Reticulum cell sarcoma (histiocytic lymphoma) of the orbit

SURVEY OF OPHTHALMOLOGY VOLUME 22 . NUMBER 4-JANUARY-FEBRUARY 1978

CLINICAL PATHOLOGICAL REVIEW MILTON M . BONIUK, EDITOR

Reticulum Cell Sarcoma (Histiocytic Lymphoma) of the Orbit FREDERICK A. JAKOBIEC, M .D., PAMELA WILLIAMS, M .D . AND MARIANNE WOLFF, M .D . The Edward S. Harkness Eye Institute and the Department of Surgical Pathology, Columbia-Presbyterian Medical Center, New York, New York

Abstract . The clinical and pathologic features of 13 patients with biopsy-proven reticulum cell sarcoma of the orbit are reviewed . All of the patients were adults, in contrast to many previous reports that have emphasized how common this tumor is in children . Eight patients presented with proptosis and without prior diagnosis of lymphoma, and 5 patients developed orbital deposits in the course of a known systemic lymphoma . Of the 8 patients whose orbital biopsies established the diagnosis, 4 were found concomitantly to have other sites of disease, and 4 patients developed other evidence of lymphoma from 2 to 15 months after orbital biopsy . None of the cases in this series was interpreted as a primary orbital lymphoma . The histopathologic findings, the problem of histogenesis, and the need for systemic staging of cytologically malignant orbital lymphoma are discussed (Sure Ophthalmol 22 :255-270, 1978) Key words . histiocytic lymphoma ' lymphoma lymphoreticular neoplasms - orbit - reticulum cell sarcoma he diagnosis and prognosis of lymphoid lesions of the orbit present vexing problems for both the clinician and the pathologist . Many lesions fall into a "gray zone" because they are composed of cells without frankly neoplastic cellular detail .s' , aa'as Even for those lesions that are composed of cytologically malignant cells, the data are sparse regarding outcome and especially regarding the question of whether the orbit is the site of origin of a malignant lymphoma or is merely the site of an atypical presentation of a systemic disease . The present study, consisting of 13 patients with biopsy proven monomorphous reticulum cell sarcoma of the orbit, was undertaken in order to analyze the clinical characteristics of this

-

tumor

most malignant type of the non-Hodgkin's orbital lymphomas . The present data will be placed in the context of recent developments in hematopathology which have clarified the subject of systemic lymphoreticular neoplasms and which should be taken into account in interpreting ophthalmic lesions .

T

Materials and Methods Four-hundred-ten cases of orbital lymphoid lesions, accumulated over the past 40 years at the Algernon B . Reese Laboratory of Ophthalmic Pathology at the Edward S . Harkness Eye Institute, were reviewed . These cases included 90 classified as reticulum cell sarcoma, 6 as benign lymphoma, 5 as follicular lymphoma, 13 as unclassified

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lymphosarcoma, II as malignant histiocytoma, 93 as lymphocytic lymphosarcoma and 192 as pseudotumors . Fourteen cases were found that satisfied the cytologic criteria for reticulum cell sarcoma and that were located in the orbit, but one case had to be excluded because no clinical information at all could be obtained on the patient . Care was taken to exclude all cases in which the tumor was located exclusively in the lids or conjunctiva. Also excluded were cases in children who, on clinical follow-up, were discovered to have leukemic disease or metastatic neuroblastoma . Positive evidence of an intraorbital lesion included proptosis, findings at the time of surgical exploration, and evidence on x-ray studies and ultrasonography .

two were black . Five patients had known history of reticulum cell sarcoma (Table 1), and the diagnosis of reticulum cell sarcoma was made from orbital biopsy in the other eight patients (Table 2) . Seven patients had proptosis (Fig . 1) as a presenting symptom, and 5 had swelling of one or both lids with anterior orbital involvement (Fig . 2) . Swelling and proptosis occurred together in three cases . The degree of proptosis ranged from 4 to 10 mm . Two patients had unmeasured proptosis . The duration of orbital symptoms ranged from 9 days to 5 years in I I patients for whom this information could be obtained, with a median of 4 months . Only four patients with advanced proptosis complained of significant pain. Visual acuity was reduced in six patients, ranging from 20/40 to 20/400 ; another patient had light perception only . Papilledema was noted in three patients ; no signs of intraocular tumor involvement were recorded . Eleven patients had palpable masses, three presenting in the superior temporal quadrant, two superonasally, two in the inferior orbit,

Results CLINICAL FINDINGS

Among the 13 cases selected, nine were females and four were males . Ages ranged from 24 to 75, with 11 cases occurring after 50 years of age . The median age was 57 . The three cases between ages 24 and 50 were in males . Eleven of the patients were white and

TABLE 1 Five Known Reticulum Cell Sarcomas Spreading to Orbit

Age at Case onset of Number disease

Age at onset of orbital mass Race Sex

Location of orbital lesion

Duration of orbital symptoms

Previous sites

Interval for spread of orbit 4 yrs.

