Publications by authors named "Frederick A Jakobiec"

263 Publications

Conjunctival Actinic Granuloma: A Clinicopathological and Immunohistochemical Study With a Review of the Literature and a Differential Diagnosis.

Ophthalmic Plast Reconstr Surg 2021 Feb 11. Epub 2021 Feb 11.

David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary/ Harvard Medical School, Boston, Massachusetts Lakewood Eye Center, Lakewood, Colorado, U.S.A.

Purpose: To document a case of actinic granuloma (AG) of the conjunctiva, provide an extensive histopathologic and immunohistochemical description, review previously reported cases, and supply a differential diagnosis.

Methods: Both a retrospective chart review and comprehensive literature review were performed. The distinctive histopathologic pattern of the current case was defined with histochemical and immunohistochemical stains (CD163, p63, and a Verhoeff-Van Gieson elastic stain). Clinical follow up was obtained.

Results: A granulomatous process composed of CD163-positive mononuclear epithelioid cells and multinucleated giant cells was characterized by displaced extracellular actinic-related elastic fibers to the base of the lesion. Small elastic fibers were phagocytosed in epithelioid cells. Pseudoepitheliomatous hyperplasia of the overlying squamous epithelium was present; p63 assisted in defining the squamous proliferation and highlighted its noninvasive nature. Conjunctival AGs, according to the literature review, occur almost exclusively in young females, clinically manifest as nodular foci with painless injection over the course of weeks, and histologically featured granulomatous inflammation and elastophagocytosis. The etiology of this entity is likely multifactorial, but its genesis revolves around actinic injury.

Conclusion: AGs of the conjunctiva have likely been an underreported entity in the past. The authors' review underscores the importance of including conjunctival AGs in the differential diagnosis of painless, subacute injected masses of the perilimbal conjunctiva. While it is benign, histopathologically separating AGs from neoplasia and other mimickers such pinguecula, foreign body granulomas, allergic, or rheumatoid nodules is essential for optimal management.
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http://dx.doi.org/10.1097/IOP.0000000000001950DOI Listing
February 2021

Epibulbar Proliferative Fasciitis, a Variant of Nodular Fasciitis: A Differential Diagnosis of Conditions With Focal or Diffuse Myxoid Stromas.

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

David G. Cogan Laboratory of Ophthalmic Pathology, Department of Ophthalmology, Massachusetts Eye and Ear/Harvard Medical School Department of Dermatopathology, Brigham and Women's Hospital, Boston, Massachusetts, U.S.A.

Purpose: To describe the clinical and pathologic features of a case of epibulbar proliferative fasciitis and to compare it with other focal or diffuse myxoid lesions.

Methods: A clinical, histopathologic, and immunohistochemical analysis was performed. The clinical history, photographic documentation, history, and referred slides were reanalyzed. Additional immunohistochemical stains were performed at our institution.

Results: A 68-year-old woman developed over a week a brightly vascularized and focally hemorrhagic placoid lesion on the temporal side of the OS. She had had earlier augmentation breast surgery that had been mistakenly initially reported to us to be for breast carcinoma. Hematoxylin- and eosin-stained reactions revealed microscopically a spindle cell lesion with an intact nonkeratinizing epithelium and a background myxoid stroma with prominent capillaries and a light dispersion of small T-cell lymphocytes. Most striking among the spindle cells were some widely separated large atypical cells. The atypical cells were cytokeratin positive, but an expansive panel of immunohistochemical stains for breast carcinoma was negative. The lesion was diagnosed as proliferative fasciitis and has not recurred after 1-year follow up.

Conclusion: A rapidly evolving conjunctival lesion is unlikely to be a primary or metastatic carcinoma. In the current case, the large ganglioform or rhabdomyoblast-like cells displayed diffuse cytokeratin positivity, still consistent with a mesenchymal or connective tissue cell lineage. Cytokeratin expression has been a finding previously reported in connective tissue tumors and in lymphoma cells. While the current lesion clinically resembles a conventional nodular fasciitis, the presence of the large atypical cells can lead to the misdiagnosis of a sarcoma, which typically displays a much higher Ki-67 proliferation index in comparison with nodular/proliferative fasciitis.
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http://dx.doi.org/10.1097/IOP.0000000000001872DOI Listing
January 2021

Lacrimal Gland Intravascular Micrometastasis From a Human Papillomavirus-Driven Anorectal Squamous Cell Carcinoma With a Review of Metastatic Disease to the Lacrimal Gland.

Ophthalmic Plast Reconstr Surg 2020 Dec 7. Epub 2020 Dec 7.

David G. Cogan Laboratory of Ophthalmic Pathology, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, U.S.A.

Purpose: To document a unique case of anorectal squamous cell carcinoma that was metastatic to the microvasculature of the lacrimal gland in a patient with human immunodeficiency virus and to review previously reported cases of metastases to the lacrimal gland.

Methods: Both a retrospective chart review and comprehensive literature review were performed. The unusual histopathologic pattern of the current case was illustrated with immunohistochemical studies (CD31, D2-40, pancytokeratin, p16, and p63) and in situ hybridization studies for high-risk human papillomavirus types 16 and 18.

Results: The authors describe the first case of metastatic anorectal squamous cell carcinoma to the lacrimal gland. Only 24 cases of metastatic disease to the lacrimal gland have been reported, the majority from breast carcinomas. The metastasis did not form a macroscopic lesions, instead was composed of microscopic intravascular and intraparenchymal tumor deposits, a subtle phenomena. Immunohistochemistry confirmed the presence of the intravascular neoplastic cells. p16 served as a surrogate marker for human papillomavirus-associated squamous cell carcinoma and was confirmed with in situ hybridization for human papillomavirus 16 and 18. This testing, combined with the clinical history, defined the diagnosis and confirmed human papillomavirus as the tumor driver.

