Publications by authors named "Lynn Schoenfield"

61 Publications

Intramuscular Orbital Schwannoma With Cystic Degeneration: Serial Changes in MRI Signal Characteristics.

Ophthalmic Plast Reconstr Surg 2021 Jan 19. Epub 2021 Jan 19.

Department of Ophthalmology and Visual Sciences Department of Radiology Department of Pathology, The Ohio State University Wexner Medical Center and The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute, Columbus, OH, U.S.A.

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http://dx.doi.org/10.1097/IOP.0000000000001916DOI Listing
January 2021

Prognosis of Macrophage Density in the Absence of Neutrophils in Differentiated Thyroid Cancer.

J Surg Res 2020 12 12;256:458-467. Epub 2020 Aug 12.

Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center and James Cancer Hospital, Columbus, Ohio.

Background: Despite the advances in treatment of differentiated thyroid cancer (DTC), predicting prognosis remains a challenge. Immune cells in the tumor microenvironment may provide an insight to predicting recurrence. Therefore, the objective of this study was to investigate the association of tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) with recurrence in DTC and to identify serum cytokines that correlate with the presence of these immune cells in the tumor.

Materials And Methods: Forty-two DTC tissues from our institutional neoplasia repository were stained for immunohistochemistry markers for TAMs and TANs. In addition, cytokine levels were analyzed from these patients from preoperative blood samples. TAM and TAN staining were compared with clinical data and serum cytokine levels.

Results: Neither TAM nor TAN scores alone correlated with tumor size, the presence of lymph node metastases, multifocal tumors, lymphovascular or capsular invasion, or the presence of BRAFV600E mutation (all P > 0.05). There was no association with recurrence-free survival (RFS) in TAN density (mean RFS, 169.1 versus 148.1 mo, P = 0.23) or TAM density alone (mean RFS, 121.3 versus 205.2 mo, P = 0.54). However, when scoring from both markers were combined, patients with high TAM density and TAN negative scores had significantly lower RFS (mean RFS, 50.7 versus 187.3 mo, P = 0.04) compared with the remaining cohort. Patients with high TAM/negative TAN tumors had significantly lower serum levels of interleukin 12p70, interleukin 8, tumor necrosis factor alpha, and tumor necrosis factor beta.

Conclusions: In DTCs, high density of TAMs in the absence of TANs is associated with worse outcome. Assessment of multiple immune cell types and serum cytokines may predict outcomes in DTC.
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http://dx.doi.org/10.1016/j.jss.2020.07.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878585PMC
December 2020

Stromal Platelet-Derived Growth Factor Receptor-β Signaling Promotes Breast Cancer Metastasis in the Brain.

Cancer Res 2021 Feb 23;81(3):606-618. Epub 2020 Apr 23.

The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Platelet-derived growth factor receptor-beta (PDGFRβ) is a receptor tyrosine kinase found in cells of mesenchymal origin such as fibroblasts and pericytes. Activation of this receptor is dependent on paracrine ligand induction, and its preferred ligand PDGFB is released by neighboring epithelial and endothelial cells. While expression of both PDGFRβ and PDGFB has been noted in patient breast tumors for decades, how PDGFB-to-PDGFRβ tumor-stroma signaling mediates breast cancer initiation, progression, and metastasis remains unclear. Here we demonstrate this paracrine signaling pathway that mediates both primary tumor growth and metastasis, specifically, metastasis to the brain. Elevated levels of PDGFB accelerated orthotopic tumor growth and intracranial growth of mammary tumor cells, while mesenchymal-specific expression of an activating mutant PDGFRβ (PDGFRβ) exerted proproliferative signals on adjacent mammary tumor cells. Stromal expression of PDGFRβ also promoted brain metastases of mammary tumor cells expressing high PDGFB when injected intravenously. In the brain, expression of PDGFRβ was observed within a subset of astrocytes, and aged mice expressing PDGFRβ exhibited reactive gliosis. Importantly, the PDGFR-specific inhibitor crenolanib significantly reduced intracranial growth of mammary tumor cells. In a tissue microarray comprised of 363 primary human breast tumors, high PDGFB protein expression was prognostic for brain metastases, but not metastases to other sites. Our results advocate the use of mice expressing PDGFRβ in their stromal cells as a preclinical model of breast cancer-associated brain metastases and support continued investigation into the clinical prognostic and therapeutic use of PDGFB-to-PDGFRβ signaling in women with breast cancer. SIGNIFICANCE: These studies reveal a previously unknown role for PDGFB-to-PDGFRβ paracrine signaling in the promotion of breast cancer brain metastases and support the prognostic and therapeutic clinical utility of this pathway for patients..
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581545PMC
February 2021

Whole Exome Sequencing Identifies Candidate Genes Associated with Hereditary Predisposition to Uveal Melanoma.

Ophthalmology 2020 05 18;127(5):668-678. Epub 2019 Nov 18.

Department of Ophthalmology and Visual Science, Havener Eye Institute, The Ohio State University, Columbus, Ohio.

Purpose: To identify susceptibility genes associated with hereditary predisposition to uveal melanoma (UM) in patients with no detectable germline BAP1 alterations.

Design: Retrospective case series from academic referral centers.

Participants: Cohort of 154 UM patients with high risk of hereditary cancer defined as patients with 1 or more of the following: (1) familial UM, (2) young age (<35 years) at diagnosis, (3) personal history of other primary cancers, and (4) family history of 2 or more primary cancers with no detectable mutation or deletion in BAP1 gene.

