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Lymphoid Tumors of the Ocular Adnexa
Lympho id Tumors of the Ocula·r Adnexa Clinical Correlation With the Worl
Abstract: Eighty-eight patients with ocular adnexal lymphoid lesions examined at the Mayo Clinic between 1970 and 1982 were evaluated. The histopathologic type was reclassified using the working formulation. Paraffin sections were evaluated with immunoperoxidase staining. There were 11 "pseudotumors" and 77 lymphomas. Sixty lymphomas were small lymphocytic type A; 27 tissues had a monoclonal staining pattern, and 4 had a polyclonal staining pattern. Five of the pseudotumors had a polyclonal staining pattern; none had a monoclonal pattern. The remainder did not stain or tissue was not available. Thirty-six of the 44 lymphomas that presented in the ocular adnexa remained localized. There were no distinguishing features between conjunctival and orbital lymphomas. Significant damage to the ocular tissue occurred in 15 of the 63 patients treated with radiation therapy. Older, asymptomatic patients with a favorable histologic type may not require treatment; therapy is reserved for specific indications. The probability of survival to five or seven years differs little from that expected in the general population. [Key words: cytoplasmic immunoglobulin, immunoperoxidase stain, lymphoma, lymphoproliferative disorder, monoclonal, polyclonal, pseudotumor, working formulation.] Ophthalmology 92:13111324, 1985
Lymphomas are solid tumors of the immune system; most are composed of (monoclonal) B cells. They arise From the Department of Ophthalmology* and the Section of Surgical Pathology,t Mayo Clinic and Foundation, Rochester, Minnesota. Presented at the Eighty-ninth Annual Meeting of the American Academy of Ophthalmology, Atlanta, Georgia, November 11-15, 1984. Supported in part by Research to Prevent Blindness, Inc. Reprint requests to Thomas J. Liesegang, MD, Department of Ophthalmology, Mayo Clinic, Rochester, MN 55905.
most commonly in the lymph nodes, but about 10 to 25% of all non-Hodgkin's lymphomas arise in extranodal sites, 1 including the orbit. The orbit and conjunctiva are frequently involved primarily or as part of a systemic lymphoma. The diagnosis and treatment oflymphoid lesions of the conjunctiva and orbit are a nemesis for both the pathologist and clinician because a benign inflammatory lesion may be difficult to distinguish from a lymphoma by histopathologic criteria alone. In extranodal sites, the usual criteria for lymphoma (for example, effacement ofpreex1311
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Table 1. Comparison of the Proposed Working Formulation With other Systems of Classification for Non-Hodgkin's Lymphoma* Working Formulation 1 Low grade (A) Small lymphocytic with or without plasmacytoid (B) Follicular, small cleaved (C) Follicular, mixed Intermediate (D) Follicular, large cell (E) Diffuse, small cleaved (F) Diffuse, mixed (G) Diffuse, large cell (FCC, not immunoblastic)
High grade (H) Large cell, immunoblastic (I) Lymphoblastic (J) Small noncleaved Others Hairy cell, mycosis fungoides, etc.
Rappaport 4 (A) Lymphocytic: B-cell T-cell T-zone Hairy cell Mycosis fundoides and Sezary cell lmmunocytomas: Lymphoplasmacytic Lymphoplasmacytoid Polymorphous (?A) Plasmacytoma (E) Centrocytic Centroblastic-Centrocytic: (B, C, D) Follicular (F) Diffuse (G) Centroblastic Lymphoblastic: (J) Burkitt's type (I) T-type lmmunoblastic: (H) B or T
(A) Well differentiated lymphocytic (plasmacytoid) (B) Nodular-poorly differentiated lymphocytic lymphoma (E) Diffuse-poorly differentiated lymphocytic lymphoma (C) Nodular-mixed (F) Diffuse-mixed (D) Nodular-histiocytic (large cell) (G, H) Diffuse-histiocytic (large cell) (I) Lymphoblastic Undifferentiated: (J) Burkitt's (G, J) Pleomorphic
*Modified from Morgan TW, Banks PM. Histopathology of Malignant Lymphomas. In: Hematology, 3rd edition, chapter 117, Williams WJ, Beutler E, Ersler AJ, Lichtman MA, eds. New York: McGraw-Hill, 1983; 1003-12.
isting nodal architecture and capsular invasion) cannot be applied, and thus evaluation is difficult. The error rate, both for the histopathologic diagnosis and the ability to predict clinical outcome, may range from 20 to 50%. 2 •3 The situation is further confused by the multiple histopathologic classification systems used over the years, including those of Rappaport (1966, modified 1976),4 LukeCollins (1974, modified 1979), 5 and Kiel (1978). 6 The working formulation ( 1982) 1 is now used by pathologists and clinicians generally to classify non-Hodgkin's lymphoma because it is based solely on histologic criteria and is of demonstrated prognostic accuracy (Table 1); it is not, however, based on immunologic characterization. Studies in immunology and genetics have opened new avenues for the study of lymphomas and also for nonneoplastic disorders of the immune system. 3 The use of monospecific or monoclonal antibodies with the immunoperoxidase stain to detect surface or cytoplasmic immunoglobulin light chains characteristic of the B-cell lymphomas was a significant advance and is performed without special equipment_1 Ideally, immunoperoxidase stain is used on fresh frozen tissue, in which even small amounts of immunoglobulin, including surface immunoglobulin, are antigenically preserved; this is in contrast to fixed paraffin sections, in which only small amounts of cytoplasmic antigen are preserved. 8 In recent years, we have used immunoperoxidase stain on fresh frozen tissue for investigation of all orbital and conjunctival lymphoproliferative disorders. The immu1312
noperoxidase technique, however, has been applied to formalin-fixed and Zenker-fixed tissue, 9- 11 and techniques are being developed to detect surface antigen that is resistant to the fixation process. 12 The purpose of this review is to apply the working formulation classification scheme, to correlate this with immunoglobulin light-chain immunoperoxidase determinations performed on paraffin sections of formalin-fixed tissues from previous cases, and to compare these findings with those in a group of patients with a known clinical outcome. Within the study period, computed tomography markedly enhanced our ability to define the site of involvement and follow the progression of the disease or response to therapy.
MATERIALS AND METHODS All patients with the pathologic diagnosis of benign or malignant lymphoid lesions of the orbit or conjunctiva who were examined at the Mayo Clinic between 1970 and 1982 were identified; 153 cases were reviewed. Patients with an acute inflammatory pseudotumor accompanied by a vasculitis were excluded because this entity is readily distinguished from lymphoma microscopically; additional cases were excluded because tissue was not available or was unsatisfactory for histologic evaluation. Hematoxylin-eosin stained sections from 88 cases were then available for reevaluation.
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Fig I. Top, definitely malignant lesion of conjunctiva exhibits only moderately dense infiltrative pattern at low magnification (left), but at high magnification (right) the lymphoplasmacytic infiltrate is recognizably abnormal due to the abundant intranuclear immunoglobulin inclusions ("Dutcher bodies"). Process was therefore classified as small lymphocytic with plasmacytoid differentiation (Working Formulation) or as immunocytoma, lymphoplasmacytic (Kiel system) (hematoxylin-eosin, left X40, right X400). Fig 2. Second row, definitely malignant lesion of orbit, recognizable as such on the basis of expansive, displacing growth pattern (left) and uniform small lymphocytic composition (right). Tumor was classified as small lymphocytic with (slight) plasmacytoid differentiation (Working Formulation) or immunocytoma, lymphoplasmacytoid (Kiel system) (hematoxylineosin, left X40, right X400). Fig 3. Third row, apparently malignant lymphoid lesion of orbit shows a solid, displacing infiltrative growth pattern (left), but at higher magnification (right) the small lymphocytic population shows some subtle heterogeneity, and rare histiocytes are interspersed. This presumed neoplasm was classified as small lymphocytic without plasmacytoid differentiation (working formulation) or lymphocytic (B-ee!!) in the Kiel system (hematoxylin-eosin, left X I 00, right X400). Fig 4. Bottom, lymphoid orbital infiltrate, equivocal in nature, is present in only a small sampling (left). Although the process is infiltrative in pattern, high magnification (right) reveals vascular proliferation and moderate cellular heterogeneity, features suggestive of an inflammatory immune response (hematoxylin-eosin, left X 100, right X400).
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The lesions were considered benign histologically (ie. Type II pseudotumor) when the cellular components were heterogeneous and appeared functional (for example, with groupings of plasma cells, with follicles, granulocytes, or with clusters of small lymphocytes). An infiltrate that did not resemble an organized immune response (that is, a dense monomorphic meaningless cellular proliferation or one composed of abnormal cell types) was interpreted as malignant. The degree of certainty was recorded because this factor was limited in some cases by small sampling, by poor cellular preservation or by the equivocal nature of the histologic appearance. The five categories of certainty were: definitely malignant, apparently malignant, equivocal, apparently benign, and definitely benign (Figs 1-6 ). Tumors classified by other investigators as "atypical lymphoid hyperplasia" 13 - 15 were classified as "apparently malignant" (Fig 3). Malignant lesions were classified according to the Working Formulation (Table 1). The Kiel classification (Table I) was also applied; this system is based primarily on morphologic traits and discriminates among variants of small lymphocytic lymphoma with or without plasmacytic differentiation. Sections from paraffin blocks were stained by a simple two-step method of immunoperoxidase staining using rabbit primary serum against kappa or lambda human lg light chains, muramidase, and albumin (Dako, Santa Barbara, CA); goat anti-rabbit lg peroxidase-conjugated serum (Tago, Burlingame, CA) was then used as the second step reagent. The paraffin sections stained with immunoperoxidase were reviewed independent of those stained with hematoxylin-eo~in. Positive controls were sections of a hyperplastic lymph node, showing both kappa- and lambda-producing plasma cells. Negative controls were sectioned from this same lymph node in which nonimmunized rabbit serum was substituted for the anti-kappa or anti-lambda primary serum. Each case was also studied for the presence of human albumin, as a control for the passive presence of plasma proteins, which might be a basis for misinterpretation of (polyclonal) immunoglobin. lmmunostained preparations were interpreted as monoclonal (monotypic) when the normal 2: I kappa: lambda ratio of light chain staining was definitely not maintained, ie. by a deviation of greater than 4: 1 or less than I :2 ratios (Fig 7). This finding of monoclonality was interpreted as such, only when staining plasmacytic or plasmacytoid cells were dispersed throughout the lymphoid infiltrate and therefore presumably representative of the process itself. Preparations were considered polyclonal (polytypic) when the kappa:lambda ratio was between 4: 1 and 1:2, and when the anti-albumin control preparation demonstrated that the light chains which stained did not correspond to passively present plasma proteins (Fig 8). The clinical presentation, treatment, and course were documented by reviewing the records which included recent correspondence with the patients or their physicians. Computed tomography scanning became available during this time and was extremely helpful in establishing the location and extent of the lymphoproliferative disorder. 1314
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The clinical review was conducted independent of the pathologic review.
