invited lecture topic from the proceedings of the International Society of Ocular Oncology meeting in Leiden in 2022. Mechanism of action, indications, and the authors' clinical experience with immune checkpoint inhibitors in patients with locally advanced ocular adnexal squamous cell carcinoma are summarized. Several cases of locally advanced conjunctival, eyelid, and lacrimal sac/duct squamous cell carcinoma that were successfully treated with immune checkpoint inhibitors (PD-1 directed) are shared. Immune checkpoint inhibitors are effective at reducing tumor size and enabling eye-preserving surgery in patients with locally advanced ocular adnexal squamous cell carcinoma with orbital invasion. They present a new strategy for the treatment of locally advanced squamous cell carcinoma of the ocular adnexa and orbit.

Graves' Eye Disease: Clinical and Radiological Diagnosis.

Graves' disease is an autoimmune disorder in which hyperthyroidism results in various systematic symptoms, with about 30% of patients presenting with Graves' eye disease (GED). The majority of patients with GED develop mild symptoms, including eyelid retraction, exposure of the globe, superior rectus-levator muscle complex inflammation, and fat expansion, leading to exophthalmos. More severe cases can result in extraocular muscle enlargement, restricted ocular movement, eyelid and conjunctival edema, and compression of the optic nerve leading to compressive optic neuropathy (CON). GED severity can be classified using the Clinical Activity Score, European Group on Graves' Orbitopathy scale, NO SPECS Classification system, and VISA system. CT and MRI aid in the diagnosis of GED through the demonstration of orbital pathology. Several recent studies have shown that MRI findings correlate with disease severity and can be used to evaluate CON. Mild cases of GED can be self-limiting, and patients often recover spontaneously within 2-5 years. When medical treatment is required, immunomodulators or radiotherapy can be used to limit immunologic damage. Surgery may be needed to improve patient comfort, preserve the orbit, and prevent vision loss from optic nerve compression or breakdown of the cornea.

The combined profunda artery perforator-gracilis flap for immediate facial reanimation and resurfacing of the radical parotidectomy defect.

BACKGROUND: A radical parotidectomy with facial nerve sacrifice results in facial nerve paralysis as well as a volume and often cutaneous defect. Prior experience with nerve grafting and static suspension has yielded suboptimal results. The present report aims to examine the feasibility and outcomes of a combined free gracilis and profunda artery perforator (PAP) flap from a single donor site can reconstruct these extensive defects and potentially restore dynamic facial reanimation even in the setting of adjuvant radiation. PATIENTS AND METHODS: A retrospective review of 10 patients (6 males and 4 females) was performed from 2016 to 2020 that underwent a combined PAP-gracilis reconstruction of a radical parotidectomy defect. All patients (mean age: 71.3 years; range: 52-83 years) received adjuvant radiation. A chimeric PAP-gracilis flap requiring a single microvascular anastomosis was performed in three patients while the remaining patients underwent a double free flap reconstruction. RESULTS: The gracilis flap was innervated using the facial nerve stump, spinal accessory and massecteric nerve in three patients each. One patient's gracilis was innervated using the hypoglossal nerve. Three patients also underwent nerve grafting of the facial nerve. One patient was taken back to the operating room for a hematoma in the recipient site and there were not flap losses of either the PAP or gracilis flap. Two patients had delayed wound healing of the donor site that healed with conservative management. Average follow-up was 11.1 months (range: 8.1-19.5 months). Six patients were able to achieve dynamic animation while the others obtained a static reconstruction and did not have issues with drooling, eating, or speaking. CONCLUSIONS: Immediate functional muscle transfer can potentially restore dynamic facial reanimation even following radiation. Combining reconstruction using a PAP-gracilis flap addresses the soft tissue deficit and facial paralysis using a single donor site in a single operation.

Visual outcome and ocular complications in patients with lacrimal gland carcinoma after eye-sparing surgery and adjuvant radiation therapy.

BACKGROUND: We report visual outcomes and ocular complications in patients with lacrimal gland carcinoma who had eye-sparing surgery followed by radiotherapy. METHODS: This review included consecutive patients with lacrimal gland carcinoma who underwent eye-sparing surgery and adjuvant radiotherapy or concurrent chemoradiation therapy between 2007 and 2018. Clinical data, including details of ophthalmological examinations and radiation treatment were reviewed. RESULTS: The study included 23 patients, 15 males and 8 females, with median age 51 years. Twenty patients (87%) received intensity-modulated proton therapy; 3 (13%) received intensity-modulated radiotherapy. Nineteen patients (83%) received concurrent chemotherapy. After a median follow-up time of 37 months (range: 8-83), 13 patients (57%) had best-corrected visual acuity 20/40 or better, 3 (13%) had moderate vision loss (between 20/40 and 20/200) and 7 (30%) had severe vision loss (20/200 or worse). The most common ocular complications were dry eye disease (21 patients; 91%), radiation retinopathy (16; 70%) and cataract progression (11; 49%). Tumour crossing the orbital midline (p=0.014) and Hispanic ethnicity (p=0.014) were associated with increased risk of severe vision loss. The risk of radiation retinopathy was significantly different among the three racial groups; Hispanic patients (n=3) had the highest rate of retinopathy (p<0.001). Tumour size, initial T category and total prescribed radiation dose were not significantly associated with severe vision loss. CONCLUSION: Eye-sparing surgery followed by adjuvant radiotherapy in patients with lacrimal gland carcinoma has a reasonable overall visual prognosis. Patients with tumours crossing the orbital midline and Hispanic patients have a higher risk of severe vision loss.

