Controversies and Perspectives

It has been nearly 60 years since the first description of an intraocular masquerade syndrome secondary to lymphoma [11]. Much has been learned in these six decades yet there is still plenty to learn. Perhaps one of the main unanswered remaining quests is the elusive cellular origin of PVRL [10]. Some evidence points to a germinal center origin, whereas other evidence points to an early post-germinal center origin [10]. The cellular origin has important implications since in systemic DLBCL, the prognosis depends on the molecular subtypes. There is conflicting evidence as to whether the treatment of PVRL influences the prognosis for survival [29, 45]. There is no general consensus with regard to the best treatment in patients with isolated PVRL. The initial excitement with systemic chemotherapy has been dampened by the high rates of ocular relapse and progression to CNS disease [46]. It is possible that precise genetic profiling of each individual patient with PVRL may allow to individualize treatment to improve the outcomes in this devastating disease [39].

Focal Points

•PVRL forms part of the spectrum of PCNSL.

•PVRL is a high-grade NHL, usually of B-cell type, with a poor prognosis due to CNS disease.

•A high index of suspicion, in particular of any patient with a uveitis that is unresponsive to steroids, is essential in diagnosing PVRL.

•A single vitreous biopsy may not always be diagnostic of PVRL.

•Cytological analysis remains the gold standard for diagnosing PVRL.

•Cytokine analysis, flow cytometry, and molecular analysis are useful adjuncts in the diagnosis of PVRL.

•Methotrexate is the cornerstone of any chemotherapeutic regimen for PCNSL/PVRL.

•Systemic chemotherapy alone may not be sufficient treatment for PVRL, even with

drugs that penetrate the eye such as ARA-C and MTX.

•Ocular relapse is common both in patients treated for CNS disease and those successfully treated for ocular disease.

Acknowledgments None of the authors have a financial interest in the subject matter of this chapter.

References

1. Jaffe ES, Harris NL, Stein H, Vardiman JW. World Health Organization classification of tumours. Tumours of haematopoietic and lymphoid tissues, Pathology and genetics. Lyon: IARC Press; 2001.

2.Rappaport H. Tumors of the hematopoietic system. In: Atlas of tumor pathology, vol. 3. Washington, DC:

Armed Forces Institute of Pathology; 1966.

3. Kaplan HJ, Meredith TA, Aaberg TM, Keller RH. Reclassification of intraocular reticulum cell sarcoma (histiocytic lymphoma). Immunologic characterization of vitreous cells. Arch Ophthalmol. 1980;98(4): 707–10.

4.Pinkus GS, Said JW. Characterization of non-Hodgkin’s lymphomas using multiple cell markers. Immunologic, morphologic, and cytochemical studies of 72 cases. Am J Pathol. 1979;94(2):349–80.

5.Lukes RJ. Functional classification of malignant lymphoma of Lukes and Collins. Recent Results Cancer Res. 1978;64:19–30.

6. Sen HN, Bodaghi B, Hoang PL, Nussenblatt R. Primary intraocular lymphoma: diagnosis and differential diagnosis. Ocul Immunol Inflamm. 2009;17(3): 133–41.

7.Coupland SE, Damato B. Understanding intraocular lymphomas. Clin Exp Ophthalmol. 2008;36(6): 564–78.

8.Brown SM, Jampol LM, Cantrill HL. Intraocular lymphoma presenting as retinal vasculitis. Surv Ophthalmol. 1994;39(2):133–40.

9.National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer. 1982;49(10):2112–35.

10.Coupland SE, Chan CC, Smith J. Pathophysiology of retinal lymphoma. Ocul Immunol Inflamm. 2009;17(4):227–137.

11.Cooper EL, Riker JL. Malignant lymphoma of the uveal tract. Am J Ophthalmol. 1951;34:1153–8.

12.Givner I. Malignant lymphoma with ocular involvement. Am J Ophthalmol. 1955;39:29–32.

13.Vogel MH, Font RL, Zimmerman LE, Levine RA. Reticulum cell sarcoma of the retina and uvea. Report

of six cases and review of the literature. Am J Ophthalmol. 1968;66(2):205–15.

