Acta Ophthalmologica 2015
hypothesis as the microrip is not lying perpendicular to the CNV’s contraction force as it is usually the case in conventional RPE tears. However, in this case, it is located parallel to the axis of CNV’s contraction force, which makes it rather improbable that contraction forces cause the microrip. Secondly, the fact that the microrip is located parallel to the axis of CNV’s contraction force results in lower tensile forces acting on the microrip, which may be the reason that the microrip had not further increased before injection. Nevertheless, microrips supposedly lower the threshold of RPE resistance and the increase in contraction after anti-VEGF therapy eventually results in the anatomic failure of the RPE. Thirdly, the localization of microrips detectable prior to tear development at the temporal edge of the lesion is identical to the edge of the RPE tear suggesting that microrips may be regarded as a predetermined tearing edge. Therefore, microrips must be regarded as a risk factor for the development of RPE tears similar to other risk factors as discussed above. A microrip should not be regarded as a prestage RPE tear or the beginning of a RPE tear. Much more likely, microrips and RPE tears represent two separate entities based on different etiologic mechanisms as postulated by Ie et al. This case shall encourage clinicians to look for microrips, in addition to the previously established RPE tear risk factors, prior to anti-VEGF therapy in patients with svPED and to perform a thorough examination including OCT and FAF after each injection in highrisk patients. If several RPE tear risk factors accumulate or single risk factors significantly grow during the course of anti-VEGF treatment, we suggest to pause injection therapy, to re-evaluate the svPED lesion 1–2 weeks later and to reinject if signs of CNV contraction have declined. Such an adapted regimen may lead to a safer anti-VEGF therapy with regard to RPE tear development in svPED patients at high risk. Notably, not all known risk factors are present in all cases prior to RPE tear development. A future prospective study stratifying the weight of each individual risk factor to quantify the risk of RPE tear development of individual patients seems promising. In conclusion, microrips in OCT and FAF and the angiographic ‘ring sign’, respectively, may be regarded as a
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potential risk factor for impending RPE tear development in patients under anti-VEGF treatment for svPED.
Clinical and Molecular Cancer Medicine, University of Liverpool, Liverpool, UK doi: 10.1111/aos.12682
References Chan CK, Meyer CH, Gross JG et al. (2007): Retinal pigment epithelial tears after intravitreal bevacizumab injection for neovascular age-related macular degeneration. Retina 27: 541–551. Chan CK, Abraham P, Meyer CH et al. (2010): Optical coherence tomography-measured pigment epithelial detachment height as a predictor for retinal pigment epithelial tears associated with intravitreal bevacizumab injections. Retina 30: 203–211. Clemens CR, Bastian N, Alten F, Milojcic C, Heiduschka P & Eter N (2014): Prediction of retinal pigment epithelial tear in serous vascularized pigment epithelium detachment. Acta Ophthalmol 92: e50–e56. Ie D, Yannuzzi LA, Spaide RF, Woodward KP, Singerman LJ & Blumenkranz MS (1992): Microrips of the retinal pigment epithelium. Arch Ophthalmol 110: 1443–1449. Sarraf D, Reddy S, Chiang A, Yu F & Jain A (2010): A new grading system for retinal pigment epithelial tears. Retina 30: 1039–1045.
Correspondence: Christoph R. Clemens, MD Department of Ophthalmology University of Muenster Medical Centre Domagkstrasse 15 48149 Muenster Germany Tel: +49 251 83 56004 Fax: +49 251 83 56003 Email: [email protected] Author Disclosure: C.R. Clemens, Heidelberg Engineering, Novartis, Bayer; F. Alten, Heidelberg Engineering, Novartis, Bayer; N. Eter, Heidelberg Engineering, Novartis, Bayer, Sanofi Aventis, Allergan, Bausch and Lomb.