Methods: Whole exome sequencing, a cancer gene panel, or both were carried out. Probands included 27 patients with familial UM, 1 patient with bilateral UM, 1 patient with congenital UM, and 125 UM patients with strong personal or family histories, or both, of cancer. Functional validation of variants was carried out by immunohistochemistry, reverse-transcriptase polymerase chain reaction, and genotyping.

Main Outcome Measures: Clinical characterization of UM patients with germline alterations in known cancer genes.

Results: We identified actionable pathogenic variants in 8 known hereditary cancer predisposition genes (PALB2, MLH1, MSH6, CHEK2, SMARCE1, ATM, BRCA1, and CTNNA1) in 9 patients, including 3 of 27 patients (11%) with familial UM and 6 of 127 patients (4.7%) with a high risk for cancer. Two patients showed pathogenic variants in CHEK2 and PALB2, whereas variants in the other genes each occurred in 1 patient. Biallelic inactivation of PALB2 and MLH1 was observed in tumors from the respective patients. The frequencies of pathogenic variants in PALB2, MLH1, and SMARCE1 in UM patients were significantly higher than the observed frequencies in noncancer controls (PALB2: P = 0.02; odds ratio, 8.9; 95% confidence interval, 1.5-30.6; MLH1: P = 0.04; odds ratio, 25.4; 95% confidence interval, 1.2-143; SMARCE1: P = 0.001; odds ratio, 2047; 95% confidence interval, 52-4.5e15, respectively).

Conclusions: The study provided moderate evidence of gene and disease association of germline mutations in PALB2 and MLH1 with hereditary predisposition to UM. It also identified several other candidate susceptibility genes. The results suggest locus heterogeneity in predisposition to UM. Genetic testing for hereditary predisposition to cancer is warranted in UM patients with strong personal or family history of cancers, or both.
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http://dx.doi.org/10.1016/j.ophtha.2019.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183432PMC
May 2020

Fine-needle aspiration cytology of a thyroid nodule: Challenging morphologic considerations.

Cytojournal 2019 11;16. Epub 2019 Feb 11.

Address: Department of Pathology, The Ohio State University Wexner Medical Center, Chillicothe, Columbus, OH, USA.

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http://dx.doi.org/10.4103/cytojournal.cytojournal_8_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388538PMC
February 2019

Undifferentiated Pleomorphic Sarcoma Metastatic to the Orbit.

Ophthalmic Plast Reconstr Surg 2018 Nov/Dec;34(6):e193-e195

Department of Ophthalmology and Visual Science.

Undifferentiated pleomorphic sarcoma is a malignancy of mesenchymal origin, which was previously known as malignant fibrous histiocytoma. It is known to occur on rare occasion as a primary orbital tumor, but no known cases of metastatic orbital involvement have been reported since 2002, when the reclassification of these tumors took place. The authors report a patient who presented with a metastasis to the left orbit 2 years after undergoing treatment of a high-grade undifferentiated pleomorphic sarcoma of the right thigh. Histopathology of the orbital mass was similar to the primary tumor biopsy prior to neoadjuvant chemotherapy and radiation. The appearance was markedly altered in the subsequent excisional tissue, which showed treatment changes. Immunohistochemistry and genetic testing also supported the metastatic nature of the orbital lesion. The patient's tumor progressed rapidly despite systemic targeted therapy and orbital exenteration was performed. At 2 years follow up, the patient remained without evidence of tumor recurrence in the socket.
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http://dx.doi.org/10.1097/IOP.0000000000001240DOI Listing
May 2019

: A novel cause of fungal keratitis.

IDCases 2018 14;14:e00440. Epub 2018 Aug 14.

Havener Eye Institute, Department of Ophthalmology, The Ohio State University Wexner Medical Center, 915 Olentangy River Road, Columbus, Ohio 43212, USA.

A 45-year-old female with history of contact lens wear presented with a persistent corneal ulcer that was unresponsive to topical moxifloxacin. The patient's exam was concerning for fungal keratitis. Cultures were obtained, and the patient was started on fortified amphotericin B drops and oral voriconazole. The cultures identified as the causative organism. The patient's exam worsened despite treatment, and the decision was made for surgery. At the time of surgery, her cornea was found to have unexpectedly perforated. She underwent cryotherapy; tectonic penetrating keratoplasty; anterior chamber tap; intracameral voriconazole, amphotericin B, and cefuroxime; and a partial conjunctival flap. Pathology from the cornea showed GMS and PAS stains positive for fungal forms. is a yeast closely related to that was first described in 1995 as a cause of oral candidiasis in patients with AIDS. There are a few published cases of endophthalmitis due to in the ophthalmology literature, but to our knowledge, no cases of fungal keratitis due to this organism have been reported. is a novel cause of fungal keratitis that can be difficult to identify and treat but is felt to be less virulent than and generally susceptible to available anti-fungal therapies.
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http://dx.doi.org/10.1016/j.idcr.2018.e00440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140800PMC
August 2018

Atypical Fibroxanthoma of the Bulbar Conjunctiva: A Unique Case Describing the Pathology, Clinical Presentation, and Management.

Ocul Oncol Pathol 2018 Apr 20;4(3):152-156. Epub 2017 Oct 20.