Survival after spread to orbit

Total Survival Time

1

52

56

W

F

L. inferior nasal

9 days

Lymphoma of stomach, ileum, cemm, hard palate, multiple nodes

2

57

58

W

F

R . superior temporal

6 wks

Diagnosis from R . cervical nodes ; multiple nodes ; spleen, liver, kidney, uterus, ovary, serosa colon, marrow

10 mos .

I year 8 mos .

2 yrs . 6 mos.

3

57

61

W

F

Massengulfed L . globe

Diagnosis from parotid mass ; multiple nodes, marrow, lungs, abdomen, subcut. nodules, spine

3 yrs. 8 mos .

14} yrs .

5 yrs. 3 mos.

4

57

58

W

M L . orbit

Diagnosis from retroperitoneal mass, lung nodule

1 yr .

Imo .

1 yr .

5

61

62

W

M L . medial orbit

Diagnosis from retroperitoneal mass ; mediastinal nodes, L . parotid, CNS, thyroid

6 mos .

6 mos.

I yr .

2 wks.

Not known Not known



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two engulfing the globe, one inferonasally, and one medially . One patient presented with a huge tumor (Fig . 3) described as being the size of an orange, and another had bilateral orbital and lid involvement (Fig . 4) . Eight patients had either skull or orbital xrays . Three showed enlarged orbits, three showed an increased soft tissue density, and two showed both . One patient showed an incidental osteoma in the frontal sinus with a soft tissue density . One patient had an ultrasonogram which showed nodular densities in both lids and an irregular, sonodense tumor in the posterior orbit . In the five patients with known reticulum cell sarcoma, the interval for spread to the orbit after the diagnosis had been made ranged from 6 months to 4 years . In these patients, survival after presentation in the orbit lasted from I month to 20 months ; one patient was lost to followup . Total survival time for the patients with known reticulum cell sarcoma

from onset of disease extended from 1 year to 5 years-and-3 months . Of the eight patients lacking a diagnosis of reticulum cell sarcoma at the time they presented with eye signs, four were found to have concomitant disease elsewhere at the time of orbital biopsy . In four patients, the interval from appearance of the orbital lesion to signs of systemic disease ranged from 2 months to 15 months . The patients who presented with orbital lesions survived from 6 months to 6 1h years . Two patients were lost to followup, although one was known to be alive 2 years later . Radiotherapy was administered to 12 patients . One patient had an exenteration only . One patient had an exenteration plus radiotherapy while another had radiotherapy initially and exenteration 5 months later, followed by additional courses of radiotherapy . Total tumor doses ranged from 2000 to 5000 rads, 2500 to 3000 rads being the

TABLE2 Eight Reticulum Cell Sarcomas Presenting in Orbit

Case Number

Age at onset of disease

6

Location of orbital lesion

Duration of orbital symptoms

Subsequent spread

Interval before spread to other sites

Race

Sex

Final outcome

W

M

R . superior temporal

I yr .

R .preauricular & cervical nodes ; 6 mos . later widespread disease

Concomitant

Unknown

7

75

W

F

R . retrobulbar

4 mos .

L. parotid ; L. V Ith N .

4months

Alive 1 years later

8

75

W

F

L . superior nasal

2 mos .

Nasal wall ; L. submandibular node ; L . Soarsnodes ; abdomen

Concomitant

Death 10 months

9

61

W

F

R . superior nasal

4 mos .

Liver

I vr . 3 mos.

Lnktown

10

39

B

M

R . inferior orbit

8 mos .

Recurrences in orbit ; subcutaneous nodules ; multiple nodes; multiple skeletal lesions

5 mos .

Death 6 years

II

24

M

Engulfed L . globe

4 mos .

Brain stem; lungs

2 mos .

Death 8 months

12

68

W

F

R . superior temporal

IS yrs .

Subcutaneous nodules ; hilar nodes ; gastro . intestinal tract; R . parotid; multiple nodes

Concomitant

Death 64, years

13

67

B

M

Bilateral orbits & lids

5 yrs .

Scalene and multiple nodes

Concomitant

Death 3 years 5 months



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PATHOLOGIC FINDINGS

most frequent dosage used . Most patients living for any appreciable length of time underwent multiple courses of radiotherapy . When responses became unsatisfactory, the patients were placed on chemotherapy along with radiotherapy . Of the six patients who received chemotherapy, two received cytoxan, one received vincristine, one received cytoxan and vincristine, one received cytoxan and chlorambucil, and another cytoxan, halotestin and prednisone . There was no apparent correlation between chemotherapeutic agents used and length of survival . The cause of death is known for ten patients . All died from complications revolving around their reticulum cell sarcoma or their therapy . One patient had marrow aplasia which was thought to be caused by cytoxan and radiotherapy . Another had multiple bowel ulcerations secondary to radiation . One patient was comatose for about 6 weeks prior to death because of central nervous system involvement by his reticulum cell sarcoma .