Conjunctival extranodal marginal zone B-cell lymphoma with crystalstoring histiocytosis Ruchi Mittal,1 Bertil Damato2 and Sarah E. Coupland3 1
Dalmia Ophthalmic Pathology Services, L.V. Prasad Eye Institute, Bhubaneswar, India; 2Ocular Oncology Service, University of California, San Francisco, CA, USA; 3Pathology, Department of
Editor, rystal-storing histiocytosis (CSH) is a rare immunoglobulin storage disorder, associated with lymphoproliferative diseases or seldom with inflammatory or infective conditions (Coupland et al. 2002). The head-andneck region is most commonly affected by CSH, usually in association with plasma cell neoplasms (Tsuji et al. 2014). Conjunctival involvement by CSH is distinctly uncommon (Yu et al. 2013). Herein, we describe a case of conjunctival CSH associated with an extranodal marginal zone B-cell lymphoma (EMZL). A 58-year-old man was referred to the Liverpool Ocular Oncology Centre in 2008 with a tumour of the right (OD) eye of 2 years duration. The patient had been treated previously for retinal detachment OD, bilateral cataracts and bilateral primary open-angle glaucoma. The best-corrected visual acuity was 6/60 OD and 6/6 OS. A subconjunctival, pink ‘salmon-coloured’ tumour with prominent blood vessels was visible infero-temporally OD (Fig. 1A), extending up to the fornix. There was restriction of right lateral gaze. On echography, the conjunctival tumour had a low internal acoustic reflectivity and measured 12.4 9 10.4 9 6.2 mm on magnetic resonance imaging (MRI). The clinical suspicion was of lymphoma: consequently, a large incisional biopsy was performed and processed for pathological assessment. Conventional histological sections demonstrated conjunctival tissue with diffuse and dense infiltration of small- to medium-sized lymphoid cells (Fig. 1B), comprising small lymphocytes, centrocyte-like cells, monocytoid cells and plasma cells. There were interspersed sheets of larger ‘Gaucher-like’ cells taking up at least 40% of the lesion with abundant eosinophilic pale cytoplasm and small-sized nuclei (Fig. 1C). At higher magnification, ill-defined crystal-like structures could be seen within the cytoplasm of these cells. Immunohistochemically, the atypical lymphoid cells expressed B-cell antigens (Fig. 1E) and demonstrated a monotypical expression for IgM. They were negative for CD5, CD23, CD10 and cyclin D1. In
C
Acta Ophthalmologica 2015
(A)
(B)
(C)
(D)
(E)
(F)
Fig. 1. (A) Salmon-coloured, fleshy, subconjunctival mass of right ocular surface with prominent feeder vessels and intrinsic vasculature. (B) Low-power photomicrograph showing diffuse and dense infiltration of small- to medium-sized lymphoid cells (H&E stain, original magnification 9100). (C) Photomicrograph shows sheets of larger cells with abundant eosinophilic cytoplasm with interspersed aggregates of small lymphoid cells and plasma cells (Giemsa stain, original magnification 9200). (D) Higher magnification shows cytoplasmic crystals (arrow marked), cells have bland eccentric nuclei with small conspicuous nucleoli (H&E stain, original magnification 9400). (E) B lymphocytes are positive for the immunostain directed against the CD20 antigen (PAP immunostaining, 9400). (F) CD68 staining highlights the histiocytes with intracytoplasmic crystals (PAP immunostaining, 9400).
contrast, the above-described larger cells were immunoreactive for CD68 (Fig. 1F), and the cytoplasmic crystals were positive for immunoglobulin kappa light chain. These findings were consistent with conjunctival EMZL with CSH, confirmed on polymerase chain reaction. Subsequent clinical staging investigations revealed Ann-Arbor stage III disease and T2N3 with involvement of mediastinal and abdominal lymph nodes. The bone marrow trephine excluded any underlying plasma cell dyscrasia, such as multiple myeloma or monoclonal gammopathy of unclear significance. The patient was subsequently treated with R-CHOP (rituximab 375 mg/m2 iv; cyclophosphamide 750 mg/m2 iv; vincristine 1.4 mg/m2 iv; prednisone 40 mg/m2 iv). Two months after initiation of chemotherapy, MRI scanning showed complete regression of the residual conjunctival tumour. Five years after initial diagnosis, the patient was disease free but undertaking regular oncological review. This case illustrates a very rare example of conjunctival EMZL with CSH: to date only nine cases of CSH involving the ocular adnexa have been described (Grossniklaus et al. 1990; Coupland et al. 2002; Yu et al. 2013; Radhakrish-
nan et al. 2014). Most CSH cases have involved the orbit with the conjunctiva being less commonly affected. The CSH component of the tumour can be extensive and can potentially lead to misdiagnoses through sampling error, particularly if a fine needle (aspiration) biopsy has been employed. CSH associated with EMZL typically has a good prognosis, particularly if diagnosed at an early clinical stage, and it usually responds either to localized surgery, radiotherapy and chemotherapy, or combinations thereof. Included in the list of differential diagnosis are infectious aetiologies – for example tuberculosis and fungal infections – as well as non-lymphoid neoplastic conditions, including rhabdomyosarcoma, and pleomorphic sarcoma. These diagnoses are, however, usually possible to exclude on the basis of morphological and immunohistochemical features, as well as special stains for micro-organisms. In conclusion, when diagnosing conjunctival EMZL, a simultaneous CSH should always be considered.