The Ohio State University Department of Ophthalmology, Columbus, OH, USA.

Background/aims: Atypical fibroxanthoma is an uncommon tumor that usually occurs in the skin of the head and neck of the elderly with significant sun exposure. We describe a unique case featuring a rare ocular surface conjunctival tumor (atypical fibroxanthoma) and provide insight on its characteristic clinical features, surgical management, and histology.

Methods: A 71-year-old male fisherman with no pertinent ocular history presented to an academic center with a rapidly enlarging bulbar conjunctival mass in the right perilimbal region for the past several months. The patient underwent surgical excisional biopsy with cryotherapy, adjuvant alcohol, and amniotic membrane transplantation.

Results: Pathology specimen illustrated an atypical spindle cell tumor with inflammatory cells, increased mitotic activity, cytologic atypia, and positive diffuse staining with CD163 and CD10 consistent with an atypical fibroxanthoma.

Conclusion: Atypical fibroxanthoma is an extremely rare ocular surface tumor that may simulate conjunctival or ocular surface squamous neoplasia. While this lesion typically pursues a benign clinical course, it may recur or rarely metastasize. Thus it should be treated aggressively with excisional biopsy, cryotherapy, absolute alcohol, and/or amniotic membrane transplantation.
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http://dx.doi.org/10.1159/000480088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939675PMC
April 2018

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma.

Cancer Cell 2017 08;32(2):204-220.e15

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.
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http://dx.doi.org/10.1016/j.ccell.2017.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619925PMC
August 2017

Circulating myeloid-derived suppressor cells increase in patients undergoing neo-adjuvant chemotherapy for breast cancer.

Cancer Immunol Immunother 2017 Nov 7;66(11):1437-1447. Epub 2017 Jul 7.

Division of Surgical Oncology, Department of Surgery, The Ohio State University, 410 W 10th Ave, N911 Doan Hall, Columbus, OH, 43210-1267, USA.

This study sought to evaluate whether myeloid-derived suppressor cells (MDSC) could be affected by chemotherapy and correlate with pathologic complete response (pCR) in breast cancer patients receiving neo-adjuvant chemotherapy. Peripheral blood levels of granulocytic (G-MDSC) and monocytic (M-MDSC) MDSC were measured by flow cytometry prior to cycle 1 and 2 of doxorubicin and cyclophosphamide and 1st and last administration of paclitaxel or paclitaxel/anti-HER2 therapy. Of 24 patients, 11, 6 and 7 patients were triple negative, HER2+ and hormone receptor+, respectively. 45.8% had pCR. Mean M-MDSC% were <1. Mean G-MDSC% and 95% confidence intervals were 0.88 (0.23-1.54), 5.07 (2.45-7.69), 9.32 (4.02-14.61) and 1.97 (0.53-3.41) at draws 1-4. The increase in G-MDSC by draw 3 was significant (p < 0.0001) in all breast cancer types. G-MDSC levels at the last draw were numerically lower in patients with pCR (1.15; 95% CI 0.14-2.16) versus patients with no pCR (2.71; 95% CI 0-5.47). There was no significant rise in G-MDSC from draw 1 to 3 in African American patients, and at draw 3 G-MDSC levels were significantly lower in African Americans versus Caucasians (p < 0.05). It was concluded that G-MDSC% increased during doxorubicin and cyclophosphamide therapy, but did not significantly differ between patients based on pathologic complete response.
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http://dx.doi.org/10.1007/s00262-017-2038-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647220PMC
November 2017

NUT Midline Carcinoma of the Sublingual Gland: Clinical Presentation and Review.

Head Neck Pathol 2017 Dec 27;11(4):460-468. Epub 2017 Mar 27.

Department of Otolaryngology-Head and Neck Surgery, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Wexner Medical Center, 4000 Eye and Ear Institute, 915 Olentangy River Road, Columbus, OH, 43212, USA.

NUT midline carcinoma (NMC) is a rare and aggressive disease encountered in the midline of the head and neck or mediastinum. Due to its sparse incidence and subtle pathologic features, we aim to increase knowledge and awareness for this pathologic entity. We present an exemplary case of a young, healthy male presenting with oral cavity pain and cervical lymphadenopathy. This patient was initially diagnosed with an unspecified, highly aggressive sublingual gland malignancy and underwent locoregional resection with free flap reconstruction however suffered a rapid local recurrence and widely extensive metastasis within just 1 month. After rigorous analysis, final pathologic diagnosis revealed a poorly differentiated carcinoma with evidence of squamous differentiation that eventually, post-mortem tested positive for NMC. Only one prior case of sublingual gland NMC has been previously reported as we discuss the literature regarding all sublingual gland malignancies as well as the pathologic features and treatment options for NMC. We recommend consideration of testing for the NUT proto-oncogene at the time of biopsy in the clinical setting of a poorly differentiated midline carcinoma, especially with squamous differentiation, of the head or neck in order to identify patients for clinical trial enrollment and appropriately counsel on the poor clinical prognosis. Improving clinician awareness is critical to increase diagnostic accuracy and need to study prospective treatment outcomes as the first step toward improving management of this difficult disease.
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http://dx.doi.org/10.1007/s12105-017-0809-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677058PMC
December 2017

Recurrent Conjunctival Myofibrosarcoma Managed With Triple Application of Episcleral Brachytherapy.

