Ординатура / Офтальмология / Английские материалы / Ocular Pathology_6th edition_Yanoff, Sassani_2009

TABLE 14.3 Diagnostic Criteria for Extranodal Lymphomas

(From Salhany KE, Pietra GC: Am J Clin Pathol 99:472, 1993.)

2.Lymphomatoid granulomatosis is an uncommon, often fatal, lymphoreticular disease that primarily involves the lungs, skin, and central nervous system.

3.Ocular findings are usually lid lesions, but also reported are uveitis, scleritis and episcleritis, central retinal artery occlusion, and peripheral vasculitis.

4.Histologically, an angiocentric pattern of polymorphic cellular infiltrate (atypical mononuclear cells, plasma and plasmacytoid cells, epithelioid cells, inflammatory giant cells) is seen invading blood vessels (necrotizing vasculitis)

VII. Inflammatory pseudotumor†—any nonneoplastic, spaceoccupying orbital lesion that presents clinically as a neoplasm (Table 14.3)

Rarely, the tumors can extend beyond the orbit, intracranially or into the sinuses.

A.The signs and symptoms include pain, proptosis, chemosis, lid swelling, and ductional (motility) defects.

Similar findings occur in carotid–cavernous fistula, infectious cellulitis, metastatic neoplasm, cavernous sinus thrombosis, and Graves’ ophthalmopathy.

B.On the basis of combined histologic and immunologic information, these tumors show unequivocal chronic inflammation, either granulomatous or nongranulomatous.

C.Chronic granulomatous

1.Foreign body

2.Ruptured dermoid

3.Fat necrosis or lipogranuloma

4.Sarcoidosis

5.Tuberculosis

6.Many others (see Chapter 4)

D.Chronic nongranulomatous

1.Inflammatory—localized (Fig. 14.42)

a.Most inflammatory pseudotumors are idiopathic (also called idiopathic orbital inflammation), are usually unilateral but often are bilateral, have an equal sex incidence, and mostly occur in the fourth, fifth, and sixth decades.

b.The histologic presentation may be quite varied.

1). Inflammatory pseudotumor is probably an abnormal response pattern with multiple causes, involving predominantly a fibrohistiocytic cell [vimentin and CD68

(KP-1)-positive].

2). The hallmark is the following histologic tetrad:

a). Cellular polymorphism (i.e., di erent types of inflammatory cells, including lymphocytes,non-Dutcher body-contain- ing plasma cells, histiocytes, and eosinophils).

b). Lymphoid follicles with germinal centers.

Mitotic figures are normally found in the germinal centers of lymphoid follicles. Although lymphoid follicles are highly suggestive of inflammatory pseudotumors, they may occur in small B-cell lymphomas [e.g., mucosal-associ- ated lymphoid tissue (MALT) lymphomas].

c). Absence of atypia.

Absence of atypia, however, can also occur in small B-cell lymphomas.

d). Ancillary evidence of inflammation (e.g., plasmacytoid cells, Russell bodies, and proliferation of capillaries with swollen, enlarged endothelial cells)

3). The response can be cellular, or predominantly collagen and relatively acellular.

4). The response can also involve mainly ocular muscles (myositis), the lacrimal gland (dacryoadenitis), or the orbital vessels (vasculitis), or result from changes in a pre-existing hemangioma with hemorrhage, organization, and inflammation.

c.Idiopathic sclerosing inflammation of the orbit

1). Idiopathic sclerosing inflammation is a clinicopathologic entity, similar to retroperitoneal

fibrosis, characterized by primary, chronic, and immunologically mediated fibrosis, poor response to steroid therapy or radiation therapy, and frequent visual disability.

2). Histologically, the fibrosis appears consistently and early.

2.Inflammatory—part of systemic disease

a.Graves’ ophthalmopathy

b.Sjögren’s syndrome

c.Abnormalities of IgA, IgG, or IgM serum fractions (polyclonal), and may be associated with inflammation and PAS-positive inclusions called

Dutcher bodies (see Fig. 14.43D).

