Case Series and Brief Reports Received: January 13, 2015 Accepted after revision: March 30, 2015 Published online: June 17, 2015
Ocul Oncol Pathol 2016;2:24–28 DOI: 10.1159/000430098
Pulmonary Adenocarcinoma Metastatic to the Choroid Diagnosed by Biopsy of an Extrascleral Nodule Frederick A. Jakobiec a, b David J. Ramsey a Anna M. Stagner a, b David M. Wu a Michael K. Yoon a
a
b
Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, and David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Boston, Mass., USA
Key Words Choroid · Orbit · Lung carcinoma · Metastasis · Immunohistochemistry
Abstract Purpose/Background: To report a patient with orbital extension of a choroidal metastasis produced by a pulmonary adenocarcinoma which was diagnosed by biopsy of the extrascleral nodule. Methods: Clinical history and imaging studies (including fundus photography, autofluorescence, fluorescein angiography, B-scan, and orbital MRI) were reviewed along with histopathologic and immunohistochemical studies. Results: A 60-year-old woman presented with decreased vision in the right eye. Fundus examination revealed a leopard-spotted choroidal lesion and associated serous retinal detachment. Imaging disclosed an enhancing orbital lesion abutting the sclera near the choroidal mass, which had spread outside of the eye. Histopathology revealed lumen-forming cells elaborating mucin. The cells were immunohistochemically positive for epithelial membrane antigen, thyroid transcription factor 1, and cytokeratin 7 and negative for cytokeratin 20. This was consistent with a pulmonary adenocarcinoma. Widespread
© 2015 S. Karger AG, Basel 2296–4681/15/0021–0024$39.50/0 E-Mail [email protected] www.karger.com/oop
metastases were subsequently found. Conclusions: This is the first detailed case report of a successful biopsy of the orbital extension of an essentially posterior intraocular tumor. Such a maneuver permits a much more generous tissue sample than a needle biopsy. In the current case, a large tissue sample provided the basis for complete immunohistochemical evaluation, leading to the diagnosis of an intraocular metastatic mucin-producing adenocarcinoma of lung origin. © 2015 S. Karger AG, Basel
Introduction
Metastatic tumors to the eye far outnumber primary intraocular malignancies [1, 2]. The most common site for an ophthalmic metastasis is the uveal tract, with the choroid being more frequently involved than the iris or ciliary body [3–5]. Breast and lung carcinomas are the usual primaries [6–9]. Although there are many articles devoted to orbital and choroidal metastases [3, 10, 11], there are only 2 reports [12, 13] of a posterior extrascleral extension from a choroidal pulmonary metastasis from non-small cell lung cancer (NSCLC). Taking diagFrederick A. Jakobiec, MD, DSc David G. Cogan Laboratory of Ophthalmic Pathology Massachusetts Eye and Ear Infirmary, Suite 328 243 Charles Street, Boston, MA 02114 (USA) E-Mail Fred_Jakobiec @ meei.harvard.edu
Fig. 1. Radiographic features of a patient
with metastatic pulmonary adenocarcinoma to the choroid and orbit. a T1-weighted MRI in the axial projection discloses a crescent-shaped, well-circumscribed inferolateral orbital mass tightly adherent to the globe with adjacent choroidal thickening (arrow). b Positron emission tomography scan showing multiple areas of FDG avidity in the lung, hilum, orbit, peritoneum, and bones. Fig. 2. Clinical photography of a patient with metastatic pulmonary adenocarcinoma to the choroid and orbit. Wide-field pseudo-color fundus image of the right eye. a An orange, leopard-spotted choroidal lesion occupies much of the nasal and inferonasal retina. Arrowheads denote a subtle color change from the border of subretinal fluid. Wide-field autofluoresence image of the right eye. b Areas of retinal pigment epithelial (RPE) hypertrophy are hyperfluorescent secondary to lipofuscin accumulation, alternating with hypofluoresence in areas of RPE loss. A subtle hyperfluoresence correlates with the presence of subretinal fluid (arrowheads). Wide-field fluorescein angiogram. c In the area of the tumor, there is a pinpoint and lobular hyperfluorescent pattern that remains constant from the mid-stage of the angiogram without change in later frames. In the periphery (arrows), vascular leakage secondary to ischemia from chronic serous retinal detachment can be seen. B-Scan. d Nasal transverse B-scan of the right eye. The curved arrow shows the retinal detachment. The two linear segments through the posterior eye wall into the orbit denote choroidal thickening (yellow), the sclera (purple), and intraconal mass (green). The arrowhead is at the 4:30 meridian, showing a discontinuity in the posterior sclera, possibly a dilated emissary vein.
