Molecular profiling of a primary cutaneous signet-ring cell/histiocytoid carcinoma of the eyelid.

Primary cutaneous signet-ring cell/histiocytoid carcinoma of the eyelid is a rare and aggressive neoplasm. Fewer than 50 cases have been reported in the literature, and the genetic driving mutations are unknown. Herein, we present a case of this rare disease along with the results of molecular profiling via targeted next-generation sequencing. The patient is an 85-year-old man who presented with left eyelid swelling initially thought to be a chalazion. After no response to incision and drainage and antibiotics, an incisional biopsy was performed. Histopathologic sections revealed a proliferation of cells with signet-ring and histiocytoid morphology arranged singly and in cords infiltrating the dermis, subcutaneous tissue, and muscle. The lesional cells strongly expressed cytoplasmic cytokeratin 7 and nuclear androgen receptor. Next-generation sequencing revealed a CDH1 mutation, which is known to confer signet-ring morphology in other carcinomas. Pathogenic mutations in NTRK3, CDKN1B, and PIK3CA were also detected. To our knowledge, this is the first documented genetic analysis of this rare disease with findings that offer insights into disease pathogenesis and potential therapeutic targets.

Malignant optic glioma masked by suspected optic neuritis and central retinal vein occlusion.

Malignant optic glioma presents a clinical and diagnostic challenge, as early imaging findings overlap with other more common causes of optic nerve enhancement and enlargement, potentially leading to delay in diagnosis. This rare diagnosis carries an extremely poor prognosis, with death usually occurring within 1 year. We present a case of malignant optic glioma that was initially diagnosed as optic neuritis and central retinal vein occlusion, and we emphasize the importance of serial imaging and definitive biopsy to promote early diagnosis and treatment of this entity.

Orbital floor fracture with entrapment: Imaging and clinical correlations in 45 cases.

Orbital floor fractures (OFF) with entrapment require prompt clinical and radiographic recognition for timely surgical correction. Correct CT radiographic interpretation of entrapped fractures can be subtle and thus missed. We reviewed the clinical, radiographic and intraoperative findings of 45 cases of entrapped OFF to correlate pre- and intraoperative findings with radiography. Retrospective review and statistical analysis of 45 patients with OFF using the chi squared and Kruskal-Wallis tests. Main outcome measures included patient demographics, clinical features, radiologic interpretation, intraoperative findings, and treatment outcomes. Twenty-one cases (47%) had radiologic evaluations of orbital CT scans that included commentary on possible entrapment. Intraoperatively, 16 (76%) of these patients had the inferior rectus muscle incarcerated in the fracture, while 5 (24%) patients had incarceration of the orbital fat. Possibility of entrapment was not commented on in the radiology reports of the remaining 24 (53%) cases. Intraoperatively, 13 (54%) of these patients had the inferior rectus muscle incarcerated in the fracture, while 11 (46%) patients had incarceration of the orbital fat. It is vital to assess the possibility of entrapment, especially in young patients, in the setting of OFF as a delay in diagnosis may lead to persistent diplopia, disfigurement, or bradycardia. Most radiology reports did not mention the possibility of entrapment in this cohort. A key concept is that entrapment occurs when any orbital tissue (muscle or fat) is trapped in the fracture site.

Neuropathic Pain Following Poly-L-Lactic Acid (Sculptra) Injection.

Injectable fillers have become a prevalent means of facial rejuvenation and volume expansion. While typically well tolerated, serious complications have been reported. The authors present a case in which an otherwise healthy female with a history of multiple filler injections including poly-L-lactic acid, developed 3 weeks of neuropathic pain in the left temporal fossa following injection. To the best of the authors knowledge, neuropathic pain has not been reported as a complication following poly-L-lactic acid injection. The patient was treated with an injection of steroid and long-acting anesthetic with resolution of symptoms.

Intraocular pressure changes in emergent surgical decompression of orbital compartment syndrome.