Conclusions: Metastases to the lacrimal gland remain rare, but clinicians and pathologists alike must be attuned to the possibility of subtle microscopic foci of tumor as a pattern of metastasis in scenarios without a discrete mass-forming lesion, as this may portend a poor prognosis.
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http://dx.doi.org/10.1097/IOP.0000000000001894DOI Listing
December 2020

Multicameral Steatocystoma Simplex of the Caruncle.

Ophthalmic Plast Reconstr Surg 2020 Nov 5. Epub 2020 Nov 5.

Department of Ophthalmology, New York University Langone Medical Center, New York, New York.

A yellow cyst of the caruncle in a 68-year-old man displayed the characteristic sebaceous glands and sebocytes of steatocystoma within the cyst wall, with a unique configuration of multiple branching compartments. The cyst lining was of trichilemmal character, lacking a keratohyalin granular layer, and replicated the immunohistochemical characteristics of a previously reported caruncular steatocystoma with the exception of a positive trichilemmal marker, calretinin, in the present case. Four previous cases of caruncular steatocystoma have been described, only one of which incorporated immunohistochemical analysis. Steatocystoma develops from a sebaceous gland duct, which displayed in this case multiple chambers subdividing what is usually a single round lumen.
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http://dx.doi.org/10.1097/IOP.0000000000001861DOI Listing
November 2020

Sebaceoma of a Meibomian Gland of the Upper Eyelid.

Ocul Oncol Pathol 2020 Aug 22;6(4):297-304. Epub 2020 Jan 22.

Department of Oculoplastics, Massachusetts Eye and Ear/Harvard Medical School, Boston, Massachusetts, USA.

Over a period of 1 year, a 74-year-old man slowly developed a painless left upper eyelid intratarsal mass. The skin was movable over the lesion. At surgery, a well-circumscribed, yellow-white, partially cystic tumor was encountered. Histopathologically it was composed of a random mixture of basaloid and sebaceous cells arranged in interconnecting cords. Immunohistochemical evaluation disclosed epithelial membrane antigen, adipophilin, and cytokeratin 14 positivity. These findings led to the diagnosis of a sebaceoma. The tumor cells abnormally failed to express mismatch repair proteins for MLH1 and PMS2. The patient did not have a personal history of any visceral malignancy, but his father had died at the age of 46 years and a daughter at the age of 33 years from colonic carcinomas. The implications of this periocular sebaceoma for the Muir-Torre syndrome are explored.
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http://dx.doi.org/10.1159/000504627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506298PMC
August 2020

Villous Sebaceous Adenoma Arising from the Caruncular Surface Squamous Epithelium.

Ocul Oncol Pathol 2020 Aug 10;6(4):280-286. Epub 2020 Mar 10.

Department of Ophthalmic Pathology, Wills Eye Hospital, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

A 68-year-old woman developed an asymptomatic left caruncular multilobular lesion over one year. Excision of the lesion displayed a benign sebaceous neoplasm taking origin from the surface squamous epithelium which invaginated into the stroma to create crypts resembling the conjunctival pseudoglands of Henle or the glands of Lieberkuhn of the small intestine. Scattered sebaceous cells were also discovered in the surface squamous epithelium. The cryptal walls spawned lateral sebaceous gland lobules that were adipophilin positive. p16 was positive in the surface epithelium, the cryptal walls, and in the basal cells of the sebaceous lobules. No defects in nuclear mismatch repair protein expression were identified, which together with the absence of a familial cancer history, rendered unlikely an association with the Muir-Torre syndrome.
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http://dx.doi.org/10.1159/000505488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506216PMC
August 2020

Sclerosing Signet Ring Cell Carcinoma of the Lacrimal Gland: A Potentially New Primary Entity.

Ocul Oncol Pathol 2020 Aug 7;6(4):265-274. Epub 2020 Feb 7.

David G. Cogan Laboratory of Ophthalmic Pathology, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA.

An 88-year-old man presented with diplopia, limitation of extraocular movements, and a firm palpable mass in the superolateral orbit. Biopsy revealed a sclerosing signet ring cell carcinoma with histopathologic features mimicking those of a primary signet ring cell (histiocytoid) carcinoma of the eyelid of eccrine or apocrine gland origin, a metastasis from an invasive lobular breast carcinoma or a metastatic diffuse-type gastric carcinoma. An extensive panel of immunohistochemical stains and molecular genetic analyses unequivocally failed to establish a precise diagnosis. Electron microscopy demonstrated features of a primary lacrimal gland lesion with intracytoplasmic lumens and zymogen granules typical of lacrimal secretory pyramidal cells. A thorough initial systemic work-up failed to reveal a primary visceral malignancy. Fifteen months of follow-up have failed to detect the emergence of another primary malignancy. To the best of our knowledge, a tumor with the morphology of the current lesion has not been previously described in the major or accessory lacrimal glands.
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http://dx.doi.org/10.1159/000505490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506292PMC
August 2020

Relationship between Conjunctival Intraepithelial Dendritic Melanocytes and Nevocytes.

Ocul Oncol Pathol 2020 Aug 14;6(4):251-258. Epub 2020 Feb 14.

Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear/Harvard Medical School, Boston, Massachusetts, USA.

A 52-year-old male presented with a perilimbal-epibulbar, flat, pigmented lesion of 7 months' duration. Microscopic evaluation disclosed a proliferation of intraepithelial dendritic melanocytes without frank atypia, a lesion formerly termed "primary acquired melanosis." Within the lesion there were also intraepithelial basal junctional nevocytic nests and occasional small subepithelial nevocytic clusters which were positive for MART-1, HMB-45, and SOX-10 and negative for Ki-67. This remarkable lesion was suggestive of dendritic melanocytes transforming into rounded nevocytes lacking dendrites. The embryologic and biologic implications of these findings are explored, notably in regard to the unusual acquisition in mature adults of common nevomelanocytic nevi.
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http://dx.doi.org/10.1159/000505492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506288PMC
August 2020

Orbital Involvement by Biphenotypic Sinonasal Sarcoma With a Literature Review.

