Primary orbital peripheral T-cell lymphoma is an exceedingly rare neoplastic disorder. Advances in laboratory methods and molecular pathology have greatly improved our ability to accurately diagnose this lymphoid malignant neoplasm. We report a case of primary extranodal peripheral T-cell lymphoma arising within the orbit. Atypical features of the clinical course are described.
A 44-year-old man developed progressive diplopia and retro-orbital pain. Uncorrected visual acuity was 20/20 in both eyes. Examination findings included hypertropia in the left eye, esotropia, and proptosis in the right eye (Figure 1). Orbital magnetic resonance imaging showed bilateral enlargement of the extraocular muscles, more pronounced on the right. Thyroid ultrasonography disclosed mild thyromegaly, but results of serum thyroid functions tests were normal. The patient was diagnosed as having thyroid-related immune orbitopathy and high-dose oral prednisone was prescribed, with prompt resolution of symptoms and proptosis. However, prednisone was poorly tolerated and its use was discontinued, leading to a recurrence of symptoms.
Initial clinical presentation. A, Proptosis and ptosis in the right eye in primary gaze. B, Globe restriction with limited upgaze. C and D, Orbital computed tomography demonstrating asymmetric enlargement of extraocular muscles.
Neuro-ophthalmology consultation noted mild hypertropia and 2 mm of proptosis in the right eye. A second round of thyroid function testing, erythrocyte sedimentation rate, rapid plasma reagin, antinuclear antigen, and rheumatoid factor findings were all normal. Magnetic resonance imaging of the brain and orbits was negative for vascular lesions. External beam orbital radiotherapy (20 Gy in 10 divided doses [to convert gray to rad, multiply by 100]) for presumed active thyroid-related immune orbitopathy yielded clinical improvement.
Six months later, the patient developed edema in the right lower eyelid and conjunctival injection with chemosis, retro-orbital pain, and proptosis due to recurrent enlargement of extraocular muscles, all in the right eye. A biopsy specimen of the lateral rectus muscle from that eye demonstrated a polymorphous lymphocytic infiltrate composed of small T and B lymphocytes with clumped chromatin, round to irregular nuclear contours, and scant cytoplasm consistent with interstitial chronic inflammation.
Rheumatologic evaluation showed a slightly elevated antinuclear antigen level. A regimen of parenteral methotrexate sodium with low-dose prednisone led to temporary resolution of the proptosis and chemosis. Three months later, the patient again developed proptosis in the right eye, a pupil-sparing oculomotor nerve palsy with hypotropia in the right eye, and exotropia. A biopsy specimen of a palpable anterior orbital nodule disclosed a dense lymphohistiocytic infiltrate without overt angiocentricity or hypervascularity. There were small lymphocytes with clumped chromatin, round to irregular nuclear contours, and scant cytoplasm admixed with occasional larger, atypical lymphocytes with complex nuclei and moderately abundant clear cytoplasm (Figure 2). The larger, atypical lymphocytes were marked as T cells by using CD2, surface CD3, and CD45RO but demonstrated loss of other T-cell markers CD5 and CD7, indicative of an aberrant T-cell population. CD4 and CD8 staining were both present on small lymphocytes, but a specific pattern on the large atypical lymphocytes was difficult to interpret. Immunostains for Epstein-Barr virus latent membrane protein and CD56 were negative. There was insufficient tissue for additional stains such as CD30 or cytotoxic markers. Polymerase chain reaction gene rearrangement studies of both paraffin-embedded biopsy specimens were inconclusive owing to insufficient DNA quantity or quality. However, on the basis of tumor morphologic characteristics and aberrant loss of T-cell antigens, a diagnosis of peripheral T-cell lymphoma was rendered.
Tumor histopathology. A, Dense lymphohistiocytic infiltrate harboring atypical lymphocytes (hematoxylin-eosin [HE], original magnification ×100). B, Intense immunostaining pattern with CD2 (pan–T-cell marker, original magnification ×100). C, Intense immunostaining to CD3 (pan–T-cell marker, original magnification ×100). D, Aberrant diminished expression of CD7 in large atypical lymphocytes (arrow) (pan–T-cell marker, original magnification ×100).
A systemic evaluation including bone marrow biopsy; computed tomographic scans of the chest, abdomen, and pelvis; and magnetic resonance imaging of the brain gave completely normal findings. Given that molecular confirmation of peripheral T-cell lymphoma was unavailable, the oncology team elected to observe the patient conservatively for any changes.
Three months later, the patient developed right periorbital cellulitis that clinically improved with intravenous antibiotic therapy. Because of persistent swelling, biopsies were repeated, and the specimens showed a superficial and deep perivascular/periadnexal lymphohistiocytic infiltrate with frequent mitoses. Individual lymphocytes infiltrated adnexal structures, and mild epidermal tropism was present. Immunostains demonstrated a qualitative drop-off of T-cell staining similar to the previous biopsy specimen (positive for CD2, surface CD3, CD45RO, CD43, and some CD4 and CD8 staining, with drop-off of CD5 and CD7). The neoplastic cells were also negative for CD30 and positive for cytotoxic markers TIA-1 and granzyme B. These findings were consistent with a diagnosis of peripheral T-cell lymphoma, not otherwise specified. Polymerase chain reaction gene rearrangement studies with T-cell receptor γ-primers showed a monoclonal peak corresponding to a V γ-11 gene rearrangement, thus confirming a clonal T-cell process.