Grossly, at the time of surgery the tumors were described as being soft, pink-to-gray, friable tumors that bled only modestly on excision . Necrosis was not typical . The tumors frequently conformed to the orbital spaces, and in the anterior orbit they rolled up against the orbital septum . Microscopically, the tumors included in this study were overwhelmingly composed of a single population of large cells (Fig . 5), measuring from 3 to 4 times the size of a mature lymphocyte . The nuclei of these cells were large, vesicular and often indented or kidney-shaped (Fig . 6) . The chromatin tended to be dispersed in coarse blocks and peripherally marginated, imparting the appearance of thickening of the nuclear membrane . There was usually a single dominant amphophilic or eosinophilic nucleolus that stood out in the center of the vesicular nucleus . Mitotic activity was high, with up to three mitotic figures often in evidence per high power field . The cytoplasm was

Fir . 1 . Case 8 . Seventy-five-year-old female discovered to have reticulum cell sarcoma on biopsy of the left orbit . Disease was present elsewhere at the time of biopsy and patient expired 10 months later.

. 2 . Case 10 . Thirty-nine-year-old male Fir presented with anterior orbital tumor and lid swelling. Other sites of disease developed within 5 months and patient died 6 years after orbital biopsy and multiple orbital recurrences .

Fm . 3 . Case 11 . Twenty-four-year-old male developed massive orbital tumor . Systemic disease discovered 2 months later . Patient died 8 months later of central nervous system disease.

Fic . 4 . Case 13 . Sixty-seven-year-old patient with 5 year history of slowly progressive bilateral orbital disease with lid swelling .

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generally indistinct and stained pale pink . Reticulin and trichrome stains revealed a paucity of extracellular fibrils and no evidence of a follicular or nodular pattern in any of the tumors . One tumor, however, displayed a pseudoalveolar pattern (Fig . 7) in which fine strands of reticulin fibers regularly subdivided the tumor cells into small compartments . The cytoplasm of these cells was more conspicuous than usual because of the separation of the individual cells in the central spaces (Fig . 8) . While most of the cells were anaplastic, occasional fields displayed cells with eccentric nuclei and paired nuclei, as well as chromatin clumping; these cells

possessed basophilic cytoplasm, suggestive of plasmacytic differentiation . Electron microscopy was performed on one tumor (Fig . 9) . The nuclei were irregular and indented ("cleaved"), and the nuclear envelope frequently manifested blebs . The cytoplasm contained only scattered mitochondria, polyribosomes, and only a few short profiles of rough surfaced endoplasmic reticulum . No desmosomes were seen . Discussion INCIDENCE

The incidence of orbital reticulum cell sarcoma among biopsied orbital tumors can

Fic . 5 . Tumor composed o single population of anaplastic cells (H & E, x 160) . I

i

Fit, . 6 . Nuclei are irregularly shaped and vesicular, with chromatin clumping and prominent nucleoli (H & E, x 375) .

FIG . 7 .

Tumor is subdivided by fine, fibrovascular strands (H & E, X 94) .

i 16 Fm . 8 . Cytoplasm is seen more distinctly than usual due to separation of tumor cells lying free in the alveolar spaces . In this uncharacteristic field, eccentricity of the nuclei and occasional hinucleate forms suggest plasmacytic differentiation (H & E, x 375) . be calculated from published reports . Reese' reported a series of 504 primary orbital tumors, of which 10% were diagnosed as lymphomas and another 8% as orbital pseudotumors, also considered lymphoid . In Henderson's series of 465 orbital tumors (many of which were secondary orbital invaders), somewhat over 8% were diagnosed as lymphomas .'O In Henderson's group of 39 lymphomatous tumors of the orbit, eight cases were reticulum cell sarcomas . In the Eye Institute material that we reviewed for this paper, consisting of 410 cases of benign and malignant lymphoid lesions of the orbit,

14 cases satisfied the histopathologic criteria that we had critically applied for reticulum cell sarcoma, constituting only 3 .4% of this subgroup of orbital neoplasms . Since Reese found that at our institution 18% of primary orbital tumors were lymphoid lesions, and we found that 3 .4% of lymphoid lesions were reticulum cell sarcoma, we can multiply Reese's 18% by our 3 .4% to estimate the incidence of reticulum cell sarcoma of the orbit at 0 .6% of biopsied cases of primary orbital tumor . Another way of analyzing the incidence of orbital lymphomatous deposits is to consider

FIG . 9 . Electron micrograph of tumor cells which have indented and blebbed nuclei (arrows) and a sparsity of cytoplasmic organelles (X 4800) .

how often the orbit is involved in systemic lymphomas . Rosenberg and associates" collated clinical and autopsy data on 1269 patients with systemic lymphoma and found that 3 patients (0 .24%) presented because of proptosis, while in the course of their disease 13 other patients developed proptosis after their diagnosis had been established, bringing the total number of cases of systemic lymphoma with orbital involvement to 16, or 1 .3% . Approximately two-thirds of these orbital cases constituting 0 .8% of the total of 1269 cases, were diagnosed as reticulum cell sarcoma, a figure similar to the statistic based on Reese's study and ours . Today, however, many of these systemic tumors would be

reclassified as poorly differentiated lymphocytic lymphomas, a point conceded by the senior author in a later paper" (see section on Pathologic Diagnosis), and therefore the incidence of systemic reticulum cell sarcoma involving the orbit is probably less than 0 .5% . Our own material demonstrates this shift in diagnosis as well, since of the 90 cases coded in our files as reticulum cell sarcoma, only 14 were acceptable for this study on critical review . CLINICAL CHARACTERISTICS