Ophthalmic Plast Reconstr Surg 2020 Sep 25. Epub 2020 Sep 25.

Ophthalmic Plastic Surgery Service, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, U.S.A.

Purpose: To document a case of a biphenotypic sinonasal sarcoma that impinged on the orbit via a tumor-induced mucocele and review the previous literature devoted to this condition.

Methods: A clinicopathologic case report with detailed histopathologic, immunohistochemical, and radiological studies with tabulations of previously reported cases and immunohistochemical stains for ruling out mimicking lesions.

Results: A biphenotypic sinonasal sarcoma arose from the ethmoid sinus in a middle-aged man. The tumor induced a mucocele that bowed the medial orbital lamina papyracea into the orbit and caused diplopia and mild proptosis. The biopsy's dual positivity for S100 and smooth muscle actin together with positive paired box 3 immunohistochemical staining established the diagnosis of biphenotypic sinonasal sarcoma.

Conclusion: Biphenotypic sinonasal sarcoma, which can involve the orbit in 25% of cases, is a rare head and neck malignancy that has only recently been described. Biphenotypic sinonasal sarcoma is a low-grade, locally aggressive, nonmetastasizing sarcoma displaying both neural and muscle differentiation. It is further characterized by rearrangements of the PAX3 gene with multiple fusion partners, most commonly MAML3 (Mastermind like transcriptional coactivator 3). It occurs predominantly in middle-aged women and exclusively in the sinonasal tract. However, it can spread throughout the central facial structures to invade the brain if not detected early. Ophthalmologists should be aware of this new entity to avoid delays in diagnosis and treatment. The previous literature devoted to this condition was reviewed and analyzed for clinical, radiological, histopathological, and immunohistochemical features. In circumstances where molecular testing is not available, paired box 3 immunohistochemical staining can be used as an alternative diagnostic marker. The current case is most unusual because the orbital findings were induced by a mucocele caused by the tumor that obstructed the sinus ostium. This produced diplopia without direct tumor invasion into the orbital fat.
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http://dx.doi.org/10.1097/IOP.0000000000001839DOI Listing
September 2020

Subretinal Mononuclear Cells in Coats' Disease Studied with RPE65 and CD163: Evidence for Histiocytoid Pigment Epithelial Cells.

Am J Ophthalmol 2021 02 18;222:388-396. Epub 2020 Sep 18.

Departments of Pathology and Ophthalmology, Duke University Medical Center, Durham, North Carolina, USA; Department of Pathology, Campbell University Jerry M. Wallace School of Osteopathic Medicine, Lillington, North Carolina, USA. Electronic address:

Purpose: To evaluate the mononuclear cells in the subretinal exudate in Coats' disease.

Design: Retrospective case series.

Methods: Five enucleated globes and 1 cytology sample from a patient with Coats' disease and 1 case of chronic retinal detachment following repair of an open globe injury were examined immunohistochemically to identify intraretinal and subretinal exudative cells. The 2 biomarkers were RPE65 for retinal pigment epithelium and CD163 for histiocytes, each tagged with different chromogens, yellow for pigment epithelium and purple for CD163-positive (CD163) monocytes/histiocytes. Expression levels were sought from both biomarkers together and singly. A color shift to red in the cells' chromogenic reaction indicated the simultaneous presence of the 2 biomarkers.

Results: Most of the mononuclear cells in Coats' disease samples were CD163 (purple), and a minority were RPE65 (yellow). An intermediate number of cells were RPE65/CD163 (orange-red). The eye with a chronic retinal detachment had an equal distribution of CD163 and RPE65/CD163 cells.

Conclusions: RPE has several well-delineated phenotypes and functions. In normal visual physiology, the pigment epithelium supports photoreceptors and participates in their renewal by phagocytosis of the tips of the photoreceptors. The expression of CD163, a feature of hematopoietically derived monocytes, together with RPE65 in the retinal pigment epithelium, supports differentiation toward histiocytes. Yellow staining of detached pigment epithelial cells were rare. The presence of histiocytoid pigment epithelium at the Bruch membrane probably also has implications for macular degeneration.
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http://dx.doi.org/10.1016/j.ajo.2020.09.020DOI Listing
February 2021

Hereditary Palpebro-Gingival Fibrosis Syndrome.

Ophthalmic Plast Reconstr Surg 2020 Aug 25. Epub 2020 Aug 25.

San Diego Eyelid Specialists, Encinitas, California, U.S.A.

This is a case report involving 3 siblings, ages 22, 21, and 3 years old, of consanguineous parents and Syrian descent with a particularly unique clinical phenotype and eyelid/gingival findings that have not been previously characterized. Full-thickness eyelid biopsies for 2 of the siblings were evaluated by ophthalmic pathology showed generalized fibrosis without any active destructive process or amyloid. Three of the 9 siblings were affected by this order with no familial history. Ophthalmic plastic surgeons should be aware of this new entity as genetic localization and further identification may help families affected by this disorder.
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http://dx.doi.org/10.1097/IOP.0000000000001812DOI Listing
August 2020

High Expression of Programmed Death Ligand 1 and Programmed Death Ligand 2 in Ophthalmic Sebaceous Carcinoma: The Case for a Clinical Trial of Checkpoint Inhibitors.

Am J Ophthalmol 2020 12 28;220:128-139. Epub 2020 Jul 28.

Division of Head and Neck Pathology, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Purpose: To evaluate the expression of programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2) in ocular adnexal sebaceous carcinoma (OASC), and to appraise these findings within the context of recent comparable studies.

Designs: Retrospective case series.