Cornea 2017 May;36(5):628-630

*Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH; †Department of Pathology, The Ohio State University, Columbus, OH; ‡Department of Ophthalmology, Northwestern Medicine, Chicago, IL; and §Department of Pathology, Cleveland Clinic, Cleveland, OH.

Purpose: To report a case of recurrent conjunctival myofibrosarcoma treated with wide surgical excision, cryotherapy, and triple sequential applications of episcleral brachytherapy.

Methods: A single case of recurrent conjunctival myofibrosarcoma.

Results: A 54-year-old man with a history of a renal transplant presented with a recurrent conjunctival tumor. Histopathologic diagnosis was established through immunohistochemistry. In total, 3 iodine radiation episcleral plaques were used over a period of 49 weeks. After cicatricial ectropion repair and cataract surgery, visual acuity was 20/20 at 4.5-year follow-up without evidence of recurrence or radiation retinopathy.

Conclusions: Myofibrosarcoma is a rare mesenchymal tumor that can present as ocular surface tumor. Final histopathologic diagnosis can be challenging, and immunohistochemistry is important for evaluation. Myofibrosarcoma should be considered in the clinical differential diagnosis of atypical ocular surface lesions and the histopathologic differential diagnosis of ocular spindle neoplasms.
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http://dx.doi.org/10.1097/ICO.0000000000001158DOI Listing
May 2017

Uveal Melanoma Mimicking Advanced Coats' Disease in a Young Patient.

Ocul Oncol Pathol 2016 Apr 20;2(3):140-3. Epub 2015 Nov 20.

Havener Eye Institute, Department of Ophthalmology and Visual Science, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Background/aims: To report a case and the unique histopathology of a necrotic uveal melanoma mimicking advanced Coats' disease in a young adult.

Method: A 26-year-old male presented with a blind, painful eye, total exudative retinal detachment, and bulbous aneurysms consistent with Coats' disease. No masses were visualized on ultrasound or CT scan, and the patient underwent enucleation of the eye.

Results: Histopathology of the involved eye confirmed a necrotic uveal melanoma with persistent spindle cells forming a collar around residual tumor vessels.

Conclusion: Careful consideration is needed in approaching any patient with a blind, painful eye and opaque media, even in younger populations.
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http://dx.doi.org/10.1159/000441526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881292PMC
April 2016

Multimodal Imaging and Clinicopathologic Correlation in Primary Uveal Lymphoma.

Case Rep Ophthalmol 2016 Jan-Apr;7(1):39-43. Epub 2016 Jan 12.

Department of Ophthalmology and Visual Sciences, Havener Eye Institute, Columbus, Ohio, USA.

Purpose: We report a rare case of primary uveal lymphoma and characterize it using histopathology and multimodal imaging.

Patient And Methods: A 41-year-old male presented with a 2-year history of increasingly blurry vision in his right eye and no systemic symptoms. Examination revealed a retinal detachment and mass lesion in the right eye. Radiologic and histologic testing was performed.

Results: Multimodal imaging localized the lesion to the choroid, and fine needle aspiration biopsy diagnosed the lesion as a low-grade B-cell lymphoma. The patient was treated with external beam radiation, resulting in regression of the mass and resolution of the retinal detachment.

Conclusions: Primary uveal lymphoma is a rare, usually indolent tumor that carries a good prognosis. In this case, we show that primary uveal lymphoma has distinct findings via histopathology and multimodal imaging, and that imaging after radiation treatment documents disease regression.
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http://dx.doi.org/10.1159/000442743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748778PMC
February 2016

Congenital uveal melanoma?

Surv Ophthalmol 2016 Jan-Feb;61(1):59-64. Epub 2015 Aug 12.

Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio, USA.

A 3-month-old infant with a white mother and Asian father presented with discoloration and prominence of the left eye since birth. Examination revealed a normal right eye. The left eye had hyperchromic heterochromia and an enlarged cornea (diameter, 13.0 mm) with intraocular pressure of 26 mm Hg. There were multiple areas of subconjunctival nodular pigmentation that extended posteriorly into the superior fornix. Fundus examination showed a large ciliochoroidal pigmented mass extending from 10:30 to 3:00 o'clock position involving the superior half of the choroid and adjacent ciliary body. The eye was enucleated, confirming the diagnosis of diffuse uveal melanoma with extraocular extension. Systemic surveillance (hepatic panel and ultrasonography of the liver) performed every 6 months for 5 years was has been negative for metastases. The tumor was investigated intensively for the panel of genes (BAP1, BRAF, NRAS12, NRAS61, GNAQ, Kit 9,11,13,17,18) implicated in pathogenesis of blue nevus, cutaneous melanoma, and mucosal melanomas with negative results. Moreover, germline BAP1 mutation could not be identified. This case possibly represents as yet unidentified uveal melanocytic proliferation rather than a true variant of uveal melanoma.
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http://dx.doi.org/10.1016/j.survophthal.2015.07.005DOI Listing
September 2016

Genomic microarray analysis on formalin-fixed paraffin-embedded material for uveal melanoma prognostication.

Cancer Genet 2014 Jul-Aug;207(7-8):306-15. Epub 2014 Aug 29.