IMPORTANCE: Orbital compartment syndrome is an acute rise in intraorbital volume resulting in increased intraorbital pressure and possible ischemic compromise of the optic nerve. Tonometric pressure measurement of intraocular pressure can aid surgeons in the diagnosis of this condition and in choosing the need to proceed with emergent surgical intervention. In addition, we present an unexpected cause of orbital compartment syndrome following routine frontal sinus irrigation. OBSERVATIONS: An emergent lateral canthotomy and cantholysis followed by endoscopic medial wall decompression were performed, with intraocular pressure measurements performed throughout the evolution of this successful, and vision sparing, set of procedures. The techniques and continuous improvements in intraocular pressure measurements are described. CONCLUSIONS AND RELEVANCE: There are only rare reports of the progression of intraocular pressure prior to, and concurrent with, surgical orbital decompression. While no absolute threshold for intraocular pressure exists for when surgical decompression should be performed, the decision of when and which decompression procedures to undertake should be based on clinical judgment and experience. Availability of tonometry in the operating room serves to measure response to management in these rare but challenging settings where intervention may be required to prevent irreversible visual loss.

Ophthalmic complications of targeted cancer therapy and recently recognized ophthalmic complications of traditional chemotherapy.

As our understanding of cancer pathophysiology has increased, so have the number of targeted therapeutic agents available. By targeting specific molecules involved in tumorigenesis, targeted therapeutic agents offer the potential for significant efficacy against tumor cells while minimizing the adverse effects. We highlight the recently recognized ophthalmic complications of targeted cancer therapy, as well as recently recognized complications of traditional chemotherapeutic agents.

Correlation of American Joint Committee on Cancer T category for eyelid carcinoma with outcomes in patients with periocular Merkel cell carcinoma.

PURPOSE: Merkel cell carcinoma is a rare but potentially deadly cancer of the eyelid. To date, no studies have reported on clinical parameters at initial presentation of the eyelid tumor that may correlate with disease-free survival (DFS). The purpose of this study was to determine whether the American Joint Committee on Cancer (AJCC) T category for eyelid carcinoma correlates with metastasis and DFS in patients with Merkel cell carcinoma of the periocular region. METHODS: This is a retrospective cohort study from a tertiary referral cancer center. All consecutive patients treated for eyelid or periocular Merkel cell carcinoma between November 1, 1998, and November 1, 2012, were reviewed. The main outcome measures included AJCC T category for eyelid carcinoma and Merkel cell carcinoma at presentation, nodal metastasis at presentation, metastasis during follow up, and DFS. RESULTS: The study included 18 patients, 7 men and 11 women, with median age of 68.5 years. The AJCC T categories for both eyelid carcinoma and Merkel cell carcinoma were significantly correlated with DFS. Using the T categories for eyelid carcinoma, when TX and T2a were grouped into a single category and T2b and T3a into another category, the estimated DFS rate at 3 years was 100% for patients with TX or T2a lesions and 57% for patients with T2b or T3a lesions (p=0.0298). Four patients (22%) had lymph node metastasis at presentation. Presence of lymph node metastasis at presentation was the strongest single predictor of shorter DFS and an increased risk of metastasis during follow up (p=0.0222). CONCLUSIONS: The AJCC eyelid carcinoma T at presentation correlates with DFS in patients with Merkel cell carcinoma of the periocular region. The DFS rate at 3 years was significantly worse for patients with T2b or more extensive tumors by eyelid carcinoma T category. Presence of lymph node metastasis at presentation was predictive of shorter DFS and an increased risk of metastasis during follow up.

Impact of AJCC 'T' designation on risk of regional lymph node metastasis in patients with squamous carcinoma of the eyelid.