Methods: Twenty cases of primary OASC were immunostained for PD-L1, PD-L2 and CD8. PD-L1 and PD-L2 expression were graded with both the combined positive score (CPS) and the tumor proportion score (TPS). Both raw CPS and TPS were reported, as well as positivity with TPS and CPS ≥1. CD8 expression was graded on a 0-3 scale. Charts were reviewed for clinical correlations. The results of the current study were compared with results of similar recent investigations.

Results: For the 20 cases, mean expression of PD-L1 with CPS was 29.7 (range 0-101.5) and with TPS was 12.2 (range 0-95.8); mean expression of PD-L2 with CPS was 7.9 (range 0-37.3) and with TPS was 1.9 (range 0-12.9). PD-L1 CPS ≥1 was detected in 95% of OASC, while PD-L1 TPS ≥1 was found in 75%. PD-L2 CPS ≥1 was present in 60%, while only 20% had PD-L2 TPS ≥1. Immune cells appeared to contribute to a substantial proportion of PD-L1 and PD-L2 positivity, and a conspicuous CD8-positive T-lymphocytic infiltrate was present in most tumors. Significant correlations were identified between tissue expression of PD-L1, PD-L2, and CD8. Tissues with greater levels of PD-L1 tended to express higher levels of PD-L2 and CD8. The degree of PD-L1 and PD-L2 expression was also associated with the area in millimeters squared of the immunostained tumor, suggesting that tumor sampling may influence interpretation of PD-L1 and PD-L2 expression in ocular adnexal tumors.

Conclusions: The current and preceding studies confirm that PD-L1 and PD-L2 are expressed in a high percentage of OASCs. These results support the premise that checkpoint inhibitor drugs hold considerable therapeutic promise for patients with OASC and stimulate the institution of clinical trials.
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http://dx.doi.org/10.1016/j.ajo.2020.07.031DOI Listing
December 2020

Complex Intratarsal Cyst with a Mixed Ciliated Respiratory-Type and Squamous Epithelial Lining.

Ocul Oncol Pathol 2020 May 8;6(3):151-158. Epub 2019 Oct 8.

Department of Oculoplastics, Massachusetts Eye and Ear Infirmary/Harvard Medical School, Boston, Massachusetts, USA.

A 55-year-old woman developed a painless, non-ulcerated left upper eyelid swelling over 6 months. Examination disclosed a fluctuant mass that permitted movement of the eyelid skin over the lesion. A full-thickness eyelid resection contained a well-encapsulated cyst with milky contents that was predominantly located in the tarsus. The cyst's lining was partially composed of segments of ciliated respiratory-type and non-keratinizing squamous epithelia. Immunohistochemical evaluation with cytokeratins 17, 18, and 19 confirmed the staining pattern of a respiratory-type epithelial cell (whether or not cilia were present in the non-squamous epithelial zones). In the squamous region, entirely different cytokeratin results were obtained vis-a-vis the non-squamous regions of the lining. The current lesion is interpreted as congenital and representing an in situ persistence of embryonic ciliated glandular epithelium that normally exists only transitorily. A more remote possibility is that the lesion was the result of ectopic epithelial cells displaced from an adjacent sinus. A recurrence has not developed during 6 months of follow-up.
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http://dx.doi.org/10.1159/000501369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250357PMC
May 2020

Lacrimal Gland Hamartoma (Formerly Termed Dacryoadenoma).

Am J Ophthalmol 2020 09 29;217:189-197. Epub 2020 Apr 29.

Department of Pathology, Wills Eye Hospital, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA.

Purpose: Since the original description of "dacryadenoma" by Jakobiec and associates, the data on this unusual epibulbar lacrimal gland lesion remain sparse. The aim of this study was to characterize clinically, morphologically, and immunohistochemically this isolated epibulbar lacrimal gland lesion.

Design: Retrospective observational case series.

Methods: Institutional pathology records between 2000 and 2019 were searched for all cases of isolated epibulbar lacrimal gland lesions. Tissue from 3 normal lacrimal glands and 1 complex choristoma were included for comparative analysis. Clinical, histopathologic, and immunohistochemical findings were recorded.

Results: Four patients with isolated epibulbar lacrimal gland lesions, 2 male and 2 female, with a median age of 18 years (range, 12-57) were identified. All patients presented with recent onset of unilateral pink-to-orange, well-circumscribed subepithelial juxtaforniceal (3/4, 75%), or nasal (1/4, 25%) bulbar conjunctival nodules, which were asymptomatic (3/4, 75%) or associated with foreign body sensation (1/4, 25%). When compared with the normal lacrimal gland and complex choristoma, all isolated epibulbar lacrimal gland lesions were composed predominantly of variably dilated, branching tubular structures with pseudo-apocrine snouts, and either totally absent (2/2, 50%) or rare (2/2, 50%) ducts and rare acinar zymogen granules (3/4, 75%).

Conclusion: Our study confirms that a subset of isolated epibulbar lacrimal gland lesions differs morphologically and immunohistochemically from normal lacrimal gland tissue and the lacrimal gland in a complex choristoma. These differences range from subtle to overt, suggesting that isolated epibulbar lacrimal gland lesions may have originated from precursor cellular elements indigenous to the conjunctiva (hamartia) and grew into disorganized lacrimal gland tissue.
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http://dx.doi.org/10.1016/j.ajo.2020.04.015DOI Listing
September 2020

Conjunctival Implantation Cyst in the Orbicularis Oculi Muscle: Review of a Possible Origin From Displaced Stem Cells With a Differential Diagnosis.

Ophthalmic Plast Reconstr Surg 2021 Jan-Feb 01;37(1):1-11

Ophthalmic Plastic Surgery Service, Department of Ophthalmology, Massachusetts Eye and Ear/Harvard Medical School, Boston, Massachusetts, U.S.A.