RESULTS Of the 88 cases included in the study, 60 (68%) were originally interpreted as malignant; after review, however, 77 (87%) were considered to be malignant using the histopathologic criteria of the working formulation (Table 2). Among the 88 cases, 59 originally diagnosed as lymphoma were confirmed as lymphoma (55 definite, 2 apparent, 2 equivocal), but one case was reclassified as a pseudotumor (definitely benign). Of the 59 lymphomas, 42 were diffuse small lymphocytic lymphomas (type A). Of the 38 considered to be definitely malignant, 17 had a monoclonal immunoperoxidase reaction ( 11 with lambda and 6 with kappa), 1 had a polyclonal reaction, and 16 had no immunoperoxidase staining; in 4 no tissue was available for immunoperoxidase staining. Two tissues were apparently malignant type A (absent stain in both), and two were equivocal for malignant type A (one polyclonal stain and one absent stain). The remainder of the lymphomas were low grade (four type B and four type C) or intermediate grade (one type D, three type E, four type F, and one type G). There were no high-grade lymphomas. Four of the lymphomas that were not type A had a monoclonal staining pattern, but none had a polyclonal staining pattern. The reclassified pseudotumor from the original group of malignant lymphomas had a polyclonal staining pattern (Fig 8). Eighteen cases originally classified as a benign lymphoproliferative disorder (that is, pseudotumor, lymphoproliferative disorder, lymphoid hyperplasia, and atypical lymphoid hyperplasia) were reclassified as lymphoma. In this group, all 18 were classified as type A lymphoma ( 12 definite and 6 apparent). Of the 12 definitely malignant lesions, 4 had a monoclonal pattern; of the 6 apparently malignant lesions, 2 had a monoclonal pattern and 1 had a polyclonal pattern. Ten cases originally considered to be pseudotumor were confirmed as benign (9 definite and 1 apparent); 4 of these had a polyclonal staining pattern; none had a monoclonal pattern. Thus, in this series of 88 cases, 77 (87%) were diagnosed histomorphologically as lymphomas, and 60 (78%) of these were type A lymphomas. A monoclonal immunoperoxidase response was noted in 27 cases. A polyclonal immunoperoxidase response was seen in eight cases, and three of these were in patients with a histopathologic diagnosis of lymphoma. The clinical signs in this ~eries, as in others, 16 •17 were not sufficient to distinguish a benign process from a lymphoma. Patients presented similarly with proptosis, an orbital or conjunctival mass, swelling of the lids, diplopia, tearing, pain, and visual difficulty. Of the 88 patients, 34 were males and 54 were females. The age at onset ranged from 7 to 94 years (mean, 59 years). The age range of the patients with a diagnosis oflymphoma was 17 to 94 years
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Fig 5. Top, apparently benign orbital infiltrate exhibits infiltration of fatty tissue (left), but with extreme cellular heterogeneity (right). There are zones of plasma cells, lymphocytes, and histiocytes, features of an organized (benign) immune response (hematoxylin-eosin stain, left X 100, right X400). Fig 6. Second row, definitely benign orbital infiltrate manifests only scant, scattered infiltrates amidst edematous, fibrotic muscular tissues (left). High magnification (right) reveals clusters of small lymphocytes with conspicuous zones of plasma cells (left side of field) (hematoxylin-eosin, left X I 00, right X400). Fig 7. Third row, definite monotypic Ig light chain staining marks a lymphoplasmacytic process as containing monoclonal immunoglobulin and, therefore, as a neoplasm (same case as in Figure 1). Left, positive among most cells for kappa; Right, only a few scattered plasma cells are positive for lambda (hematoxylin nuclear counterstain; ethylcarbazole color reagent; X400). Fig 8. Bottom, polytypic Ig light chain immunostaining in a benign orbital lymphocytic infiltrate (same case as in Figure 6). In both kappa (left) and lambda (right) preparations, a moderate proportion of the plasma cells and lymphoplasmacytic cells stain, marking the process as polyclonal Ig-producing (hematoxylin nuclear counterstain; ethylcarbazole color reagent; X400).
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Table 2. Comparison of Original Diagnoses with Current Diagnoses in 88 Cases of Lymphoid Lesions of the Ocular Adnexa
Original Diagnosis* 60 "Malignant" lymphoma
18 "Benign lymphoproliferative disease"
Current Diagnosist Based on Working Formulation
Current Diagnosis Based on Kiel Classification 6 16 Lymphoplasmacytoid 17 Lymphoplasmacytic 1 Plasmacytomajlymphoplasmacytoid 1 Follicular 7 Follicular/chronic lymphocytic
42 Type A, 38 definite, 2 apparent, 2 equivocal
lmmunostaining Response 17 Monoclonal, 11 lambda, 6 kappa 1 Polyclonal 4 No tissue 16 Absent tissue 2 Absent stain 1 Polyclonal 1 Absent stain
4 Follicular
4 Type B, 4 definite
2 Absent stain 2 No tissue
3 Follicular 1 Lymphoplasmacytoid
4 Type C, 4 definite
2 Absent stain 2 No tissue
1 Follicular diffuse centroblastic
1 Type D, definite
1 Monoclonal (lambda)
2 Follicular 1 Diffuse centroblastic
3 Type E, 3 definite
3 Absent stain
1 Follicular 2 Diffuse mixed 1 Centroblasticjcentrocytic
4 Type F, 4 definite
2 Absent stain 2 Monoclonal (kappa)
1 Follicular
1 Type G, 1 definite 1 (Pseudotumor type II), 1 definite
1 Monoclonal (lambda) 1 Polyclonal
6 Lymphoplasmacytoid 1 Lymphoplasmacytic 11 Follicular/chronic lymphocytic
18 Type A, 12 definite
12 Inflammatory pseudotumor Type II
4 Monoclonal, 3 lambda, 1 kappa 5 Absent stain 3 No tissue
2 Atypical lymphoid hyperplasia 3 Lymphoproliferative disorder 1 Pseudolymphoid hyperplasia
6 Apparent
2 Monoclonal, 1 lambda, 1 kappa 1 Polyclonal 1 Absent stain 2 No tissue
10 Inflammatory pseudotumor type II
10 inflammatory pseudotumor type II, 9 definite, 1 apparent
4 Polyclonal 5 No tissue 1 No stain
* The system of Rappaport 4 was generally used to determine this diagnosis.
t Diagnosis was based on the working formulation. 1
(mean, 62 years). The age range of those with a diagnosis of a benign lymphoproliferative disorder was 7 to 70 years (mean, 41 years). The duration of follow-up of the 88 patients ranged from 1 to 173 months (mean, 57 months). Among the 77 patients with a histopathologic diagnosis of lymphoma, 36 had localized ocular disease without ever developing systemic lymphoma (Table 3). In this group of 36 patients, 32 had type A lymphoma, 1 type B, 1 type E, and 2 type F. In 41 patients systemic lymphoma developed at some time during the course of disease; 8 of these patients presented with ocular adnexal lymphoma and later developed systemic disease, 18 had systemic 1316
lymphoma prior to the ocular disease; and 15 patients had simultaneous systemic and ocular lymphoma. One patient with a histopathologic diagnosis of pseudotumor and a polyclonal immunoperoxidase reaction developed systemic lymphoma. Although computed tomography shows a highly characteristic picture with a distinctive growth pattern and contouring, no radiographic feature distinguishes histologically benign from malignant disorders. 18 On the basis of clinical examination and radiographic evaluation, the ocular lymphomas were confined to the orbit in 43 patients, to the lacrimal gland in 5, and to the
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Table 3. Occurrence of Systemic Lymphoma in 77 Patients with Ocular Lymphoma Type of Lymphoma (working formulation 1), no. Patients
No. Patients Dead
No. Patients Alive With Lymphoma
Without Lymphoma
Unknown Cause
2
2
Mean Follow-up (months)
Without Recurrence
With Recurrence
32 1 1 2
25
3 1
8
A, 7 D, 1
2
5
84 14
Systemic lymphoma simultaneous with ocular adnexal lymphoma
15
A, 8 B, 3 C, 1 E, 2 G, 1
4
2 2 1 1 1
44 57 30 25 25
Systemic lymphoma prior to ocular adnexal lymphoma
18
A, 13 C, 3 F, 2
5 2 1
6 1 1
Disease Pattern
No. Patients
Localized to ocular adnexa
36
Systemic lymphoma after ocular adnexal lymphoma
Total
77
A, B, E, F,
2
42
conjunctiva in 21 patients and presented in both the orbit and conjunctiva in 8 (Table 4). The benign lymphoproliferative disorders occurred in the orbit or lacrimal gland (Table 4). Specific note should be made of the absence of benign conjunctival lesions and of the one benign pseudotumor involving the lacrimal gland that was associated with a systemic lymphoma. We did not find sufficient reason to consider these sites separately; thus, these sites were considered together on further analysis. Bilateral ocular adnexal disease occurred in 18 patients, all of whom had lymphoma ( 17 definite and 1 apparent) (Table 5). Eleven patients had bilateral disease in the conjunctiva, three in the orbit, one in the lacrimal gland, and three in both the orbit and conjunctiva. Nine cases remained localized to the ocular tissues and nine were part of a prior or simultaneous systemic lymphoma. Among these bilateral cases, 16 were type A, 1 type B, and 1 type E. The follow-up data are listed in Table 5. Bilateral disease did not necessarily presage systemic disease, and only four of these patients died of lymphoma. Seventeen patients had a systemic illness other than lymphoma (Table 6). Two patients had chronic lymphocytic leukemia; one of these patients had the leukemia 16 years prior to lymphoma and one patient had the leukemia just prior to the onset of lymphoma. Both of these lymphomas were type A. Three patients had Sjogren's syndrome; one of these patients had the disease three years prior to the diagnosis of lymphoma and the other two had it after lymphoma had been diagnosed. Two of the patients with Sjogren's syndrome had orbital lymphoma and one had conjunctival lymphoma. Three patients had macroglobulinemia; two of these patients had the disease
6
19
2 1 4
65 84 97 80
53 32 52
6
three to seven years prior to lymphoma, and one had it five years after the diagnosis of lymphoma. The patient with Wegener's granulomatosis had no ocular adnexal involvement from the disease and had type A lymphoma of both the conjunctiva and the orbit. Prior radiation had been used in three patients (for previous cancer) and prior chemotherapy in one patient (for leukemia). Previous ocular diseases were absent in all but one of the patients; in 1969, this patient had a conjunctival biopsy and a benign lymphoproliferative disorder (recently confirmed) was diagnosed and in 1972 had a conjunctival biopsy and type A lymphoma (definite) diagnosed. This latter tissue did not stain with immunoperoxidase. The patient is presently alive without recurrent disease but has systemic lymphoma. Serum protein electrophoresis was performed in 23 patients. A normal pattern was found in 13 patients, a monoclonal pattern in 8, and a polyclonal pattern in 2 (Table 7). The monoclonal pattern appears indicative of a systemic disease. Eight patients with systemic disease still demonstrated a normal pattern, and two patients with systemic disease demonstrated a polyclonal pattern. Table 8 correlates the results of the immunoperoxidase staining with the pattern of disease, histopathologic diagnosis, and the clinical outcome in the total series of 88 patients (including the 11 with benign lymphoproliferative disorders). Monoclonal staining was demonstrated in 27 patients from the paraffin-embedded sections, and in all instances correlation was made with the histologic diagnosis of lymphoma. Lymphoma-related deaths occurred in six patients (five type A, one type G). Eight polyclonal patterns were identified, and these correlated with a benign 1317
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Table 4. Site of Disease in 88 Patients with Lymphoid Lesions of the Ocular Adnexa
Site
Location
No. Patients
Localized Superior Inferior Systemic Superior Inferior & other
22 14 8 21 13 8
Ocular lymphoma (77 patients) Orbit alone
43
Lacrimal gland
5
Conjunctiva alone
Localized Systemic
21
Both orbit and conjunctiva
1 4
Localized Superior Inferior & other Systemic Superior Inferior & other Localized Superior Inferior & other Systemic Superior Inferior & other
8
9 2 7 12
6 6
4
0
4 4 2 2
Benign lymphoproliferative disorder Orbit
8
Lacrimal gland
3
Localized Superior Inferior & other
3
Localized Systemic
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histopathologic diagnosis in five and with a diagnosis of lymphoma in three. In these three lymphoma cases, the histopathologic diagnosis was independent of the immunologic staining pattern and was interpreted as definitely malignant in one, apparently malignant in one, and equivocal in one. The clinical course was benign in all three. In 35 patients, no staining was demonstrable with the immunoperoxidase technique on paraffin-embedded sec Lions, and in 18 patients no additional tissue was available for immunoperoxidase stain. With the use of paraffinembedded immunoperoxidase staining, the clinical courses did not differ significantly between those patients whose tissues stained or failed to stain with immunoperoxidase if the patients had the same histopathologic diagnosis. Polyclonality, however, was correlated with a good prognosis in the patients identified. The clinical outcomes of these 88 patients, followed for a mean of 57 months, are as follows: 50 patients are alive without recurrence, 8 had a local ocular recurrence of the disease, and 18 died of lymphoma. Among the 18 patients who died, I3 were type A, 2 type B, 2 type C, I type E, and I type G. The effects of treatment on the clinical outcome are shown in Tables 9 through I2 according to the results of immunoperoxidase staining and the histopathologic diagnosis. Treatment consisted of radiation alone in 43 patients, chemotherapy alone in 9, combined radiation and chemotherapy in 20, and neither radiation nor chemotherapy in 16. Of the 16 patients who were not treated, 6 has pseudotumors and 10 had type A lymphomas. The treatment was usually directed by the physician in the lymphoma clinic at our institution. In general, chemotherapy was recommended for systemic disease, radiation for localized ocular adnexal disease, and a combination of treatment when both ocular and systemic disease compromised function. In more recent years, no treatment has been given for localized low-grade lymphomas. For
Disease Pattern and Ocular Adnexal
No. Patients with
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Table 5. Prognosis of 18 Patients with Bilateral Ocular Adnexal Disease
Site Orbit Conjunctiva
No. Patients
Presence of Systemic Lymphoma (pattern), No. Patients
Type of Lymphoma, No. Patients
3
1° + 2°, 3
A, 3
+ 20 or 2° _, 1°,4
A,9 B, 1 E, 1
11
10
Lacrimal gland
1
1° _, 2°' 1
A, 1
Both orbit and conjunctiva
3
1° + 2°' 1
A, 3
Total
18
No. Patients Alive Without Recurrence
With Recurrence
No. Patients Dead With Lymphoma
Without Lymphoma
Unknown Cause
1 5 1
2
7
4
4
2
1o = ocular lymphoma; 2° = systemic lymphoma; 1o _, 2° = ocular lymphoma preceded systemic lymphoma; 2° _, 1o = systemic lymphoma preceded ocular lymphoma; 1o + 2° = simultaneous occurrence.