BACKGROUND/AIMS: Squamous cell carcinoma (SCC) of eyelid is the second most common cancer of the eyelid with the potential for nodal metastasis. The purpose of this report is to determine whether primary tumour size and 'T' designation in the American Joint Committee on Cancer (AJCC) staging system, 7th edition, correlate with the risk of regional nodal metastasis in patients with eyelid SCC. METHODS: Sixty-five consecutive patients with eyelid SCC treated by one ophthalmologist from March 1999 through July 2011 were included in this retrospective cohort study. Disease was staged using the AJCC 7th edition criteria based on clinical, pathological and radiographical data. Main outcome measures included regional lymph node metastasis at presentation, local recurrence, distant metastasis and survival at last follow-up. RESULTS: 40 men and 25 women had a median age of 67.0 years (range 41-89). TNM designations at presentation per the AJCC 7th edition were as follows: T1N0M0, 6 patients; T2aN0M0, 11 patients; T2bN0M0, 17 patients; T2bN1M0, 2 patients; T3aN0M0, 22 patients; T3bN0M0, 2 patients; T3bN1M0, 1 patient; T4N0M0, 3 patients; and T4N1M0, 1 patient. Median follow-up was 27 months (range 1-150). Four patients had nodal metastasis at presentation. Two of these four patients had T2bN1M0 disease, one had T3bN1M0 disease and one had T4N1M0 disease. Two patients, with T3aN0M0 and T4N0M0 tumours, respectively, at presentation, developed lymph node metastasis at 2 weeks and 8.4 months, respectively, after tumour excision. The four patients who had lymph node metastases at presentation and the two who developed lymph node metastases during follow-up had tumours ≥18 mm in greatest dimension or T2b or higher at presentation. Seven local recurrences were observed during follow-up. Two-year and 3-year recurrence-free survival rates were 93% (95% CI 80% to 98%) and 82% (95% CI 63% to 92%), respectively. No distant metastasis or tumour-related death was observed during follow-up. The 2-year and 3-year disease-free survival rates were 90% (95% CI 77% to 96%) and 79% (95% CI 61% to 89%), respectively. CONCLUSIONS: Regional nodal metastases were observed among patients who presented with tumours >T2b. Tumour size and the AJCC TNM designations correlate with metastasis and should be reported more often for eyelid SCCs to allow comparisons across centres.

Clinical value of magnetic resonance imaging and other baseline testing for conjunctival mucosa-associated lymphoid tissue lymphoma.

Abstract The objective of this study was to assess the value of magnetic resonance imaging (MRI) of the orbit for conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma. The yield of other staging tests at baseline were also evaluated. Twenty-one consecutive patients treated for conjunctival MALT lymphoma were retrospectively studied. Lymphoma was staged according to both the Ann Arbor system and the seventh edition of the AJCC [American Joint Committee on Cancer] cancer staging manual. Findings on MRI of the orbit, whole-body positron emission tomography/computed tomography (PET/CT), CT of the chest/abdomen/pelvis, bone marrow (BM) biopsy and gastrointestinal (GI) endoscopy were recorded. Seventeen patients had orbital MRI. Fourteen of 17 patients (82%) with obvious conjunctival MALT lymphoma on clinical examination had a negative MRI scan. Only three patients had subtle conjunctival enhancement on orbital MRI. Ann Arbor stage at presentation was as follows: stage IE (15 patients), stage IIE (two patients) and stage IV (four patients). Eighteen of 21 patients had total-body PET/CT; four patients (22%) had hypermetabolic activity evident on PET scan. All 21 patients had bilateral BM biopsies. Fifteen of 21 patients (71%) had GI endoscopy. None of the patients had a positive BM biopsy or findings on GI endoscopy. Our data suggest that orbital MRI has a very low yield for identification of conjunctival MALT lymphoma. Clinical examination is critical in diagnosing and assessing treatment response in conjunctival MALT lymphoma. The yield for GI endoscopy and BM biopsy may also be low in staging of conjunctival MALT lymphoma.

Primary orbital melanoma in association with cellular blue nevus.