Purpose: To document a unique case of a corneal/conjunctival epithelial inclusion cyst located in the orbicularis oculi muscle with a comprehensive review of variant conjunctival cysts and simulating conditions.

Methods: Clinicopathologic case report with detailed histopathologic and immunohistochemical evaluation for cytokeratins combined with a tabulation of mimicking lesions and relevant literature citations.

Results: A 59-year-old man experienced severe blunt left periorbital trauma that resulted in a limbal partial-thickness corneal wound with an associated epithelial abrasion and a full-thickness eyelid laceration extending from the superior fornix to the margin. Several months after surgical repair of the eyelid a cyst appeared in the superior pretarsal skin. Histopathologic and immunohistochemical investigations supplied data suggesting that the cyst had a high probability of a corneoscleral limbal stem cell origin. Distinctive features of the lesion are contrasted with those of allied or simulating cysts.

Conclusions: Stem cells are now believed to be located at the corneoscleral limbus, in the inferior fornix, in the medial canthal region, and at the eyelid margin where transitions from conjunctival epithelium to epidermal epithelium occur. Due to their replicative, hardy and robust nature, stem cells displaced to alien environments are most likely to survive and produce cysts. The cyst's corneal-type cytologic characteristics, the absence of goblet cells, and the expression of a broad spectrum of cytokeratin biomarkers in the current case give support to the proposal that limbal stem cells in the region of the corneal laceration were displaced to the eyelid orbicularis muscle and were responsible for this most extraordinary cyst. Comparison with other epithelial cystic linings lends further evidence for this conclusion.
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http://dx.doi.org/10.1097/IOP.0000000000001631DOI Listing
April 2021

Clinical Implications of Goblet Cells in Dacryoadenosis and Normal Human Lacrimal Glands.

Am J Ophthalmol 2020 05 30;213:267-282. Epub 2020 Jan 30.

Ocular Oncology Service, Wills Eye Hospital, Philadelphia, Pennsylvania, USA.

Purpose: The purpose of this study was to investigate an enlarged dacryoadenotic lacrimal gland and normal lacrimal glands for the presence of goblet cells (mucocytes).

Design: Retrospective clinicopathologic series.

Methods: An enlarged lacrimal gland (dacryoadenosis) without obvious histopathologic alterations was extensively evaluated histochemically, immunohistochemically, and ultrastructurally to detect the presence of goblet cells and to compare the findings with those in five normal lacrimal glands.

Results: Granular, zymogen-rich pyramidal acinar cells in normal glands predominated over a previously not reported subpopulation of nongranular, pale-staining cells in both dacryoadenotic and normal lacrimal glands. These cells histochemically stained positively with mucicarmine and Alcian blue. Immunohistochemical and electron microscopic evaluations established that there was a displacement or replacement of cytoplasmic gross cystic disease fluid protein-15 and CK 7-positive tonofilaments in the pale acinar cells by myriad mucus granules. The goblet cells constituted approximately 2% of the normal acinar cells and 5% of dacryoadenotic acinar cells. A depletion of myoepithelial cells and ectopic intra-acinar ductular cells were also observed in dacryoadenosis.

Conclusion: Dacryoadenosis is caused by an increase in the number of acini without individual acinar cell hyperplasia. A normal cytologic feature of the lacrimal gland is the presence of acinar goblet cells that had been long overlooked; they are increased in number in dacryoadenosis. Intra-acinar ductular cells and the scattered loss of myoepithelial cells are other abnormalities in dacryoadenosis. The presence of lacrimal gland goblet cells may have physiologic implications for the precorneal tear film and its derangements as well as for the histogenesis of mucus-producing carcinomas.
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http://dx.doi.org/10.1016/j.ajo.2020.01.029DOI Listing
May 2020

PD-L1 and PD-L2 Expression Levels Are Low in Primary and Secondary Adenoid Cystic Carcinomas of the Orbit: Therapeutic Implications.

Ophthalmic Plast Reconstr Surg 2020 Sep/Oct;36(5):444-450

Division of Head and Neck Pathology, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A.

Purpose: To determine if there is a biologic rationale for using checkpoint inhibitor drugs targeting programmed cell death ligand 1 (PD-L1) and PD-L2 in the treatment of adenoid cystic carcinoma of the orbit.

Methods: Twenty-three cases of adenoid cystic carcinoma involving the orbit (13 primary lacrimal gland, 5 secondarily extending into the orbit, and 5 unspecified) were examined histopathologically. Immunohistochemistry for PD-L1, PD-L2, and CD8 was performed. Charts were reviewed for clinical correlations.

Results: Expression of PD-L1 and of PD-L2 was overall low in adenoid cystic carcinoma (mean expression 1.4 ± 0.9 of 5 for PD-L1, mean 0.83 ± 1.1 of 5 for PD-L2), and tumor-infiltrating CD8-positive T-lymphocytes were sparse (mean 1.1 ± 0.51 of 3). Only 13 of the 23 (57%) cases expressed PD-L1 as a combined positive score ≥1 of cells. No associations were found between expression levels of these markers and patient sex, tumor site of origin, Tumor, Node, Metastasis stage, or patient outcome. A significant association was observed between stromal PD-L1 expression and tumor histopathologic subtype (p = 0.05), and between tumor PD-L1 expression and prior exposure to radiation (p = 0.03).

Conclusions: Checkpoint inhibitor drugs may have limited impact in the treatment and clinical course of orbital adenoid cystic carcinoma based on the low frequency of CD8 infiltrate and low expression of PD-L1 and PD-L2. Pretreatment with radiation, however, may improve tumor response to checkpoint inhibitor drugs.
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http://dx.doi.org/10.1097/IOP.0000000000001585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423458PMC
March 2021

Adult Primary Capillary Hemangioma of the Sclera: A Previously Undescribed Entity With a Review of Epibulbar Vascular Lesions.