References Coupland SE, Foss HD, Hummel M & Stein H (2002): Extranodal marginal zone B-cell
lymphoma of the lacrimal gland associated with crystal-storing histiocytosis. Ophthalmology 109: 105–110. Grossniklaus HE, Stulting RD & L’Hernault N (1990): Corneal and conjunctival crystals in paraproteinemia. Hum Pathol 21: 1181–1183. Radhakrishnan S, Mnaeksha V & Adulkar N (2014): Crystal-storing histiocytosis masquerading ocular adnexal lymphoma: a case report and review of literature. Ophthal Plast Reconstr Surg 30: e67–e69. Tsuji T, Yamasaki H, Hirano T, Arima N & Tsuda H (2014): Crystal-storing histiocytosis complicating marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Int J Hematol 100: 519–520. Yu SC, Yao M & Liao SL (2013): Crystalstoring histiocytosis in a patient with ocular extranodal marginal zone lymphoma. Br J Haematol 160: 419.
Correspondence: Prof. Sarah E. Coupland, MBBS, PhD, FRCPath Molecular and Clinical Cancer Medicine Institute of Translational Medicine University of Liverpool 6th Floor Duncan Building Daulby Street Liverpool L69 3GA, UK Tel: +44 151 706 5885 Fax: +44 151 706 5859 Email: [email protected]
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hypothesis as the microrip is not lying perpendicular to the CNV’s contraction force as it is usually the case in conventional RPE tears. However, in this case, it is located parallel to the axis of CNV’s contraction force, which makes it rather improbable that contraction forces cause the microrip. Secondly, the fact that the microrip is located parallel to the axis of CNV’s contraction force results in lower tensile forces acting on the microrip, which may be the reason that the microrip had not further increased before injection. Nevertheless, microrips supposedly lower the threshold of RPE resistance and the increase in contraction after anti-VEGF therapy eventually results in the anatomic failure of the RPE. Thirdly, the localization of microrips detectable prior to tear development at the temporal edge of the lesion is identical to the edge of the RPE tear suggesting that microrips may be regarded as a predetermined tearing edge. Therefore, microrips must be regarded as a risk factor for the development of RPE tears similar to other risk factors as discussed above. A microrip should not be regarded as a prestage RPE tear or the beginning of a RPE tear. Much more likely, microrips and RPE tears represent two separate entities based on different etiologic mechanisms as postulated by Ie et al. This case shall encourage clinicians to look for microrips, in addition to the previously established RPE tear risk factors, prior to anti-VEGF therapy in patients with svPED and to perform a thorough examination including OCT and FAF after each injection in highrisk patients. If several RPE tear risk factors accumulate or single risk factors significantly grow during the course of anti-VEGF treatment, we suggest to pause injection therapy, to re-evaluate the svPED lesion 1–2 weeks later and to reinject if signs of CNV contraction have declined. Such an adapted regimen may lead to a safer anti-VEGF therapy with regard to RPE tear development in svPED patients at high risk. Notably, not all known risk factors are present in all cases prior to RPE tear development. A future prospective study stratifying the weight of each individual risk factor to quantify the risk of RPE tear development of individual patients seems promising. In conclusion, microrips in OCT and FAF and the angiographic ‘ring sign’, respectively, may be regarded as a
e602
potential risk factor for impending RPE tear development in patients under anti-VEGF treatment for svPED.
