Ординатура / Офтальмология / Английские материалы / Tumors of the Eye and Ocular Adnexa_Char_2001

430 TUMORS OF THE EYE AND OCULAR ADNEXA

There is a cooperative study under the auspices of the Histiocytosis Society, using newer chemotherapeutic agents, including etoposide, with promising results for systemic histiocytosis syndrome.85

Nodular fasciitis can simulate orbital pseudotumor. At surgery, this process appears very similar to the fibrotic form of pseudotumor. Approximately 10 percent of pseudotumors are predominantly fibrotic.86–88 A CT scan of such a case is shown in Figure 24–3. The histologic differential diagnosis in the case of nodular fasciitis is between benign and malignant fibrotic lesions.

Rarely, an orbital pseudotumor-like picture can be produced by a drug. Two different calcium antagonists have been implicated in this process.89 As previously discussed, infectious agents can simulate orbital myositis, and several cases have been reported as either a myositis or a diffuse pseudotumor with a viral or fungal etiology.90,91

The most important differential diagnosis in patients suspected of having a lymphoid variant of orbital pseudotumor is differentiation between this benign condition and orbital lymphoma. Pain is more common in pseudotumor than in lymphoma, but it is not a useful differentiating feature. Even histologically, it can be difficult to differentiate these two conditions. As in other body sites, lymphoid proliferations can occur in a spectrum from obviously benign to frankly malignant.92,93 Rarely, some other neoplasms, such as an infiltrating granular cell tumor, can simulate a sclerosing pseudotumor.94

An atypical subgroup in this lymphoid spectrum is patients with isolated orbital plasmacytomas. These are extremely uncommon, with approximately 50 cases of orbital plasma cell tumors having been reported.95,14 Approximately 25 percent of orbital plasmacytoma patients developed multiple myeloma.96–98 Such patients should have a bone marrow biopsy, skeletal survey, and a protein electrophoresis; urine should be analyzed for BenceJones proteins. Figure 26–21 compares analogous CT and MRI scans in a patient with a biopsy-proven orbital plasmacytoma. This patient had a gamma globulin spike on protein electrophoresis but no evidence of widespread disease. Occasionally, these patients present with orbital myositis.99 Waldenstrom’s macroglobulinemia can involve the orbit.100

Figure 26–22 shows a case that was proven on biopsy. The pattern is certainly not diagnostic.

There are few pathognomonic findings on ultrasonography, CT, or MRI scans, which allow the differentiation of idiopathic orbital pseudotumor from other causes of orbital inflammation or from either lymphoma or tumors metastatic to the orbit.26,101 The advantage of either CT or MRI over ultrasonography is spatial resolution, anatomic detail, improved diagnostic orbital accuracy, and their ability to better demonstrate sinus abnormalities and detect small foreign bodies. In pseudotumors which produce fluid in the sub-Tenon’s space, the “T” sign on immersion B-scan is a finding which is specific for inflammation and is helpful in the differential diagnosis (Figure 26–23).102–104 Usually, neither lymphoma nor pseudotumor invades orbital bone. While some investigators have felt that lymphoma can be differentiated from pseudotumor on both CT or ultrasonography, most experienced ophthalmic oncologists do not believe this differentiation is possible.101,105,106 Usually, on T1- and T2-weighted images, lymphoid lesions are hypointense, although many will become hyperintense with gadolinium.100 Some authors have felt that the relative homogeneity of the lesion on CT is suggestive of a lymphoma. In one series, this was noted in 75 percent of lymphomas versus 23 percent of orbital pseudotumors.107 The streaky appearance of orbital fat is similarly nondiagnostic to distinguish a benign lymphoid process, metastatic orbital tumor, and a primary lymphoma.108 Our experience has not allowed us to differentiate pseudotumors from lymphoma on the basis of T1- and T2-weighted images (see Table 15–2). A T1-weighted image of a biopsyproven orbital lymphoma is shown in Figure 26–22; the lesion is isodense with brain. Sinus disease producing orbital inflammation is readily apparent on CT scans or plain x-ray films.109 Metastatic orbital tumors can simulate an inflammatory process. Figure 26–24 shows the CT scan of a patient with an unknown primary tumor who presented with apparently diffuse myositis that was shown to be a metastasis. Fine-needle aspiration biopsy (FNAB) demonstrated metastatic tumor. Similarly, leukemic involvement of the extraocular muscles is not diagnostic on imaging studies (Figure 26–25).