Ophthalmic Plast Reconstr Surg 2020 Jul/Aug;36(4):327-333

Cornea and Refractive Surgery Service, Department of Ophthalmology, Massachusetts Eye and Ear/Harvard Medical School, Boston, Massachusetts, U.S.A.

Purpose: The objective of this article is to document a unique case of a primary hemangioma and review epibulbar vascular tumors of the conjunctiva and episclera.

Methods: A case report with detailed histopathologic, histochemical, and immunohistochemical studies coupled with a comprehensive review of the relevant literature with a tabulation of previously reported epibulbar vascular lesions was performed.

Results: A vascular tumor developed in a 46-year-old woman over 2-3 months that histopathologically was located in the superficial third of the normally avascular sclera and was composed of capillary caliber vessels. CD31 and CD34 positivity established the vascular nature of the lesion. Despite its adult onset, the tumor was also glut-1 positive, a vascular characteristic of childhood capillary hemangiomas that will ultimately involute. Smooth muscle actin was positive in the endothelial cells and associated pericytes. An ectatic muscular vessel identified in the midst of the lesion was interpreted as an anomalous intrascleral branch of an epibulbar anterior ciliary artery, where it perforated the sclera in the vicinity of the insertion of an extraocular rectus muscle. It was deduced to be the source of the capillary proliferation. A literature review failed to identify any previously reported epibulbar vascular tumor that originated primarily in the sclera or secondarily infiltrated this ocular tunic.

Conclusion: An adult primary capillary intrascleral neoplasm is described as the rarest of all epibulbar vascular tumors and in keeping with the exceptional status of the ocular endothelium was glut-1 positive. This lesion must be distinguished from an array of other common and esoteric epibulbar vascular conditions.
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http://dx.doi.org/10.1097/IOP.0000000000001582DOI Listing
March 2021

Congenital respiratory-type ciliated cyst of the lacrimal sac.

Can J Ophthalmol 2020 02 26;55(1):e30-e33. Epub 2019 Jun 26.

Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1016/j.jcjo.2019.05.001DOI Listing
February 2020

Doxycycline-associated conjunctival cysts.

Clin Exp Ophthalmol 2020 01 11;48(1):134-136. Epub 2019 Nov 11.

Ophthalmic Plastic Surgery Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1111/ceo.13669DOI Listing
January 2020

Ocular Adnexal Adenomatoid Sebaceous Gland Hyperplasia: A Clinical and Immunopathologic Analysis in Relation to the Muir-Torre Syndrome.

Ophthalmic Plast Reconstr Surg 2020 Jan/Feb;36(1):e6-e12

Department of Plastic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A.

The purpose of this study is to codify the microscopic diagnostic criteria for ocular adnexal brow and caruncular sebaceous gland hyperplasias (pseudoadenomatoid) that distinguish it from an adenoma. Clinical records and photographs were critically reviewed and microscopic slides were stained with hematoxylin and eosin and immunochemically stained for adipophilin, androgen receptor, p16, p53, a spectrum of cytokeratins, Ki-67 and mismatch repair nuclear protein expression for MLH1, MSH2, PMS2, and MSH6. The patients and their close relatives had no history of cancer. Cytokeratin 7 and especially cytokeratin 17 highlighted the presence of ducts in the hyperplastic lesion, which are not present in adenomas. p16 and p53 were negative and Ki-67 immunostaining demonstrated similar low proliferation indices for normal and hyperplastic glands. The mismatch repair nuclear protein expressions were preserved in both lesions. Histopathologic misdiagnosis of adenomatoid sebaceous gland hyperplasia as an adenoma can lead to the impression of an association with the Muir-Torre syndrome. Cytokeratins 7 and 17 immunostaining can be helpful in highlighting compressed ducts that in exuberant sebaceous gland hyperplasias may lead to a diagnosis of an adenoma (in which ducts are absent). Negative immunostaining for p16 rules out a possible etiologic role of human papillomavirus in hyperplasias and the negative p53 staining indicates the lesions are not truly neoplastic. The preservation of mismatch repair nuclear protein expression rules out the likelihood of the Muir-Torre syndrome. The current cases convincingly establish that sebaceous hyperplasia is not associated with the Muir-Torre syndrome by both clinical findings and immunohistochemical testing.Two yellow lesions, from the brow and caruncle, were examined microscopically and immunohistochemically to establish the diagnosis of sebaceous gland hyperplasia and to rule out the Muir-Torre syndrome.
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http://dx.doi.org/10.1097/IOP.0000000000001497DOI Listing
March 2021

Large Cell Acanthoma of the Conjunctiva: Clinicopathologic and Immunohistochemical Features.

Ocul Oncol Pathol 2019 Aug 16;5(5):312-318. Epub 2019 Jan 16.

Eye Health Services, Quincy, Massachusetts, USA.

Large cell acanthoma (LCA) was first described as a lesion on sun-exposed skin. All LCAs feature keratinocytes twice the size of normal cells (cytomegaly). Although infrequently diagnosed in the skin, it has been even more rarely described by ophthalmic pathologists in the eyelid skin and the conjunctiva. This report describes the third case of a conjunctival epithelial LCA, with the first published clinical photograph highlighting its leukoplakic and well-circumscribed character, as well as the most thorough analysis of the immunohistochemical features of this lesion. It is contrasted with squamous dysplasias and papillomas of the conjunctiva. A review of previous conjunctival LCA lesions discloses frequent recurrences after initial surgery and the remote but real potential for squamous dysplastic transformation. Immunohistochemical stains for certain cytokeratins, p53, and Ki-67 (proliferation index) will in the future be particularly helpful in establishing an early and accurate diagnosis of conjunctival LCA.
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http://dx.doi.org/10.1159/000495250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751469PMC
August 2019

Intraductal sebaceous papilloma of a meibomian gland: a new entity possibly associated with the MSH6 subtype of the Muir-Torre syndrome.