a
1 a
b
c
nostic advantage of a posterior extraocular extension of an intraocular lesion is a low-morbidity approach that has not been employed often enough judging from the lack of attention it has received in the literature. There have, however, been occasional descriptions of biopsies of anterior epibulbar extensions of ciliary body masses [14–16]. In contrast to a needle biopsy, a posterior orbital biopsy permits the preservation of the architecture of the metastasis and enables a fuller spectrum of immunostaining. Ocular Metastasis from Lung Carcinoma
b
d
2
Case Report Clinical Findings A 60-year-old Caucasian woman was referred with a 3-month history of gradual-onset blurry vision in the right eye. She had a history of NSCLC, adenocarcinoma stage T2bN0M0, 14 years earlier treated with resection of the right middle and lower lobes without adjuvant chemotherapy or radiotherapy. Unfortunately, the microscopic slides could not be located at another hospital for review. A CT scan of the head ordered to evaluate her visual complaint was interpreted as normal. Her symptoms progressed and diplopia developed, prompting an MRI scan that demon-
Ocul Oncol Pathol 2016;2:24–28 DOI: 10.1159/000430098
25
a
b
c
d
e
f
Fig. 3. Histopathologic and immunohisto-
chemical features of metastatic lung adenocarcinoma to the choroid and orbit. a Patulous lumens are filled with mucus (M) as revealed in the orbital biopsy. b Small clusters of tumor cells with oval-to-round nuclei lacking pleomorphism possess a moderate amount of eosinophilic cytoplasm. Note the intervening fibrosclerotic stroma. c The Alcian blue stain highlights tumor cells with intracytoplasmic vacuoles containing mucus, as well as surrounding extracellular mucus. d Mucicarmine stain displaying intracytoplasmic red-staining mucus. e Cytokeratin 7 uniformly stains the tumor cells’ cytoplasm. f Thyroid transcription factor 1 immunostains the nuclei of most of the tumor cells. a, b Hematoxylin and eosin, ×100, ×200. c Alcian blue, ×400. d Mucicarmine, ×600. e, f Immunoperoxidase reaction, diaminobenzine chromogen, hematoxylin counterstain, ×100, ×100.
strated a right orbital mass with adjacent choroidal thickening and indentation of the globe (fig. 1a). Visual acuity was 20/40 in the right eye and 20/20 in the left. There was anisocoria with a larger pupil on the right, but no relative afferent pupillary defect. On dilated fundus examination, there was a leopard-spotted, orange choroidal lesion inferonasal to the optic disc with subretinal fluid extending through the inferonasal macula of the right eye (fig. 2a). Autofluorescence showed hyperfluorescence secondary to lipofuscin accumulation alternating with hypofluoresence in areas of retinal pigment epithelial cell loss (fig. 2b). Fluorescein angiography transiting the right eye demonstrated hyperfluorescence in a pinpoint and lobular pattern (fig. 2c). Optical coherence tomography of the right macula (not shown) demonstrated distortion of the inferonasal macular contour secondary to the choroidal mass. Echography revealed an irregularly contoured lesion from the 12 to 7 o’clock meridians with high, but irregular internal reflectivity, and a maximal elevation of 3.1 mm (fig. 2d). The foregoing clinical and imaging findings were consistent with a choroidal metastasis. A discontinuity was noted in the posterior sclera, possibly a dilated emissary vein. The extra-
26
Ocul Oncol Pathol 2016;2:24–28 DOI: 10.1159/000430098
scleral component was located within the intraconal space and had maximal measurements of 7.3 mm in height and 11.6 mm in length. A right transconjunctival orbitotomy was performed. A 3-cm superior fornix incision was made in the conjunctiva in the superomedial quadrant. Blunt dissection was carried out in the episcleral plane until the mass was encountered. Silk traction sutures were looped around the superior and medial rectus muscle insertions to stabilize the globe. The encountered extrascleral mass was very firm and tightly adherent to the globe. A periosteal elevator was used to bluntly elevate an edge of the tumor. Then an incisional biopsy was performed with Westcott scissors. The incision did not extend into the sclera so as to reduce any change of rupture. Histopathologic and Immunohistochemical Findings Hematoxylin-and-eosin-stained paraffin sections disclosed lumen-forming eosinophilic cells elaborating intracellular and extracellular mucin (fig. 3a) forming small clusters of cells set in a fibrosclerotic stroma (fig. 3b). The Alcian blue (fig. 3c) and mucicarmine stains (fig. 3d) highlighted the mucin. Epithelial mem-