Signature Genomics Laboratories, Perkin Elmer, Spokane, WA, USA. Electronic address:

Cytogenetic alterations are strong outcome prognosticators in uveal melanoma (UVM). Monosomy 3 (-3) and MYC amplification at 8q24 are commonly tested by fluorescence in situ hybridization (FISH). Alternatively, microarray analysis provides whole genome data, detecting partial chromosome loss, loss of heterozygosity (LOH), or abnormalities unrepresented by FISH probes. Nonfixed frozen tissue is conventionally used for microarray analysis but may not always be available. We assessed the feasibility of genomic microarray analysis for high resolution interrogation of UVM using formalin-fixed paraffin-embedded tissue (FFPET) as an alternative to frozen tissue (FZT). Enucleations from 44 patients (clinical trial NCT00952939) yielded sufficient DNA from FFPET (n = 34) and/or frozen tissue (n = 41) for comparative genomic hybridization and select single nucleotide polymorphism analysis (CGH/SNP) on Roche-NimbleGen OncoChip arrays. CEP3 FISH analysis was performed on matched cytology ThinPrep material. CGH/SNP analysis was successful in 30 of 34 FFPET and 41 of 41 FZT samples. Of 27 paired FFPET/FZT samples, 26 (96.3%) were concordant for at least four of six major recurrent abnormalities (-3, +8q, -1p, +6p, -6q, -8p), and 25 of 27 (92.6%) were concordant for -3. Results of CGH/SNP were concordant with the CEP3 FISH results in 27 of 30 (90%) FFPET and 38 of 41 (92.6%) FZT cases; partial -3q was detected in two CEP3 FISH-negative cases and whole chromosome 3, 4, and 6 SNP-LOH in one case. CGH detection of -3, +8q, -8p on FFPET and FZT showed significant correlation with the clinical outcome measures (metastasis development, time to progression, survival). Results of the UVM genotyping by CGH/SNP on FFPET are highly concordant with those of the FZT analysis and with those of the CEP3 FISH analysis, and therefore CGH/SNP is a practical method for UVM prognostication. Genome-wide coverage provides additional data with potential relevance to UVM biology, diagnosis, and prognosis.
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http://dx.doi.org/10.1016/j.cancergen.2014.08.005DOI Listing
January 2015

Molecular profiling of primary uveal melanomas with tumor-infiltrating lymphocytes.

Oncoimmunology 2019;8(10):e947169. Epub 2014 Oct 31.

Cole Eye Institute; Cleveland Clinic Foundation; Cleveland, OH USA.

In contrast to other cancers, the presence of tumor-infiltrating lymphocytes (TILs) in uveal melanoma is associated with a poor prognosis. However, how TILs may promote disease progression and what regulates their infiltration has not yet been established. To address these clinically relevant outstanding questions, T cell, immune regulatory, and chemokine gene expression profiles of 57 enucleated uveal melanoma tumors were compared, encompassing 27 with TILs and 30 without,. Tumors with infiltrating lymphocytes expressed more mRNA, as well as , , and transcripts. Other T helper associated cytokines and T helper transcription factors were not differentially expressed, nor were mediators of lymphocyte cytotoxicity. The immune inhibitors , , , and , and the non-classical MHC Class I target of CD8 T regulatory cells, , were significantly higher in tumors with TILs. FAS was also significantly higher. The C-C chemokine ligands CCL4, CCL5, and CCL20 were higher in tumors with TILs. Levels of CCL5 were most strongly correlated with levels of CD8A. Chemokine receptors were not differentially expressed. Molecular profiling of uveal melanoma tumors with TILs supports the existence of an immunosuppressive tumor microenvironment and suggests roles for CD8 regulatory T cells, as well as specific chemokines, in fostering uveal melanoma disease progression.
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http://dx.doi.org/10.4161/21624011.2014.947169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791435PMC
February 2021

Diagnostic pitfalls of differentiating desmoplastic small round cell tumor (DSRCT) from Wilms tumor (WT): overlapping morphologic and immunohistochemical features.

Am J Surg Pathol 2014 Sep;38(9):1220-6

*Department of Pathology, The Ohio State University Wexner Medical Center †Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH ‡Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD.

Desmoplastic small round cell tumor (DSRCT) and blastemal-predominant Wilms tumor (WT) share overlapping histologic features, yet accurate distinction is critical because of differing prognosis and treatment. We encountered a neck mass in a young adult with a concomitant abdominal mass. The neck mass was initially concerning for DSRCT on the basis of the poorly differentiated morphology, desmoplastic stroma, and immunoreactivity for desmin and cytokeratin. However, focal triphasic elements and glomeruloid bodies were identified on deeper sections, WT1 immunoreactivity was seen with antibodies to both the amino-terminus and carboxy-terminus, and EWSR1-WT1 rearrangement studies were negative, supporting the ultimate diagnosis of WT. On the basis of the overlapping histologic features of DSRCT and blastemal-predominant WT, we undertook a comparison study of desmin and cytokeratin reactivity patterns. We found that, whereas desmin reactivity was more frequent in DSRCT (11 of 12) than in WT blastema (11 of 22, P=0.024), dot-like perinuclear reactivity was seen with equal frequency in desmin-reactive DSRCT (10 of 11) and WT blastema (10 of 11), illustrating an important diagnostic pitfall. Moreover, we demonstrate coexpression of desmin and cytokeratin in both DSRCT (9 of 12) and WT blastema (11 of 22). Importantly, although dot-like desmin reactivity and coexpression of desmin and cytokeratin are historically associated with DSRCT, we demonstrate that these features can be seen in either DSRCT or blastemal-predominant WT. In these challenging cases, detection of an EWSR1-WT1 rearrangement and selective WT1 carboxy-terminus immunoreactivity (characteristic of DSRCT) or dual immunoreactivity for the WT1 amino-terminus and carboxy-terminus (characteristic of WT) remain the most discriminating diagnostic tools.
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http://dx.doi.org/10.1097/PAS.0000000000000231DOI Listing
September 2014

Uveal melanoma: A pathologist's perspective and review of translational developments.