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Table 6. Associated Systemic Disease in 88 Patients With Lymphoid Lesions of the Ocular Adnexa Systemic Disease
No. Patients
Chronic lymphocytic leukemia Prior to lymphoma Sjogren's syndrome Prior to lymphoma After lymphoma Macroglobulinemia Prior to lymphoma After lymphoma Systemic lupus* Wegener's granulomatosist Lung sarcomat Adenocarcinoma, abdomen* Prostate carcinomat Sphenoid ridge meningiomat Cancer of esophagust Herpes zostert
2 2 3 1 2 3 2 1 1 1 1 1 1 1 1 5
* Disease developed after diagnosis of lymphoma. t Disease developed prior to diagnosis of lymphoma.
Table 7. Serum Protein Electrophoresis Pattern in 23 Patients No. Patients
No. Patients with System Disease
13
8
A, 7 B, 2 C, 2 E, 1 F, 1
Monoclonal
8
8
A, 7 F, 1
Polyclonal
2
2
A, 2
Pattern Normal
Type, No. Patients
the management of pseudotumors at our institution, radiation therapy is reserved for disease not responding to systemic steroids. These guidelines were not strictly followed with these patients because of an erroneous original diagnosis, different interpretations of the information, or change in philosophies among the treating physicians.
Table 8. Correlation of lmmunoperoxidase Staining, Histopathologic Diagnosis, Clinical Features, and Outcome in 88 Patients with Lymphoid Lesions of the Ocular Adnexa Results of lmmunoperoxidase Staining, No. Patients Monoclonal, 27 Kappa, 10 Lambda, 17
Polyclonal, 8
No. Patients Alive Pattern of disease, No. Patients
Total, 88
Without Recurrenee
A, 11 F, 1
73 41
10 1
Systemic lymphoma, 25
A, 12 D, 1 F, 1 G, 1
56 14 92 25
5
Localized, 7
Pseudotumor, 4 A, 3 Pseudotumor, 1
21 28 23
4 2
A, 13 B, 1 E, 1 F, 1 Pseudotuinor, 1 A, 12 B, 1 C, 2 E, 2 F, 1
79 84 97 118 82 59 20 42 38 11
10
A, 5 Pseudotumor, 5 A,4 B, 2 C, 2
54 27 73 75 27 Mean 57
3 5 2
Localized, 17
Systemic lymphoma, 18
No tissue available, 18
Mean Follow-up (Months)
Localized, 12
Systemic lymphoma, 1 Absent staining, 35
Type (working fomulation), No. Patients
Localized, 10 Systemic lymphoma, 8 Systemic disease, 42
With Recurrenee
With Lymphoma
Without Lymphoma
Of Unknown Cause
5
2
1 1 3
50
No. Patients Dead
6 1 1 1
2 1 1 8
18
5
7
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Table 9. Results of Treatment in 27 Patients with Monoclonal Staining* Dead
Alive
<
8 (1°) 9A 1 W + 2o) 1FW)
Radiation alone, 14 Radiation and chemotherapy, 8
2 (2° _, 1°) 4A(2 W + 2o) 1F (2° _, 1°)
No treatment, 3
2A (1 °)
From Lymphoma
With Ocular Recurrence
Without Ocular Recurrence
Treatment, No. Patients
Unknown Cause
1A (2° _, 1°) 1D
w _, 2°)
1AW) 1A (1 o _, 2°) 1G W + 2°)
Chemotherapy alone, 2
0
6
3
17
27
Total
Without Lymphoma
* 1o = ocular lymphoma; 1o _, 2° = ocular lymphoma preceded systemic lymphoma; 2° _, 1o = systemic lymphoma preceded ocular lymphoma; 1o + 2o = simultaneous occurrence.
Seven deaths occurred in the group of 43 patients treated with radiation alone; four deaths occurred in the group of nine treated with chemotherapy alone; seven deaths occurred in the group of 20 patients treated with irradiation and chemotherapy; and no deaths occurred in the 16 patients treated with neither radiation nor chemotherapy. When Kaplan-Meier actuarial techniques 19 are used to examine the expected versus the observed probability of survival in our group of patients, several concepts about this disease entity emerge. When all 60 ocular adnexal type A lymphomas are combined, the probability of survival to five or seven years is not much less than that expected in a comparative general population. The probability is better than that for type A lymphomas reported from other nodal or extranodal sites, as garnered from the National Cancer Institute's statistics, 1 although not statistically significant (Fig 9). When we further compared the probability of survival in patients with type A lym-
phoma of the orbit with that of patients with disease in the conjunctiva with the use of the same Kaplan-Meier methods and chi-squared two-tailed tests, there was no significant difference in survival. We therefore conclude, on the basis of several analyses in our study, that there was essentially no reason to differentiate conjunctival from orbital lymphomas. We could not demonstrate a significant difference in survival among patients who demonstrated a monoclonal pattern in paraffin-embedded sections from those who also had lymphoma but whose tissues did not stain or in whom no tissues were available for staining. Ocular complications of radiation therapy occurred in 15 (23%) of the 63 patients treated with this method, in spite of described efforts directed toward ocular shielding. All received between 1000 and 4000 rad; complications included cataracts (8 patients), radiation keratitis (2), keratitis sicca (3), radiation retinopathy (2), ptosis and madarosis (2), and orbital fat atrophy (1); some patients had
Table 10. Results of Treatment in Eight Patients with Polyclonal Staining* Dead
Alive Treatment, No. Patients
Without Ocular Recurrence
With Ocular Recurrence
Radiation alone, 2 Radiation and chemotherapy, 1 No treatment, 4 Chemotherapy alone, 1
1A (1 °)
1AW)
Total
8
1AW) 3A (1°) 1A (1 °)
6
* 1o = ocular lymphoma; 1o + 2° = simultaneous occurence.
1320
From Lymphoma
Without Lymphoma
Unknown Cause
Pseudo tumor (1 o + 2°)
0
0
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Table 11. Results of Treatment in 35 Patients with Absent Staining* Alive Without Ocular Recurrence
Treatment, No. Patients
Radiation and chemotherapy, 9
1(1 °) 3A 1(2o _, 1o) 1po _, 2°)
No treatment, 2
1AW)
Chemotherapy alone, 4
1E W + 2°) 1 Pseudotumor
Total
With Ocular Recurrence
10A 2(2o _, 1o) 8(1 °) 1F (2° _, 1°)
Radiation alone, 20
35
Dead From Lymphoma (1 0 _, 20) 3A (2o _, 1o) + 2°)
18W)
w
(10 _, 20) 2A (2o _, 1o) 18W+2°) 1CW+2°)
With Lymphoma
Unknown Cause
1EW) 1A (1 °)
2Wl 3A (2o _, 1o)
1A W + 2°)
1C (2° _, 1°)
1F{2°_,1°) 1A (2° _, 1°) 1E W + 2°)
9
17
3
5
* 1o = ocular lymphoma; 1o __, 2° = ocular lymphoma preceded systemic lymphoma; 2° _, 1o = systemic lymphoma preceded ocular lymphoma; 1o + 2° = simultaneous occurrence.
more than one complication. The larger doses of radiation were associated with the more severe complications, and several patients had significantly limited vision as a result ofthis form oftherapy.
DISCUSSION Studies have emphasized that benign and malignant lymphoproliferative disorders cannot be distinguished by clinical examination alone, 16 and others9•20•21 have found it impossible to make a definitive diagnosis even with histopathologic examination and believe that it can be concluded only after prolonged follow-up. The question of whether the ocular tissues can be the primary site of malignant lymphoma or merely an atypical presentation of systemic lymphoma continues to be debated. In this series,
it was evident that many tumors remain localized and did not extend beyond the confines of the orbit. Some investigators have suggested that the natural histories of conjunctival and orbital lymphoid lesions differ. 16 Conjunctival tissues normally contain lymphoid tissue and are more likely to develop a localized benign lymphoid reaction. The orbit lacks the normal architecture of a lymph node; thus, lesions in this region cannot be compared with normal lymphoid structures. Benign pathologic processes of the conjunctiva are reported to have a higher incidence and a good prognosis-only 10% are associated with systemic lymphoma. 15 Orbital lymphomas apparently have a higher incidence (up to 50%) of association with systemic lymphomas. 14 Sigelman and Jakobiec 15 believe that current histopathologic criteria can be used to predict the clinical outcome of patients with conjunctivallymphoproliferative disorders better than for
Table 12. Results of Treatment in 18 Patients with No Tissue Available for Staining* Dead
Alive Without Ocular Recurrence
Treatment, No. Patients
With Ocular Recurrence
From Lymphoma
w
Radiation alone, 7
4AW)
18 + 2°) 1A (2° _, 1°)
Radiation and chemotherapy, 2
1C{2°-1°)
1A (2° __, 1°)
No treatment, 7
5 pseudotumor 1AW)
Chemotherapy alone, 2
1C{2°_,1°)
Total
18
12
Without Lymphoma
Unknown Cause 18
w + 2°)
1AW) 1A (1 °) 3
* 1o = ocular lymphoma; 2° _, 1o = systemic lymphoma preceded ocular lymphoma; 1o + 2° = simultaneous occurrence.