Dutcher bodies appear as intranuclear inclusion bodies but are cytoplasmic invaginations of immunoglobulin into the nucleus. Usually, if Dutcher bodies are found, the lymphoma is malignant.

d.Kimura’s disease (angiolymphoid hyperplasia with eosinophilia)‡

1). Kimura’s disease is characterized by single or multiple painless, subcutaneous tumors of the head and neck in young Asian males; the orbit is rarely involved.

2). Increased serum IgE levels and peripheral blood eosinophilia are common.

3). Histologically, vascular hyperplasia with plump endothelial cells is accompanied by varying degrees of mixed cellular infiltrate, usually a significant number of eosinophils in a background of lymphoid cells.

Kimura’s disease and epithelioid hemangioma, also called angiolymphoid hyperplasia with eosinophilia

(see later) are two different distinct clinicopathologic entities. Kimura’s disease occurs almost exclusively in Asian men and shows florid lymphoid infiltrates with formation of prominent lymphoid follicles, germinal center necrosis and vasculariza-

tion, marked eosinophilia with or without abscess formation, proliferation of cuboidal endotheliumlined venules, and focal fibrosis. Epithelioid hemangioma occurs in all races, has smaller lesions, and is characterized by exuberant proliferation of “epithelioid” endothelium-lined vessels with irregular nuclei and cytoplasmic vacuoles, supported in a fibromyxoid stroma containing infiltrates of small lymphocytes and eosinophils.

e.Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia)‡

1). Epithelioid hemangioma is a benign vascular tumor typically occurring in middle-aged women.

2). A small proportion of patients have regional lymphadenopathy and peripheral blood eosinophilia.

3). Histologically, the lesions are mainly vascular and show characteristic plump endothelial cells that contain abundant eosinophilic cytoplasm and have scalloped borders, simulating epithelial cells (plump epithelioid cells), lining blood vessels and protruding into the lumina.

VIII. Malignant lymphoma† (Figs 14.43 to 14.46; see Tables 14.3 and 14.4)

A.Among extraconal orbital tumors, 22% are reactive lymphoid hyperplasia and 20% are malignant lymphoma.

In one study, 20% of orbital lymphoid lesions were idiopathic chronic inflammation, 40% were lymphoid hyperplasias, and 40% were lymphomas. The relative percentage of B cells in the various lesions was inflammation, 35%; hyperplasia, 65.9%; and lymphoma, 87.3%. If one considers ophthalmic and intraocular

non-Hodgkin’s lymphoma, 42% are intraorbital and 35% are conjunctival. There may be a high incidence of orbital malignant lymphoma among Japanese patients. About 3% of patients who have chronic lymphocytic leukemia develop non-Hodgkin’s syndrome (usually large B-cell lymphoma); this sequence of malignancies is called Richter’s syndrome. In general, ocular involvement with chronic lymphocytic leukemia is rare.

1.Orbital lymphomatoid lesions usually present as a palpable mass with proptosis, diplopia, and conjunctival (“salmon-pink”) swelling. Uncommon presentations include ptosis.

B.Reactive lymphoid or plasma cell hyperplasia (see Fig. 14.43)

1.Although previously classified as inflammatory pseudotumors, these tumors are in the “gray zone” and are very di cult to di erentiate histologically from malignant lymphomas (or plasmacytomas), and probably many, if not most represent small

B-cell lymphomas.

They probably represent approximately 11% of the cases of lymphoproliferative lesions of the ocular adnexa.