In lacrimal gland lesions, it is especially important to differentiate lymphoid tumors from primary epithelial cancers; the latter group of malignancies has over 90 percent tumor-related mortality.110 Epithelial lacrimal tumors in their benign form commonly produce expansion of the fossa, whereas malignant processes are associated with bone invasion. Bone destruction, however, is not uniformly present in malignant epithelial lacrimal tumors.111 Wright and co-workers have stressed the use of an

incisional biopsy of lacrimal gland lesions to avoid penetrating the periosteum, which can be a barrier to malignant spread. The author routinely uses a lateral orbitotomy to approach these isolated lacrimal gland lymphoid lesions but carefully isolates the area and tags the cut edges of periosteum with a 4-0 silk suture. A frozen section is obtained during the operation to determine whether there is an adequate sample and also to make sure that this is not a malignant epithelial tumor. If it is a malignant epithelial tumor,

Figure 26–22. Axial MRI scan showing an orbital lymphoid lesion that was shown to be a Waldenstrom’s macroglobulinemia.

an en bloc resection with periosteum is performed at the time of surgery (see Chapter 20).

Rarely, lymphoma predominantly involves extraocular muscles, as shown in Figures 19–2 and 19–3.112

In our experience, only 10 percent of orbital lymphomas have known systemic spread at the time the patient is examined. In most series, the orbit is involved in about 2 percent of lymphoma patients.113 Most patients with known systemic lymphoma secondarily involving the orbit or those with simultaneous ophthalmic and systemic presentation of lym-

Figure 26–24. Parasagittal reformatted CT scan demonstrating involvement of the rectus muscles by an adenocarcinoma of unknown origin.

phomas have a history of chills, weight loss, and lymphadenopathy. These patients often have evidence of widespread lymphoma on bone marrow aspiration and biopsy.

Most patients with orbital lymphoma do not have simultaneous systemic disease, and only a minority of those in whom this diagnosis is histologically proven develop widespread dissemination. Jakobiec and co-workers noted, on the basis of lymphocyte surface marker studies, that 29 percent of patients with polyclonal orbital lymphoid proliferations developed nonocular lymphoma. Other investigators believe that these patients, especially those with monoclonal proliferations, will develop systemic lymphoma in as many as 50 percent of cases.114 Forty-five percent of patients with monoclonal B-cell proliferations in the orbit developed systemic lymphoma, as did 67 percent of patients with histo-

logically poorly differentiated orbital lymphoid lesions.35,115 Generally, there was a lower incidence of systemic spread in patients with disease confined to the conjunctiva (24%) than in patients with orbital disease (21 of 53 [40%]) or lid involvement (4 of 5).35,115 In a series of 112 cases from Glascow and Berlin, there was an equal incidence of malignant lymphoma with systemic spread in the conjunctiva, compared with those with orbital and lid involvement.116 In that study, all patients with diffuse large B-cell lymphoma and T-cell lymphoma were more likely to have systemic spread, as were those with greater proliferation rates.116 The patient shown in Figure 20–1 had simultaneous orbital and systemic lymphoma. Figures 26–26 and 26–27 show two biopsy-proven orbital lymphomas on axial and direct coronal CT scans. The vast majority of orbital lymphomas are non–Hodgkin’s, although rarely nodular sclerosis of the Hodgkin’s type has been described.117,118 Approximately 20 percent of orbital lymphomas have bilateral involvement.118,119 Orbital involvement is more commonly noted in systemic lymphomas that are high-grade disease.120

The optimal histologic classification of all lymphoid lesions, but especially those in the orbit, remains uncertain. There have been a number of different histologic classifications and working formulations for lymphoma, including those described by Rappaport, Lukes, and Collins, and the group in Kiel, the working formulation, Revised European American Lymphoma (REAL), and the World

Figure 26–26. Direct coronal CT scan of biopsy-proven orbital lymphoma with systemic involvement.

Figure 26–27. Axial CT scan of orbital lymphoma. The diagnosis was confirmed by bone marrow biopsy as well as fine-needle biopsy of the orbit. The axial CT scan shows the needle in correct position.

