Lymphoma
Key Points
Lymphoma is a malignant neoplasm originating from clonal proliferations of monoclonal B cell, T cell, and natural killer cell lymphocytes
The ocular adnexa is involved in 2% of extranodal lymphomas, and 5% of these are located in the eyelid
The majority of eyelid lymphomas are non-Hodgkin B-cell lymphomas
They are associated with several chronic inflammatory disorders, such as chronic infection by Helicobacter pylori in the stomach, and unique genetic abnormalities have been seen in each specific subtype
Most eyelid lymphomas extend from the orbit or conjunctiva; primary eyelid lymphoma typically involves the anterior lamella or preseptal tissues of the skin, subcutaneous tissue, and orbicularis oculi muscle
Symptoms include painless eyelid swelling, epiphora, irritation or pain, ptosis, chemosis, ectropion, and a palpable mass
Treatment of primary cutaneous lymphoma can be with surgery, radiotherapy, or chemotherapy depending upon the subtype and extent of the disease
Prognosis varies and depends on the stage at presentation, tumor histology, primary or secondary status, and whether the tumor is unilateral or bilateral
Lymphoma is a malignant neoplasm originating from clonal proliferations of white blood cells, including monoclonal B cell, T cell, and natural killer (NK) cell lymphocytes. Lymphomas are usually divided into several broad types, Hodgkin and non-Hodgkin. Hodgkin lymphomas (HLs) are uncommon, and the classic form accounts for about 90% of HLs. It arises from a large, abnormal, multinucleated transformed type of B-cell lymphocyte called Reed-Sternberg cell. HLs rarely involve the periorbital region. Non-Hodgkin lymphomas (NHLs) are far more common. They constitute a large heterogeneous group of tumors mostly consisting of B-cell lymphomas (80%), and less frequently T-cell lymphomas (14%) or NK-cell lymphomas (6%), and all can occur in the eyelid.1
Based on the US Surveillance, Epidemiology, and End Results (SEER) database, it is estimated that in 2022 there will be 80,470 new cases of NHL and 20,250 tumor related deaths. Less than 5% of these will be primary cutaneous lymphomas. The incidence of primary cutaneous lymphoma has been increasing, and the condition occurs with an incidence of about four per million persons per year,2,3,4 and cutaneous B-cell lymphomas make up about 25% to 30% of these. The majority of primary cutaneous lymphomas are cutaneous T-cell lymphomas. The highest incidence rates are among males, non-Hispanic whites, and adults over the age of 50 years.5
Lymphomas can occur within lymph nodes or extranodally in a variety of soft tissues. Those involving the ocular adnexa constitute about 2% of all extranodal lymphomas, and 5% of ocular adnexal lymphomas are located in the eyelid.1,6 The majority of eyelid lymphomas are non-Hodgkin B-cell lymphomas, including extranodal marginal-zone lymphoma (EMZL), follicular center cell lymphoma (FCL), and diffuse large B-cell lymphomas (DLBCL), and follicular lymphomas (FCL).7,8,9,10,11 Less common B-cell lymphoma subtypes in the eyelid include lymphoplasmacytic lymphoma/immunocytoma, plasmocytoma, and immunoblastic lymphoma in decreasing freque ncy.8,9,12,13 Burkitt lymphoma very rarely involves the ocular adnexa in children.14,15 The nonendemic form can also occur in adults, typically associated with acquired immunodeficiency syndrome and other forms of immunosuppression.13,16
Adnexal lymphomas of non-B-cell type are uncommon, representing approximately 1% to 3% of all ocular adnexal lymphomas.8,12,17 The majority of non-B-cell lymphomas represent secondary manifestations of a systemic T-cell lymphoma, or they occur as an eyelid extension of mycosis fungoides (MF).17,18,19 Very few cases of primary T-cell lymphomas of the ocular adnexa have been reported in the literature,17,20,21,22,23 although it has been debated whether some of these represent true clonal T-cell proliferations.24
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL-MALT) represents 8% of all NHLs.25 It is the second most common primary cutaneous B-cell lymphoma in the skin, and the eyelid is the third most common site for MALT-type lymphomas (12%) after the gastrointestinal tract (70%), and the lung (14%).25 It comprises about 75% of all ocular adnexal lymphomas of which 46% occur in the orbit, 35% in the lacrimal gland, 10% in the conjunctiva, and 8% in the eyelid.26
EMZL is an indolent lymphoma that accounts for approximately 25% of patients with cutaneous lymphoma.2 The median age at presentation is 50 to 53 years, with a range of 6 to 93 years, and it occurs more commonly in men than in women.27,28,29
FCL is another indolent subtype comprising 60% of primary cutaneous B-cell lymphomas. Patients present at a
median age of 50 years, and it is slightly more common in men than in women. DLBCL, leg type, comprises 10% to 20% of primary cutaneous B-cell lymphomas and usually presents at a median age of 70 to 75 years.2,30 DLBCL is more common in females, and Asians and Pacific Islanders are at increased risk of developing this subtype.31
median age of 50 years, and it is slightly more common in men than in women. DLBCL, leg type, comprises 10% to 20% of primary cutaneous B-cell lymphomas and usually presents at a median age of 70 to 75 years.2,30 DLBCL is more common in females, and Asians and Pacific Islanders are at increased risk of developing this subtype.31
Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma. It originates in the peripheral skin-tropic memory T-lymphocytes.32,33 The incidence is about six cases per million population, it is more common in adults over the age of 50 years, there is a slight male predominance, and it is more common in blacks than in Caucasians and Asians (Chapter 129).34 Sézary syndrome is a related condition in which malignant T cells are present in the blood in addition to skin involvement. It is unclear if this represents an advanced form of MF or a distinct disease.