Jakobiec/Ramsey/Stagner/Wu/Yoon
brane antigen and cytokeratin 7 (fig. 3e) were positive, whereas cytokeratin 20 was negative. Thyroid transcription factor 1 immunostained most of the nuclei of the tumor cells (fig. 3f). Postoperative Clinical Findings Positron emission tomography scan 1 week postoperatively revealed bilateral multifocal lung cancer with a dominant FDGavid superior lingular mass with left hilar lymphadenopathy (fig. 1b). Other involved sites included the right orbit, multiple sites in the skeleton and peritoneal nodules consistent with peritoneal carcinomatosis. The patient elected to undergo palliative radiotherapy to the right orbital lesion followed by systemic therapy at a local hospital. At the most recent follow-up visit, 5 months after palliative radiotherapy to the right orbit, the patient’s ophthalmic status was stable with respect to no progression in proptosis, but visual acuity had worsened to 20/400 with an advanced retinal detachment surrounding the tumor. Ocular and nonocular metastatic adenocarcinoma of the lung is notoriously nonresponsive to chemo- and radiotherapy. The patient is on maintenance palliative chemotherapy consisting of carboplatin and pemetrexed, a multitarget antifolate approved for advanced NSCLC [17], but she has displayed increased weakness with a very poor prognosis.
Discussion
About 85% of lung cancers are NSCLCs. Non-small cell tumors are traditionally divided into 3 main subtypes: adenocarcinoma (approx. 50%), squamous cell (epidermoid) carcinoma (approx. 35%), and large cell (undifferentiated) carcinoma (approx. 15%). NSCLCs have a poor prognosis primarily due to their advanced stage at the time of diagnosis [17]. The incidence of choroidal metastases from lung cancer has been reported to be 2–6.7% [18, 19]. When choroidal metastases do occur, multiple foci of metastatic disease may be present with bilateral involvement in 20–40% of cases [2]. Ocular metastases are relatively insensitive to chemotherapy and radiotherapy. Death from disseminated disease usually occurs 7.4 months after globe involvement [1]. The incidence of extraocular extension from a choroidal metastasis is unclear. It is less characteristic than in diffuse choroidal melanoma and diffuse lymphoid infiltration of the uvea (now generally diagnosed as a lowgrade extranodal marginal zone lymphoma). The point of this article is to emphasize the opportunity to diagnose a metastatic choroidal lesion from biopsy of an extraocular nodule, especially when a primary lesion may not have been discovered, as is the case in 34% of overall ocular metastases [2]. Both a metastatic renal carcinoma [20] and a papillary thyroid carcinoma [21] to the choroid and contiguous orbit have recently been reported. Ocular Metastasis from Lung Carcinoma
Histopathologically, the juxtascleral incisional orbital biopsy revealed clusters of cells with eosinophilic cytoplasm forming lumens with surrounding extracellular mucin, outside of which was a fibrosclerotic stroma – consistent with a mucin-producing adenocarcinoma. The mucinous material was Alcian blue and mucicarmine positive. These findings are compatible with any mucin-producing primary carcinoma, such as lung, breast, or bowel carcinoma. Immunohistochemical studies were therefore performed. Cytokeratin 7 was positive, while cytokeratin 20 was negative. The former is typically positive in cancers arising above the diaphragm, while the latter is found in those originating below the diaphragm. Thyroid transcription factor 1 further helped to confirm the diagnosis because it is often positive in lung carcinomas. Thyroid transcription factor 1, also referred to as thyroid-specific enhancer-binding protein, is a 35-kDa nuclear protein that normally stains thyroid follicular and parafollicular cells, as well as pulmonary type II pneumocytes and Clara cells. This factor regulates the transcription of thyroglobulin, thyroperoxidase, and calcitonin, which makes it a valuable adjunct in the diagnosis of the better differentiated thyroid and parathyroid neoplasms, but of less service in poorly differentiated ones. Additionally, this same transcription factor promotes the synthesis of surfactant proteins A, B, and C, which makes it diagnostically useful for primary and metastatic lung carcinomas. In the lung, small cell carcinomas are 90% positive, adenocarcinomas are 