Henderson 28 has commented on the lack of adequate data on the natural history of orbital lymphomas and particularly of



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reticulum cell sarcoma . Other serious impediments to the comparison of previous studies to current work are the inclusion of other adnexal lymphomas along with orbital tumors in previous reviews, and the radical changes in nomenclature and cytogenetic concepts of lymphomas that have occurred over the years', " ,27•d6,57,68 '°' 87 The problem is further aggravated by the frequent absence in earlier publications of photomicrographs which would have allowed reinterpretation according to modern diagnostic morphologic criteria. HendersonP6 reported 8 new cases of orbital reticulum cell sarcoma and reviewed 22 other cases from the literature . In this pool of 30 cases, he discovered that 17 patients (most of these were reported in the literature) were aged 20 years or less, the youngest being 17 months of age . Our own data are more in agreement with those on Henderson's new patients and those of McGavic ;6a we have all found that the overwhelming majority of our own cases of orbital reticulum cell sarcoma have occurred in adults . This disparity with the literature will be further discussed below . Henderson' 8 did not separate the patients presenting with orbital involvement as the primary manifestation from those who developed it as a complication of a previously diagnosed systemic lymphoma . He noted, however, that most patients with reticulum cell sarcoma of the orbit died within 2-3 years of the onset of this complication . Nonetheless, Henderson felt the course of reticulum cell sarcoma of the orbit in an individual patient might be difficult to predict, in view of the fact that one patient in his Mayo series" lived 8 years after the appearance of the orbital lesion, and another reported by McGavic survived 7 .2 years ." Two patients reported by Rouher, 74 aged 6 and 16 years, were followed after radiotherapy for 6 and 8 years, respectively, and found to be in otherwise good health . However, one might want to question the validity of the diagnoses in these cases (see section on Histogenesis) . The two children aged 9 and 13 in the Mayo series,'e on the other hand, did not survive beyond 13 months, and all except the one patient alluded to above in the Mayo series died within 3 112 years after onset of their orbital tumors . Our own cases of 9 females and 4 males ranged in age from 24 to 75 years, with 11 patients being 50 years of age or older . The median age was 57 . Our data, therefore, es-

sentially agree with those of McGavic and Henderson that reticulum cell sarcoma of the orbit is predominantly a disease of adults and not of children . Patients were usually symptomatic for about 4 months, although one patient appeared to develop proptosis in slightly over a week and another patient developed proptosis slowly over 5 years . Three of the 13 patients developed tumors in the lacrimal gland region, a not uncommon site for lymphoid lesions of the orbit . Eleven patients had palpable masses . Only one patient had bilateral orbital disease . In the 8 patients who had either skull or orbital xrays, it is worth mentioning that none showed destruction of the orbital bones ; however, 5 displayed an enlarged orbit on the side of the lesion, indicating that the tumor may have been occultly present in the orbit for some time. One peculiar aspect of reticulum cell sarcoma that is reflected in our cases is its tendency for central nervous system involvement . Of all the lymphomas, reticulum cell sarcoma is the most apt to produce paraspinal tumors 17 or a superficial and diffuse infiltration of the meninges, a lymphomatous "meningitis" analogous to carcinomatous "meningitis . 1124 One of our patients died from CNS complications, while two others had probable CNS disease based on spinal cord and abducent nerve dysfunctions . In a series of 21 patients with reticulum cell sarcoma seeding the meninges, one patient developed proptosis ; since a biopsy was not performed, it was never established whether lymphomatous meningitis of the optic nerve or an orbital soft tissue mass was responsible for the proptosis . It is worth underscoring that involvement of the globe was not manifest in any of our cases . With rare exceptions, 11,49 systemic nodal lymphoma spares the intraocular structures, in contrast to leukemia, in which the globe may be seeded in over 50% of cases' The clinical course of patient #10 is also noteworthy . He presented with a tumor that was initially diagnosed as a "histiocytoma," a diagnosis that was maintained several months later when a biopsy of a cervical node revealed a "metastasis" with invasion of the surrounding musculature. Over several years multiple orbital recurrences, widespread nodal disease, and skin nodules developed together with osseous lesions . On reexamination of the microscopic sections, we have revised the diagnosis to plasmacytic

CLINICAL PATHOLOGICAL REVIEW

reticulum cell sarcoma . The eventual appearance of osseous lesions is clinically consistent with the diagnosis ; however, due to the early involvement of the orbital soft tissues and the nodal pattern of spread, we feel that this tumor is essentially a lymphoma rather than a myeloma . With respect to overall clinical behavior, 5 of the 13 patients with orbital disease had known systemic reticulum cell sarcoma, with an interval for spread to the orbit ranging from 6 months to 4 years . Death ensued rapidly after the appearance of the orbital lesion in this group of patients, occurring from I month to 20 months later . In the group of eight patients not known to have systemic lymphoma when they developed proptosis which led to the diagnosis, four were found to have concomitant extraorbital disease on further workup . In the remaining four patients, signs of systemic lymphoma were manifested from 2 months to 15 months after orbital biopsy . The patients who presented with an orbital lesion at first glance might appear to have fared better than those patients who had known systemic disease, because they survived for longer periods after orbital biopsy . Total survival, however, among those patients in the former group whose final outcome could be determined ranged from 8 months to 6%2 years, and is equivalent to the total survival in the latter group which spanned from I year to 5-years-and-3 months . The development of an orbital deposit early in reticulum cell sarcoma appears, therefore, to be a random event that does not materially influence the total course of the disease.