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100
80
Probability of surviving at least until timet,
Ocular adnexal 60
(n=60)
40
Other extranodal s1tes (n=41)
% 20
0'----'---'---'-------'---'---'----' 0
2
3
4
5
6
Years (t) from onset of symptoms
MAYO ©t984 86.5781
Fig 9. Kaplan Meier survival curve showing expected vs. observed probability of survival in patients with Type A ocular adnexal lymphoma. Comparison is made with Type A lymphomas in other sites as compiled by the National Cancer Institute.'
those with orbitallymphoproliferative disorders. Benign conjunctival lesions tend to have a pebbly, multinodular, and minimally elevated clinical appearance, whereas malignant conjunctival tumors are more likely to be smooth, larger, and more elevated and more apt to involve the orbit. These authors are more cautious in diagnosing lymphoma in the conjunctiva; it is interesting that followup data in their patients indicate that several lesions eventuated in systemic lymphoma. There is evidence that the percentage of patients with systemic lymphoma varies directly with the histologic type oflymphoma (that is, the degree of cytologic atypia). 16 In other series oflymphoproliferative disorders of ocular tissues, 25% orwell-differentiated small cell lymphomas and 68% ofless well-differentiated lymphomas were associated with systemic lymphoma; yet reactive lymphoid hyperplasia and atypical lymphoid hyperplasia were also associated with the eventual onset of systemic lymphoma in from 15 to 29%, respectively. 14·22 Our data represent an attempt to approach these questions from a conventional perspective, as has been applied to malignant lymphomas per se, without considerations specific to ocular lymphomas. Along with other authors, 20·23 we prefer general terms such as "apparent" or "equivocal" rather than specific terms such as "atypical lymphoid hyperplasia" or "reactive hyperplasia" because "atypia" and "reactive" implied a worrisome nature or known pathogenesis. Using these criteria to define lymphoma histologically, we did not find a more benign pattern for conjunctivallymphoproliferative disorders than for orbitallymphoproliferative disorders, and we observed subsequently the development of systemic lymphoma in a similar proportion of both groups. The working formulation, as established by the National Cancer Institute sponsored study for the classification of non-Hodgkin's lymphomas, is based on morphologic findings alone and does not depend on immunologic findings. 1The availability of immunologic surface 1322
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markers is of unquestioned use in the resolution of equivocal cases. The immunoperoxidase technique developed by Sternberger and adapted for paraffin section study of lymphomas by Taylor 24 resulted in frequent false-negative results. 25 This is attributed to denaturization or elution of surface immunoglobulin-differentiation antigens from the cell surface during fixation and paraffin embedding. 8•25 Frozen section immunoperoxidase staining is more sensitive than paraffin-embedded immunoperoxidase staining for the detection of immunoglobulin, 26 although paraffin sections do allow simultaneous histologic resolution, which may be important when small samples are used. The purpose of our study was to use the immunoperoxidase-staining techniques to correlate the histologic diagnosis in cases in which the clinical outcome was known. The ocular tissues may be especially suited to the immunoperoxidase technique in paraffin-embedded tissue because of the high incidence of plasma cell differentiation in these tissues with a large amount of cytoplasmic immunoglobulin that could potentially be detected. 9·10 •27 Distinction between cytoplasmic or surface-staining immunoglobulin is not possible with the immunoperoxidase technique. Monoclonality or polyclonality are not in themselves absolute prognostic indicators. The patients with polyclonal staining in the present series did predictably well, and those with monoclonal staining had a poorer prognosis. Although monoclonality is a characteristic of malignancy, growing evidence shows that localized lymphoproliferative disorders in extra-nodal sites can be polyclonal in demonstrable immunostaining.Z8•29 Further, such hyperplastic polyclonallesions may proceed on occasion to yield a monoclonal lymphoma (up to 29%)9·30 as a result of subsequent progression or mutation, or the lymphoma may simply be part of a mixed benign and malignant process. Jakobiec 30 suggested that patients with benign lymphoproliferative disorders of the ocular adnexa may be manifesting a breakdown in immunoregulation and that this could further erode and manifest with a preneoplastic or paraneoplastic condition or, later, lymphoma. An increase in immature forms has been observed in patients with repeat orbital biopsies who have lymphoproliferative disorders. 31 New hybridoma monoclonal antibody techniques are being developed to antigens other than immunoglobulin determinants that may permit better segregation of the subsets of ocular B-celllymphoproliferative disorders that are peculiar to ocular adnexal tissue and further elucidate those associated with systemic disease. 32 Other studies are focusing on T -lymphocytic subsets and their role in immunoregulation and neoplasia.33 The small cell lymphocytic lymphoma is by far the most common ocular lymphoma, in sharp contrast to non-Hodgkin's lymphoma found in other nodal or extranodallocations. 1 This low-grade lymphoma is also the lesion that is most difficult to distinguish from benign lymphoproliferative disorders, as noted by the reclassification in the present report and the comments of others.13·14 This tumor may represent a tissue manifestation
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of chronic lymphocytic leukemia, be associated with monoclonal gammopathy, or be observed alone in the orbit or conjunctiva. Lennert34 commented on the high frequency of orbital involvement with this type of lymphoma and believes that it may be more closely related to an "immunocytoma" than a leukemia. 35 The frequent plasma cell-like features and intracytoplasmic immunoglobulin may explain why these small cell types demonstrated the monoclonal staining pattern with immunoperoxidase in paraffin sections. 11 Other studies also support the concept that orbital and adnexal lymphomas have a more favorable prognosis than corresponding types in nodal and extranodal sites. 10 The small cell lymphomas frequently remain localized and also demonstrate this favorable prognosis. 10•11 ·30·36 Approximately 75% ofthe small cell lymphomas remain localized, but only 32% of the less well-differentiated lymphomas remain localized. 14 In our study, 32 of 39 type A lymphomas that presented only in the ocular adnexa remained confined to this area on follow-up; four of the five higher-grade lymphomas that presented only in the ocular adnexa remained confined to this region after follow-up. The management of lymphomas is complex and controversial.15·37·38 Factors that determine management include the different subgroups based on immunologic and morphologic techniques as well as the extent of the disease, the site and size of involvement, the age and symptoms of the patient, the tempo of the disease pattern, the bone marrow function, and the threat to vital organs. 39 Patiems with low-grade lymphomas in other sites generally have a long clinical evolution but are rarely cured. Increasing numbers of these patients are now being followed without treatment. Some of these patients may undergo spontaneous remission, some will develop specific indications for treatment, or some may have transformation into an intermediate or higher grade lymphoma, but many will also remain stable for prolonged periods. Patients with higher-grade lymphoma, however, more frequently have associated systemic disease and are more frequently treated. Paradoxically, the newer therapeutic regimens have obtained longer disease-free survival (but not cure) in a significant and increasing proportion of lymphoma patients with unfavorable histologic types, whereas patients with tumors offavorable histologic types frequently have an indolent clinical course and a limited response to these regimens. Ideally, patients with an orbital or conjunCtival lymphoma should be subjected to a relatively noninvasive examination, including examination for lymphadenopathy or liver and spleen enlargement, a chest roentgenogram, serum protein electrophoresis, bone marrow aspiration, and an abdominal computed tomographic scan. Until better histologic and immunologic criteria become available, patients with equivocal or apparently malignant lymphoproliferative disorders (reactive lymphoid hyperplasia and atypical lymphoid hyperplasia of Jakobiec) should be studied because they have a 15-20% chance of developing a systemic lymphoma.
In the presence of localized ocular adnexal disease, many authors recommend treatment with radiotherapy in the presence of either a monoclonal pattern or polyclonal pattern on immunoperoxidase stain. 32 Radiotherapy is touted to prevent possible metastases of the lymphoma. Because truly localized lymphocytic lymphomas are uncommon in other sites, we do not have a large amount of data from other disciplines; cure rates are dif·ficult to rely on because the disease is so- indolent that recurrences may not be evident for many years. 39 In the group with a favorable prognosis, some good (although uncontrolled and retrospective) data show that, for asymptomatic patients, delay of therapy until clinically required does not affect the ultimate prognosis in terms of response rate or survival. 38 Thus, no treatment is a rational choice in older, asymptomatic patients with a favorable histologic type; therapy is then reserved for constitutional symptoms, progression of disease, or compromise of vital organs. It is expected that many older patients may never require treatment. 37 Repeat biopsy at the time of progression is indicated because the histologic pattern may change to a more aggressive type. 40 In a younger patient, a more aggressive approach is indicated, although no substantial data are available to support this approach.39 For practical purposes it is perhaps more important to confidently identify higher grade lymphomas than to distinguish the specific nature of a small lymphocytic proliferation as benign or neoplastic. In patients with intermediate or higher grade lymphomas, in patients with rapid growth of previously indolent lymphoma, or in younger patients, a more aggressive approach is indicated with radiation or multiagent chemotherapy directed by the oncologist. 37
REFERENCES 1. The Non-Hodgkin's Lymphoma Pathologic Classification Project. National Cancer Institute sponsored study of classifications of nonHodgkin's lymphomas: summary and description of a working formulation for clinical usage. Cancer 1982; 49:2112-35. 2. Morgan G. Lymphocy1ic tumours of the orbit. Mod Probl Ophthalmol 1975; 14:355-60. 3. Knowles OM II, Jakobiec FA, Halper JP. Immunologic characterization of ocular adnexal lymphoid neoplasms. Am J Ophthalmol1979; 87: 603-19. 4. Nathwani BN, Kim H, Rappaport H. Malignant lymphoma, lymphoblastic. Cancer 1976; 38:964-83. 5. Lukes RJ. The immunologic approach to the pathology of malignant lymphomas. Am J Clin Pathol1979; 72(Suppl4):657-69. 6. Lennert K. Malignant Lymphomas: Other Than Hodgkin's Disease; Histology, Cy1ology, Ultrastructure, Immunology. New York: SpringerVerlag, 1978. 7. Harris NL, Poppema S, Data RE. Demonstration of immunoglobulin in malignant lymphomas; use of an immunoperoxidase technic on frozen sections. Am J Clin Pathol 1982; 78:14-21. 8. Warnke R. Alteration of immunoglobin-bearing lymphoma cells by fixation. J Histochem Cytochem 1979; 27:1195-6. 9. Evans HL. Extranodal small lymphocytic proliferation: a clinicopathologic and immunocytochemical study. Cancer 1982; 49:84-96.
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10. Astarita RW, Minckler D, Taylor CR, et al. Orbital and adnexal lymphomas; a multiparameter approach. Am J Clin Pathol1980; 73:61521. 11. Hara Y. Lymphoid tumors of the orbit and ocular adenxa: a clinicopathologic study of 42 cases. Jpn J Ophthalmol1982; 26:345-58. 12. Warnke RA, Gatter KC, Falini B, et al. Diagnosis of human lymphoma with monoclonal antileukocyte antibodies. N Engl J Med 1983; 309: 1275-81. 13. Knowles OM II, Halper JP, Jakobiec FA. The immunologic characterization of 40 extranodallymphoid infiltrates: usefulness in distinguishing between benign pseudolymphoma and malignant lymphoma. Cancer 1982; 49:2321-35. 14. Knowles OM II, Jakobiec FA. Orbital lymphoid neoplasms: a clinicopathologic study of 60 patients. Cancer 1980; 46:576-89. 15. Sigelman J, Jakobiec FA. Lymphoid lesions of the conjunctiva: relation of histopathology to clinical outcome. Ophthalmology 1978; 85:81843. 16. Knowles OM II, Jakobiec FA. Ocular adnexal lymphoid neoplasms: clinical, histopathologic, electron microscopic, and immunologic characteristics. Hum Pathol 1982; 13:148-62. 17. Turner RR, Egbert P, Warnke RA. Lymphocytic infiltrates of the conjunctiva and orbit: immunohistochemical staining of 16 cases. Am J Clin Pathol1984; 81:447-52. 18. Yeo JH, Jakobiec FA, Abbott GF, Trokel SL. Combined clinical and computed tomographic diagnosis of orbital lymphoid tumors. Am J Ophthalmol1982; 94:235-45. 19. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. JAm Stat Assoc 1958; 53:457-81. 20. Morgan G, Harry J. Lymphocytic tumours of indeterminate nature: a 5-year follow-up of 98 conjunctival and orbital lesions. Br J Ophthalmol 1978; 62:381-3. 21. Vogiatzis KV. Lymphoid tumors of the orbit and ocular adnexa: a long-term follow-up. Ann Ophthalmol1984; 16:1046-55. 22. Jakobiec FA, Mclean I, Font RL. Clinicopathologic characteristics of orbital lymphoid hyperplasia. Ophthalmology 1979; 86:948-66. 23. Harris NL, Pilch BZ, Bhan AK, et al. Immunohistologic diagnosis of orbital lymphoid infiltrates. Am J Surg Pathol1984; 8:83-91. 24. Taylor CR. An immunohistological study of follicular lymphoma, reticulum cell sarcoma and Hodgkin's disease. Eur J Cancer 1976; 12: 61-75. 25. Warnke R, Pederson M, Williams C, Levy R. A study of lymphoproliferative diseases comparing immunofluorescence with immunohistochemistry. Am J Clin Pathol1978; 70:867-75. 26. Tubbs RR, Sheibani K, Weiss RA, Sebek BA. Immunohistochemistry
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28.