2.“True” reactive lymphoid hyperplasia usually consists of a virtually pure lymphoproliferative lesion of small lymphocytes that, by immunophenotyping and immunogenotyping, shows a polyclonal T- and B-cell infiltrate and an absence of Dutcher bodies; mitoses, if present, are restricted to germinal centers where macrophages contain scattered debris (tingible bodies).

a.Reactive lymphoid follicles reminiscent of normal lymphoid architecture are usually seen within the infiltrate.

b.No polymorphism or ancillary evidence of inflammation occurs.

c.The tumors lack anaplasia. C. Non-Hodgkin’s lymphoma—B-cell

1.The following diagnostic criteria point to malignant extranodal B-cell lymphoma:

a.The absence of the following histologic tetrad:

1). Cellular polymorphism (i.e., di erent types of inflammatory cells, including lymphocytes, non-Dutcher body-containing plasma cells, histiocytes, and eosinophils)

2). Lymphoid follicles with germinal centers.

Mitotic figures are normally found in the germinal centers of lymphoid follicles. Although lymphoid follicles are highly suggestive of inflammatory pseudotumors, they may occur in small B-cell lymphomas (e.g., MALT lymphomas).

3). Absence of atypia.

Absence of atypia, however, can also occur in small B-cell lymphomas.

4). Ancillary evidence of inflammation (e.g., plasmacytoid cells, Russell bodies, and proliferation of capillaries with swollen, enlarged endothelial cells)

b.Formation of a mass, tissue architectural e acement, cellular monomorphism, cytologic atypia, presence of proliferative centers, and plasma cells containing Dutcher bodies are all features of low-grade B-cell lymphomas.

c.Immunoglobulin light-chain restriction or an aberrant B-cell phenotype are immunologic features that, if demonstrated, help to support a

malignant diagnosis.

1). A ratio of κ/λ immunoglobulin light-chain-

expressing B lymphocytes in excess of 5 :1 or less than 0.5 :1 indicates a monoclonal κ or

λB-cell population.

2). In general, CD5+ B-cell proliferative disorders are considered to be malignant.

1.Immunoglobulin light-chain restriction is accepted as a marker of clonality in identifying B-cell lymphomas.

Abnormal chromosome translocations are important mechanisms in the pathogenesis of non-Hodgkin’s lymphoma, especially translocations involving the region of the immunoglobulin heavy-chain gene on band 14q32.

2.Small B-cell lymphomas can be classified in many ways.

a.Kiel classification of nodal, low-grade B-cell lymphomas composed of small B cells with a minority of blast cells: chronic lymphocytic leu-

kemia, centrocytic (mantle cell) lymphoma, centroblastic/centrocytic lymphoma, MALT or bronchial-associated lymphoid tissue, lymphoma/immunocytoma/monocytoid B-cell lymphoma, and unclassified. In the World Health Organization classification, system MALT lymphomas are classified as extranodal marginal-zone lymphomas.

1). Primary orbital lymphomas have a favorable prognosis.

2). A high percentage of them have clinical, pathologic, and biologic MALT characteristics.

a). Clinically, MALT tumors arise in extranodal sites from postgerminal center memory B cells, mainly mucosal.

b). Nongastric marginal-zone B-cell lymphomas present in a single site in 90% of cases. The most frequent such locations are: skin (26%), salivary glands (18%), orbit (14%), Waldeyer’s ring (13%), and 39% and 28% have nodal involvement and bone marrow involvement, respectively.

c). Pathologically, the tumors recapitulate Peyer’s patches (i.e., reactive follicles), marginal-zone or monocytoid B cells, plasma cells, occasional Dutcher bodies, scattered transformed blasts (entoblasts and immunoblasts), and sometimes epithelial lesions in the form of lymphoepithelium.

The tumor cells are CD5–, CD10–, cyclin D1–, CD23 and CD43-variable, and proliferating cell nuclear antigen (PCNA) KI 67+.

TABLE 14.4 Morphological, Immunophenotypic, Molecular-Biological and Clinical Characteristics of the 5 Lymphoma Subtypes Presented

•Possibly “Follicular Colonization”

•Possibly “Lymphoepithelial lesions”

•Often multifocal growth

577 tumors other and Neoplasms

TABLE 14.4 Continued

*These results arise from investigations of Non-Hodgkin lymphomas in other locations. **Rearrangements demonstrable only in 50–70% of cases due to presence of somatic mutations.

