the most frequent tumors and simulating lesions in ocular adnexa are lymphoproliferative disorders ( lpds ) , including malignant lymphomas and orbital inflammation with lymphoid hyperplasia or infiltration , some of which are historically called  orbital pseudotumors .  in japanese studies , goto   reported that the rate of lpd among 409 cases with orbital tumors and simulating lesions was 43% , while ohtsuka et al . described that the rate was 49% out of 213 cases . in the united states , lpd is a common orbital disease although the rate seems to be somewhat lower : 24% of lpd out of 703 cases with orbital lesions was reported by shields et al . , and 26% of lpd out of 268 cases was reported by shinder et al . .   when patients with suspected orbital lpd are encountered , tissue biopsy is preferred since image examinations alone can not distinguish inflammatory lesions from malignant lymphomas . igg4-related disease ( igg4-rd ) often involves lacrimal glands , which is now known as igg4-related mikulicz 's disease [ 5 , 6 ] or igg4-related dacryoadenitis [ 7 , 8 ] by many recent reports over several years . recently , it was also elucidated that igg4-related orbital inflammatory lesions include other ocular adnexal tissues such as extraocular muscles   and periorbital membrane . therefore , igg4-rd is a differential diagnosis in orbital lpd . the question is then raised as to what percentage of orbital lpd is related to igg4 . in this study , an orbital lpd case series was investigated and clinical aspects of igg4-related orbital lymphoproliferative disorders were evaluated . in kanazawa university hospital in japan , a 47-year - old woman with igg4-immunopositive histopathology and an elevated serum igg4 level of 1000  mg / dl was diagnosed as a first case of igg4-related dacryoadenitis in november , 2004 . from that time through march , 2011 , sixty - two cases ( 27 men and 35 women ; mean age , 66  14 yrs ; range 3289 yrs ) were pathologically diagnosed with orbital lymphoproliferative diseases ( lpd ) from surgical samples of ocular adnexal tissue . the two main categories of orbital lpd were malignant lymphomas and orbital inflammations : the latter included reactive lymphoid hyperplasia , lymphoid infiltrated lesions , and inflammatory pseudotumor . conjunctival lesions were not enrolled in this study because conjunctival involvement in igg4-rd has never been experienced in previous reports [ 9 , 11 ] or in the author 's institution . intraocular lymphoma belongs to cns lymphoma and thus was also excluded in this study . in most cases , immunoglobulin heavy chain gene rearrangement in surgical samples was also examined to support the differential diagnosis of malignant lymphoma . diagnostic criterion for positive igg4-immunostaining in orbital tissue ( igg4-related orbital disease ) was either ( 1 ) the ratio of igg4-positive cells to igg - positive cells ( igg4+/igg+ cells ) was more than 40% , or ( 2 ) the number of igg4-positive cells was more than 30 per high power microscopy field . mouse monoclonal antibody anti - human igg4 ( 05 - 3800 , zymed , usa ) and rabbit polyclonal antibody anti - human igg ( a0423 , dako , usa ) were used for immunostaining . serum igg and igg4 were measured in all of the cases with an igg4-positive pathological diagnosis . igg4-related orbital lesions including lacrimal gland swelling , extraocular muscle enlargement , and other mass lesions were evaluated using computed tomography ( ct ) and/or magnetic resonance imaging ( mri ) . histological types of the 62 orbital lpd were 22 cases ( 35% ) with extranodal marginal zone lymphoma of mucosa - associated lymphoid - tissue type ( malt lymphoma ) , 11 cases ( 18% ) with diffuse large b - cell lymphoma ( dlbcl ) , 3 cases ( 5% ) with other malignant lymphomas ( 1 mantle cell lymphoma , 1 nk / t cell lymphoma , 1 small lymphocytic lymphoma ) , 16 cases ( 26% ) with igg4-related orbital inflammation ( igg4-roi ) , and 10 cases ( 16% ) with non - igg4-related orbital inflammation ( non - igg4-roi ) ( figure 1 ) . none of the malignant lymphomas showed a relationship with igg4 in this case series . figure 2 depicts the ages of the four groups of dlbcl , malt lymphoma , igg4-roi , and non - igg4-roi . ages of the igg4-roi group averaged 56  10 yrs , which was significantly lower than those of the malt lymphoma ( 71  12 yrs , p = 0.00027 in a student 's t - test ) and dlbcl ( 75  14 yrs , p = 0.00107 ) groups . clinical data of sixteen cases of igg4-roi are summarized in table 1 , which were sorted in ascending order of serum igg4 level . the age ranged between 41 to 76 yrs ( mean  sd ;  56  10  yrs , median ; 58 yrs ) , and there was no sex difference ( 8 men and 8 women ) . these cases except one ( number 1 , detailed in the discussion ) were accompanied by elevated serum igg4 