Authors:
Lynn Schoenfield

Adv Anat Pathol 2014 Mar;21(2):138-43

Department of Pathology, Wexner Medical Center, Ohio State University, Columbus, OH.

The eye and periorbital soft tissue are derived from the neuroectodermal neural crest, leading to a wide range of tumor types that arise at this site. The uveal tract (iris, ciliary body, and choroid) normally contains melanocytes, and thus both benign nevi and malignant melanoma can arise there, the choroid being the most frequent site. Uveal melanoma (UM) in adults and retinoblastoma (in young children) are the 2 most common primary intraocular malignancies. Retinoblastoma is the most common eye cancer worldwide, but the most common ocular cancer in the United States and Europe is UM. This review will focus on UM and will include the epidemiology, pathologic findings, prognosis and treatment, and review of ongoing molecular discoveries aimed at elucidating the pathways that could lead to adjuvant therapy. These tumors are not uncommon to dedicated ocular pathologists and may occasionally be encountered by general pathologists as well. First, a short word about metastases to the uveal tract is in order, because of its importance in the differential diagnosis. Although the most common primary malignancy in the adult eye is UM, the most frequent adult intraocular malignancy identified in autopsy studies is metastatic carcinoma to the uveal tract. Metastases usually occur late, and the eye is thus rarely enucleated in this setting. However it is important to be aware of this as sometimes, the ophthalmologist cannot determine clinically if an amelanotic tumor represents melanoma or metastasis, possibly from an unknown primary. Shields and colleagues reported on their experience and found that the most common primary sites for uveal metastasis are breast, followed by lung, and then the gastrointestinal tract. Immunohistochemical stains for cytokeratin or more specific markers such as CK7, CK20, TTF-1, BRST-2, CDX2, and PSA may be helpful if there is no known primary. Metastases to the eye also occur in the orbit, eyelid, and rarely to the retina.
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http://dx.doi.org/10.1097/PAP.0000000000000010DOI Listing
March 2014

Chronic eyelid dermatitis secondary to cocamidopropyl betaine allergy in a patient using baby shampoo eyelid scrubs.

JAMA Ophthalmol 2014 Mar;132(3):357-9

Havener Eye Institute, The Ohio State University Wexner Medical Center, Columbus.

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http://dx.doi.org/10.1001/jamaophthalmol.2013.6254DOI Listing
March 2014

Orbital xanthogranuloma in an adult patient with xanthelasma palpebrarum and hypercholesterolemia.

Ophthalmic Plast Reconstr Surg 2014 Jan-Feb;30(1):e6-8

Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.

A 44-year-old man with a history of hypercholesterolemia presented with eyelid lesions and a separate orbital mass. Pathology of eyelid lesions confirmed xanthelasma palpebrarum, and pathology of the orbital mass showed a non-Langerhans cell xanthogranuloma, consistent with a lesion within the spectrum of adult orbital xanthogranulomatous disorders. While xanthelasma palpebrarum is associated with increased serum lipids, adult orbital xanthogranuloma does not share a clear association. Distinct, histology-proven xanthelasma palpebrarum and orbital xanthogranuloma rarely occur together in the literature. This case further represents a unique coexistence between these 2 lesions in an adult with hypercholesterolemia.
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http://dx.doi.org/10.1097/IOP.0b013e3182873d13DOI Listing
June 2014

Validation of whole slide imaging for primary diagnosis in surgical pathology.

Arch Pathol Lab Med 2013 Apr 16;137(4):518-24. Epub 2013 Jan 16.

Department of Anatomic Pathology, The Cleveland Clinic, Cleveland, Ohio 44106, USA.

Context: High-resolution scanning technology provides an opportunity for pathologists to make diagnoses directly from whole slide images (WSIs), but few studies have attempted to validate the diagnoses so obtained.

Objective: To compare WSI versus microscope slide diagnoses of previously interpreted cases after a 1-year delayed re-review ("wash-out") period.

Design: An a priori power study estimated that 450 cases might be needed to demonstrate noninferiority, based on a null hypothesis: "The true difference in major discrepancies between WSI and microscope slide review is greater than 4%." Slides of consecutive cases interpreted by 2 pathologists 1 year prior were retrieved from files, and alternate cases were scanned at original magnification of ×20. Each pathologist reviewed his or her cases using either a microscope or imaging application. Independent pathologists identified and classified discrepancies; an independent statistician calculated major and minor discrepancy rates for both WSI and microscope slide review of the previously interpreted cases.

Results: The 607 cases reviewed reflected the subspecialty interests of the 2 pathologists. Study limitations include the lack of cytopathology, hematopathology, or lymphoid cases; the case mix was not enriched with difficult cases; and both pathologists had interpreted several hundred WSI cases before the study to minimize the learning curve. The major and minor discrepancy rates for WSI were 1.65% and 2.31%, whereas rates for microscope slide reviews were 0.99% and 4.93%.