PATHOLOGIC DIAGNOSIS

Two important pathologic considerations regarding location and cytologic criteria for diagnosis should be amplified . In this study, we analyzed only those cases which appeared to be predominantly situated within the orbit . Therefore, lesions of the lids or the conjunctiva were excluded, although we included orbital lesions that we thought had secondarily encroached on these adnexal tissues . The orbit, in contrast to the conjunctiva, normally does not have its own indigenous lymphoid tissue. From the theoretical and clinical standpoints, the conjunctiva is therefore more apt to develop localized lymphoid tumors

263

from its own native tissue . Lymphomas are known to have a better prognosis when they develop in extranodal lymphoidal tissues, such as those of the gastrointestinal tract or of the medullary spaces of bones 52,75 B 5 indeed, the two patients in our series with significant gastrointestinal involvement were among the longest survivors . McGavic5A and Zimmerman" have both noted that conjunctival lymphoid lesions behave better than orbital lesions, perhaps because many of the former truly originate as well as present in the conjunctiva . It is possible that, in the future, immunochemical techniques will be applied to conjunctival lesions to determine whether they are primary or metastatic, since it is known that conjunctival lymphoid cells are able to produce IgA'° in common with other lymphoid cells at mucosal interfaces (e .g ., tracheo-bronchial tree or gut) ." The production of IgA is not encountered in most systemic nodal lymphomas and would not be expected in orbital lymphomas with the exception of those arising in the lacrimal gland . Regarding the histopathologic aspects of our cases, we applied rather stringent criteria for the diagnosis of reticulum cell sarcoma and included only those tumors composed predominantly of one cell type . Ncoplastic reticulum cells are usually 2-4 times the size of mature lymphocytes and, therefore, measure from 10-25 microns ." They have large, often indented, vesicular nuclei with prominent margination of the chromatin along the nuclear membrane . Almost invariably the nuclei possess one or more very prominent nucleoli . The cytoplasm in our cases tended to be inconspicuous and stained faintly with eosin, although one case (Fig . 4) had more generous amounts of well outlined cytoplasm . We excluded from the present study cases of "mixed lymphoma," in which larger reticulum cells are admixed in roughly even proportions with more mature, but still neoplastic, lymphocytes . It has been shown that such cases of mixed lymphoma carry a prognosis that is more favorable than that of reticulum cell sarcoma and closer to that of poorly differentiated lymphocytic (lymphoblastic) lymphoma ." We excluded all tumors with rounder nuclei, less prominent nucleoli and scantier cytoplasm, which we considered to be poorly differentiated lymphocytic (lymphoblastic) lymphomas, Of the 90 cases coded in our files as reticulum cell sarcoma of the orbit, we accepted only 14 as true



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reticulum cell sarcomas and placed the others in different diagnostic categories . Rosenberg et al ." had combined such cases with reticulum cell sarcoma in their earlier study, but later refined their criteria ." None of our tumors produced large amounts of reticulin or were heavily collagenized . The sclerosing variant 6p ,80 of reticulum cell sarcoma that features tracts of collagen carries a more favorable prognosis, but it was not represented in our material, nor did we discover any examples of the especially malignant pleomorphic reticulum cell sarcoma ." Since we excluded mixed lymphomas with any conspicuous element of more mature lymphocytic cells, no cases were diagnosed as follicular or nodular (lymphohistiocytic) lymphomas . The reticulin stain also failed to detect any cases of nodular reticulum cell sarcoma, in which monomorphous cells are nonetheless grouped into nodular subunits circularly outlined by reticulin fibers . While nodularity confers a much more favorable prognosis,'""' all of our cases were of the diffuse variety (more common in extranodal sites) and consequently carried a poorer prognosis .'6 53

We diagnosed one of our cases as a plasmacytic reticulum cell sarcoma (case 10), although one might also categorize it as a poorly differentiated plasmacytoma . While most of the orbital tumor on multiple recurrences was composed of large, undifferentiated cells, a focus from the first biopsy specimen contained cells with more obvious plasmacytic traits - namely, binucleation, eccentric nuclei with clumped chromatin reminiscent of that of plasma cells, and generous amphophilic to slightly basophilic cytoplasm . The reticulin stain disclosed a regular pattern of compartments created by capillarized septa, a feature reported in one of Rodman and Font's cases of multiple myeloma with orbital involvement ." Because of the essential nodal and soft tissue patterns of this patient's disease, we have included his tumor among our cases of reticulum cell sarcoma . Since the B lymphocyte (immunoglobulin-producing) is related to the plasma cell, it should not be surprising that rare lymphomas retain a capacity to express plasmacytoid characteristics, which can be manifested at all levels of differentiation . HISTOGENESIS AND THE PROBLEM OF PRIMARY ORBITAL LYMPHOMA