PURPOSE: To describe 3 cases of primary orbital melanoma associated with either known or subsequently discovered cellular blue nevus. METHODS: The clinical records and surgical specimens of 3 patients who underwent orbital exenteration for primary orbital melanoma and who had a cellular blue nevus diagnosed before or after detection of the melanoma were retrospectively reviewed. RESULTS: All 3 patients presented with signs and symptoms of an orbital mass. Subsequent biopsy revealed invasive melanoma. One patient had a known history of congenital cellular blue nevus of the eyelid from which the orbital melanoma originated. The other 2 patients had no known history of cutaneous pigmentation or blue nevus. In these 2 patients, the cellular blue nevus was detected on pathologic review of the orbital exenteration specimen (1 patient) or surgical biopsy specimen (1 patient). All 3 patients underwent total body positron emission tomography/computed tomography, and in all 3 results were negative for other sites of disease involvement. In the 2 patients without a previously known nevus a total body skin check was negative for other primary melanoma lesions. All 3 patients underwent orbital exenteration followed by postoperative radiation therapy. CONCLUSIONS: Thorough evaluation of biopsy specimens of "primary" orbital melanoma is warranted to ensure identification of any associated blue nevus because blue nevi are precursor lesions for orbital melanoma, and the presence of a blue nevus would support a primary orbital melanoma rather than a metastatic lesion. Patients with a known blue nevus of the periocular skin and ocular adnexa should be monitored closely for signs of malignant transformation.

Multidisciplinary management of lacrimal sac/nasolacrimal duct carcinomas.

PURPOSE: To determine the rates of globe-sparing treatment and useful final visual function in patients with primary lacrimal sac/nasolacrimal duct carcinomas treated with multidisciplinary therapy. METHODS: The medical records of 14 patients with primary lacrimal sac/nasolacrimal duct carcinoma treated at 1 institution were retrospectively reviewed. RESULTS: The patients were 9 men and 5 women; the median age at diagnosis was 58.5 years (range, 45-73 years). Seven patients presented with epiphora, 7 with a palpable mass in the inferomedial orbit, and 2 with dacryocystitis. In 3 patients, the diagnosis of cancer was not considered until during or after dacryocystorhinostomy. Seven patients had squamous cell carcinoma, 2 transitional cell carcinoma, 2 adenoid cystic carcinoma, and 1 each adenocarcinoma, poorly differentiated carcinoma, and inverted papilloma with carcinoma in situ transformation. Nine patients underwent surgical resection of the lacrimal sac and nasolacrimal duct and resection of the medial upper and lower eyelids, including canaliculi, partial ethmoidectomy, and medial maxillectomy. One patient underwent lacrimal sac biopsy only as another primary malignancy was discovered during the work-up for systemic disease. Four patients underwent orbital exenteration because of extensive involvement of the orbital soft tissue. Radiotherapy was recommended for 13 patients; in 1 patient, radiotherapy was not recommended because the patient had an inverted papilloma with carcinoma in situ transformation that was completely excised. The median radiation dose was 60 Gy. Eight patients received chemotherapy either concurrent with radiation therapy (5 patients), as neoadjuvant treatment (1 patient), or for progressive or metastatic disease (3 patients). The median follow-up time was 27 months (range, 6-96 months). In 10 patients, the globe was spared. In 9 of these 10 patients, visual acuity was the same as at baseline or better than 20/40 at last follow up. CONCLUSIONS: With multidisciplinary therapy, the eye can be spared and reasonable visual function can be preserved in most patients with primary lacrimal sac/nasolacrimal duct carcinomas.

Multidisciplinary management of primary adenoid cystic carcinoma of the eyelid with perineural invasion.

Primary cutaneous adenoid cystic carcinoma of the eyelid is an extremely rare entity with the propensity to recur locally, spread to regional lymph nodes, and invade perineural spaces. Of the 8 cases previously reported in the literature, only 2 were noted to be associated with perineural invasion, and neither of these was treated with radiation therapy. The authors report the case of a 35-year-old woman who presented with a progressively enlarging left lower eyelid lesion. An excisional biopsy with wide margins revealed a diagnosis of primary adenoid cystic carcinoma of the eyelid with perineural invasion. Because of the high risk of recurrence associated with perineural invasion, the patient received postoperative adjuvant radiation in the form of 50 Gy relative biological effectiveness of proton beam therapy to the postoperative tumor bed and to the infraorbital nerve tracking back to the apex of the orbit, followed by a 10-Gy boost to the lower eyelid tumor bed with orthovoltage x-rays.