EMZL = Extranodal marginal zone B-cell lymphoma; DLBCL = Diffuse large cell B-cell lymphoma+; FL = Follicular lymphoma; BL = Burkitt lymphoma; HL = Hodgkin’s lymphoma; NHL = Non-Hodgkin’s lymphoma; FDC-MW = follicular dendritic cell meshworks; Ig-L = Immunoglobulin Light chain: Ig-H = Immunoglobin Heavy chain; EBV = Epstein-Barr Virus.

(From Coupland SE, Hummel M, Stein H: Ocular adnexal lymphomas: five case presentations and a review of the literature. Surv Ophthalmol 47:470, 2002, with permission from Elsevier.)

Orbit :14 .Ch 578

d). Biologically, the tumor cells are B cells, proliferate in mucosal and other extranodal sites, and usually show reactive germinal centers, often interacting with epithelium.

1). Chronic antigenic stimulation, particularly in the setting of chronic infection, may contribute to the development of these lesions.

e). Rarely, MALT tumors can present as a scleritis.

f ). These lesions are radiosensitive, with orbital lesions and ocular adnexal lesions demonstrating a high rate of complete response to radiotherapy.

g). Somatostatin receptor scintigraphy may be helpful in the staging and noninvasive therapy-monitoring in extragastric MALT-type lymphoma irrespective of the site of presentation.

b.Modified Rappaport and the working formulation classification of di use B-cell lymphomas composed of small to medium-sized B cells: well-di erentiated lymphocytic lymphoma (without bone marrow involvement) or well-dif- ferentiated lymphocytic leukemia (with bone marrow involvement), intermediate lymphocytic lymphoma, and poorly di erentiated lymphocytic lymphoma (small cleaved-cell lymphoma)

c.Others classify small B-cell lymphomas in different ways [e.g., Pangalis: small lymphocytic

(well-di erentiated) non-Hodgkin’s lymphoma, lymphoplasmacytic lymphoma (Waldenström’s macroglobulinemia), and chronic lymphocytic leukemia].

d.Obviously, the perfect classification does not yet exist, but the World Health Organization has completed a “consensus” classification of hematologic malignant lymphomas, which is a modi-

fication of the Revised European American

Lymphoma (REAL) classification.

The use of in vitro immunologic and immunohistochemical techniques can aid in the diagnosis of orbital lymphoreticular neoplasms by demonstrating immu-

nologic markers. Most lymphoid malignancies in adults have been shown to be B-cell (e.g., CD19+, CD20+, and CD22+). For example, non-Hodgkin’s lymphoma of the central nervous system (reticulum cell sarcoma) is

composed of B cells at least 70% of the time, T cells (e.g., CD2+, CD3+, CD4+, CD5+, and CD7+) approximately 20% of the time, and histiocytes (e.g., CD1+, CD4+, CD11b+ and CD11c+, CD14+, CD15+, and CD45+) less than 10%. The most common acute lymphoblastic leukemia in children does not have demonstrable immunologic markers (null cell). More than 90% of T- cell lymphomas, mantle cell lymphomas (MCLs), B-cell small lymphocytic lymphomas, and Burkitt’s lymphomas are positive for CD43.

e.According to Bertoni and Zucca, at least three di erent, apparently site-specific, chromosomal translocations, all a ecting the NF-kappaB pathway, have been implicated in the development and progression of MALT lymphoma.The most common is said to be the translocation t(11;18)(q21;q21), which is present in more than one-third of cases, but is rare in the conjunctiva and orbit. Among MALT lymphomas screened by Streubel and colleagues for translocations t(11;18)(q21;q21), t(14;18)(q32;q21), and t(1;14)(p22;q32), and trisomies 3 and 18, these translocations occurred mutually exclusively and were detected overall in 13.5%, 10.8%, and 1.6% of cases respectively; trisomy 3 and/or 18 occurred in 42.1%. t(14;18)(q32;q21) was most commonly found in lesions of the ocular adnexa/orbit, skin, and salivary glands, and trisomies 3 and 18 each occurred most frequently in intestinal and salivary gland MALT lymphomas. Another study of orbital MALT lymphoma found aneuploidy in six of 10 cases studied, and gains were more frequent than losses. Duplications of chromosome 3 (common region at 3q24-qter), which is said to be expected in mar- ginal-zone lymphoma, and chromosome 6