29.
30. 31. 32.
33. 34.
35.
36.
37.
38.
39.
40.
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of fresh-frozen lymphoid tissue with the direct immunoperoxidase technic. Am J Clin Pathol1981; 75:172-4. Burns J. Background staining and sensitivity of the unlabelled antibodyenzyme (PAP) method; comparison with the peroxidase labelled antibody sandwich method using formalin fixed paraffin embedded material. Histochemistry 1975; 43:291-4. Banerjee 0, Ahmad D. Malignant lymphoma complicating lymphocytic interstitial pneumonia: a monoclonal B-cell neoplasm arising in a polyclonallymphoproliferative disorder. Hum Pathol1982; 13:780-2. Abo W, Takada K, Kamada M, et al. Evolution of infectious mononucleosis into Epstein-Barr virus carrying monoclonal malignant lymphoma. Lancet 1982; 1:1272-6. Jakobiec FA. Ocular inflammatory disease; the lymphocyte redivivus. Am J Ophthalmol 1983; 96:384-91. Chavis RM, Garner A, Wright JE. Inflammatory orbital pseudotumor; a clinicopathologic study. Arch Ophthalmol1978; 96:1817-22. Garner A, Rahi AHS, Wright JE. Lymphoproliferative disorders of the orbit: an immunological approach to diagnosis and pathogenesis. Br J Ophthalmol1983; 67:561-9. Jakobiec FA, Lefkowitch J, Knowles OM II. B- and T-lymphocytes in ocular disease. Ophthalmology 1984; 91 :635-54. Lennert K. Histopathology of Non-Hodgkin's Lymphomas (Based on Kiel Classification); Translated by Soehring M, Stansfeld AG. New York: Springer-Verlag, 1981; 46. Papadimitriou CS, MOIIer-Hermelink V, Lennert K. Histologic and immunohistochemical findings in the differential diagnosis of chronic lymphocytic leukemia of B-cell type and lymphoplasmacyticjlymphoplasmacytoid lymphoma. Virchows Arch [Pathol Anat]1979; 384:14958. Jakobiec FA, Iwamoto T, Knowles OM II. Ocular adnexal lymphoid tumors; correlative ultrastructural and immunologic marker studies. Arch Ophthalmol1982; 100:84-98. Rassiga AL. Advances in adult non-Hodgkin's lymphoma; current concepts of classification, diagnosis, and management. Arch Intern Med 1980; 140:1647-51. Portlock CS, Rosenberg SA. No initial therapy for stage Ill and IV nonHodgkin's lymphomas of favorable histologic types. Ann Intern Med 1979; 90:10-3. Rosenberg SA. Current concepts in cancer: non-Hodgkin's lymphoma-selection of treatment on the basis of histologic type. N Engl J Med 1979; 301 :924-8. Risdall R, HoppeRT, Warnke R. Non-Hodgkin's lymphoma: a study of the evolution of the disease based upon 92 autopsied cases. Cancer 1979; 44:529-42.
Abstract: Eighty-eight patients with ocular adnexal lymphoid lesions examined at the Mayo Clinic between 1970 and 1982 were evaluated. The histopathologic type was reclassified using the working formulation. Paraffin sections were evaluated with immunoperoxidase staining. There were 11 "pseudotumors" and 77 lymphomas. Sixty lymphomas were small lymphocytic type A; 27 tissues had a monoclonal staining pattern, and 4 had a polyclonal staining pattern. Five of the pseudotumors had a polyclonal staining pattern; none had a monoclonal pattern. The remainder did not stain or tissue was not available. Thirty-six of the 44 lymphomas that presented in the ocular adnexa remained localized. There were no distinguishing features between conjunctival and orbital lymphomas. Significant damage to the ocular tissue occurred in 15 of the 63 patients treated with radiation therapy. Older, asymptomatic patients with a favorable histologic type may not require treatment; therapy is reserved for specific indications. The probability of survival to five or seven years differs little from that expected in the general population. [Key words: cytoplasmic immunoglobulin, immunoperoxidase stain, lymphoma, lymphoproliferative disorder, monoclonal, polyclonal, pseudotumor, working formulation.] Ophthalmology 92:13111324, 1985
Lymphomas are solid tumors of the immune system; most are composed of (monoclonal) B cells. They arise From the Department of Ophthalmology* and the Section of Surgical Pathology,t Mayo Clinic and Foundation, Rochester, Minnesota. Presented at the Eighty-ninth Annual Meeting of the American Academy of Ophthalmology, Atlanta, Georgia, November 11-15, 1984. Supported in part by Research to Prevent Blindness, Inc. Reprint requests to Thomas J. Liesegang, MD, Department of Ophthalmology, Mayo Clinic, Rochester, MN 55905.
most commonly in the lymph nodes, but about 10 to 25% of all non-Hodgkin's lymphomas arise in extranodal sites, 1 including the orbit. The orbit and conjunctiva are frequently involved primarily or as part of a systemic lymphoma. The diagnosis and treatment oflymphoid lesions of the conjunctiva and orbit are a nemesis for both the pathologist and clinician because a benign inflammatory lesion may be difficult to distinguish from a lymphoma by histopathologic criteria alone. In extranodal sites, the usual criteria for lymphoma (for example, effacement ofpreex1311
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Table 1. Comparison of the Proposed Working Formulation With other Systems of Classification for Non-Hodgkin's Lymphoma* Working Formulation 1 Low grade (A) Small lymphocytic with or without plasmacytoid (B) Follicular, small cleaved (C) Follicular, mixed Intermediate (D) Follicular, large cell (E) Diffuse, small cleaved (F) Diffuse, mixed (G) Diffuse, large cell (FCC, not immunoblastic)
High grade (H) Large cell, immunoblastic (I) Lymphoblastic (J) Small noncleaved Others Hairy cell, mycosis fungoides, etc.
Rappaport 4 (A) Lymphocytic: B-cell T-cell T-zone Hairy cell Mycosis fundoides and Sezary cell lmmunocytomas: Lymphoplasmacytic Lymphoplasmacytoid Polymorphous (?A) Plasmacytoma (E) Centrocytic Centroblastic-Centrocytic: (B, C, D) Follicular (F) Diffuse (G) Centroblastic Lymphoblastic: (J) Burkitt's type (I) T-type lmmunoblastic: (H) B or T
(A) Well differentiated lymphocytic (plasmacytoid) (B) Nodular-poorly differentiated lymphocytic lymphoma (E) Diffuse-poorly differentiated lymphocytic lymphoma (C) Nodular-mixed (F) Diffuse-mixed (D) Nodular-histiocytic (large cell) (G, H) Diffuse-histiocytic (large cell) (I) Lymphoblastic Undifferentiated: (J) Burkitt's (G, J) Pleomorphic
*Modified from Morgan TW, Banks PM. Histopathology of Malignant Lymphomas. In: Hematology, 3rd edition, chapter 117, Williams WJ, Beutler E, Ersler AJ, Lichtman MA, eds. New York: McGraw-Hill, 1983; 1003-12.
isting nodal architecture and capsular invasion) cannot be applied, and thus evaluation is difficult. The error rate, both for the histopathologic diagnosis and the ability to predict clinical outcome, may range from 20 to 50%. 2 •3 The situation is further confused by the multiple histopathologic classification systems used over the years, including those of Rappaport (1966, modified 1976),4 LukeCollins (1974, modified 1979), 5 and Kiel (1978). 6 The working formulation ( 1982) 1 is now used by pathologists and clinicians generally to classify non-Hodgkin's lymphoma because it is based solely on histologic criteria and is of demonstrated prognostic accuracy (Table 1); it is not, however, based on immunologic characterization. Studies in immunology and genetics have opened new avenues for the study of lymphomas and also for nonneoplastic disorders of the immune system. 3 The use of monospecific or monoclonal antibodies with the immunoperoxidase stain to detect surface or cytoplasmic immunoglobulin light chains characteristic of the B-cell lymphomas was a significant advance and is performed without special equipment_1 Ideally, immunoperoxidase stain is used on fresh frozen tissue, in which even small amounts of immunoglobulin, including surface immunoglobulin, are antigenically preserved; this is in contrast to fixed paraffin sections, in which only small amounts of cytoplasmic antigen are preserved. 8 In recent years, we have used immunoperoxidase stain on fresh frozen tissue for investigation of all orbital and conjunctival lymphoproliferative disorders. The immu1312
noperoxidase technique, however, has been applied to formalin-fixed and Zenker-fixed tissue, 9- 11 and techniques are being developed to detect surface antigen that is resistant to the fixation process. 12 The purpose of this review is to apply the working formulation classification scheme, to correlate this with immunoglobulin light-chain immunoperoxidase determinations performed on paraffin sections of formalin-fixed tissues from previous cases, and to compare these findings with those in a group of patients with a known clinical outcome. Within the study period, computed tomography markedly enhanced our ability to define the site of involvement and follow the progression of the disease or response to therapy.
MATERIALS AND METHODS All patients with the pathologic diagnosis of benign or malignant lymphoid lesions of the orbit or conjunctiva who were examined at the Mayo Clinic between 1970 and 1982 were identified; 153 cases were reviewed. Patients with an acute inflammatory pseudotumor accompanied by a vasculitis were excluded because this entity is readily distinguished from lymphoma microscopically; additional cases were excluded because tissue was not available or was unsatisfactory for histologic evaluation. Hematoxylin-eosin stained sections from 88 cases were then available for reevaluation.
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Fig I. Top, definitely malignant lesion of conjunctiva exhibits only moderately dense infiltrative pattern at low magnification (left), but at high magnification (right) the lymphoplasmacytic infiltrate is recognizably abnormal due to the abundant intranuclear immunoglobulin inclusions ("Dutcher bodies"). Process was therefore classified as small lymphocytic with plasmacytoid differentiation (Working Formulation) or as immunocytoma, lymphoplasmacytic (Kiel system) (hematoxylin-eosin, left X40, right X400). Fig 2. Second row, definitely malignant lesion of orbit, recognizable as such on the basis of expansive, displacing growth pattern (left) and uniform small lymphocytic composition (right). Tumor was classified as small lymphocytic with (slight) plasmacytoid differentiation (Working Formulation) or immunocytoma, lymphoplasmacytoid (Kiel system) (hematoxylineosin, left X40, right X400). Fig 3. Third row, apparently malignant lymphoid lesion of orbit shows a solid, displacing infiltrative growth pattern (left), but at higher magnification (right) the small lymphocytic population shows some subtle heterogeneity, and rare histiocytes are interspersed. This presumed neoplasm was classified as small lymphocytic without plasmacytoid differentiation (working formulation) or lymphocytic (B-ee!!) in the Kiel system (hematoxylin-eosin, left X I 00, right X400). Fig 4. Bottom, lymphoid orbital infiltrate, equivocal in nature, is present in only a small sampling (left). Although the process is infiltrative in pattern, high magnification (right) reveals vascular proliferation and moderate cellular heterogeneity, features suggestive of an inflammatory immune response (hematoxylin-eosin, left X 100, right X400).