Health Organization (WHO) classifications.121–127 The lymphoma classification continues to evolve. The newer classifications contain over 20 distinct lymphoid neoplasms and incorporate histology as well as immunology and molecular biologic alterations.121,128 In mucosal associated lymphomas (MALT), which often involve the orbit, approximately one-third will have an obvious molecular alteration.129 In one study of ophthalmic lymphoid tumors, over 70 percent exhibited at least one gene rearrangement, and in that series, 53 percent developed systemic disease.130 Unfortunately, even the newer molecular analyses have a number of diagnostic pitfalls.131,132

As expected, since CNS lymphoma is markedly increased in the immunocompromised population, several reports have described orbital lymphoma involvement in patients with AIDS.133–138 Sometimes subjective findings make the differentiation between benign and malignant lymphoid lesions more difficult. The patient whose axial and coronal MRI scans are shown in Figure 26–28 had a history

of radiation of a Hodgkin’s lymphoma over 20 years previously. She presented with this lesion, which was a benign lymphoid process on marker studies, and she had no other evidence of systemic involvement. On the other hand, a patient with a history of lymphoma who presents with an orbital problem should be assumed to have that process until proven otherwise. The patient shown in Figure 26–29A was initially treated for a viral illness and was only referred when the eye went blind. A needle biopsy demonstrated recurrent lymphoma, which responded quite dramatically after the first radiation session with 200 cGy of photons (Figure 26–29B).

MANAGEMENT

Orbital Pseudotumor

The management of orbital pseudotumor varies, depending on its presentation. In a young patient presenting with painful ophthalmoplegia, ptosis, and mild proptosis along with an orbital CT pattern showing only myositis (see Figures 26–1 to 26–4), we administer 80 mg of oral prednisone every morning at 8 a.m. for 1 week and then stop the medication. In the majority of cases, a short-term course of steroids (< 10 days) will produce disease resolution, and this approach will not produce pituitary-adrenal suppression. The author would rather re-treat these patients than produce the complications associated

with long-term steroids.139,140 Unlike the British experience described earlier, the author has not had as good results with nonsteroidal therapy. While metastatic orbital tumors can involve the extraocular muscles, these are relatively uncommon in young patients, are more focal on CT or MRI, and usually do not produce similar symptoms.

Young patients with orbital apex syndrome (Tolosa-Hunt syndrome) are also treated with highdose systemic steroids without biopsy.8–14 In older patients who present with a Tolosa-Hunt-like picture, the probability of another cause is likely. Figure 26–30 shows such a case in an older man who was treated as having Tolosa-Hunt syndrome, when, in fact, he had a carcinoma. We have seen a few patients who had infections, metastatic tumors to the orbital apex, or contiguous sinus carcinoma involving that region, and were misdiagnosed as having Tolosa-Hunt syndrome (see Figure 22–15). In the last group of patients, pain was not a common symptom, and FNAB under CT control usually allowed the correct diagnosis to be made. In Tolosa-Hunt syndrome, high-dose steroids must often be continued for longer periods of time to obtain a remission of signs and symptoms.8–10 Some of these patients require oral steroids for several months.

A biopsy should be performed on all other patients with possible orbital pseudotumor, especially those who present with an isolated mass. We have found that FNAB appears to be as efficacious

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Figure 26–29. A, Axial CT scan with placement of FNAB. The patient had a history of systemic lymphoma treated 3 years previously. An incorrect diagnosis of a viral problem led to delay in treatment. B, Shows the patient 1 day later, after the first fraction of 200 cGy of photons.

as an open biopsy in the management of most orbital pseudotumor patients. We have been able to differentiate most benign simulating lesions as well as lymphomas from orbital pseudotumors on the basis of standard cytopathology interpretation as well as ancillary studies. Others have used cytologic techniques and have reported a good correlation with the working formulation classification of lymphoma.141 The availability in many laboratories of flow cytometry that can be performed on fine-needle aspirates has also markedly improved the ability to delineate these processes. From a single or multiple fine-nee- dle aspirate, as many as 107 cells can be obtained; these cells can be individually labeled with monoclonal antibodies, and this pattern can be detected by the laser, as the cells individually pass it in the flow cytometer.28 In several centers, FNAB with flow cytometry has been used in this setting with promising results.141–146 Figure 26–31 shows flow cytometry printouts of a benign heterogeneous collection of

lymphocytes, compared with a monotonous, monoclonal malignant lymphoma from the orbit. Some cases of inaccurate biopsies have been reported, and we noted a 10 percent false-negative rate.25,147

