Identification and classification of lymphoproliferative disorders

Non-Hodgkin lymphoma encompasses a heterogeneous group of malignancies and includes many subtypes. The Revised European-American Lymphoma Classification applies immunophenotypic and genetic features to identify distinct clinicopathologic NHL entities, including extranodal sites such as the orbit. The World Health Organization’s classification elaborates on this approach. Orbital extranodal disease appears to represent a biological continuum and behaves unpredictably. By molecular genetic studies, approximately 90% of orbital lymphoproliferative disease is monoclonal, and 10% is polyclonal; however, both types of lesions may involve prior, concurrent, or future systemic spread. Approximately 20%–30% of periocular lymphoproliferative lesions have a history of previous or concomitant systemic disease, and an additional 30% develop it over 5 years. The risk of systemic disease remains elevated for decades after the original lesion is diagnosed, regardless of the initial lesion’s location in the orbit or its clonality.

The risk of having or developing systemic NHL is lowest for conjunctival lesions, greater for orbital lesions, and highest for lesions arising in the eyelid. Lymphoid lesions developing in the fossa of the lacrimal gland may carry a greater risk of systemic disease than those occurring elsewhere in the orbit. Bilateral periocular involvement markedly increases the risk of systemic disease, but such involvement is not definitive evidence of systemic disease. Most orbital lymphomas are derived from B cells (98%). T-cell lymphoma is rare and more lethal. B-cell lymphoma is divided into Hodgkin and non-Hodgkin tumors, with the former rarely metastasizing to the orbit. The 4 most common types of orbital lymphomas are presented in order below:

• Extranodal marginal zone B-cell lymphoma, EMZL (also known as mucosa-associated lymphoid tissue, or MALT). EMZL accounts for approximately 57% of orbital lymphomas and is associated with upregulation of nuclear factor κB (NF-κB). NF-κB is a major transcription factor that is involved in the innate and adaptive immunologic system. Inactivating mutations in the A20 gene, an inhibitor of NF-κB, have also been noted in cases of EMZL. In the gastrointestinal tract, EMZL has been associated with Helicobacter pylori in gastric lymphomas where antimicrobial therapy has been shown to be effective. EMZL has been weakly associated with chlamydial infection, and antibiotic therapy is generally not recommended.

  EMZLs are low-grade malignancies, and 5%–15% of cases undergo spontaneous remission. However, systemic disease develops in at least 50% of patients at 10 years, and 15%–20% of cases undergo histologic transformation to a higher-grade lesion, usually of a large cell type. Such transformation usually occurs after several years and is not related to therapy.

• Diffuse large B-cell lymphoma (DLBCL) comprises 15% of orbital lymphomas. DLBCL also occurs in various intraocular compartments. It has been associated with multiple chromosomal translocations and alterations in the BCL2, BCL6, MYC, EZH2, and MEF2B genes.

• Follicular lymphoma (FL). This type of lymphoma represents a low-grade lesion with follicular centers and is the third-most-common orbital lymphoma (11%). The most common translocation associated with FL is t(14;18)(q32;q21), which results in high levels of the antiapoptotic protein BCL2.

• Mantle cell lymphoma (MCL) accounts for 8% of orbital lymphomas. Translocation t(11;14)(q13;q32) that is associated with overexpression of CCND1 (Cyclin D-1) is classically seen with MCL.

See also BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors.

• Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–2390.

Clinical presentation

The typical lymphoproliferative lesion presents as a gradually progressive, painless mass, resulting in proptosis, a visible periocular mass, or ptosis (Fig 5-17). These tumors are often located anteriorly in the orbit or beneath the conjunctiva, where they may show the typical salmon-patch appearance (Fig 5-18). Lymphoproliferative lesions, whether benign or malignant, usually mold to surrounding orbital structures rather than invading them; consequently, disturbances of extraocular motility or visual function are unusual. Reactive lymphoid hyperplasia and low-grade lymphomas often have a history of slow expansion over a period of months to years. Regional lymph nodes should be palpated during the clinical examination.

Diagnosis

Orbital imaging reveals a characteristic puttylike molding of the tumor to normal structures (see Fig 5-17B). Bone erosion or infiltration is usually not seen except with high-grade malignant lymphomas. Up to 50% of orbital lymphoproliferative lesions arise in the fossa of the lacrimal gland. Lymphomas in the retrobulbar fat may appear more infiltrative. Approximately 17% of orbital lymphoid lesions occur bilaterally, but this does not necessarily indicate the presence of extraorbital disease.