Outcomes of dacryocystorhinostomy in patients with head and neck cancer treated with high-dose radiation therapy.

PURPOSE: To evaluate the outcomes of dacryocystorhinostomy (DCR) in patients with head and neck cancer treated with high-dose radiation therapy. METHODS: The clinical records of 43 consecutive patients with head and neck cancer who underwent DCR after high-dose external beam radiation therapy plus ablative surgery and/or chemotherapy between December 2001 and April 2011 were retrospectively reviewed. RESULTS: There were 23 men and 20 women. The median age was 56 years (range, 2-92 years). Thirty-one patients were Caucasian, 6 Hispanic, 4 Asian, and 2 African American. Thirty patients (70%) presented with epiphora, 3 (7%) with dacryocystitis, and 10 (23%) with both epiphora and dacryocystitis. Symptoms were unilateral in 34 patients (79%) and bilateral in 9 patients (21%). The most common primary cancer diagnoses were squamous cell carcinoma (n = 14), sarcoma (n = 8), adenoid cystic carcinoma (n = 4), and basal cell carcinoma (n = 4). The most common primary tumor locations were the sinonasal cavity (n = 16), maxillary sinus (n = 9), palate (n = 3), and ethmoid sinus (n = 3). Thirty-seven patients (43 eyes) had DCR with silicone tube placement, and 6 patients (7 eyes) had DCR with Pyrex glass tube placement. Following DCR, 31 patients (72%) had resolution of their symptoms, and 12 patients (28%), 9 with silicone tubes and 3 with Pyrex glass tubes, had persistent or recurrent epiphora (DCR failure). The most common reason for failure was significant residual canalicular and nasal mucosal scar tissue. Eight of these 12 patients underwent additional surgery, most commonly with placement of a Pyrex glass tube. Seven (35%) of the 20 patients who underwent DCR less than 12 months after radiation therapy and 5 (21%) of the 23 patients who underwent DCR at least 12 months after radiation therapy had recurrent symptoms. CONCLUSIONS: Dacryocystorhinostomy in patients with head and neck cancer previously treated with high-dose radiation therapy is generally successful, especially when delayed until at least 12 months after the completion of radiation therapy. A common reason for DCR failure after high-dose radiation therapy is severe canalicular and nasal mucosal scarring.

Retinoblastoma presenting in a child with hypomelanosis of Ito.

PURPOSE: To describe a case of a child with a known history of pigmentary mosaicism suggestive of Hypomelanosis of Ito presenting with unilateral leukocoria, who was ultimately diagnosed with retinoblastoma. METHODS: A report of a 16-month-old girl with pigmentary mosaicism and unilateral retinoblastoma. RESULTS: A previously healthy 16-month-old girl with a diagnosis of a mosaic hypopigmentation at the age of 6 months based on a linear and whorled pattern of skin hypopigmentation along the lines of Blaschko, presented with unilateral strabismus, leukocoria, retinal detachment, and sub-retinal exudation. Hypomelanosis of Ito and other similar neurocutaneous syndromes are known to be associated with abnormal retinal pigmentation, vascular abnormalities, and retinal detachment. Examination included a fluorescein angiogram, ultrasonography, and an MRI of the brain and orbits that demonstrated features consistent with retinoblastoma. Given these findings and a flat electroretinogram, the eye was enucleated with final pathologic confirmation of retinoblastoma. CONCLUSIONS: Previously unreported presentation of unilateral retinoblastoma in a child with pigmentary mosaicism.

Acute orbitocranial inflammation following radioimmunotherapy for non-Hodgkin lymphoma.