The patient declined additional treatment and did not return for follow-up until 8 additional months had elapsed (20 months after he was first evaluated). Marked proptosis and orbital congestion were present in the right eye (Figure 3A). Another systemic workup was performed, and a computed tomographic scan of the head showed a mass at the base of the tongue (Figure 3B). A biopsy specimen showed an infiltrate of large atypical lymphoid cells similar in appearance to the previous orbital biopsy specimens. T-cell immunophenotype and polymerase chain reaction gene rearrangement confirmed a clonal T-cell process similar to that found earlier in the orbit. Bone marrow biopsy was performed, and the specimen was free of tumor involvement. Computed tomographic imaging of the chest, abdomen, and pelvis was negative for adenopathy. Mild splenomegaly at 16 mm was palpated and, combined with biopsy-proved orbital and sublingual disease, led to a clinical diagnosis of stage IIIB peripheral T-cell lymphoma. The patient successfully completed 8 cycles of chemotherapy with cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone. Three years after his initial visit, all tumor masses had resolved. Apart from mild vertical diplopia and postchemotherapy epiphora, all ophthalmic symptoms had cleared at the last follow-up examination.
Recurrence of orbital T-cell lymphoma 20 months following initial clinical presentation. A, Proptosis and orbital congestion. B, Coronal computed tomographic scan of the skull demonstrating a sublingual soft-tissue mass, diagnosed with biopsy as a T-cell lymphoma.
Orbital and ocular adnexal lymphoid neoplasms are not uncommon, representing 6% to 8% of all orbital tumors1 and up to 15% of all ocular adnexal tumors.2 On the basis of published data from multiple large clinical series, most orbital lymphoproliferative disorders are (1) peripheral extranodal B-cell non-Hodgkin malignant lymphoma, (2) atypical lymphoid hyperplasia, or (3) benign reactive lymphoid hyperplasia.1,3,4 Primary orbital/ocular adnexal T-cell extranodal lymphoma is rare and most often represents mycosis fungoides and secondary involvement by systemic malignant non-Hodgkin lymphoma.2 In 1999, Coupland et al2 described the first case of primary T-cell orbital lymphoma confirmed both immunophenotypically and genotypically. Woog and coworkers5 recently analyzed the diagnostic features and clinical course of 8 patients with orbital and adnexal involvement by natural killer/T-cell lymphoma, an Epstein-Barr virus–associated neoplasm of noncytotoxic T lymphocytes. Our case of primary orbital peripheral T-cell lymphoma, not otherwise specified, was discovered in a 44-year-old man. Nearly 2 years elapsed before a confirmatory diagnosis was established.
Several unusual clinical features in this challenging case contributed to the delay in diagnosis. Diplopia was the initial symptom for which the patient sought treatment. Orbital imaging studies identified bilateral, asymmetric enlargement of the extraocular muscles, not the diffuse, molded soft-tissue density ordinarily encountered in a lymphoid infiltrate. Proptosis slowly developed during a period of months. Orbital external beam radiotherapy offered temporary improvement. Furthermore, the patient experienced retrobulbar pain and multiple cranial nerve pareses. Taken as a whole, this constellation of clinical findings is usually not associated with orbital lymphoid infiltrates.6- 8
Interpretation of tissue specimens in this case was equally challenging. The first of 3 biopsy specimens showed chronic inflammation localized to extraocular muscle tissue. A second biopsy specimen exhibited histopathologic findings and immunohistochemical staining strongly suggestive of peripheral T-cell lymphoma; however, confirmatory gene rearrangement studies were inconclusive. The third biopsy specimen, taken from the inferior part of the orbit, established the definitive diagnosis. A subsequent mass at the base of the tongue exhibited identical immunophenotype and genotype.
The diagnosis of primary orbital adnexal T-cell lymphoma was approached with caution. The eye and orbit harbor no native lymphoid tissue.6 Previously published reviews have claimed that the entity does not exist4; however, such statements predated contemporary advances in molecular pathology.2,9 It remains unclear why the overwhelming preponderance of orbital lymphoid neoplasms originate from B lymphocytes.10,11 Saga and coworkers12 observed that most extranodal lymphomas arise in extranodal lymphoid tissue, although some extranodal lymphomas involve extralymphatic sites such as the orbit. Bardenstein13 postulates that orbital adnexal lymphoma arises from transformed lymphocytes that were replicating as part of an ongoing reactive inflammatory process such as orbital pseudotumor (idiopathic orbital inflammation). This explanation mirrors the clinical course observed in our patient. Papalkar et al14 reported a fatal case of rapidly progressive orbital T-cell lymphoma that was originally diagnosed as idiopathic orbital inflammation.
Most cases of orbital peripheral T-cell lymphoma represent secondary orbital involvement by distant spread of systemic disease.3 Although biopsy-proved T-cell lymphoma was confirmed in a nearby extranodal site (oral cavity), we believe this second mass represents regional spread of primary orbital disease. Its appearance was first noted nearly 2 years after the initial orbital symptoms. Our experience shows that clinicians must be persistent when orbital disorders exhibit unusual examination findings or paradoxical clinical behavior. Anecdotal case reports describe clinical scenarios involving orbital T-cell lymphomas that were initially diagnosed as idiopathic orbital inflammation or orbital cellulitis.14,15
Correspondence: Dr Lloyd, 2600 American River Dr, Sacramento, CA 95864 (firstname.lastname@example.org).
Financial Disclosure: None reported.
Funding/Support: This study was supported by an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology and Vision Science, University of California, Davis.
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