Surv Ophthalmol 2020 Mar - Apr;65(2):227-238. Epub 2019 Sep 23.

Department of Ophthalmic Pathology, Wills Eye Hospital, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Over several months, a painless, multinodular, non-erythematous swelling of the deep tissues of his left upper eyelid developed in a 63-year-old man. An excisional biopsy with histopathologic evaluation disclosed a unique sebaceous papilloma within a cyst lined by non-keratinizing squamous epithelium that focally displayed a variably thick, superficial, eosinophilic cuticular layer. Immunohistochemical staining demonstrated that the tumor and its epithelial cystic lining had a profile consistent with Meibomian gland duct epithelium. Adipophilin highlighted cytoplasmic vacuolar lipid positivity. The encapsulation of the lesion, absence of nuclear atypia, and Ki-67 nuclear positivity restricted to the basilar cells established its intrinsically benign nature. The patient's clinical history was remarkable for pulmonary and colonic carcinomas resected, respectively, 20 years and 8 years earlier. DNA mismatch repair protein expression studies disclosed loss of nuclear immunostaining of MSH6 protein, pointing to the possibility of an underlying rare MSH6 variant of the Muir-Torre syndrome, not yet described in the ophthalmic literature. p16 nuclear positivity was also found in the tumor cells, indicating the possible role of high-risk human papillomavirus as an additional factor in the genesis of the tumor. Genetic evaluation of normal and tumoral tissues in future similar cases will detect if there is an underlying germline mutation versus a somatic mutation limited to the tumor. This will be required to fully establish a predictable linkage with this new subtype of the Muir-Torre syndrome.
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http://dx.doi.org/10.1016/j.survophthal.2019.09.002DOI Listing
March 2021

Angiofibroma of the Eyelid: A Rare Clinical and Histologic Variant.

Ophthalmic Plast Reconstr Surg 2019 Jul/Aug;35(4):e199-e102

Departments of Ophthalmology.

A flesh-colored, supraciliary lesion of the left upper eyelid in a 47-year-old man was excised for cosmetic reasons. Histopathology and immunohistochemistry demonstrated CD34-positive benign spindle cells, factor XIIIa-positive dendritic cells, and CD163-positive histiocytes, all dispersed within a diffuse collagenous background. Prominent loose perivascular cuffs of fibroblastic cells and collagen surrounded small blood vessels. Interpreted as an angiofibroma, the histopathology bore resemblance to that of a single previously-reported forearm lesion termed a "dermal fibroma with a distinctive perivascular cell arrangement." The lesion represents the first eyelid example of an unusual variant of angiofibroma.
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http://dx.doi.org/10.1097/IOP.0000000000001423DOI Listing
December 2019

A Review of Next-Generation Sequencing (NGS): Applications to the Diagnosis of Ocular Infectious Diseases.

Semin Ophthalmol 2019 6;34(4):223-231. Epub 2019 Jun 6.

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

: To review the value of next-generation sequencing (NGS) in identifying the pathogens which cause ocular infections, thereby facilitating prompt initiation of treatment with an optimal anti-microbial regimen. Both contemporary and futuristic approaches to identifying pathogens in ocular infections are covered in this brief overview. : Review of the peer reviewed literature on conventional and advanced methods as applied to the diagnosis of infectious diseases of the eye. : NGS is a novel technology for identifying the pathogens responsible for ocular infections with the potential to improve the accuracy and speed of diagnosis and hastening the selection of the best therapy.
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http://dx.doi.org/10.1080/08820538.2019.1620800DOI Listing
July 2019

A Review of the Role of Cytogenetics in the Diagnosis of Orbital Rhabdomyosarcoma.

Semin Ophthalmol 2019 30;34(4):243-251. Epub 2019 May 30.

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

Rhabdomyosarcoma (RMS) is the most common sarcoma of childhood and adolescence. Approximately 10% arise in the orbit, where the embryonal type is most common variant. The alveolar variant is less frequent and has a worse prognosis. Cytogenetic studies have revealed that most alveolar rhabdomyosarcomas have translocations involving the PAX and the FOX01 genes, giving rise to fusion genes that contribute to lack of differentiation and proliferation of the tumor cells. However, approximately 20% of alveolar rhabdomyosarcomas lack translocations and have been found to behave more similarly to embryonal cases. Histopathology remains the basis of diagnosis, but cytogenetic features and molecular signatures are becoming part of the routine analysis of RMS, since they determine not only prognosis, but also management and treatment regimens. A comprehensive review of the recent published literature in relation to orbital rhabdomyosarcomas and their cytogenetic features as well as clinical and therapeutic implications will be discussed.
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http://dx.doi.org/10.1080/08820538.2019.1620802DOI Listing
July 2019

Atypical Case of Rosai-Dorfman Disease of the Lacrimal Gland with Adjacent Bone Erosion.

Ocul Oncol Pathol 2019 Feb 18;5(2):128-134. Epub 2018 Jul 18.

Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

Background/aims: Rosai-Dorfman disease (RDD) is a rare, self-limited disorder of unknown etiology that affects children and young adults worldwide and typically manifests as chronic, painless cervical lymphadenopathy. Orbital involvement is very rare and may be an isolated extranodal manifestation or associated with concurrent systemic disease. Adjacent bone involvement is most exceptional, and secondary optic neuropathy has never been reported.

Methods: This is a case report with review of the literature.