75% positive, large cell carcinomas are 40% positive, and squamous cell carcinomas are only 5% positive [22]. Biopsy of an orbital extension may lead to expedited diagnosis. Needle biopsy might be attempted if the patient is deemed to be too ill for an open surgical approach. A previous patient with an extensive choroidal breast metastasis presented with the clinical picture of scleritis including pain [13]. The sclera was massively thickened; an opportunity to biopsy this component was not seized. The diagnosis of metastatic breast carcinoma with scleral and epibulbar invasion was made only following an enucleation [13]. Another previously reported case describing an intraocular needle biopsy of a metastatic tumor in a 51-year-old woman ultimately came to enucleation due to therapeutic failure [12]. The surgical technique for biopsying an ocular/orbital metastasis is rapid and safe. An important caveat is that, once the episcleral nodule has been isolated from surrounding normal orbital tissues, the incisional biopsy does not proceed any deeper than the episcleral plane in order to avoid any further Ocul Oncol Pathol 2016;2:24–28 DOI: 10.1159/000430098
27
weakening of the infiltrated sclera. The more traditional eyelid crease incision with a subperiosteal plane dissection is more challenging for accessing the intraconal space. A vertical eyelid crease incision permits excellent visualization of the intraconal space, but entails a visible cutaneous incision-scarred site when healed. In our technique, the tumor was accessed transconjunctivally without incision into the skin or detachment of any extraocular muscles.
Acknowledgements The authors thank Ms. Karen Capaccioli (sonographer) for imaging support, and Louise Collins (Howe Library, Massachusetts Eye and Ear Infirmary) for research support.
Statement of Ethics This study was conducted in compliance with the rules and regulations of the Health Insurance Portability and Accountability Act, and in adherence to the Declaration of Helsinki and all other relevant federal and state laws.
References 1 Ferry AP, Font RL: Carcinoma metastatic to the eye and orbit. 1. A clinicopathologic study of 227 cases. Arch Ophthalmol 1974;92: 276– 286. 2 Shields CL, Shields JA, Gross NE, et al: Survey of 520 eyes with uveal metastases. Ophthalmology 1997;104:1265–1276. 3 Abundo RE, Orenic CJ, Anderson SF, et al: Choroidal metastases resulting from carcinoma of the lung. J Am Optom Assoc 1997; 68: 95–108. 4 Bianciotto C, Demirci H, Shields CL, et al: Metastatic tumors to the eyelid: report of 20 cases and review of the literature. Arch Ophthalmol 2009;127:999–1005. 5 Chen CJ, McCoy AN, Brahmer J, et al: Emerging treatments for choroidal metastases. Surv Ophthalmol 2011;56:511–521. 6 Eliassi-Rad B, Albert DM, Green WR: Frequency of ocular metastases in patients dying of cancer in eye bank populations. Br J Ophthalmol 1996;80:125–128. 7 Nelson CC, Hertzberg BS, Klintworth GK: A histopathologic study of 716 unselected eyes in patients with cancer at the time of death. Am J Ophthalmol 1983;95:788–793. 8 Su HT, Chen YM, Perng RP: Symptomatic ocular metastases in lung cancer. Respirology 2008;13:303–305.
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9 Weiss L: Analysis of the incidence of intraocular metastasis. Br J Ophthalmol 1993; 77: 149–151. 10 Lardinois D, Weder W, Roudas M, et al: Etiology of solitary extrapulmonary positron emission tomography and computed tomography findings in patients with lung cancer. J Clin Oncol 2005;23:6846–6853. 11 Macedo JE, Machado M, Araujo A, et al: Orbital metastasis as a rare form of clinical presentation of non-small cell lung cancer. J Thorac Oncol 2007;2:166–167. 12 Kaur H, Buettner H, Salomao DR, et al: Transscleral orbital invasion by a radiation and chemotherapy-resistant choroidal metastasis of a pulmonary adenocarcinoma. Am J Ophthalmol 2007;143:369–370. 13 Yeo JH, Jakobiec FA, Iwamoto T, et al: Metastatic carcinoma masquerading as scleritis. Ophthalmology 1983;90:184–194. 14 Jakobiec FA, Gragoudas ES, Colby KA: Biopsy of an anterior episcleral nodule as an aid in managing a ciliary body melanocytic tumor. Cornea 2013;32:1174–1177. 15 Mohamed MD, Gupta M, Parsons A, et al: Ultrasound biomicroscopy in the management of melanocytoma of the ciliary body with extrascleral extension. Br J Ophthalmol 2005;89: 14–16. 16 Reddy SC, Madhavan M, Mutum SS: Anterior uveal and episcleral metastases from carcinoma of the breast. Ophthalmologica 2000;214: 368–372.