If FNAB does not yield sufficient cells or if the result is ambiguous, an open biopsy should be obtained. At surgery, a number of different patterns of orbital pseudotumor can be observed. Sometimes the preoperative CT or MRI pattern demonstrates the fibrotic or cellular nature of the lesion. Figure 26–32 shows a case in which the orbit was almost entirely replaced by fibrosis, obscuring all intraorbital detail. This degree of fibrosis is rare; at surgery, these fibrotic tumors are found have a somewhat gritty nature and usually do not involve bone. We routinely obtain a frozen section biopsy at the time of surgery. This is not done to establish a definitive diagnosis but to ensure that an adequate, representative biopsy has been obtained. At the time of orbital biopsy, if lymphoma is suspected on frozen section, we do bilateral bone marrow biopsies and later obtain chest-abdominal scans.

There are a number of histologic classifications of orbital pseudotumors, but few findings which correlate with either response to therapy or prognosis. Reese initially divided pseudotumors into five histologic groups: (1) those with lymphoid follicles,

(2) follicular and perivascular lymphocytic infiltration, (3) diffuse inflammation, (4) early fibrosis, and

(5) inflammation with a pre-existing vascular lesion. Farrow classified pseudotumors into those with vasculitis and necrosis versus those with generalized lymphocytic infiltration.7 As Garner has pointed out,

Figure 26–30. Tolosa-Hunt syndrome in older patients should be biopsied. This patient was managed for 2 years with progressive cranial nerve problems, and carcinoma was finally diagnosed on biopsy.

there is marked similarity between the orbital lymphoid lesions and those that are mucosa associated in the intestine.148

The lack of normal lymph node architecture precludes the use of capsular invasion as one of the diagnostic criteria which can be used to differentiate a lymphoma from a benign lymphoid proliferation. Germinal follicles, mixed cell populations, and intranuclear lymphocyte inclusions are more common in benign lymphoid proliferations. Histologic differentiation between benign and malignant lymphoid lesions is difficult. As Morgan and Harry first noted, the histologic differentiation of lymphoma from pseudotumor has an error rate which can approach 50 percent in difficult cases.149 Similar long-term retrospective studies from the Armed Forces Institute of Pathology (AFIP) have demonstrated up to a 40 percent error rate in the differentiation of lymphoma from pseudotumor.150

Figure 26–32. Orbital “wipeout” syndrome shown in axial CT scan with coronal re-formation. Extensive orbital fibrosis occurred. (From

Char,152 with permission).

A number of different approaches have been tried to improve the ability to differentiate lymphomas from benign orbital lymphoid lesions. Immunohistologic and DNA hybridization approaches appear to be the most promising, utilizing both monoclonal antibodies against lymphocyte subset surface markers and Southern blot techniques. These approaches are based on the premise that lymphomas are a monotonous proliferation of a monoclonal population of malignant lymphocytes. In contrast, pseudotumors are a heterogenous proliferation of cells. An individual B lymphocyte produces a single class of either lambda or kappa light chains. Normal B cells consist of mixed populations with a predominance of cells having surface kappa light chains. The individual gene arrangement for a given B cell’s immunoglobulin (or a T-cell’s immune receptor) and its progeny is unique.151

A number of groups, including our own, have used various techniques to attempt to differentiate lymphoma from pseudotumor on the basis of enumeration of subsets of T and B cells.106,152,153 These early studies were performed using functional assays to distinguish lymphocyte monoclonality on the basis of subset analysis. A number of workers have demonstrated that orbital lymphomas are predominantly malignant B-cell proliferations.106,143,152–159 Unfortunately, a significant number of T cells can either infiltrate or surround a B-cell lymphoma, making diagnosis using monoclonal antibodies dif-

ficult.160 A number of theoretical and technical problems have limited the accuracy of these monoclonal antibody techniques in the differentiation of pseudotumor from lymphoma.161,162 Some lymphomas have been demonstrated to be polyclonal in nature, and some benign diseases have been demonstrated to have monoclonal proliferations.160,163–165