Conclusions: Based on our assumptions and study design, diagnostic review by WSI was not inferior to microscope slide review (P < .001).
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http://dx.doi.org/10.5858/arpa.2011-0678-OADOI Listing
April 2013

Chromosome 3 status in uveal melanoma: a comparison of fluorescence in situ hybridization and single-nucleotide polymorphism array.

Invest Ophthalmol Vis Sci 2012 Jun 5;53(7):3331-9. Epub 2012 Jun 5.

Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.

Purpose: To compare fluorescence in situ hybridization (FISH) using a centromeric probe for chromosome 3 (CEP3) and 3p26 locus-specific probe with single-nucleotide polymorphism array (SNP-A) analysis in the detection of high-risk uveal melanoma.

Methods: Fifty cases of uveal melanoma (28 males, 22 females) treated by enucleation between 2004 and 2010 were analyzed. Fresh tissue was used for FISH and SNP-A analysis. FISH was performed using a CEP3 and a 3p26 locus-specific probe. Tumor size, location, and clinical outcome were recorded during the 7-year study period (median follow-up: 35.5 months; mean: 38.5 months). The sensitivity, specificity, positive predictive value, and negative predictive value were calculated.

Results: Monosomy 3 was detected by FISH-CEP3 in 27 tumors (54%), FISH-3p26 deletion was found in 30 (60%), and SNP-A analysis identified 31 (62%) of the tumors with monosomy 3. Due to technical failures, FISH and SNP-A were noninterpretable in one case (2%) and two cases (4%), respectively. In both cases of SNP-A failure, tumors were positive for FISH 3p26 deletion and in a single case of FISH failure, monosomy 3 was found using SNP-A. No statistically significant differences were observed in any of the sensitivity or specificity measures.

Conclusions: For prediction of survival at 36 months, FISH CEP3, FISH 3p26, and SNP-A were comparable. A combination of prognostication techniques should be used in an unlikely event of technical failure (2%-4%).
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http://dx.doi.org/10.1167/iovs.11-9027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625803PMC
June 2012

Diffuse large B-cell lymphoma of the orbit: clinicopathologic, immunohistochemical, and prognostic features of 20 cases.

Am J Ophthalmol 2012 Jul 13;154(1):87-98.e1. Epub 2012 Apr 13.

David G. Cogan Ophthalmic Pathology Laboratory, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.

Purpose: To evaluate a series of orbital diffuse large B-cell lymphomas (DLBCL) for prognostic features and therapeutic outcomes.

Design: Retrospective multicenter case study of clinical and immunohistochemical features of 20 patients.

Methods: Clinical, histopathologic, and immunohistochemical features were correlated with outcomes. Immunohistochemistry for biomarkers including Bcl-6, CD5, CD10, CD20, FOXP1, GCET1, and MUM1 was performed to differentiate between 2 major genetic subtypes of DLBCL: activated B-cell-like (ABC) and germinal center B-cell-like (GCB).

Results: Sixteen patients presented with unilateral and 4 with bilateral tumors. Three had bony erosion of the orbit on imaging studies. Of 14 patients with detailed follow-ups, 3 had a prior or concurrent lymphomatous disease; 8 had stage I disease (limited to the orbit) at presentation; and 3 were newly diagnosed with systemic (stage IV) DLBCL. Localized disease was treated with combined systemic chemotherapy, including rituximab and radiation with no deaths to date; there was 1 death related to systemic DLBCL. Clinical staging was the best predictive method and no immunohistochemical feature or subcategory (ABC vs GCB) correlated with outcome.

Conclusions: Primary orbital DLBCL has a more favorable prognosis than systemic DLBCL and may arise from a preexistent hematolymphomatous neoplasm (4 out of 20 cases). In our series, orbital DLBCL had a 57% likelihood of being restricted to the ocular adnexa. Clinical staging was more helpful in predicting outcome than any single immunohistopathologic feature or combination of biomarkers. Orbital radiation of 30 gray in conjunction with systemic chemotherapy with rituximab can achieve disease-specific survival approaching 100% in purely localized cases.
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http://dx.doi.org/10.1016/j.ajo.2012.01.021DOI Listing
July 2012

Collagenase-mediated tissue modeling of corneal ectasia and collagen cross-linking treatments.

Invest Ophthalmol Vis Sci 2012 Apr 30;53(4):2321-7. Epub 2012 Apr 30.

Lerner College of Medicine, SurgeryInstitute, Cleveland Clinic, Cleveland, Ohio 44120, USA.

Purpose: Corneal collagen cross-linking (CXL) is a method for modifying the natural history of keratoconus and other corneal ectatic diseases. The authors evaluated the use of collagenase for generating an experimental model of ectasia to evaluate the topographic effects of CXL interventions.

Methods: Nine human corneoscleral specimens unsuitable for transplantation were used. After epithelial debridement, mounting, and pressurization on an artificial anterior chamber, a solution of 10 mg/mL collagenase type II with 15% dextran was applied to five corneas for three hours. Three of these corneas subsequently underwent riboflavin/UV-A CXL. Scheimpflug-based tomography was performed before collagenase exposure, after collagenase exposure, and after CXL to evaluate changes in maximum axial curvature of the anterior surface (K(max)) at three IOP levels. Results were compared to four control eyes exposed to dextran alone.