14.Qualman SJ, Mendelsohn G, Mann RB, Green WR. Intraocular lymphomas. Natural history based on a clinicopathologic study of eight cases and review of the literature. Cancer. 1983;52(5):878–86.

15. Nevins Jr RC, Frey WW, Elliott JH. Primary, solitary, intraocular reticulum cell sarcoma (microgliomatosis). (A clinicopathologic case report). Trans Am Acad Ophthalmol Otolaryngol. 1968;72(6):867–76.

16. Barr CC, Green WR, Payne JW, et al. Intraocular reticulum-cell sarcoma: clinico-pathologic study of four cases and review of the literature. Surv Ophthalmol. 1975;19(4):224–39.

17. Neault RW, Van Scoy RE, Okazaki H, MacCarty CS. Uveitis associated with isolated reticulum cell sarcoma of the brain. Am J Ophthalmol. 1972;73(3):431–6.

18.Appen RE. Posterior uveitis and primary cerebral reticulum cell sarcoma. Arch Ophthalmol. 1975;93(2): 123–4.

19.Kennerdell JS, Johnson BL, Wisotzkey HM. Vitreous cellular reaction. Association with reticulum cell sarcoma of brain. Arch Ophthalmol. 1975;93(12):1341–5.

20.Michels RG, Knox DL, Erozan YS, Green WR. Intraocular reticulum cell sarcoma. Diagnosis by pars plana vitrectomy. Arch Ophthalmol. 1975;93(12): 1331–5.

21.Klingele TG, Hogan MJ. Ocular reticulum cell sarcoma. Am J Ophthalmol. 1975;79(1):39–47.

22.Rockwood EJ, Zakov ZN, Bay JW. Combined malignant lymphoma of the eye and CNS (reticulum-cell sarcoma). Report of three cases. J Neurosurg. 1984;61(2):369–74.

23.Rubenstein JL, Treseler P, O’Brien JM. Pathology and genetics of primary central nervous system and intraocular lymphoma. Hematol Oncol Clin North

Am. 2005;19(4):705–17. vii.

24. Eby NL, Grufferman S, Flannelly CM, et al. Increasing incidence of primary brain lymphoma in the US. Cancer. 1988;62(11):2461–5.

25.Peterson K, Gordon KB, Heinemann MH, DeAngelis LM. The clinical spectrum of ocular lymphoma. Cancer. 1993;72(3):843–9.

26.Kheterpal S, Kirkby GR, Neuberger JM, et al. Intraocular lymphoma after liver transplantation. Am J Ophthalmol. 1993;116(4):507–8.

27.Rivero ME, Kuppermann BD, Wiley CA, et al. Acquired immunodeficiency syndrome-related intraocular B-cell lymphoma. Arch Ophthalmol. 1999;117(5):616–22.

28.Matzkin DC, Slamovits TL, Rosenbaum PS. Simultaneous intraocular and orbital non-Hodgkin lymphoma in the acquired immune deficiency syndrome. Ophthalmology. 1994;101(5):850–5.

29.Hormigo A, Abrey L, Heinemann MH, DeAngelis LM. Ocular presentation of primary central nervous

system lymphoma: diagnosis and treatment. Br J Haematol. 2004;126(2):202–8.

30. Whitcup SM, de Smet MD, Rubin BI, et al. Intraocular lymphoma. Clinical and histopathologic diagnosis. Ophthalmology. 1993;100(9):1399–406.

31.Chatzistefanou K, Markomichelakis NN, Christen W, et al. Characteristics of uveitis presenting for the first

time in the elderly. Ophthalmology. 1998;105(2): 347–52.

32.Gass JDM. Stereoscopic atlas of macular diseases diagnosis and treatment, vol. 2. St Louis: Mosby Year Book; 1997. p. 880–8.

33.Blumenkranz MS, Ward T, Murphy S, et al. Applications and limitations of vitreoretinal biopsy techniques in intraocular large cell lymphoma. Retina. 1992;12(3 Suppl):S64–70.

34.Velez G, Chan CC, Csaky KG. Fluorescein angiographic findings in primary intraocular lymphoma. Retina. 2002;22(1):37–43.

35. Fardeau C, Lee CP, Merle-Beral H, et al. Retinal fluorescein, indocyanine green angiography, and optic coherence tomography in non-Hodgkin primary intraocular lymphoma. Am J Ophthalmol. 2009;147(5):886–94.