Ocul Oncol Pathol 2016;2:24–28 DOI: 10.1159/000430098
17 Reck M, Paz-Ares LG, de Marinis F, et al: PARAMOUNT: descriptive subgroup analyses of final overall survival for the phase III study of maintenance pemetrexed versus placebo following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol 2014;9:205–213. 18 Albert DM, Rubenstein RA, Scheie HG: Tumor metastasis to the eye. 1. Incidence in 213 adult patients with generalized malignancy. Am J Ophthalmol 1967;63:723–726. 19 Kreusel KM, Wiegel T, Stange M, et al: Choroidal metastasis in disseminated lung cancer: frequency and risk factors. Am J Ophthalmol 2002;134:445–447. 20 Rai R, Jakobiec FA, Fay A: Ocular metastatic renal carcinoma presenting with proptosis. Ophthal Plast Reconstr Surg, Epub ahead of print. 21 Kiratli H, Tarlan B, Soylemezoglu F: Papillary thyroid carcinoma: bilateral choroidal metastases with extrascleral extension. Korean J Ophthalmol 2013;27:215–218. 22 Pelosi G, Fraggetta F, Pasini F, et al: Immunoreactivity for thyroid transcription factor-1 in stage I non-small cell carcinomas of the lung. Am J Surg Pathol 2001;25:363–372.
Jakobiec/Ramsey/Stagner/Wu/Yoon
Ocul Oncol Pathol 2016;2:24–28 DOI: 10.1159/000430098
Pulmonary Adenocarcinoma Metastatic to the Choroid Diagnosed by Biopsy of an Extrascleral Nodule Frederick A. Jakobiec a, b David J. Ramsey a Anna M. Stagner a, b David M. Wu a Michael K. Yoon a
a
b
Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, and David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Boston, Mass., USA
Key Words Choroid · Orbit · Lung carcinoma · Metastasis · Immunohistochemistry
Abstract Purpose/Background: To report a patient with orbital extension of a choroidal metastasis produced by a pulmonary adenocarcinoma which was diagnosed by biopsy of the extrascleral nodule. Methods: Clinical history and imaging studies (including fundus photography, autofluorescence, fluorescein angiography, B-scan, and orbital MRI) were reviewed along with histopathologic and immunohistochemical studies. Results: A 60-year-old woman presented with decreased vision in the right eye. Fundus examination revealed a leopard-spotted choroidal lesion and associated serous retinal detachment. Imaging disclosed an enhancing orbital lesion abutting the sclera near the choroidal mass, which had spread outside of the eye. Histopathology revealed lumen-forming cells elaborating mucin. The cells were immunohistochemically positive for epithelial membrane antigen, thyroid transcription factor 1, and cytokeratin 7 and negative for cytokeratin 20. This was consistent with a pulmonary adenocarcinoma. Widespread
© 2015 S. Karger AG, Basel 2296–4681/15/0021–0024$39.50/0 E-Mail [email protected] www.karger.com/oop
metastases were subsequently found. Conclusions: This is the first detailed case report of a successful biopsy of the orbital extension of an essentially posterior intraocular tumor. Such a maneuver permits a much more generous tissue sample than a needle biopsy. In the current case, a large tissue sample provided the basis for complete immunohistochemical evaluation, leading to the diagnosis of an intraocular metastatic mucin-producing adenocarcinoma of lung origin. © 2015 S. Karger AG, Basel
Introduction
Metastatic tumors to the eye far outnumber primary intraocular malignancies [1, 2]. The most common site for an ophthalmic metastasis is the uveal tract, with the choroid being more frequently involved than the iris or ciliary body [3–5]. Breast and lung carcinomas are the usual primaries [6–9]. Although there are many articles devoted to orbital and choroidal metastases [3, 10, 11], there are only 2 reports [12, 13] of a posterior extrascleral extension from a choroidal pulmonary metastasis from non-small cell lung cancer (NSCLC). Taking diagFrederick A. Jakobiec, MD, DSc David G. Cogan Laboratory of Ophthalmic Pathology Massachusetts Eye and Ear Infirmary, Suite 328 243 Charles Street, Boston, MA 02114 (USA) E-Mail Fred_Jakobiec @ meei.harvard.edu