Immune checkpoint inhibitors for treatment of periorbital squamous cell carcinoma.

PURPOSE: To report on the outcomes of immunotherapy in patients with locally advanced periorbital squamous cell carcinoma. METHODS: We performed a retrospective chart review of seven consecutive patients with locally advanced periorbital cutaneous squamous cell carcinoma treated with anti-PD-1 immunotherapy. Treatments and therapeutic outcomes were reviewed. RESULTS: Of the seven patients, six were treated with cemiplimab, and one was treated with pembrolizumab. Five patients were treated with immunotherapy as neoadjuvant therapy before planned surgical resection; two patients received immunotherapy for treatment of advanced recurrent lesions deemed unresectable following multiple previous excisions and radiation therapy. In all seven patients, measurable clinical and/or radiologic response was observed. CONCLUSIONS: Our findings support the emerging role of anti-PD-1 immunotherapy in the management of locally advanced periorbital cutaneous squamous cell carcinoma.

Specific location of ocular adnexal lymphoma and mortality: an international multicentre retrospective study.

AIMS: To examine whether the specific location of ocular adnexal lymphoma (OAL) and the American Joint Committee on Cancer (AJCC) TNM tumour stage are prognostic factors for mortality in the main OAL subtypes. METHODS: Clinical and survival data were retrospectively collected from seven international eye cancer centres. All patients from 1980 to 2017 with histologically verified primary or secondary OAL were included. Cox regression was used to compare the ocular adnexal tumour locations on all-cause mortality and disease-specific mortality. RESULTS: OAL was identified in 1168 patients. The most frequent lymphoma subtypes were extranodal marginal zone B-cell lymphoma (EMZL) (n=688, 59%); follicular lymphoma (FL) (n=150, 13%); diffuse large B-cell lymphoma (DLBCL) (n=131, 11%); and mantle cell lymphoma (MCL) (n=89, 8%). AJCC/TNM tumour-stage (T-stage) was significantly associated with disease-specific mortality in primary ocular adnexal EMZL and increased through T-categories from T1 to T3 disease. No associations between AJCC/TNM T-stage and mortality were found in primary ocular adnexal FL, DLBCL, or MCL. EMZL located in the eyelid had a significantly increased disease-specific mortality compared with orbital and conjunctival EMZL, in both primary EMZL and the full EMZL cohort. In DLBCL, eyelid location had a significantly higher disease-specific mortality compared with an orbital or lacrimal gland location. CONCLUSION: Disease-specific mortality is associated with AJCC/TNM T-stage in primary ocular adnexal EMZL patients. Lymphoma of the eyelid has the highest disease-specific mortality in primary EMZL, and in the full cohort of EMZL and DLBCL patients.

Update on Immune Checkpoint Inhibitors for Conjunctival Melanoma.

The management of conjunctival melanoma is challenging due to the more frequent local recurrence and metastasis compared to other conjunctival neoplasms. Locally advanced conjunctival melanoma may require an orbital exenteration, and treatment options for metastatic conjunctival melanoma have been limited until recently. This review aims to provide comprehensive updates on immunotherapy for conjunctival melanoma, focusing on immune checkpoint inhibitors. We reviewed the available literature on the use of immunotherapy for the treatment of conjunctival melanoma. Systemic immunotherapy, particularly with checkpoint inhibitors, has recently been reported to have improved outcomes for patients with conjunctival melanoma. Immune checkpoint inhibitors that are currently approved by the US Food and Drug Administration for melanoma include anti-PD-1 (nivolumab and pembrolizumab), anti-PDL-1 (avelumab and atezolizumab), and anti-CTLA-4 inhibitors (ipilimumab). Most recent reports described using immune checkpoint inhibitors in patients with locally advanced conjunctival melanoma in an attempt to avoid orbital exenteration or in patients with metastatic conjunctival melanoma.Although the current data are limited to case reports and small case series, eye care providers should be aware of the potential role of immunotherapy for patients with locally advanced, recurrent, or metastatic conjunctival melanoma.

Multifocal recurrence of pleomorphic adenoma of the lacrimal gland.

Purpose: To report two cases of multifocal recurrent pleomorphic adenoma of the lacrimal gland, and to highlight the clinical and magnetic resonance imaging findings. Observations: The authors present two patients with recurrent pleomorphic adenoma of the lacrimal gland. During their previous primary surgical resection at outside institutions, one patient reportedly had a macroscopically complete excision, while the second patient had violation of the pseudocapsule. Both patients had multiple recurrent nodular lesions detected on magnetic resonance imaging with extension beyond the surgical field of the primary resection. Both underwent subsequent lateral orbitotomy with resection of all identifiable nodules and histopathology was consistent with pleomorphic adenoma. In one patient, two nodules were found two months after the surgery, which grew slowly over the last four years. The second patient had no clinical or radiologic sign of recurrence at last follow up, three years after resection of multinodular recurrence. Conclusions and importance: The two cases demonstrate the challenges in the management of multifocal recurrence of lacrimal gland pleomorphic adenoma. The multicentric nature of recurrent lesions in these two cases increase the risk of future recurrence, malignant transformation, and morbidity caused by surgery and radiation. Magnetic resonance imaging is the imaging study of choice, but it may still be inadequate in identifying all the nodules.