Results: A statistically significant increase in K(max) was seen across all IOP levels in the collagenase group compared to the control group (+6.6 ± 1.1 diopters [D] and +0.3 ± 0.8 D, respectively, at physiological IOP). After CXL, K(max) decreased (-7.6 ± 2.0 D at physiological IOP). Anterior corneal aberrations increased after collagenase exposure and decreased after CXL. Light microscopy showed loss of normal stromal collagen architecture and localized edema after collagenase exposure.

Conclusions: A method for generating topographic features of corneal ectasia in human tissue is demonstrated. No significant sensitivity of K(max) to IOP was observed. CXL caused regression of steepening and induced aberrations in this model, consistent with clinical trends. The model may be useful for testing modifications to standard CXL techniques.
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http://dx.doi.org/10.1167/iovs.11-9327DOI Listing
April 2012

Ocular surface squamous neoplasia in an anophthalmic socket 60 years after enucleation.

Surv Ophthalmol 2011 Nov-Dec;56(6):539-43

Department of Cornea, External Disease and Refractive Surgery, The Cleveland Clinic, Cleveland, Ohio, USA.

Ocular surface squamous cell neoplasia in an anophthalmic socket is an exceptionally rare occurrence. We report a 62-year-old white man who had his left eye enucleated at age 2 and developed an invasive squamous cell carcinoma 60 years later. He received multiple treatments, including excisional biopsy, topical mitomycin C chemotherapy, cryotherapy, and finally exenteration. We review the literature to evaluate the clinical characteristics, time of onset following enucleation, treatment, and outcome of previously reported cases. Our case emphasizes the importance of a thorough examination of the anophthalmic socket, including upper and lower lid eversion.
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http://dx.doi.org/10.1016/j.survophthal.2011.06.005DOI Listing
January 2012

Prediction of adenocarcinoma in esophagectomy specimens based upon analysis of preresection biopsies of Barrett esophagus with at least high-grade dysplasia: a comparison of 2 systems.

Am J Surg Pathol 2012 Jan;36(1):134-41

Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA.

Distinguishing Barrett esophagus with high-grade dysplasia (BE-HGD) from intramucosal and submucosal adenocarcinomas on biopsies is challenging, yet important, in the choice of therapy. The current study evaluates preresection biopsies from patients who underwent esophagectomy for at least BE-HGD, to compare the recently published histologic categories by the University of Michigan (UM) and Cleveland Clinic (CC), correlate preresection and final resection diagnosis, and identify histologic features in biopsies that might be predictive of adenocarcinoma on esophagectomy. A total of 112 cases with a consensus biopsy diagnosis (agreement by ≥4 of 7 gastrointestinal pathologists) were statistically analyzed to identify histologic features that predicted adenocarcinoma on resection. Applying the UM criteria to the biopsy series showed excellent agreement with the CC system (κ=0.86) and significant correlation between preoperative and esophagectomy diagnoses (P<0.001). The likelihood of finding carcinoma on resection was significantly higher with the category of HGD with marked glandular distortion cannot exclude intramucosal adenocarcinoma [CC; odd ratio (OR), 2.8; P=0.046] or HGD suspicious for adenocarcinoma (UM; OR, 4.3; P=0.008), compared to HGD alone. The presence of "never-ending" glands (OR, 3.7; P=0.008), sheet-like growth (P<0.001), angulated glands (OR, 8.5; P<0.001), ≥3 dilated glands with intraluminal debris (OR, 2.6; P=0.05), and >1 focus of single-cell infiltration into the lamina propria (OR, 8.9; P<0.001) increased the odds of finding carcinoma on resection. The latter 2 variables remained independent predictors of adenocarcinoma in multivariable analysis. In conclusion, the CC and UM systems show excellent agreement and define histologic categories that can improve prediction of adenocarcinoma on resection.
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http://dx.doi.org/10.1097/PAS.0b013e3182354e43DOI Listing
January 2012

Orbital inflammation in IgG4-related sclerosing disease.

Orbit 2011 Oct;30(5):258-60

Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA.

IgG4-related sclerosing disease is a recently described systemic inflammatory disease that should be considered when evaluating patients with nonspecific orbital inflammation (pseudotumor). Orbital biopsy is necessary to establish a diagnosis and demonstrates lymphoplasmacytic infiltration, fibrosis, obliterative phlebitis of medium and small veins, and variable degrees of eosinophilia. We report the clinical and histopathological findings of 2 patients who developed chronic orbital inflammation as a manifestation of IgG4-related sclerosing disease. The 2 cases illustrate the widely varying clinical characteristics of this elusive disease.
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http://dx.doi.org/10.3109/01676830.2011.593677DOI Listing
October 2011

Primary dermatofibrosarcoma protuberans invading the orbit.

Ophthalmic Plast Reconstr Surg 2012 May-Jun;28(3):e65-7

Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.

A 38-year-old man presented with a slow-growing, firm cutaneous mass beneath his left eyebrow. Histopathology and immunohistochemistry confirmed the diagnosis of dermatofibrosarcoma protuberans. The mass infiltrated the medial canthal tendon and anterior orbital fat and could not be completely excised with Mohs micrographic surgery. The patient underwent exenteration and dacryocystectomy with margin-controlled excision and remained free of disease 9 months after surgery. To our knowledge, no prior case of primary dermatofibrosarcoma protuberans involving the orbit has been reported.
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http://dx.doi.org/10.1097/IOP.0b013e3182271aaeDOI Listing
July 2012