Fm . 10 . Line diagram showing that "reticulum cells" of cleaved (indented) and noncleaved (oval) varieties are transformed, blastic or large lymphocytes . Dendritic reticulum cells form desmosomes and process antigen preparatory to blast transformation, while macrophages are merely scavenger cells . Neither of the last 2 cells is in the lymphocyte series (modified from Lukes and Collins$e)

Our data provide little support for the concept that reticulum cell sarcoma may develop primarily in the orbit . Nine of our patients either had known systemic lymphoma or were found to have systemic lymphoma at the time of their orbital lesions . The other four patients developed evidence of systemic lymphoma 2 months, 4 months, 5 months and 15 months after appearance of the orbital lesion . We believe that the interval between appearance of the lesion and systemic involvement should be several years before one suspects the lesion as having begun in the orbit . Too often a distinction is not made between a lesion's "presenting" in the orbit versus its "originating" in the orbit ; reports of reticulum cell sarcoma beginning in the orbit with subsequent spread to other sites within a matter of months seem to us more accurately interpreted as cases that were generalized from the outset with atypical orbital presentation . 10,59 .79 As Henderson" has noted, nonorbital sites of a systemic lymphoma may go undetected - e.g ., in the retroperitoneum or abdomen - at the time of orbital presentation unless the patient is subjected to an intensive systemic workup . 3 Most

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of our patients did not receive such a workup face immunoglobulins on the cell memand in the literature cases, followup is short branes or the presence of intracytoplasmic and the extent of a systemic workup is immunoglobulin''10,20,23,26,34,44,", 55,62 (Fig . 10) . generally not detailed . In a series of 40 In the past it had been theorized that a patients with non-Hodgkin's lymphoma who primitive hematic cell was capable of were judged clinically to have Stage I differentiation into either the lymphocyte or lymphoma (involvement of a single lymph histiocyte .a' Now it has been determined that node chain or a single extra-lymph nodal there are true histiocytic tumors (M-cell tissue), only three were shown to have truly or macrophagic tumors) arising out of localized disease after undergoing a protocol a primitive pool of cells in the macrophagic work-up including lymphangiography, in- or phagocytic system, L,23,33,83 in contrast ferior vena cavography, laparotomy, and to large-cell or "reticulum cell" lymphomas that have adopted a morphologic aspect multiple biopsies ." In addition to the possibility of mis- recapitulating the normal blast transformadiagnosis of reticulum cell sarcoma in cases tion of lymphocytes that occurs after exof long survival, there are other reasons why posure to an immune stimulus . It also has patients have variable and at times unex- been proven that practically all lymphomas, pectedly long survivals . For example, a with rare exceptions (e .g . mycosis fungoides patient might initially have developed a less of the skin and certain mediastinal tumors), malignant form of lymphoma, such as a well are of B-lymphocytic (immunoglobulindifferentiated lymphocytic lymphoma or a producing) origin rather than of T-lymphofollicular lymphoma, which over a period of cytic (delayed hypersensitivity) origin .26, rfi time became progressively anaplastic, so that Our own case # 10 with atypical plasmacytoid when the orbital biopsy was performed, the features is an unusual morphologic dempatient had arrived at the stage of reticulum onstration of B-cell derivation, since the cell sarcoma . In this regard, it should be men- plasma cell is the immunoglobulin-producing tioned that we were unable to review the lymphocyte par excellence . In the orbit, one slides of earlier biopsies of our patients from can be relatively certain without immunothe time when they had first developed chemical techniques that most reticulum cell lymphomatous disease . Another point is that sarcomas will be of B-lymphocytic provdifferent anatomic sites in a widespread enance, because of the overall rarity of Tlymphomatous process may display different lymphocytic tumors and the rarity of orbital degrees of differentiation, so that a metastatic deposits in truly malignant macrophagic or deposit in the orbit may be poorly differen- histiocytic (M-cell) tumors . T-cell lymphtiated, while other sites within the body, omas, if they are proven to occur in the which will determine overall prognosis and orbit, can be expected to display hyperconoutcome, may be somewhat better differen- voluted, cerebriform nuclei, a characteristic tiated . One of Henderson's patients" who was of this line of tumor cells . 23 Furthermore, diagnosed as having reticulum cell sarcoma of lymphomas with a relentlessly aggressive and the orbit survived 8 years after onset ; refractory clinical course and unusual extrahowever, early in the course of this patient's nodal patterns, such as involvement of skin disease, the orbital lesion was treated by and brain 2 have in some cases been shown to radiotherapy without biopsy . It is possible be composed of T-cells . The histiocytic disthat a better differentiated lymphoma was eases that may spread to the orbit, such as present within the orbit at the outset and that Letterer-Siewe disease or Holland Schullera more malignant clone of cells had emerged Christian disease, are usually rather easily after the radiation therapy, eventuating in the diagnosed because they occur in children and picture of reticulum cell sarcoma at the time have an admixture of chronic inflammatory of biopsy . Our own patient #13 with 5 years of cells or manifest lipidization of the cytoprogressive proptosis may exemplify the same plasm of benign appearing histiocytes . Lipid phenomenon . is not contained in reticulum cell tumors of We prefer the term reticulum cell sarcoma B-lymphocytic origin . to histiocytic lymphoma for our cases It has been well documented that in other because recent immunological work has anatomic sites a lymphoma can begin preproved that many so-called histiocytic dominantly extranodally . Mycosis fungoides lymphomas in fact belong to the B-lympho- of the skin is an excellent example, and cytic series by virtue of the presence of sur- various types of lymphoma have been shown