Fig. 1. Radiographic features of a patient
with metastatic pulmonary adenocarcinoma to the choroid and orbit. a T1-weighted MRI in the axial projection discloses a crescent-shaped, well-circumscribed inferolateral orbital mass tightly adherent to the globe with adjacent choroidal thickening (arrow). b Positron emission tomography scan showing multiple areas of FDG avidity in the lung, hilum, orbit, peritoneum, and bones. Fig. 2. Clinical photography of a patient with metastatic pulmonary adenocarcinoma to the choroid and orbit. Wide-field pseudo-color fundus image of the right eye. a An orange, leopard-spotted choroidal lesion occupies much of the nasal and inferonasal retina. Arrowheads denote a subtle color change from the border of subretinal fluid. Wide-field autofluoresence image of the right eye. b Areas of retinal pigment epithelial (RPE) hypertrophy are hyperfluorescent secondary to lipofuscin accumulation, alternating with hypofluoresence in areas of RPE loss. A subtle hyperfluoresence correlates with the presence of subretinal fluid (arrowheads). Wide-field fluorescein angiogram. c In the area of the tumor, there is a pinpoint and lobular hyperfluorescent pattern that remains constant from the mid-stage of the angiogram without change in later frames. In the periphery (arrows), vascular leakage secondary to ischemia from chronic serous retinal detachment can be seen. B-Scan. d Nasal transverse B-scan of the right eye. The curved arrow shows the retinal detachment. The two linear segments through the posterior eye wall into the orbit denote choroidal thickening (yellow), the sclera (purple), and intraconal mass (green). The arrowhead is at the 4:30 meridian, showing a discontinuity in the posterior sclera, possibly a dilated emissary vein.
a
1 a
b
c
nostic advantage of a posterior extraocular extension of an intraocular lesion is a low-morbidity approach that has not been employed often enough judging from the lack of attention it has received in the literature. There have, however, been occasional descriptions of biopsies of anterior epibulbar extensions of ciliary body masses [14–16]. In contrast to a needle biopsy, a posterior orbital biopsy permits the preservation of the architecture of the metastasis and enables a fuller spectrum of immunostaining. Ocular Metastasis from Lung Carcinoma
b
d
2
Case Report Clinical Findings A 60-year-old Caucasian woman was referred with a 3-month history of gradual-onset blurry vision in the right eye. She had a history of NSCLC, adenocarcinoma stage T2bN0M0, 14 years earlier treated with resection of the right middle and lower lobes without adjuvant chemotherapy or radiotherapy. Unfortunately, the microscopic slides could not be located at another hospital for review. A CT scan of the head ordered to evaluate her visual complaint was interpreted as normal. Her symptoms progressed and diplopia developed, prompting an MRI scan that demon-
Ocul Oncol Pathol 2016;2:24–28 DOI: 10.1159/000430098
25
a
b
c
d
e
f
Fig. 3. Histopathologic and immunohisto-
chemical features of metastatic lung adenocarcinoma to the choroid and orbit. a Patulous lumens are filled with mucus (M) as revealed in the orbital biopsy. b Small clusters of tumor cells with oval-to-round nuclei lacking pleomorphism possess a moderate amount of eosinophilic cytoplasm. Note the intervening fibrosclerotic stroma. c The Alcian blue stain highlights tumor cells with intracytoplasmic vacuoles containing mucus, as well as surrounding extracellular mucus. d Mucicarmine stain displaying intracytoplasmic red-staining mucus. e Cytokeratin 7 uniformly stains the tumor cells’ cytoplasm. f Thyroid transcription factor 1 immunostains the nuclei of most of the tumor cells. a, b Hematoxylin and eosin, ×100, ×200. c Alcian blue, ×400. d Mucicarmine, ×600. e, f Immunoperoxidase reaction, diaminobenzine chromogen, hematoxylin counterstain, ×100, ×100.