Results: We present a 32-year-old man who, over a 3-month period, developed worsening vision, headache, and vertical diplopia. On examination, there was decreased vision with dyschromatopsia, proptosis, and hypotropia of the left eye. CT scan of the orbits revealed a soft tissue mass inseparable from the lacrimal gland with adjacent bone erosion. Histopathologic evaluation revealed a diffuse infiltrate of histiocytes, lymphocytes, plasma cells, and neutrophils with peripolesis and emperipolesis (tunneling of lymphocytes and plasma cells in the histiocytes' cytoplasm without destruction), consistent with RDD. Resolution of symptoms as well as of the optic neuropathy was achieved with oral corticosteroids.

Conclusion: RDD is an important diagnosis that must be considered in the differential diagnosis of an orbital mass.
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http://dx.doi.org/10.1159/000489127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422131PMC
February 2019

Small Benign Storiform Fibrous Tumor (Fibrous Histiocytoma) of the Conjunctival Substantia Propria in a Child: Review and Clarification of Biologic Behavior.

Ophthalmic Plast Reconstr Surg 2019 Sep/Oct;35(5):495-502

Department of Ophthalmology, David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, U.S.A.

Purpose: A case of a small benign storiform fibrous tumor of the conjunctival substantia propria is described to clarify the category of fibrous histiocytoma. In addition, a comparison of the various spindle cell tumors of the conjunctival substantia propria is explored.

Methods: The patient underwent a complete tumor excision, and the specimen was analyzed by histopathologic and immunohistochemical investigations.

Results: A cellular mass, composed solely of spindle cells in a storiform pattern without a component of histiocytic cells, was found beneath an undisturbed nonkeratinizing squamous epithelium and was separated from the epithelium by a grenz zone of uninvolved collagen. The lesion was sharply demarcated but not encapsulated. The Masson trichrome stain revealed scant deposition of intercellular collagen. The reticulin stain displayed numerous and delicate wiry fibers between the tumor cells and encircling capillaries. The Alcian blue stain demonstrated faint positivity in the interstitium. Immunohistochemistry revealed positivity for vimentin, factor XIIIa, smooth muscle actin, CD10, and CD45. Negative stains were obtained for CD34, CD56, S100, desmin, and Ki67.

Conclusions: The broad term of fibrous histiocytoma should be reserved for deep fibroblastic spindle cell tumors (e.g., those of the orbit) that display an aggressive behavior. More benign superficial spindle cell tumors of the dermis are now preferentially characterized as dermatofibromas. It is suggested that equally benign epibulbar tumors should no longer be designated as fibrous histiocytomas but rather as benign storiform fibrous tumors. Tumors completely composed of polygonal histiocytoid (epithelioid) cells that are CD34+ should be excluded from the benign storiform fibrous tumor category. Positive smooth muscle actin and factor XIIIa staining in conjunction with negative staining for CD34 and desmin in the current spindled tumor cells are findings consistent with those of cutaneous dermatofibromas. Both the epibulbar and dermal spindle cell lesions have displayed an indolent and nonaggressive behavior. Microscopically they contain a high proportion of dendrocytic stellate cells that are either factor XIIIa+ or XIIIa-. Given the anatomic differences between the dermis and conjunctiva, the term dermatofibroma is inappropriate for the current tumor; instead the term benign storiform fibrous tumor has been proposed for superficial tumors of the conjunctiva.
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http://dx.doi.org/10.1097/IOP.0000000000001355DOI Listing
January 2020

Orbital Nasal-Type Extranodal Natural Killer/T-Cell Lymphoma: An Ongoing Diagnostic Challenge Further Confounded by Small-Cell Predominance.

Ophthalmic Plast Reconstr Surg 2019 Sep/Oct;35(5):478-483

Division of Ophthalmic Plastic and Reconstructive Surgery, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts.

Purpose: To highlight the histopathologic diagnostic challenges of small-cell predominant extranodal nasal-type natural killer/T-cell lymphoma (ENTNKT) of the orbit.

Methods: Retrospective chart review and histopathologic study with immunohistochemistry and in situ hybridization of 3 cases.

Results: Three cases of ENTNKT presented to the Mass Eye and Ear emergency room as orbital cellulitis over 1 year. The first case was unusual in that there was a predominance of small cells, giving the ENTNKT the histopathologic appearance of a nonmalignant inflammatory process. This challenging case is juxtaposed alongside 2 other cases, which exhibited the more typical lymphomatous microscopic appearance.

Discussion: ENTNKT can extend into the orbit from the adjacent sinuses or rarely arise primarily in the orbit. A diagnosis is typically made with a biopsy. Occasionally, however, the histopathologic diagnosis can be elusive when a predominance of small lymphomatous cells that are virtually indistinguishable from non-neoplastic inflammatory cells is present. Demonstration of CD56 positivity by immunostaining and in situ hybridization for Epstein-Barr virus are essential in confirming the diagnosis.

Conclusions: ENTNKT should be considered both in the clinical and histopathologic differential diagnoses of orbital infections and idiopathic inflammations (pseudotumor).
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http://dx.doi.org/10.1097/IOP.0000000000001333DOI Listing
January 2020

Steatocystoma Simplex of the Caruncle: Case Report and Immunohistologic Study.

Ophthalmic Plast Reconstr Surg 2019 Mar/Apr;35(2):e45-e47

Department of Ophthalmology.

A yellow cystic lesion of the caruncle in a 23-year-old woman proved to be a solitary steatocystoma, a rare occurrence in that location. While the histopathologic diagnosis was evident from clusters of sebaceous cells within the cyst wall, a panel of immunohistochemical stains further distinguished the lesion from a keratinous cyst. The most useful stains for differentiating the two conditions were carcinoembryonic antigen, epithelial membrane antigen, cytokeratins 17 and 19, and calretinin. Only three previous cases of caruncular steatocystoma simplex have been reported, none of which included immunohistochemical studies. The current findings support the origin of the cyst from the small duct that connects the unilobular sebaceous gland associated with vellus hairs to the follicular canal.
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http://dx.doi.org/10.1097/IOP.0000000000001321DOI Listing
December 2019