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The lesions were considered benign histologically (ie. Type II pseudotumor) when the cellular components were heterogeneous and appeared functional (for example, with groupings of plasma cells, with follicles, granulocytes, or with clusters of small lymphocytes). An infiltrate that did not resemble an organized immune response (that is, a dense monomorphic meaningless cellular proliferation or one composed of abnormal cell types) was interpreted as malignant. The degree of certainty was recorded because this factor was limited in some cases by small sampling, by poor cellular preservation or by the equivocal nature of the histologic appearance. The five categories of certainty were: definitely malignant, apparently malignant, equivocal, apparently benign, and definitely benign (Figs 1-6 ). Tumors classified by other investigators as "atypical lymphoid hyperplasia" 13 - 15 were classified as "apparently malignant" (Fig 3). Malignant lesions were classified according to the Working Formulation (Table 1). The Kiel classification (Table I) was also applied; this system is based primarily on morphologic traits and discriminates among variants of small lymphocytic lymphoma with or without plasmacytic differentiation. Sections from paraffin blocks were stained by a simple two-step method of immunoperoxidase staining using rabbit primary serum against kappa or lambda human lg light chains, muramidase, and albumin (Dako, Santa Barbara, CA); goat anti-rabbit lg peroxidase-conjugated serum (Tago, Burlingame, CA) was then used as the second step reagent. The paraffin sections stained with immunoperoxidase were reviewed independent of those stained with hematoxylin-eo~in. Positive controls were sections of a hyperplastic lymph node, showing both kappa- and lambda-producing plasma cells. Negative controls were sectioned from this same lymph node in which nonimmunized rabbit serum was substituted for the anti-kappa or anti-lambda primary serum. Each case was also studied for the presence of human albumin, as a control for the passive presence of plasma proteins, which might be a basis for misinterpretation of (polyclonal) immunoglobin. lmmunostained preparations were interpreted as monoclonal (monotypic) when the normal 2: I kappa: lambda ratio of light chain staining was definitely not maintained, ie. by a deviation of greater than 4: 1 or less than I :2 ratios (Fig 7). This finding of monoclonality was interpreted as such, only when staining plasmacytic or plasmacytoid cells were dispersed throughout the lymphoid infiltrate and therefore presumably representative of the process itself. Preparations were considered polyclonal (polytypic) when the kappa:lambda ratio was between 4: 1 and 1:2, and when the anti-albumin control preparation demonstrated that the light chains which stained did not correspond to passively present plasma proteins (Fig 8). The clinical presentation, treatment, and course were documented by reviewing the records which included recent correspondence with the patients or their physicians. Computed tomography scanning became available during this time and was extremely helpful in establishing the location and extent of the lymphoproliferative disorder. 1314
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The clinical review was conducted independent of the pathologic review.
RESULTS Of the 88 cases included in the study, 60 (68%) were originally interpreted as malignant; after review, however, 77 (87%) were considered to be malignant using the histopathologic criteria of the working formulation (Table 2). Among the 88 cases, 59 originally diagnosed as lymphoma were confirmed as lymphoma (55 definite, 2 apparent, 2 equivocal), but one case was reclassified as a pseudotumor (definitely benign). Of the 59 lymphomas, 42 were diffuse small lymphocytic lymphomas (type A). Of the 38 considered to be definitely malignant, 17 had a monoclonal immunoperoxidase reaction ( 11 with lambda and 6 with kappa), 1 had a polyclonal reaction, and 16 had no immunoperoxidase staining; in 4 no tissue was available for immunoperoxidase staining. Two tissues were apparently malignant type A (absent stain in both), and two were equivocal for malignant type A (one polyclonal stain and one absent stain). The remainder of the lymphomas were low grade (four type B and four type C) or intermediate grade (one type D, three type E, four type F, and one type G). There were no high-grade lymphomas. Four of the lymphomas that were not type A had a monoclonal staining pattern, but none had a polyclonal staining pattern. The reclassified pseudotumor from the original group of malignant lymphomas had a polyclonal staining pattern (Fig 8). Eighteen cases originally classified as a benign lymphoproliferative disorder (that is, pseudotumor, lymphoproliferative disorder, lymphoid hyperplasia, and atypical lymphoid hyperplasia) were reclassified as lymphoma. In this group, all 18 were classified as type A lymphoma ( 12 definite and 6 apparent). Of the 12 definitely malignant lesions, 4 had a monoclonal pattern; of the 6 apparently malignant lesions, 2 had a monoclonal pattern and 1 had a polyclonal pattern. Ten cases originally considered to be pseudotumor were confirmed as benign (9 definite and 1 apparent); 4 of these had a polyclonal staining pattern; none had a monoclonal pattern. Thus, in this series of 88 cases, 77 (87%) were diagnosed histomorphologically as lymphomas, and 60 (78%) of these were type A lymphomas. A monoclonal immunoperoxidase response was noted in 27 cases. A polyclonal immunoperoxidase response was seen in eight cases, and three of these were in patients with a histopathologic diagnosis of lymphoma. The clinical signs in this ~eries, as in others, 16 •17 were not sufficient to distinguish a benign process from a lymphoma. Patients presented similarly with proptosis, an orbital or conjunctival mass, swelling of the lids, diplopia, tearing, pain, and visual difficulty. Of the 88 patients, 34 were males and 54 were females. The age at onset ranged from 7 to 94 years (mean, 59 years). The age range of the patients with a diagnosis oflymphoma was 17 to 94 years
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Fig 5. Top, apparently benign orbital infiltrate exhibits infiltration of fatty tissue (left), but with extreme cellular heterogeneity (right). There are zones of plasma cells, lymphocytes, and histiocytes, features of an organized (benign) immune response (hematoxylin-eosin stain, left X 100, right X400). Fig 6. Second row, definitely benign orbital infiltrate manifests only scant, scattered infiltrates amidst edematous, fibrotic muscular tissues (left). High magnification (right) reveals clusters of small lymphocytes with conspicuous zones of plasma cells (left side of field) (hematoxylin-eosin, left X I 00, right X400). Fig 7. Third row, definite monotypic Ig light chain staining marks a lymphoplasmacytic process as containing monoclonal immunoglobulin and, therefore, as a neoplasm (same case as in Figure 1). Left, positive among most cells for kappa; Right, only a few scattered plasma cells are positive for lambda (hematoxylin nuclear counterstain; ethylcarbazole color reagent; X400). Fig 8. Bottom, polytypic Ig light chain immunostaining in a benign orbital lymphocytic infiltrate (same case as in Figure 6). In both kappa (left) and lambda (right) preparations, a moderate proportion of the plasma cells and lymphoplasmacytic cells stain, marking the process as polyclonal Ig-producing (hematoxylin nuclear counterstain; ethylcarbazole color reagent; X400).
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Table 2. Comparison of Original Diagnoses with Current Diagnoses in 88 Cases of Lymphoid Lesions of the Ocular Adnexa
Original Diagnosis* 60 "Malignant" lymphoma
18 "Benign lymphoproliferative disease"
Current Diagnosist Based on Working Formulation
Current Diagnosis Based on Kiel Classification 6 16 Lymphoplasmacytoid 17 Lymphoplasmacytic 1 Plasmacytomajlymphoplasmacytoid 1 Follicular 7 Follicular/chronic lymphocytic
42 Type A, 38 definite, 2 apparent, 2 equivocal
lmmunostaining Response 17 Monoclonal, 11 lambda, 6 kappa 1 Polyclonal 4 No tissue 16 Absent tissue 2 Absent stain 1 Polyclonal 1 Absent stain
4 Follicular
4 Type B, 4 definite
2 Absent stain 2 No tissue
3 Follicular 1 Lymphoplasmacytoid
4 Type C, 4 definite
2 Absent stain 2 No tissue
1 Follicular diffuse centroblastic
1 Type D, definite
1 Monoclonal (lambda)
2 Follicular 1 Diffuse centroblastic
3 Type E, 3 definite
3 Absent stain
1 Follicular 2 Diffuse mixed 1 Centroblasticjcentrocytic
4 Type F, 4 definite
2 Absent stain 2 Monoclonal (kappa)
1 Follicular
1 Type G, 1 definite 1 (Pseudotumor type II), 1 definite
1 Monoclonal (lambda) 1 Polyclonal
6 Lymphoplasmacytoid 1 Lymphoplasmacytic 11 Follicular/chronic lymphocytic
18 Type A, 12 definite
12 Inflammatory pseudotumor Type II
4 Monoclonal, 3 lambda, 1 kappa 5 Absent stain 3 No tissue
2 Atypical lymphoid hyperplasia 3 Lymphoproliferative disorder 1 Pseudolymphoid hyperplasia
6 Apparent
2 Monoclonal, 1 lambda, 1 kappa 1 Polyclonal 1 Absent stain 2 No tissue
10 Inflammatory pseudotumor type II
10 inflammatory pseudotumor type II, 9 definite, 1 apparent
4 Polyclonal 5 No tissue 1 No stain
* The system of Rappaport 4 was generally used to determine this diagnosis.
t Diagnosis was based on the working formulation. 1
(mean, 62 years). The age range of those with a diagnosis of a benign lymphoproliferative disorder was 7 to 70 years (mean, 41 years). The duration of follow-up of the 88 patients ranged from 1 to 173 months (mean, 57 months). Among the 77 patients with a histopathologic diagnosis of lymphoma, 36 had localized ocular disease without ever developing systemic lymphoma (Table 3). In this group of 36 patients, 32 had type A lymphoma, 1 type B, 1 type E, and 2 type F. In 41 patients systemic lymphoma developed at some time during the course of disease; 8 of these patients presented with ocular adnexal lymphoma and later developed systemic disease, 18 had systemic 1316
lymphoma prior to the ocular disease; and 15 patients had simultaneous systemic and ocular lymphoma. One patient with a histopathologic diagnosis of pseudotumor and a polyclonal immunoperoxidase reaction developed systemic lymphoma. Although computed tomography shows a highly characteristic picture with a distinctive growth pattern and contouring, no radiographic feature distinguishes histologically benign from malignant disorders. 18 On the basis of clinical examination and radiographic evaluation, the ocular lymphomas were confined to the orbit in 43 patients, to the lacrimal gland in 5, and to the
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Table 3. Occurrence of Systemic Lymphoma in 77 Patients with Ocular Lymphoma Type of Lymphoma (working formulation 1), no. Patients
No. Patients Dead
No. Patients Alive With Lymphoma
Without Lymphoma
Unknown Cause
2
2
Mean Follow-up (months)
Without Recurrence
With Recurrence
32 1 1 2
25
3 1
8
A, 7 D, 1
2
5
84 14
Systemic lymphoma simultaneous with ocular adnexal lymphoma
15
A, 8 B, 3 C, 1 E, 2 G, 1
4
2 2 1 1 1
44 57 30 25 25
Systemic lymphoma prior to ocular adnexal lymphoma
18
A, 13 C, 3 F, 2
5 2 1
6 1 1
Disease Pattern
No. Patients
Localized to ocular adnexa
36
Systemic lymphoma after ocular adnexal lymphoma
Total
77
A, B, E, F,
2
42
conjunctiva in 21 patients and presented in both the orbit and conjunctiva in 8 (Table 4). The benign lymphoproliferative disorders occurred in the orbit or lacrimal gland (Table 4). Specific note should be made of the absence of benign conjunctival lesions and of the one benign pseudotumor involving the lacrimal gland that was associated with a systemic lymphoma. We did not find sufficient reason to consider these sites separately; thus, these sites were considered together on further analysis. Bilateral ocular adnexal disease occurred in 18 patients, all of whom had lymphoma ( 17 definite and 1 apparent) (Table 5). Eleven patients had bilateral disease in the conjunctiva, three in the orbit, one in the lacrimal gland, and three in both the orbit and conjunctiva. Nine cases remained localized to the ocular tissues and nine were part of a prior or simultaneous systemic lymphoma. Among these bilateral cases, 16 were type A, 1 type B, and 1 type E. The follow-up data are listed in Table 5. Bilateral disease did not necessarily presage systemic disease, and only four of these patients died of lymphoma. Seventeen patients had a systemic illness other than lymphoma (Table 6). Two patients had chronic lymphocytic leukemia; one of these patients had the leukemia 16 years prior to lymphoma and one patient had the leukemia just prior to the onset of lymphoma. Both of these lymphomas were type A. Three patients had Sjogren's syndrome; one of these patients had the disease three years prior to the diagnosis of lymphoma and the other two had it after lymphoma had been diagnosed. Two of the patients with Sjogren's syndrome had orbital lymphoma and one had conjunctival lymphoma. Three patients had macroglobulinemia; two of these patients had the disease