36.Ursea R, Heinemann MH, Silverman RH, et al. Ophthalmic, ultrasonographic findings in primary central nervous system lymphoma with ocular involvement. Retina. 1997;17(2):118–23.

37.Schmitz-Valckenberg S, Holz FG, Bird AC, Spaide RF. Fundus autofluorescence imaging: review and perspectives. Retina. 2008;28(3):385–409.

38. Ishida T, Ohno-Matsui K, Kaneko Y, et al. Fundus autofluorescence patterns in eyes with primary intraocular lymphoma. Retina. 2010;30(1):6–15.

39. Chan CC, Fisson S, Bodaghi B. The future of primary intraocular lymphoma (retinal lymphoma). Ocul Immunol Inflamm. 2009;17(6):375–9.

40. Read RW, Zamir E, Rao NA. Neoplastic masquerade syndromes. Surv Ophthalmol. 2002;47(2):81–124.

41. Zimmerman LE. Discussion of Freeman LN et al. Clinical features, laboratory investigations, and survival in ocular reticulum cell sarcoma. Ophthalmology. 1987;94:1633–1649.

42. DeAngelis LM, Yahalom J, Heinemann MH, et al. Primary CNS lymphoma: combined treatment with chemotherapy and radiotherapy. Neurology. 1990;40(1):80–6.

43. Sloas HA, Starling J, Harper DG, Cupples HP. Update of ocular reticulum cell sarcoma. Arch Ophthalmol. 1981;99(6):1048–52.

44.Chan CC. Molecular pathology of primary intraocular lymphoma. Trans Am Ophthalmol Soc. 2003;101:275–92.

45. Grimm SA, Pulido JS, Jahnke K, et al. Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group Report. Ann Oncol. 2007;18(11):1851–5.

46.Pe’er J, Hochberg FH, Foster CS. Clinical review: treatment of vitreoretinal lymphoma. Ocul Immunol Inflamm. 2009;17(5):299–306.

47.Soussain C, Hoang-Xuan K. Primary central nervous system lymphoma: an update. Curr Opin Oncol. 2009;21(6):550–8.

48.Swinnen LJ. Primary central nervous system lymphoma: recent progress, many remaining questions. Curr Opin Oncol. 2009;21(5):393–6.

49. Isobe K, Ejima Y, Tokumaru S, et al. Treatment of primary intraocular lymphoma with radiation

therapy: a multi-institutional survey in Japan. Leuk Lymphoma. 2006;47(9):1800–5.

50. Char DH, Ljung BM, Miller T, Phillips T. Primary intraocular lymphoma (ocular reticulum cell sarcoma) diagnosis and management. Ophthalmology. 1988;95(5):625–30.

51.Berenbom A, Davila RM, Lin HS, Harbour JW. Treatment outcomes for primary intraocular lymphoma: implications for external beam radiotherapy. Eye (Lond). 2007;21(9):1198–201.

52.Neuwelt EA, Goldman DL, Dahlborg SA, et al. Primary CNS lymphoma treated with osmotic bloodbrain barrier disruption: prolonged survival and preservation of cognitive function. J Clin Oncol. 1991;9(9):1580–90.

53. Jahnke K, Thiel E, Bechrakis NE, et al. Ifosfamide or trofosfamide in patients with intraocular lymphoma. J Neurooncol. 2009;93(2):213–7.

54. Frenkel S, Hendler K, Siegal T, et al. Intravitreal methotrexate for treating vitreoretinal lymphoma: 10 years of experience. Br J Ophthalmol. 2008;92(3): 383–8.

55.Sen HN, Chan CC, Byrnes G, et al. Intravitreal methotrexate resistance in a patient with primary intraocular lymphoma. Ocul Immunol Inflamm. 2008;16(1):29–33.

56.Velez G, Yuan P, Sung C, et al. Pharmacokinetics and toxicity of intravitreal chemotherapy for primary intraocular lymphoma. Arch Ophthalmol. 2001;119(10):1518–24.

57.Itty S, Pulido JS. Rituximab for intraocular lymphoma. Retina. 2009;29(2):129–32.