strated a right orbital mass with adjacent choroidal thickening and indentation of the globe (fig. 1a). Visual acuity was 20/40 in the right eye and 20/20 in the left. There was anisocoria with a larger pupil on the right, but no relative afferent pupillary defect. On dilated fundus examination, there was a leopard-spotted, orange choroidal lesion inferonasal to the optic disc with subretinal fluid extending through the inferonasal macula of the right eye (fig. 2a). Autofluorescence showed hyperfluorescence secondary to lipofuscin accumulation alternating with hypofluoresence in areas of retinal pigment epithelial cell loss (fig. 2b). Fluorescein angiography transiting the right eye demonstrated hyperfluorescence in a pinpoint and lobular pattern (fig. 2c). Optical coherence tomography of the right macula (not shown) demonstrated distortion of the inferonasal macular contour secondary to the choroidal mass. Echography revealed an irregularly contoured lesion from the 12 to 7 o’clock meridians with high, but irregular internal reflectivity, and a maximal elevation of 3.1 mm (fig. 2d). The foregoing clinical and imaging findings were consistent with a choroidal metastasis. A discontinuity was noted in the posterior sclera, possibly a dilated emissary vein. The extra-
26
Ocul Oncol Pathol 2016;2:24–28 DOI: 10.1159/000430098
scleral component was located within the intraconal space and had maximal measurements of 7.3 mm in height and 11.6 mm in length. A right transconjunctival orbitotomy was performed. A 3-cm superior fornix incision was made in the conjunctiva in the superomedial quadrant. Blunt dissection was carried out in the episcleral plane until the mass was encountered. Silk traction sutures were looped around the superior and medial rectus muscle insertions to stabilize the globe. The encountered extrascleral mass was very firm and tightly adherent to the globe. A periosteal elevator was used to bluntly elevate an edge of the tumor. Then an incisional biopsy was performed with Westcott scissors. The incision did not extend into the sclera so as to reduce any change of rupture. Histopathologic and Immunohistochemical Findings Hematoxylin-and-eosin-stained paraffin sections disclosed lumen-forming eosinophilic cells elaborating intracellular and extracellular mucin (fig. 3a) forming small clusters of cells set in a fibrosclerotic stroma (fig. 3b). The Alcian blue (fig. 3c) and mucicarmine stains (fig. 3d) highlighted the mucin. Epithelial mem-
Jakobiec/Ramsey/Stagner/Wu/Yoon
brane antigen and cytokeratin 7 (fig. 3e) were positive, whereas cytokeratin 20 was negative. Thyroid transcription factor 1 immunostained most of the nuclei of the tumor cells (fig. 3f). Postoperative Clinical Findings Positron emission tomography scan 1 week postoperatively revealed bilateral multifocal lung cancer with a dominant FDGavid superior lingular mass with left hilar lymphadenopathy (fig. 1b). Other involved sites included the right orbit, multiple sites in the skeleton and peritoneal nodules consistent with peritoneal carcinomatosis. The patient elected to undergo palliative radiotherapy to the right orbital lesion followed by systemic therapy at a local hospital. At the most recent follow-up visit, 5 months after palliative radiotherapy to the right orbit, the patient’s ophthalmic status was stable with respect to no progression in proptosis, but visual acuity had worsened to 20/400 with an advanced retinal detachment surrounding the tumor. Ocular and nonocular metastatic adenocarcinoma of the lung is notoriously nonresponsive to chemo- and radiotherapy. The patient is on maintenance palliative chemotherapy consisting of carboplatin and pemetrexed, a multitarget antifolate approved for advanced NSCLC [17], but she has displayed increased weakness with a very poor prognosis.