Immunoglobulin gene rearrangements, as unique clonal markers of human lymphoid neoplasms, can be detected with Southern blot techniques and were hoped to be a more sensitive and accurate method to diagnose malignant versus benign lymphoid lesions.143,146 A polyclonal population of either T or B cells shows no single immunoglobulin gene rearrangement by the Southern blot technique. As discussed in a series of publications by Jakobiec and Knowles, the initial optimism that this technique would allow better separation of lymphoma from benign lymphoid proliferation has not been borne out. A major conclusion is that approximately 25 percent of patients with benign lymphoid lesions, despite the type of technique used to identify them, will go on to develop lymphoma. The implication of that finding is that any patient with an orbital lymphoid lesion, regardless of morphology, needs sequential medical oncologic follow-up.166

An unsolved dilemma centers on the nature of those orbital lymphoid monoclonal B-cell proliferations that have not disseminated after 10 years of follow-up.165 These may be akin to the pseudolymphoma in Sjögren’s syndrome, in which some progress to full-blown lymphoma. There have been a few reports of malignant lymphomas of the orbit in association with the benign lymphoepithelial lesions of the parotid glands.167 Since only approximately one-half of histologically clear-cut lymphomas spread outside the orbit, most of the cases of monoclonal proliferations that have not been shown to disseminate on long-term follow-up may or may not be true lymphomas.106,159 Longer follow-up of these cases is necessary to answer this question.

As previously described, we do not biopsy and we empirically initiate high-dose, short-term, systemic steroid therapy for most young patients with the orbital apex syndrome or for those with inflammation isolated to the extraocular muscles. The effect of steroids on these lesions is dramatic; often,

Figure 26–33. Focal inflammatory mass prior to surgery.

there is marked or complete resolution within 1 week. Unfortunately, as others have noted, in some series over half of these cases will recur after steroids are discontinued.168

If a localized inflammatory mass is present that can be completely excised (this represents only a minority of orbital pseudotumors), surgery is performed. Figures 26–33 and 26–34 show such a patient prior to and after surgical extripation of the inflammatory mass.169 In diffuse lesions or those which involve vital structures, we use high-dose, short-term steroids as our initial form of therapy. We have observed no significant complications when 100 mg of oral prednisone is administered daily for 7 to 10 days and then abruptly discontinued. While some investigators, including ourselves, have noted that response to steroids does not have a complete correlation with response to radiation, generally those patients who have a partial steroid response will do very well with radiotherapy.170,171 Experience from a number of centers shows that approximately 50 percent of patients treated with either local or systemic steroids will have resolution of the

Figure 26–34. Patient shown in Figure 26–33 after surgical resection of a relatively focal inflammatory mass.

438 TUMORS OF THE EYE AND OCULAR ADNEXA

pseudotumor. In a series from London, 27 of 55 cases had a good response to steroids; lesions with germinal follicles or extensive eosinophils seemed to do best with this medicine.172 We retrospectively analyzed the natural history of 81 patients with orbital pseudotumors treated at some point in their course at our unit. In 49, there were essentially complete remissions. The response to therapy was difficult to assess due to five important caveats in our study: (1) it was retrospective and many of the initial treatments were done at other centers and would not have been our treatment of choice; (2) there is no reproducible scoring system either for disease-asso- ciated morbidity or response to therapy; (3) in some orbital pseudotumors, spontaneous remission can occur; (4) some patients were obviously treated with multiple modalities; and (5) in some cases, while we recommended radiation, it was done in centers that did not have experience with that approach.23

In the 42 patients who received high-dose steroids, there was a complete and lasting remission in 24 percent and nearly a complete remission in an additional 7 percent of cases. Figures 26–35 to 26–38 show an excellent response to a 1-week course of oral corticosteroids. Patients who had a myositis or marked inflammation did significantly better than those with fibrotic lesions (p < .04). A poor steroid response was observed in 10 of 11 patients who had mass lesions. Some investigators have found that the use of bonesparing agents, such as Etidronate, may decrease bone resorption, especially in the elderly on steroids.173 In a series of 32 patients with orbital pseudotumors (20 with histologic confirmation), 27 received systemic steroids, and 21 had an initially good response. Unfortunately, only 10 (31%) were cured, while 11 (34%) had recurrences.174 As discussed below, fibrotic tumors respond poorly to steroids or irradia-

Figure 26–35. Biopsy-proven pseudotumor prior to oral corticosteroid therapy.