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to arise primarily in the testes, ovary, gastrointestinal tract, thyroid, bone marrow, lungs, salivary glands, etc . 22• ee • 6 8,75 32,39, ,75,77,84,86 CerM tain tissues, such as the gut or conjunctiva, have a standing lymphocyte population . However, when lymphoid tissue exists in areas where it is not normally found, such as in the skin or orbit, it must be postulated that a primitive reticulum cell of hematic origin which is believed to be scattered throughout the body 91,87 transforms in situ into a lymphoma . In a group of 13 reticulum cell sarcomas of the skin," six patients survived for long periods of time without additional disease, supporting the concept of an origin in the skin . In a more recent series of 25 lymphomas involving the skin (excluding mycosis fungoides),88 88% of patients developed noncutaneous lymphoma after a mean interval of 21 months ; the abdomen was the most common undetected site at the time of presentation, which parallels a similar problem encountered with orbital lymphomas . Three of the 25 lymphomas in this series were of the reticulum cell sarcoma variety ; two of these patients quickly succumbed, but one patient has survived 8 years . We do not believe, however, that our data or those of Henderson prove the existence of comparable reticulum cell sarcomas developing primarily in the orbit . We are presently reviewing over 200 cases of poorly differentiated and well differentiated lymphocytic orbital lymphomas in an attempt to determine the natural history of these lesions and to establish whether any of these tumors might have begun in the orbit . It is also important to bear in mind that the bones surrounding the orbit may be the site of a primary reticulum cell sarcoma that could spread to the orbit, since lymphoid tissue is normally present in the marrow of these bones?, ",1,7' None of our cases, however, displayed any evidence of bone destruction, ruling out this possibility . Nolan67 reported a case of reticulum cell sarcoma in a 13-year old girl with cervical lymphadenopathy, proptosis and orbital bone destruction who survived after radiotherapy; it is quite possible that this patient represents a localized central facial reticulum cell sarcoma with local node involvement, although photomicrographic verification of the diagnosis was not provided in the report . In addition to theories of multicentric origin and widespread early metastases applied to lymphomas that develop in

different sites simultaneously, it is also possible to theorize that a single clone of lymphoid cells can spread throughout the body in distinctive patterns due to a homing mechanism for certain types of tissue toward which the neoplastic lymphoid cells possess receptors . This concept has been referred to as "ecotaxis ." 22 Cases of bilateral lid, conjunctival, orbital, breast and salivary gland involvement may well reflect the ecotactic properties of certain classes of lymphocytes and may indeed in time be shown to underlie unusual distributions and survival rates .22,31 A final mechanism deserves to be mentioned in connection with the development of extranodal lymphomas, such as those of the orbit . It appears that tissues which are subject to development of inflammatory pseudotumors may thereby acquire preneoplastic lymphoid tissue that is normally not present in such sites on an anatomical basis . Of 1467 patients with extranodal lymphomas, 32 had orbital disease.' The authors of this series commented that the orbit and other tissues that are known to develop extranodal lymphoma (thyroid, salivary glands, and testes) 32,39,66,77,84,86 are often the sites of benign lymphocytic infiltrates thought to present (lymphocytic autoimmune processes thyroiditis, benign lymphoepithelial lesion of salivary glands, and granulomatous orchitis) . Only the longterm study of orbital pseudotumor patients will allow some estimation of the significance of pseudotumor as a prelymphomatous lesion for those rare instances of lymphoma that seem to develop primarily in the orbit . PATHOLOGICAL DIFFERENTIAL DIAGNOSIS

Many lymphoid lesions can present atypical lymphoreticular cells without being malignant, and they are readily differentiated from reticulum cell sarcoma by their mixed cell population . They are believed to represent "blastic transformations" to various hyperimmune stimuli . 14,56,81 With respect to our case #10 of plasmacytoid reticulum cell sarcoma, the distinction from multiple myeloma was based upon the absence of skull and orbital osseous lesions at the time of presentation and the nodal pattern of spread with subcutaneous nodules, rather than upon cytologic detail . Age should be a strong consideration in the differential diagnosis of orbital reticulum cell sarcoma . It is our belief that in children, orbital reticulum cell sarcoma is an extremely rare tumor, as indeed are all types of nodal