Radioimmunotherapy with yttrium-90-ibritumomab tiuxetan may result in hemorrhagic tumor necrosis with acute orbital and intracranial inflammation.

Intravitreal injection of tissue plasminogen activator as treatment for an occluded pars plana glaucoma tube.

Implanting glaucoma tubes through the pars plana in the setting of a corneal transplant is becoming more common, and there are unique problems associated with such a procedure. A 42-year-old man with multiple previous eye surgeries presented with a nonfunctioning pars plana glaucoma tube. There was no view to the tube tip, but it was presumed to be clogged with fibrin. Intravitreal tissue plasminogen activator (tPA) was injected through the pars plana which resulted in intraocular pressure control without further surgery. This new application of intravitreal tPA has not been reported previously. Future research should investigate the optimal effective and safe dose of intravitreal tPA injection to relieve such occlusions.

Inhibition of polymorphonuclear leukocyte-mediated graft damage synergizes with short-term costimulatory blockade to prevent cardiac allograft rejection.

BACKGROUND: The early inflammatory response during reperfusion of cardiac allografts is initiated by the infiltration of polymorphonuclear leukocytes (PMNs) into the graft. The impact of early PMN infiltration on allograft rejection compared with long-term graft survival remains poorly understood. METHODS AND RESULTS: We tested the role of CXCR2, the receptor for 2 PMN attractant chemokines, KC/CXCL1 and MIP-2/CXCL2, on intragraft inflammation and vascularized cardiac allograft rejection in a murine model. Compared with allografts retrieved from control recipients, both PMN infiltration and intragraft proinflammatory cytokine expression were significantly attenuated in allografts from CXCR2-antisera-treated wild-type or from CXCR2(-/-) recipients. Adoptive transfer of alloantigen-primed T cells rapidly infiltrated and rejected allografts in control recipients, but T-cell infiltration was significantly decreased in recipients depleted of PMNs at transplantation. The influence of early PMN-mediated inflammation on the therapeutic efficacy of costimulatory blockade to prevent allograft rejection was tested. Short-term treatment of recipients with anti-CD154 mAb or CTLA-4 Ig induced modest prolongation of cardiac allograft survival. However, CD154 mAb or CTLA-4 Ig treatment, combined with either peritransplantation PMN depletion or antibodies specific for KC/CXCL1 plus MIP-2/CXCL2, prolonged cardiac allograft survival beyond 100 days. CONCLUSIONS: Results suggest that strategies attenuating PMN-mediated tissue damage during reperfusion significantly improve the efficacy of short-term costimulatory blockade to prevent T-cell-mediated rejection of cardiac allografts.

Alloreactive T cell responses and acute rejection of single class II MHC-disparate heart allografts are under strict regulation by CD4+ CD25+ T cells.

Skin but not vascularized cardiac allografts from B6.H-2bm12 mice are acutely rejected by C57BL/6 recipients in response to the single class II MHC disparity. The underlying mechanisms preventing acute rejection of B6.H-2bm12 heart allografts by C57BL/6 recipients were investigated. B6.H-2bm12 heart allografts induced low levels of alloreactive effector T cell priming in C57BL/6 recipients, and this priming was accompanied by low-level cellular infiltration into the allograft that quickly resolved. Recipients with long-term-surviving heart allografts were unable to reject B6.H-2bm12 skin allografts, suggesting potential down-regulatory mechanisms induced by the cardiac allografts. Depletion of CD25+ cells from C57BL/6 recipients resulted in 15-fold increases in alloreactive T cell priming and in acute rejection of B6.H-2bm12 heart grafts. Similarly, reconstitution of B6.Rag(-/-) recipients with wild-type C57BL/6 splenocytes resulted in acute rejection of B6.H-2bm12 heart grafts only if CD25+ cells were depleted. These results indicate that acute rejection of single class II MHC-disparate B6.H-2bm12 heart allografts by C57BL/6 recipients is inhibited by the emergence of CD25+ regulatory cells that restrict the clonal expansion of alloreactive T cells.