Discussion
About 85% of lung cancers are NSCLCs. Non-small cell tumors are traditionally divided into 3 main subtypes: adenocarcinoma (approx. 50%), squamous cell (epidermoid) carcinoma (approx. 35%), and large cell (undifferentiated) carcinoma (approx. 15%). NSCLCs have a poor prognosis primarily due to their advanced stage at the time of diagnosis [17]. The incidence of choroidal metastases from lung cancer has been reported to be 2–6.7% [18, 19]. When choroidal metastases do occur, multiple foci of metastatic disease may be present with bilateral involvement in 20–40% of cases [2]. Ocular metastases are relatively insensitive to chemotherapy and radiotherapy. Death from disseminated disease usually occurs 7.4 months after globe involvement [1]. The incidence of extraocular extension from a choroidal metastasis is unclear. It is less characteristic than in diffuse choroidal melanoma and diffuse lymphoid infiltration of the uvea (now generally diagnosed as a lowgrade extranodal marginal zone lymphoma). The point of this article is to emphasize the opportunity to diagnose a metastatic choroidal lesion from biopsy of an extraocular nodule, especially when a primary lesion may not have been discovered, as is the case in 34% of overall ocular metastases [2]. Both a metastatic renal carcinoma [20] and a papillary thyroid carcinoma [21] to the choroid and contiguous orbit have recently been reported. Ocular Metastasis from Lung Carcinoma
Histopathologically, the juxtascleral incisional orbital biopsy revealed clusters of cells with eosinophilic cytoplasm forming lumens with surrounding extracellular mucin, outside of which was a fibrosclerotic stroma – consistent with a mucin-producing adenocarcinoma. The mucinous material was Alcian blue and mucicarmine positive. These findings are compatible with any mucin-producing primary carcinoma, such as lung, breast, or bowel carcinoma. Immunohistochemical studies were therefore performed. Cytokeratin 7 was positive, while cytokeratin 20 was negative. The former is typically positive in cancers arising above the diaphragm, while the latter is found in those originating below the diaphragm. Thyroid transcription factor 1 further helped to confirm the diagnosis because it is often positive in lung carcinomas. Thyroid transcription factor 1, also referred to as thyroid-specific enhancer-binding protein, is a 35-kDa nuclear protein that normally stains thyroid follicular and parafollicular cells, as well as pulmonary type II pneumocytes and Clara cells. This factor regulates the transcription of thyroglobulin, thyroperoxidase, and calcitonin, which makes it a valuable adjunct in the diagnosis of the better differentiated thyroid and parathyroid neoplasms, but of less service in poorly differentiated ones. Additionally, this same transcription factor promotes the synthesis of surfactant proteins A, B, and C, which makes it diagnostically useful for primary and metastatic lung carcinomas. In the lung, small cell carcinomas are 90% positive, adenocarcinomas are 75% positive, large cell carcinomas are 40% positive, and squamous cell carcinomas are only 5% positive [22]. Biopsy of an orbital extension may lead to expedited diagnosis. Needle biopsy might be attempted if the patient is deemed to be too ill for an open surgical approach. A previous patient with an extensive choroidal breast metastasis presented with the clinical picture of scleritis including pain [13]. The sclera was massively thickened; an opportunity to biopsy this component was not seized. The diagnosis of metastatic breast carcinoma with scleral and epibulbar invasion was made only following an enucleation [13]. Another previously reported case describing an intraocular needle biopsy of a metastatic tumor in a 51-year-old woman ultimately came to enucleation due to therapeutic failure [12]. The surgical technique for biopsying an ocular/orbital metastasis is rapid and safe. An important caveat is that, once the episcleral nodule has been isolated from surrounding normal orbital tissues, the incisional biopsy does not proceed any deeper than the episcleral plane in order to avoid any further Ocul Oncol Pathol 2016;2:24–28 DOI: 10.1159/000430098
27
weakening of the infiltrated sclera. The more traditional eyelid crease incision with a subperiosteal plane dissection is more challenging for accessing the intraconal space. A vertical eyelid crease incision permits excellent visualization of the intraconal space, but entails a visible cutaneous incision-scarred site when healed. In our technique, the tumor was accessed transconjunctivally without incision into the skin or detachment of any extraocular muscles.
Acknowledgements The authors thank Ms. Karen Capaccioli (sonographer) for imaging support, and Louise Collins (Howe Library, Massachusetts Eye and Ear Infirmary) for research support.
Statement of Ethics This study was conducted in compliance with the rules and regulations of the Health Insurance Portability and Accountability Act, and in adherence to the Declaration of Helsinki and all other relevant federal and state laws.
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Ocul Oncol Pathol 2016;2:24–28 DOI: 10.1159/000430098
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Jakobiec/Ramsey/Stagner/Wu/Yoon