Figure 26–36. Patient shown in Figure 26–35 after 1 week of highdose oral corticosteroids.

tion; the fibrotic nature of these lesions is apparent at surgery. In patients who had fibrous mass lesions, surgery alone was effective in 19 of 25.69

We have also observed a few patients who have had sufficient orbital fibrosis to produce visual loss from optic nerve compression. Unlike orbital decompression surgery in compressive thyroid optic neuropathy, we have had to actually remove the fibrotic tissue up to the optic nerve.175 Rarely, more aggressive surgery is indicated in patients with orbital pseudotumor. We have managed a few patients who developed intractable proptosis and pain that were unresponsive to analgesics, nerve blocks, steroids, and irradiation. Very rarely, patients such as these require exenteration.

Orbital pseudotumors that are predominantly lymphoid have the most rapid and complete response to radiation or steroids. Pseudotumors which have an extensive vasculitis component are less responsive to these modalities.170

Radiation therapy has been used in the management of orbital pseudotumor for a number of years, but there is a paucity of reports on irradiated orbital pseudotumor patients in the literature.172,173,176 Most have previously received steroids but had either an incomplete or no response to them. Approximately 75 percent of irradiated patients had a complete response to orbital irradiation.176–184 Figure 26–39 shows an excellent response to 20 gray (Gy) of photon irradiation. The most recent series from Stanford University noted that 15 of 20 orbital pseudotumors treated with 20 Gy of photon irradiation had good resolution.183 In our retrospective review, radiation was effective in 64 percent of patients. We noted that radiation response was significantly better in nonfibrotic lesions, in those with a shorter interval

Figure 26–37. Pseudotumor prior to steroids.

between diagnosis and treatment, and in those who had erythema on presentation (p < 0.05).23 In the Stanford University experience, poorer responses were noted in younger and female patients. Patients with orbital vasculitis appeared to be slightly less responsive, as did those with diplopia.183 Other studies have shown similar results.184,185 Intriguingly, in one study of 65 patients, there was no difference in local or systemic recurrence rates among those patients who had benign lymphoid hyperplasia, those who had definite lymphomas, and those who had indeterminate lymphoid lesions.185

One problem in attempting to interpret the literature on irradiation of orbital pseudotumor is that it is unclear how many of these patients may have had lymphoma. In those series with a longer post-treat- ment follow-up, some patients who were initially felt to have had orbital pseudotumor have developed extraorbital lymphoma.177,179,185 A few patients treated with orbital irradiation for thyroid orbitopathy developed retinopathy. However, on re-examina- tion, it was apparent that the fractionation, dose, and beam calculations had been improper.176

We are unaware of significant ocular complications at 20 Gy of orbital irradiation. Specifically, no lens opacities or clinically apparent radiation vasculopathies have been produced.

Figure 26–38. Case shown in Figure 26–37 after 1 week of highdose steroids.

Orbital Lymphoma

The management of orbital lymphoma is predicated on the systemic status of the patient. If, at the time of orbital biopsy, the frozen section of the lesion is not pathognomonic for a benign orbital pseudotumor versus a lymphoma, we obtain bilateral bone marrow aspirations and biopsies while the patient is under general anesthesia. If the malignant lymphoid disease is confined to the orbit, as evidenced by negative chest and abdominal scans, patients receive 30 Gy of photon irradiation. At this dose, we have had approximately 95 percent success in controlling the orbital involvement.178 In most other series, orbital radiation has been curative for local disease, although systemic disease development has occurred in about a quarter of these patients.55,186,187 Donaldson feels that higher grade tumors may require combination radiation and systemic chemotherapy and also may do better at a slightly higher radiation dose.188 Figure 26–40 shows an excellent orbital response to 40 Gy of photon irradiation of an anterior orbital lymphoma. Approximately 50 percent of patients with orbital lymphoma have extraorbital dis-

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Figure 26–39. A, Orbital pseudotumor involving the superior orbit prior to 20 Gy of photon irradiation. B, Clinical photograph after irradiation.