concentration ( 549  293  mg / dl , n = 15 , normal range < 135  mg / dl ) and an increased ratio of serum igg4/igg ( 28  12% , n = 15 , normal range < 7% ) . in 9 patients , these were characterized by lymphoplasmacytic infiltration , forming lymphoid follicles ( germinal center ) and sclerosing fibrosis . orbital lesions other than lacrimal glands were detected by mri in six cases ( cases numbers 4 , 7 , 8 , 11 , 14 , and 16 in table 1 ) as shown representatively in figure 3 . swollen extraocular muscles were seen in four cases ( numbers 4 , 7 , 8 and 14 ) . supraorbital nerve ( frontal nerve ) , and/or infraorbital nerve enlargements were observed in 4 cases ( numbers 7 , 8 , 11 , and 14 ) . a mass lesion surrounding the optic nerve was detected in two patients ( numbers 8 and 11 ) . steroid therapy was performed for all the igg4-roi cases except three patients because their eyelid swellings decreased in size after biopsy surgery ( case numbers 1 , 2 , and 5 ) and because of normal serum igg4 ( case number 1 ) and diabetes mellitus ( case number 2 ) . eleven cases underwent oral prednisolone tapering therapy with an initial dose of 20 , 30 , or 40  mg per day . in two cases with diabetes mellitus , lower doses of oral prednisolone ( 10  mg daily in case number 10 and 8  mg daily in case number 15 ) were administered initially and reduced to a maintenance dose . all of the 11 cases essentially responded well to initial doses of oral prednisolone , but in 5 cases ( numbers 4 , 8 , 10 , 11 , and 14 ) ocular symptoms such as eyelid swelling deteriorated during tapering , and thus increase in the dosage was required . in case number 11 with retrobulbar mass ( figure 3(c ) ) , oral prednisolone therapy alone ( 30  mg daily initially ) failed to diminish his exophthalmos , and then intravenous methylprednisolone pulse ( 500  mg for 3 days ) was additionally performed three times . however , some previous reports suggested that orbital malignant lymphomas can be related to igg4 . cheuk reported three cases of ocular adnexal lymphoma ( 2 malt lymphoma and 1 follicular lymphoma ) arising in igg4-related dacryoadenitis , and that the rate of transformation of malignant lymphoma in the background of igg4-roi was approximately 10% . first detected igh gene rearrangement in two cases of ocular adnexal igg4-related disease   and later reported seven patients with ocular adnexal malt lymphoma arising from igg4-related orbital disease . on the other hand , he described a case of igg4-producing malt lymphoma of the lymph node . also in the orbital region , oyama reported a case of igg4-expressing malt lymphoma in the lacrimal gland . based on these findings , there could be two possibilities of orbital malt lymphoma arising from preexisting igg4-roi and de novo igg4-positive orbital malt lymphoma . in any case , orbital biopsy should be mandatory to evaluate malignancy before treatment even if serological examination already detected elevated serum igg4 . there is no doubt that igg4-roi most frequently involves the lacrimal gland , which is reported as igg4-related dacryoadenitis and mikulicz 's disease [ 58 ] . sato et al . reported that orbital masses other than the lacrimal gland were detected in 7 out of 21 cases with igg4-roi . mehta et al . presented a case of igg4-roi with enlargement of the infraorbital canal and periorbital membrane involvement . similar lesions were observed in the present case series of igg4-roi ( figure 3 ) . in addition , mass lesions around the optic nerve were seen in two cases , indicating that involvement of the optic nerve sheath may not be rare in igg4-roi . among 16 cases of igg4-roi , one patient ( case number 1 ) presented normal levels of serum igg4 . in this case , the ratio of igg4+/igg+ cells in immunohistochemistry was around 30% , somewhat lower than values in diagnostic criteria [ 6 , 12 ] , but igg4-positive cells were more than 30 per high power microscopy field . the pathological findings that lymphoplasmacytic infiltration with germinal centers and dense sclerosing fibrosis was characteristic for igg4-roi . so far , we can not resolve the reason for this discrepancy between pathological and serological findings . however , kubota previously reported a patient with an inverse discrepancy who had negative findings on the igg4 immunostaining despite presumably typical igg4-roi with elevated serum igg4 . the rate of igg4-rd in 62 cases with orbital lpd was 26% in this study and was reported to be 33% out of 58 orbital lpd cases from another japanese institute . thus , it is likely that nearly a quarter of orbital lymphoproliferative disorders are estimated to be related to igg4 . further multicenter studies will be required to confirm this rate and to evaluate the frequency and location of igg4-roi other than the lacrimal glands .