Clinical and Molecular Cancer Medicine, University of Liverpool, Liverpool, UK doi: 10.1111/aos.12682
References Chan CK, Meyer CH, Gross JG et al. (2007): Retinal pigment epithelial tears after intravitreal bevacizumab injection for neovascular age-related macular degeneration. Retina 27: 541–551. Chan CK, Abraham P, Meyer CH et al. (2010): Optical coherence tomography-measured pigment epithelial detachment height as a predictor for retinal pigment epithelial tears associated with intravitreal bevacizumab injections. Retina 30: 203–211. Clemens CR, Bastian N, Alten F, Milojcic C, Heiduschka P & Eter N (2014): Prediction of retinal pigment epithelial tear in serous vascularized pigment epithelium detachment. Acta Ophthalmol 92: e50–e56. Ie D, Yannuzzi LA, Spaide RF, Woodward KP, Singerman LJ & Blumenkranz MS (1992): Microrips of the retinal pigment epithelium. Arch Ophthalmol 110: 1443–1449. Sarraf D, Reddy S, Chiang A, Yu F & Jain A (2010): A new grading system for retinal pigment epithelial tears. Retina 30: 1039–1045.
Correspondence: Christoph R. Clemens, MD Department of Ophthalmology University of Muenster Medical Centre Domagkstrasse 15 48149 Muenster Germany Tel: +49 251 83 56004 Fax: +49 251 83 56003 Email: [email protected] Author Disclosure: C.R. Clemens, Heidelberg Engineering, Novartis, Bayer; F. Alten, Heidelberg Engineering, Novartis, Bayer; N. Eter, Heidelberg Engineering, Novartis, Bayer, Sanofi Aventis, Allergan, Bausch and Lomb.
Conjunctival extranodal marginal zone B-cell lymphoma with crystalstoring histiocytosis Ruchi Mittal,1 Bertil Damato2 and Sarah E. Coupland3 1
Dalmia Ophthalmic Pathology Services, L.V. Prasad Eye Institute, Bhubaneswar, India; 2Ocular Oncology Service, University of California, San Francisco, CA, USA; 3Pathology, Department of
Editor, rystal-storing histiocytosis (CSH) is a rare immunoglobulin storage disorder, associated with lymphoproliferative diseases or seldom with inflammatory or infective conditions (Coupland et al. 2002). The head-andneck region is most commonly affected by CSH, usually in association with plasma cell neoplasms (Tsuji et al. 2014). Conjunctival involvement by CSH is distinctly uncommon (Yu et al. 2013). Herein, we describe a case of conjunctival CSH associated with an extranodal marginal zone B-cell lymphoma (EMZL). A 58-year-old man was referred to the Liverpool Ocular Oncology Centre in 2008 with a tumour of the right (OD) eye of 2 years duration. The patient had been treated previously for retinal detachment OD, bilateral cataracts and bilateral primary open-angle glaucoma. The best-corrected visual acuity was 6/60 OD and 6/6 OS. A subconjunctival, pink ‘salmon-coloured’ tumour with prominent blood vessels was visible infero-temporally OD (Fig. 1A), extending up to the fornix. There was restriction of right lateral gaze. On echography, the conjunctival tumour had a low internal acoustic reflectivity and measured 12.4 9 10.4 9 6.2 mm on magnetic resonance imaging (MRI). The clinical suspicion was of lymphoma: consequently, a large incisional biopsy was performed and processed for pathological assessment. Conventional histological sections demonstrated conjunctival tissue with diffuse and dense infiltration of small- to medium-sized lymphoid cells (Fig. 1B), comprising small lymphocytes, centrocyte-like cells, monocytoid cells and plasma cells. There were interspersed sheets of larger ‘Gaucher-like’ cells taking up at least 40% of the lesion with abundant eosinophilic pale cytoplasm and small-sized nuclei (Fig. 1C). At higher magnification, ill-defined crystal-like structures could be seen within the cytoplasm of these cells. Immunohistochemically, the atypical lymphoid cells expressed B-cell antigens (Fig. 1E) and demonstrated a monotypical expression for IgM. They were negative for CD5, CD23, CD10 and cyclin D1. In
C
Acta Ophthalmologica 2015
(A)
(B)
(C)
(D)
(E)
(F)
Fig. 1. (A) Salmon-coloured, fleshy, subconjunctival mass of right ocular surface with prominent feeder vessels and intrinsic vasculature. (B) Low-power photomicrograph showing diffuse and dense infiltration of small- to medium-sized lymphoid cells (H&E stain, original magnification 9100). (C) Photomicrograph shows sheets of larger cells with abundant eosinophilic cytoplasm with interspersed aggregates of small lymphoid cells and plasma cells (Giemsa stain, original magnification 9200). (D) Higher magnification shows cytoplasmic crystals (arrow marked), cells have bland eccentric nuclei with small conspicuous nucleoli (H&E stain, original magnification 9400). (E) B lymphocytes are positive for the immunostain directed against the CD20 antigen (PAP immunostaining, 9400). (F) CD68 staining highlights the histiocytes with intracytoplasmic crystals (PAP immunostaining, 9400).