Etiology and Pathogenesis
Extranodal marginal zone lymphoma (MALT lymphoma) originates from the marginal zone B cells of the mucosa-associated lymphoid tissue. These lymphomas occur at diverse anatomic sites and have been associated with several chronic inflammatory disorders, such as chronic infection by Helicobacter pylori in the stomach, Borrelia burgdorferi in the skin,35 Chlamydia psittaci in the ocular adnexa,36,37,38 and Campylobacter jejuni in the small intestine.39 Evidence suggests that genetic abnormalities and antigenic drive in MALT lymphoma involve dysregulation of the molecular pathways that regulate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB),40 a small family of inducible transcription factors that control transcription of DNA, cytokine production, and cell survival. Recently, a Chinese study on ocular adnexal MALT lymphoma patients showed novel mutations in the IGLL5 gene in 24% of patients, and mutations of MSH6, DIS3, FAT1, and TMEM127 in 10%.40 The exact function of the IGLL5 gene is not known at present, but it encodes a protein that plays a critical role in B-cell development.40
 FIGURE 135.1 Superficial cutaneous lymphoma of the eyelids. B, (Courtesy of Dr. Jurij Bilyk.) |
Genetic abnormalities in lymphomas are unique to each specific subtype. In mantle cell lymphoma (MCL), t(11;14) (q13;q32) translocation and (11)(q21;q23) deletion have been described in more than 95% of tumors.41,42 It leads to overexpression of nuclear cyclin D1, and its upregulation leads to cell cycle progression.43 Genetic abnormalities in EMZL include trisomy 3 and 18, as well as the translocations t(11;18) (q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), and t(3;14) (p14.1;q32).44 Most of these translocations induce the upregulation of proteins that lead to the activation of nuclear factor κB.44 The translocation t(14;18)(q32.3;q21.3) is seen in 34% of DLBCL45 and in 85% of FCL. This translocation leads to upregulation of the BCL2 oncogene and prevents apoptosis.45
In MF, there is a clonal expansion of CD4-positive cells that often lack normal T-cell antigens such as CD7, CD5, or CD2.46 These cells are attracted to the skin by keratinocytes and accumulate in the dermis.
Clinical Presentation
Most lymphomas of the eyelid are secondary extensions from the orbit or conjunctiva and can invade all tissue layers. Primary lymphoma in the eyelid typically involves the anterior lamella or preseptal tissues of the skin, subcutaneous tissue, and the orbicularis oculi muscle (Figure 135.1). In this location primary lymphoma is rare, accounting for only 1% to 2% of NHL.47
Of ocular adnexal lymphomas, 41% occur in the orbit, 31% in the conjunctiva (Figure 135.2), 18% in the lacrimal gland, and 10% in the eyelid.48 The distribution of subtypes for eyelid lymphomas is reported as EMZL (35%-55%), FCL (15%-25%), DLBCL (15%-20%), MCL (8%-12%), and MF (9%).48 This is in contrast to orbital lymphoma where FCL and DLBCL predominate at 63% and 50%, respectively, and in the conjunctiva where EMZL-MALT lymphoma and DLBCL predominate at 41% and 38%, respectively.48 Eyelid and orbital adnexal lymphomas generally affect males more than females (60%-80%), except for EMZL, which has
been reported to predominate in females in 60% to 70%.7,48 Although the disease can be seen at any age, most periocular lymphomas occur in older patients, in the 6th to 8th decades of life. Except for MF, which is typically bilateral, more than 70% of other subtypes in the ocular adnexa occur unilaterally. The AJCC T stage is T3 in the 8th edition, which now stages these tumors according to the anatomic extent of disease.49
been reported to predominate in females in 60% to 70%.7,48 Although the disease can be seen at any age, most periocular lymphomas occur in older patients, in the 6th to 8th decades of life. Except for MF, which is typically bilateral, more than 70% of other subtypes in the ocular adnexa occur unilaterally. The AJCC T stage is T3 in the 8th edition, which now stages these tumors according to the anatomic extent of disease.49
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