Figure 5-17 Lymphoproliferative lesion. A, Ptosis of the right upper eyelid and fullness (arrow) in the superior orbit. B, Axial CT scan shows a homogeneous mass (arrow) with characteristic molding along the globe. C, Incisional biopsy through an anterior orbitotomy approach via the upper eyelid crease. D, H&E stain of this hypercellular lesion is consistent with B-cell lymphoma.

(Courtesy of Bobby S. Korn, MD, PhD.)

Figure 5-18 Lymphoproliferative lesion presenting as a salmon-patch subconjunctival lesion. Note the prominent feeder vessel (arrow) overlying the lesion.

(Courtesy of Bobby S. Korn, MD, PhD.)

For all lymphoproliferative lesions, an open biopsy is preferred to obtain an adequate tissue specimen. A portion of the tissue should be placed in a suitable fixative for light microscopy, and the majority should be sent fresh to a molecular diagnostics laboratory for possible flow cytometry, immunohistochemistry, and genomic analysis. Fine-needle aspiration biopsy may establish all but the morphologic characteristics of the lesion. Conjunctival biopsy for follicular conjunctivitis can sometimes reveal a lymphoproliferative lesion.

Both reactive lymphoid hyperplasia and malignant lymphoma are hypercellular proliferations with sparse or absent stromal components. Light microscopy may reveal a histologic continuum from reactive lymphoid hyperplasia to low-grade lymphoma to higher-grade malignancy; it may not by itself adequately characterize a given lesion. In such cases, immunopathology and molecular diagnostic studies aid in further categorization.

Malignant lymphomas are thought to represent clonal expansions of abnormal precursor cells. Immunologic identification of lymphocyte cell-surface markers can classify tumors as containing B cells or T cells. Specific monoclonal antibodies directed against surface light-chain immunoglobulins are used to determine whether the cells represent monoclonal (ie, malignant) proliferations.

Genetic analysis has shown that most lymphoproliferative lesions that appear to be immunologically polyclonal actually harbor small monoclonal proliferations of B lymphocytes. However, the finding of monoclonality, by either immunophenotype or molecular genetics, does not predict which tumors will ultimately result in systemic disease.

Management

Because there is considerable overlap among the various lymphoproliferative lesions in terms of clinical presentation and behavior, all patients with hypercellular lymphoid lesions (whether monoclonal or polyclonal) should be examined by an oncologist. Depending on the histologic type of the lesion, the examination may include a general physical examination, a complete blood count, a bone marrow biopsy, CT and/or MRI imaging, a positron emission tomography scan, and serum immunoprotein electrophoresis. The patient should be reexamined periodically because systemic lymphoma may develop many years after the occurrence of an isolated orbital lymphoid neoplasm.

For EMZL and FL, radiotherapy usually results in good outcomes, with 10-year survival rates of 92% and 71%, respectively. DLBCL and MCL have a poorer prognosis, with 10-year survival rates of 41% and 32%, respectively. Treatment of non-EMZL more often involves chemotherapy and immunomodulation in addition to radiotherapy. The optimal dose of radiation has not been established, with published amounts ranging from 20–40 Gy in fractionated doses. A surgical cure is usually not possible because of the infiltrative nature of lymphoid tumors. Alternative treatments include targeted therapies such as rituximab for CD20-positive lymphomas.

The management of low-grade lymphoid lesions that have already undergone systemic dissemination is somewhat controversial, because indolent lymphomas are generally refractory to chemotherapy and are associated with long-term survival, even if untreated. Many oncologists take a watchful waiting approach and treat only symptomatic disease.

• Andrew NH, Coupland SE, Pirbhai A, Selva D. Lymphoid hyperplasia of the orbit and ocular adnexa: A clinical pathologic review. Surv Ophthalmol. 2016;61(6):778–790.

• Olsen TG, Holm, F, Mikkelsen LH, et al. Orbital lymphoma—an international multicenter retrospective study. Am J Ophthalmol. 2019;199:44–57.

• Yen MT, Bilyk JR, Wladis EJ, Bradley EB, Mawn LA. Treatments for ocular adnexal lymphoma. A report by the American Academy of Ophthalmology. Ophthalmology. 2018;125(1): 127–136.

Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.