contrast, the above-described larger cells were immunoreactive for CD68 (Fig. 1F), and the cytoplasmic crystals were positive for immunoglobulin kappa light chain. These findings were consistent with conjunctival EMZL with CSH, confirmed on polymerase chain reaction. Subsequent clinical staging investigations revealed Ann-Arbor stage III disease and T2N3 with involvement of mediastinal and abdominal lymph nodes. The bone marrow trephine excluded any underlying plasma cell dyscrasia, such as multiple myeloma or monoclonal gammopathy of unclear significance. The patient was subsequently treated with R-CHOP (rituximab 375 mg/m2 iv; cyclophosphamide 750 mg/m2 iv; vincristine 1.4 mg/m2 iv; prednisone 40 mg/m2 iv). Two months after initiation of chemotherapy, MRI scanning showed complete regression of the residual conjunctival tumour. Five years after initial diagnosis, the patient was disease free but undertaking regular oncological review. This case illustrates a very rare example of conjunctival EMZL with CSH: to date only nine cases of CSH involving the ocular adnexa have been described (Grossniklaus et al. 1990; Coupland et al. 2002; Yu et al. 2013; Radhakrish-
nan et al. 2014). Most CSH cases have involved the orbit with the conjunctiva being less commonly affected. The CSH component of the tumour can be extensive and can potentially lead to misdiagnoses through sampling error, particularly if a fine needle (aspiration) biopsy has been employed. CSH associated with EMZL typically has a good prognosis, particularly if diagnosed at an early clinical stage, and it usually responds either to localized surgery, radiotherapy and chemotherapy, or combinations thereof. Included in the list of differential diagnosis are infectious aetiologies – for example tuberculosis and fungal infections – as well as non-lymphoid neoplastic conditions, including rhabdomyosarcoma, and pleomorphic sarcoma. These diagnoses are, however, usually possible to exclude on the basis of morphological and immunohistochemical features, as well as special stains for micro-organisms. In conclusion, when diagnosing conjunctival EMZL, a simultaneous CSH should always be considered.
References Coupland SE, Foss HD, Hummel M & Stein H (2002): Extranodal marginal zone B-cell
lymphoma of the lacrimal gland associated with crystal-storing histiocytosis. Ophthalmology 109: 105–110. Grossniklaus HE, Stulting RD & L’Hernault N (1990): Corneal and conjunctival crystals in paraproteinemia. Hum Pathol 21: 1181–1183. Radhakrishnan S, Mnaeksha V & Adulkar N (2014): Crystal-storing histiocytosis masquerading ocular adnexal lymphoma: a case report and review of literature. Ophthal Plast Reconstr Surg 30: e67–e69. Tsuji T, Yamasaki H, Hirano T, Arima N & Tsuda H (2014): Crystal-storing histiocytosis complicating marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Int J Hematol 100: 519–520. Yu SC, Yao M & Liao SL (2013): Crystalstoring histiocytosis in a patient with ocular extranodal marginal zone lymphoma. Br J Haematol 160: 419.
Correspondence: Prof. Sarah E. Coupland, MBBS, PhD, FRCPath Molecular and Clinical Cancer Medicine Institute of Translational Medicine University of Liverpool 6th Floor Duncan Building Daulby Street Liverpool L69 3GA, UK Tel: +44 151 706 5885 Fax: +44 151 706 5859 Email: [email protected]
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