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lymphoma with orbital deposits in this age group We had initially diagnosed reticulum cell sarcoma in 3 additional cases in this series on the basis of microscopic slide examination alone ; however, on clinical correlation we discovered that the patients had either leukemia or metastatic neuroblastoma . In the case of metastatic neuroblastoma, there was massive necrosis, as is typical of this tumor, whereas reticulum cell sarcoma of the orbit does not display this feature . Ewing's sarcoma is another round cell tumor that may metastasize to the orbit, but the cells of this neoplasm are more uniform in appearance than those of reticulum cell sarcoma and have more delicate nuclei without thick heterochromatin margination . Ewing's sarcoma cells also often contain glycogen in large amounts which is PASpositive and diastase-sensitive, whereas this finding is not characteristic of reticulum cell sarcoma. We consider it likely that the numerous literature reports of successfully irradiated reticulum cell sarcomas of the orbit in children are probably examples of other tumors"' - e .g ., radiosensitive undifferentiated local sarcomas or primitive round cell rhabdomyosarcomas which in the past were often unappreciated and called lymphomas . Other patients could have had other systemic diseases such as leukemia . Patients who are known clinically to have leukemia, of course, do not provide a diagnostic problem if the pathology is interpreted in conjunction with the clinical history, but there are rare instances of granulocytic sarcoma that may occur around the orbit as deposits of poorly differentiated, large cells mimicking reticulum cell sarcomas' These deposits can occur months to years in advance of signs of leukemia or of bone marrow involvement . Pathologists should bear in mind the rarity of reticulum cell sarcoma of the orbit in the pediatric age group . When they are about to make that diagnosis in a child, they should think of granulocytic sarcoma and perform a Leder stain, which can bring out early granulocytic differentiation in the cytoplasm of some of the tumor cells . In well fixed material, the blast cells of leukemic deposits also have more delicate and watery nuclei without the thick nuclear membrane and dominant nucleoli of true reticulum cell sarcoma . In adults, poorly differentiated carcinoma of squamous cell origin invading the orbit from the nasopharynx (including lympho-

epithelioma or Schminke tumor) or the surrounding sinuses should be ruled out . In these instances, a reticulin stain may disclose an epithelial growth pattern . The tumor cell nuclei are oval or round and lack the indentations and thick chromatin margination at the nuclear membrane that typify lymphomatous reticulum cells . Electron microscopy will disclose the presence of tonofilaments and desmosomes . Electron microscopic study of reticulum cell sarcoma reveals that there are no tonofilaments in the cytoplasm ; there is a sparsity of organelles and no desmosomes are found . In follicular or nodular lymphomas, so-called dendritic reticulum cells are found among the lymphopoietic reticulum cells' 0 .48 The former display desmosomes and are probably modified mesenchymal cells rather than transformed lymphocytes . In the diffuse, nonfollicular reticulum cell sarcoma that we examined by electron microscopy these cells were not present . Another differential diagnostic possibility in adults is metastatic or secondary amelanotic melanoma, in which electron microscopy will reveal the presence of premelanosomes . Microgliomatosis or primary reticulum cell sarcoma of the brain, which may present with a uveitis syndrome indicating involvement of the retina and/or vitreous, develops in older adults, generally in the absence of systemic nodal disease and also without orbital deposits C29 .31,a°s1-50 .81,65,76,82 Immunologic studies have not yet been performed to characterize this subgroup of lymphomas as B-, T- or M-cell proliferations . CLINICAL, MANAGEMENT

The diagnosis and management of patients with reticulum cell sarcoma of the orbit are obviously not very satisfying . It is our opinion that any patient who has a biopsy-proven reticulum cell sarcoma of the orbital tissues should be subjected to a vigorous systemic work-up in the almost certain expectation of finding further evidence of disease . This disease may not be clinically apparent if examination is restricted to the superficial lymph nodes . Bone marrow biopsy, lymphangiography, inferior vena cavography, intravenous pyelogram, and laparotomy with multiple biopsies of the retroperitoneal lymph nodes, liver and spleen, would be in order . Patients in whom tumor involvement is found to be restricted to the cervical lymphatic chain after a thorough evaluation have the best prognosis, 60' 88 but judging from our cases



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this situation does not exist very often when the orbit is infiltrated . The patient should also be studied for any evidence of immunoglobulin production in the blood by serum immunoelectrophoresis, since some nonmyelomatous plasmacytoid reticulum cell sarcomas are able to produce immunoglobulin, correlating with their B-cell origin' Unfortunately, our case #10 carried the diagnosis of "histiocytoma" so that the patient was never studied for the possibility of immunoglobulin production . The histopathology of this subgroup of tumors sometimes may be a clue to the presence of an aberrant immunoglobulin synthesis ; amyloid can be secreted between the tumor cells" or else the cytoplasm can have a somewhat blue appearance in hematoxylin and eosin staining which in turn is red on staining with methyl green pyronine. These tinctorial features are caused by the presence in the cytoplasm of polyribosomes and rough-surfaced endoplasmic reticulum which are the sites of the immunoglobulin synthesis . Radiotherapy can be effective in the management of these orbital tumors," although local recurrence and multiple courses of treatment are to be anticipated based upon our experience with this tumor . Our data, however, show no difference in survival between patients who had received radiotherapy or various regimens of chemotherapy . The chemotherapy is best entrusted to a general oncologist once systemic .13,30,47 disease has been discovered

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