6
19
2 1 4
65 84 97 80
53 32 52
6
three to seven years prior to lymphoma, and one had it five years after the diagnosis of lymphoma. The patient with Wegener's granulomatosis had no ocular adnexal involvement from the disease and had type A lymphoma of both the conjunctiva and the orbit. Prior radiation had been used in three patients (for previous cancer) and prior chemotherapy in one patient (for leukemia). Previous ocular diseases were absent in all but one of the patients; in 1969, this patient had a conjunctival biopsy and a benign lymphoproliferative disorder (recently confirmed) was diagnosed and in 1972 had a conjunctival biopsy and type A lymphoma (definite) diagnosed. This latter tissue did not stain with immunoperoxidase. The patient is presently alive without recurrent disease but has systemic lymphoma. Serum protein electrophoresis was performed in 23 patients. A normal pattern was found in 13 patients, a monoclonal pattern in 8, and a polyclonal pattern in 2 (Table 7). The monoclonal pattern appears indicative of a systemic disease. Eight patients with systemic disease still demonstrated a normal pattern, and two patients with systemic disease demonstrated a polyclonal pattern. Table 8 correlates the results of the immunoperoxidase staining with the pattern of disease, histopathologic diagnosis, and the clinical outcome in the total series of 88 patients (including the 11 with benign lymphoproliferative disorders). Monoclonal staining was demonstrated in 27 patients from the paraffin-embedded sections, and in all instances correlation was made with the histologic diagnosis of lymphoma. Lymphoma-related deaths occurred in six patients (five type A, one type G). Eight polyclonal patterns were identified, and these correlated with a benign 1317
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Table 4. Site of Disease in 88 Patients with Lymphoid Lesions of the Ocular Adnexa
Site
Location
No. Patients
Localized Superior Inferior Systemic Superior Inferior & other
22 14 8 21 13 8
Ocular lymphoma (77 patients) Orbit alone
43
Lacrimal gland
5
Conjunctiva alone
Localized Systemic
21
Both orbit and conjunctiva
1 4
Localized Superior Inferior & other Systemic Superior Inferior & other Localized Superior Inferior & other Systemic Superior Inferior & other
8
9 2 7 12
6 6
4
0
4 4 2 2
Benign lymphoproliferative disorder Orbit
8
Lacrimal gland
3
Localized Superior Inferior & other
3
Localized Systemic
2 1
•
NUMBER 10
histopathologic diagnosis in five and with a diagnosis of lymphoma in three. In these three lymphoma cases, the histopathologic diagnosis was independent of the immunologic staining pattern and was interpreted as definitely malignant in one, apparently malignant in one, and equivocal in one. The clinical course was benign in all three. In 35 patients, no staining was demonstrable with the immunoperoxidase technique on paraffin-embedded sec Lions, and in 18 patients no additional tissue was available for immunoperoxidase stain. With the use of paraffinembedded immunoperoxidase staining, the clinical courses did not differ significantly between those patients whose tissues stained or failed to stain with immunoperoxidase if the patients had the same histopathologic diagnosis. Polyclonality, however, was correlated with a good prognosis in the patients identified. The clinical outcomes of these 88 patients, followed for a mean of 57 months, are as follows: 50 patients are alive without recurrence, 8 had a local ocular recurrence of the disease, and 18 died of lymphoma. Among the 18 patients who died, I3 were type A, 2 type B, 2 type C, I type E, and I type G. The effects of treatment on the clinical outcome are shown in Tables 9 through I2 according to the results of immunoperoxidase staining and the histopathologic diagnosis. Treatment consisted of radiation alone in 43 patients, chemotherapy alone in 9, combined radiation and chemotherapy in 20, and neither radiation nor chemotherapy in 16. Of the 16 patients who were not treated, 6 has pseudotumors and 10 had type A lymphomas. The treatment was usually directed by the physician in the lymphoma clinic at our institution. In general, chemotherapy was recommended for systemic disease, radiation for localized ocular adnexal disease, and a combination of treatment when both ocular and systemic disease compromised function. In more recent years, no treatment has been given for localized low-grade lymphomas. For
Disease Pattern and Ocular Adnexal
No. Patients with
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5
Table 5. Prognosis of 18 Patients with Bilateral Ocular Adnexal Disease
Site Orbit Conjunctiva
No. Patients
Presence of Systemic Lymphoma (pattern), No. Patients
Type of Lymphoma, No. Patients
3
1° + 2°, 3
A, 3
+ 20 or 2° _, 1°,4
A,9 B, 1 E, 1
11
10
Lacrimal gland
1
1° _, 2°' 1
A, 1
Both orbit and conjunctiva
3
1° + 2°' 1
A, 3
Total
18
No. Patients Alive Without Recurrence
With Recurrence
No. Patients Dead With Lymphoma
Without Lymphoma
Unknown Cause
1 5 1
2
7
4
4
2
1o = ocular lymphoma; 2° = systemic lymphoma; 1o _, 2° = ocular lymphoma preceded systemic lymphoma; 2° _, 1o = systemic lymphoma preceded ocular lymphoma; 1o + 2° = simultaneous occurrence.
I3I8
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Table 6. Associated Systemic Disease in 88 Patients With Lymphoid Lesions of the Ocular Adnexa Systemic Disease
No. Patients
Chronic lymphocytic leukemia Prior to lymphoma Sjogren's syndrome Prior to lymphoma After lymphoma Macroglobulinemia Prior to lymphoma After lymphoma Systemic lupus* Wegener's granulomatosist Lung sarcomat Adenocarcinoma, abdomen* Prostate carcinomat Sphenoid ridge meningiomat Cancer of esophagust Herpes zostert
2 2 3 1 2 3 2 1 1 1 1 1 1 1 1 5
* Disease developed after diagnosis of lymphoma. t Disease developed prior to diagnosis of lymphoma.
Table 7. Serum Protein Electrophoresis Pattern in 23 Patients No. Patients
No. Patients with System Disease
13
8
A, 7 B, 2 C, 2 E, 1 F, 1
Monoclonal
8
8
A, 7 F, 1
Polyclonal
2
2
A, 2
Pattern Normal
Type, No. Patients
the management of pseudotumors at our institution, radiation therapy is reserved for disease not responding to systemic steroids. These guidelines were not strictly followed with these patients because of an erroneous original diagnosis, different interpretations of the information, or change in philosophies among the treating physicians.
Table 8. Correlation of lmmunoperoxidase Staining, Histopathologic Diagnosis, Clinical Features, and Outcome in 88 Patients with Lymphoid Lesions of the Ocular Adnexa Results of lmmunoperoxidase Staining, No. Patients Monoclonal, 27 Kappa, 10 Lambda, 17
Polyclonal, 8
No. Patients Alive Pattern of disease, No. Patients
Total, 88
Without Recurrenee
A, 11 F, 1
73 41
10 1
Systemic lymphoma, 25
A, 12 D, 1 F, 1 G, 1
56 14 92 25
5
Localized, 7
Pseudotumor, 4 A, 3 Pseudotumor, 1
21 28 23
4 2
A, 13 B, 1 E, 1 F, 1 Pseudotuinor, 1 A, 12 B, 1 C, 2 E, 2 F, 1
79 84 97 118 82 59 20 42 38 11
10
A, 5 Pseudotumor, 5 A,4 B, 2 C, 2
54 27 73 75 27 Mean 57
3 5 2
Localized, 17
Systemic lymphoma, 18
No tissue available, 18
Mean Follow-up (Months)
Localized, 12
Systemic lymphoma, 1 Absent staining, 35
Type (working fomulation), No. Patients
Localized, 10 Systemic lymphoma, 8 Systemic disease, 42
With Recurrenee
With Lymphoma
Without Lymphoma
Of Unknown Cause
5
2
1 1 3
50
No. Patients Dead
6 1 1 1
2 1 1 8
18
5
7
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Table 9. Results of Treatment in 27 Patients with Monoclonal Staining* Dead
Alive
<
8 (1°) 9A 1 W + 2o) 1FW)
Radiation alone, 14 Radiation and chemotherapy, 8
2 (2° _, 1°) 4A(2 W + 2o) 1F (2° _, 1°)
No treatment, 3
2A (1 °)
From Lymphoma
With Ocular Recurrence
Without Ocular Recurrence
Treatment, No. Patients
Unknown Cause
1A (2° _, 1°) 1D
w _, 2°)
1AW) 1A (1 o _, 2°) 1G W + 2°)
Chemotherapy alone, 2
0
6
3
17
27
Total
Without Lymphoma
* 1o = ocular lymphoma; 1o _, 2° = ocular lymphoma preceded systemic lymphoma; 2° _, 1o = systemic lymphoma preceded ocular lymphoma; 1o + 2o = simultaneous occurrence.
Seven deaths occurred in the group of 43 patients treated with radiation alone; four deaths occurred in the group of nine treated with chemotherapy alone; seven deaths occurred in the group of 20 patients treated with irradiation and chemotherapy; and no deaths occurred in the 16 patients treated with neither radiation nor chemotherapy. When Kaplan-Meier actuarial techniques 19 are used to examine the expected versus the observed probability of survival in our group of patients, several concepts about this disease entity emerge. When all 60 ocular adnexal type A lymphomas are combined, the probability of survival to five or seven years is not much less than that expected in a comparative general population. The probability is better than that for type A lymphomas reported from other nodal or extranodal sites, as garnered from the National Cancer Institute's statistics, 1 although not statistically significant (Fig 9). When we further compared the probability of survival in patients with type A lym-
phoma of the orbit with that of patients with disease in the conjunctiva with the use of the same Kaplan-Meier methods and chi-squared two-tailed tests, there was no significant difference in survival. We therefore conclude, on the basis of several analyses in our study, that there was essentially no reason to differentiate conjunctival from orbital lymphomas. We could not demonstrate a significant difference in survival among patients who demonstrated a monoclonal pattern in paraffin-embedded sections from those who also had lymphoma but whose tissues did not stain or in whom no tissues were available for staining. Ocular complications of radiation therapy occurred in 15 (23%) of the 63 patients treated with this method, in spite of described efforts directed toward ocular shielding. All received between 1000 and 4000 rad; complications included cataracts (8 patients), radiation keratitis (2), keratitis sicca (3), radiation retinopathy (2), ptosis and madarosis (2), and orbital fat atrophy (1); some patients had
Table 10. Results of Treatment in Eight Patients with Polyclonal Staining* Dead
Alive Treatment, No. Patients
Without Ocular Recurrence
With Ocular Recurrence
Radiation alone, 2 Radiation and chemotherapy, 1 No treatment, 4 Chemotherapy alone, 1
1A (1 °)
1AW)
Total
8
1AW) 3A (1°) 1A (1 °)
6
* 1o = ocular lymphoma; 1o + 2° = simultaneous occurence.
1320
From Lymphoma
Without Lymphoma
Unknown Cause
Pseudo tumor (1 o + 2°)
0
0
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LYMPHOID TUMORS OF THE OCULAR ADNEXA
Table 11. Results of Treatment in 35 Patients with Absent Staining* Alive Without Ocular Recurrence
Treatment, No. Patients
Radiation and chemotherapy, 9
1(1 °) 3A 1(2o _, 1o) 1po _, 2°)
No treatment, 2
1AW)
Chemotherapy alone, 4
1E W + 2°) 1 Pseudotumor
Total
With Ocular Recurrence
10A 2(2o _, 1o) 8(1 °) 1F (2° _, 1°)
Radiation alone, 20
35
Dead From Lymphoma (1 0 _, 20) 3A (2o _, 1o) + 2°)
18W)
w
(10 _, 20) 2A (2o _, 1o) 18W+2°) 1CW+2°)
With Lymphoma
Unknown Cause
1EW) 1A (1 °)
2Wl 3A (2o _, 1o)
1A W + 2°)
1C (2° _, 1°)
1F{2°_,1°) 1A (2° _, 1°) 1E W + 2°)
9
17
3
5
* 1o = ocular lymphoma; 1o __, 2° = ocular lymphoma preceded systemic lymphoma; 2° _, 1o = systemic lymphoma preceded ocular lymphoma; 1o + 2° = simultaneous occurrence.
more than one complication. The larger doses of radiation were associated with the more severe complications, and several patients had significantly limited vision as a result ofthis form oftherapy.
DISCUSSION Studies have emphasized that benign and malignant lymphoproliferative disorders cannot be distinguished by clinical examination alone, 16 and others9•20•21 have found it impossible to make a definitive diagnosis even with histopathologic examination and believe that it can be concluded only after prolonged follow-up. The question of whether the ocular tissues can be the primary site of malignant lymphoma or merely an atypical presentation of systemic lymphoma continues to be debated. In this series,
it was evident that many tumors remain localized and did not extend beyond the confines of the orbit. Some investigators have suggested that the natural histories of conjunctival and orbital lymphoid lesions differ. 16 Conjunctival tissues normally contain lymphoid tissue and are more likely to develop a localized benign lymphoid reaction. The orbit lacks the normal architecture of a lymph node; thus, lesions in this region cannot be compared with normal lymphoid structures. Benign pathologic processes of the conjunctiva are reported to have a higher incidence and a good prognosis-only 10% are associated with systemic lymphoma. 15 Orbital lymphomas apparently have a higher incidence (up to 50%) of association with systemic lymphomas. 14 Sigelman and Jakobiec 15 believe that current histopathologic criteria can be used to predict the clinical outcome of patients with conjunctivallymphoproliferative disorders better than for
Table 12. Results of Treatment in 18 Patients with No Tissue Available for Staining* Dead
Alive Without Ocular Recurrence
Treatment, No. Patients
With Ocular Recurrence
From Lymphoma
w
Radiation alone, 7
4AW)
18 + 2°) 1A (2° _, 1°)
Radiation and chemotherapy, 2
1C{2°-1°)
1A (2° __, 1°)
No treatment, 7
5 pseudotumor 1AW)
Chemotherapy alone, 2
1C{2°_,1°)
Total
18
12
Without Lymphoma
Unknown Cause 18
w + 2°)
1AW) 1A (1 °) 3
* 1o = ocular lymphoma; 2° _, 1o = systemic lymphoma preceded ocular lymphoma; 1o + 2° = simultaneous occurrence.
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OCTOBER 1985 •
100
80
Probability of surviving at least until timet,
Ocular adnexal 60
(n=60)
40
Other extranodal s1tes (n=41)
% 20
0'----'---'---'-------'---'---'----' 0
2
3
4
5
6
Years (t) from onset of symptoms
MAYO ©t984 86.5781
Fig 9. Kaplan Meier survival curve showing expected vs. observed probability of survival in patients with Type A ocular adnexal lymphoma. Comparison is made with Type A lymphomas in other sites as compiled by the National Cancer Institute.'
those with orbitallymphoproliferative disorders. Benign conjunctival lesions tend to have a pebbly, multinodular, and minimally elevated clinical appearance, whereas malignant conjunctival tumors are more likely to be smooth, larger, and more elevated and more apt to involve the orbit. These authors are more cautious in diagnosing lymphoma in the conjunctiva; it is interesting that followup data in their patients indicate that several lesions eventuated in systemic lymphoma. There is evidence that the percentage of patients with systemic lymphoma varies directly with the histologic type oflymphoma (that is, the degree of cytologic atypia). 16 In other series oflymphoproliferative disorders of ocular tissues, 25% orwell-differentiated small cell lymphomas and 68% ofless well-differentiated lymphomas were associated with systemic lymphoma; yet reactive lymphoid hyperplasia and atypical lymphoid hyperplasia were also associated with the eventual onset of systemic lymphoma in from 15 to 29%, respectively. 14·22 Our data represent an attempt to approach these questions from a conventional perspective, as has been applied to malignant lymphomas per se, without considerations specific to ocular lymphomas. Along with other authors, 20·23 we prefer general terms such as "apparent" or "equivocal" rather than specific terms such as "atypical lymphoid hyperplasia" or "reactive hyperplasia" because "atypia" and "reactive" implied a worrisome nature or known pathogenesis. Using these criteria to define lymphoma histologically, we did not find a more benign pattern for conjunctivallymphoproliferative disorders than for orbitallymphoproliferative disorders, and we observed subsequently the development of systemic lymphoma in a similar proportion of both groups. The working formulation, as established by the National Cancer Institute sponsored study for the classification of non-Hodgkin's lymphomas, is based on morphologic findings alone and does not depend on immunologic findings. 1The availability of immunologic surface 1322
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markers is of unquestioned use in the resolution of equivocal cases. The immunoperoxidase technique developed by Sternberger and adapted for paraffin section study of lymphomas by Taylor 24 resulted in frequent false-negative results. 25 This is attributed to denaturization or elution of surface immunoglobulin-differentiation antigens from the cell surface during fixation and paraffin embedding. 8•25 Frozen section immunoperoxidase staining is more sensitive than paraffin-embedded immunoperoxidase staining for the detection of immunoglobulin, 26 although paraffin sections do allow simultaneous histologic resolution, which may be important when small samples are used. The purpose of our study was to use the immunoperoxidase-staining techniques to correlate the histologic diagnosis in cases in which the clinical outcome was known. The ocular tissues may be especially suited to the immunoperoxidase technique in paraffin-embedded tissue because of the high incidence of plasma cell differentiation in these tissues with a large amount of cytoplasmic immunoglobulin that could potentially be detected. 9·10 •27 Distinction between cytoplasmic or surface-staining immunoglobulin is not possible with the immunoperoxidase technique. Monoclonality or polyclonality are not in themselves absolute prognostic indicators. The patients with polyclonal staining in the present series did predictably well, and those with monoclonal staining had a poorer prognosis. Although monoclonality is a characteristic of malignancy, growing evidence shows that localized lymphoproliferative disorders in extra-nodal sites can be polyclonal in demonstrable immunostaining.Z8•29 Further, such hyperplastic polyclonallesions may proceed on occasion to yield a monoclonal lymphoma (up to 29%)9·30 as a result of subsequent progression or mutation, or the lymphoma may simply be part of a mixed benign and malignant process. Jakobiec 30 suggested that patients with benign lymphoproliferative disorders of the ocular adnexa may be manifesting a breakdown in immunoregulation and that this could further erode and manifest with a preneoplastic or paraneoplastic condition or, later, lymphoma. An increase in immature forms has been observed in patients with repeat orbital biopsies who have lymphoproliferative disorders. 31 New hybridoma monoclonal antibody techniques are being developed to antigens other than immunoglobulin determinants that may permit better segregation of the subsets of ocular B-celllymphoproliferative disorders that are peculiar to ocular adnexal tissue and further elucidate those associated with systemic disease. 32 Other studies are focusing on T -lymphocytic subsets and their role in immunoregulation and neoplasia.33 The small cell lymphocytic lymphoma is by far the most common ocular lymphoma, in sharp contrast to non-Hodgkin's lymphoma found in other nodal or extranodallocations. 1 This low-grade lymphoma is also the lesion that is most difficult to distinguish from benign lymphoproliferative disorders, as noted by the reclassification in the present report and the comments of others.13·14 This tumor may represent a tissue manifestation
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LYMPHOID TUMORS OF THE OCULAR ADNEXA
of chronic lymphocytic leukemia, be associated with monoclonal gammopathy, or be observed alone in the orbit or conjunctiva. Lennert34 commented on the high frequency of orbital involvement with this type of lymphoma and believes that it may be more closely related to an "immunocytoma" than a leukemia. 35 The frequent plasma cell-like features and intracytoplasmic immunoglobulin may explain why these small cell types demonstrated the monoclonal staining pattern with immunoperoxidase in paraffin sections. 11 Other studies also support the concept that orbital and adnexal lymphomas have a more favorable prognosis than corresponding types in nodal and extranodal sites. 10 The small cell lymphomas frequently remain localized and also demonstrate this favorable prognosis. 10•11 ·30·36 Approximately 75% ofthe small cell lymphomas remain localized, but only 32% of the less well-differentiated lymphomas remain localized. 14 In our study, 32 of 39 type A lymphomas that presented only in the ocular adnexa remained confined to this area on follow-up; four of the five higher-grade lymphomas that presented only in the ocular adnexa remained confined to this region after follow-up. The management of lymphomas is complex and controversial.15·37·38 Factors that determine management include the different subgroups based on immunologic and morphologic techniques as well as the extent of the disease, the site and size of involvement, the age and symptoms of the patient, the tempo of the disease pattern, the bone marrow function, and the threat to vital organs. 39 Patiems with low-grade lymphomas in other sites generally have a long clinical evolution but are rarely cured. Increasing numbers of these patients are now being followed without treatment. Some of these patients may undergo spontaneous remission, some will develop specific indications for treatment, or some may have transformation into an intermediate or higher grade lymphoma, but many will also remain stable for prolonged periods. Patients with higher-grade lymphoma, however, more frequently have associated systemic disease and are more frequently treated. Paradoxically, the newer therapeutic regimens have obtained longer disease-free survival (but not cure) in a significant and increasing proportion of lymphoma patients with unfavorable histologic types, whereas patients with tumors offavorable histologic types frequently have an indolent clinical course and a limited response to these regimens. Ideally, patients with an orbital or conjunCtival lymphoma should be subjected to a relatively noninvasive examination, including examination for lymphadenopathy or liver and spleen enlargement, a chest roentgenogram, serum protein electrophoresis, bone marrow aspiration, and an abdominal computed tomographic scan. Until better histologic and immunologic criteria become available, patients with equivocal or apparently malignant lymphoproliferative disorders (reactive lymphoid hyperplasia and atypical lymphoid hyperplasia of Jakobiec) should be studied because they have a 15-20% chance of developing a systemic lymphoma.
In the presence of localized ocular adnexal disease, many authors recommend treatment with radiotherapy in the presence of either a monoclonal pattern or polyclonal pattern on immunoperoxidase stain. 32 Radiotherapy is touted to prevent possible metastases of the lymphoma. Because truly localized lymphocytic lymphomas are uncommon in other sites, we do not have a large amount of data from other disciplines; cure rates are dif·ficult to rely on because the disease is so- indolent that recurrences may not be evident for many years. 39 In the group with a favorable prognosis, some good (although uncontrolled and retrospective) data show that, for asymptomatic patients, delay of therapy until clinically required does not affect the ultimate prognosis in terms of response rate or survival. 38 Thus, no treatment is a rational choice in older, asymptomatic patients with a favorable histologic type; therapy is then reserved for constitutional symptoms, progression of disease, or compromise of vital organs. It is expected that many older patients may never require treatment. 37 Repeat biopsy at the time of progression is indicated because the histologic pattern may change to a more aggressive type. 40 In a younger patient, a more aggressive approach is indicated, although no substantial data are available to support this approach.39 For practical purposes it is perhaps more important to confidently identify higher grade lymphomas than to distinguish the specific nature of a small lymphocytic proliferation as benign or neoplastic. In patients with intermediate or higher grade lymphomas, in patients with rapid growth of previously indolent lymphoma, or in younger patients, a more aggressive approach is indicated with radiation or multiagent chemotherapy directed by the oncologist. 37
REFERENCES 1. The Non-Hodgkin's Lymphoma Pathologic Classification Project. National Cancer Institute sponsored study of classifications of nonHodgkin's lymphomas: summary and description of a working formulation for clinical usage. Cancer 1982; 49:2112-35. 2. Morgan G. Lymphocy1ic tumours of the orbit. Mod Probl Ophthalmol 1975; 14:355-60. 3. Knowles OM II, Jakobiec FA, Halper JP. Immunologic characterization of ocular adnexal lymphoid neoplasms. Am J Ophthalmol1979; 87: 603-19. 4. Nathwani BN, Kim H, Rappaport H. Malignant lymphoma, lymphoblastic. Cancer 1976; 38:964-83. 5. Lukes RJ. The immunologic approach to the pathology of malignant lymphomas. Am J Clin Pathol1979; 72(Suppl4):657-69. 6. Lennert K. Malignant Lymphomas: Other Than Hodgkin's Disease; Histology, Cy1ology, Ultrastructure, Immunology. New York: SpringerVerlag, 1978. 7. Harris NL, Poppema S, Data RE. Demonstration of immunoglobulin in malignant lymphomas; use of an immunoperoxidase technic on frozen sections. Am J Clin Pathol 1982; 78:14-21. 8. Warnke R. Alteration of immunoglobin-bearing lymphoma cells by fixation. J Histochem Cytochem 1979; 27:1195-6. 9. Evans HL. Extranodal small lymphocytic proliferation: a clinicopathologic and immunocytochemical study. Cancer 1982; 49:84-96.
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