(common region at 6p21.1–21.3), which is said to be typical of an orbital location, were the most frequently detected.

3.Other B-cell lymphomas (mixed small and large cell, large cell, large cell–immunoblastic, angioimmunoblastic lymphadenopathy). Spontaneous regression of a large B-cell-type lymphoma of the conjunctiva and orbit has been reported.

a.Burkitt’s lymphoma (see Fig. 14.45)

1). Burkitt’s lymphoma (a di use, poorly di erentiated, large B-cell lymphoma) is the most common malignant tumor among children in tropical Africa (it is the most common orbital tumor in Uganda, regardless of age); its distribution, however, is worldwide. It is one of the fastest-growing malignancies in the pediatric population in the United States.

a). It can be subdivided into African (endemic), sporadic, and human immuno- deficiency-associated subtypes.

Burkitt’s lymphoma and diffuse large B-cell lymphoma constitute the majority of nonlymphoblastic lymphomas in the pediatric population.

2). The tumor has a predilection for the face and jaws, and may be induced by an insect-vec- tored agent.

The incidence of Burkitt’s lymphoma is markedly increased when associated with infection with the malarial organism Plasmodium falciparum.

3). The c-myc oncogene is rearranged in Burkitt’s lymphoma so that one of the immunoglobulin genes is brought in proximity to c-myc and disrupts its normal regulation.

Considerable evidence has been accumulated associating a herpesvirus, the Epstein–Barr virus (see p. 63 in Chapter 3), with Burkitt’s lymphoma, probably by its role in the development of the point mutations in the c-myc area.

4). The prognosis for life is poor.

5). Histologically, the tumor shows tightly packed, undi erentiated, large B-type lymphoid cells and scattered large histiocytes that contain abundant, almost clear cytoplasm and phagocytosed cellular debris.

Burkitt’s lymphoma and diffuse large B-cell lymphoma have distinctive immunohistochemical profiles. Staining for c-myc, MIB-1, and bcl-2 may be useful in morphologically difficult cases.

b.Mantle cell lymphoma (MCL)

1). MCL represent about 6 to 7% of all nonHodgkin’s lymphomas.

2). It is a disease mainly of the elderly and has a male preponderance.

3). Immunohistochemical staining is generally positive for CD20 and cyclin-D1; CD5 is positive in about 70% of cases, and p53 is negative in most cases.

4). MCL presenting in the ocular adnexal region is associated with advanced-stage disease and short progression-free survival, but an overall survival similar to MCL at other sites.

c.Cutaneous precursor B-cell lymphoblastic lymphoma is rare but has presented with orbital bone involvement.

1). Immunohistochemical staining was positive for CD79a and CD43 in all six cases in one report. Cell marker studies by flow cytometry are positive for CD10 and CD19.

4.The majority of extranodal non-Hodgkin’s lymphomas, including those that involve the orbit, are of the B-cell variety (conversely, most that involve the skin are T-cell).

5.A morphologic progression of low-grade, small B- cell lymphoma to di use, large-cell lymphoma is well recognized.

D.Non-Hodgkin’s lymphoma—T-cell‡

1.No single immunologic clonal marker has been identified for malignant T-cell disorders.

a.Molecular hybridization studies have shown that rearrangements of the T-cell receptor β- chain gene provide a practical means of identifying clonal T-cell proliferations.

b.Although antibodies such as CD3 and CD4 (OPD4) are very specific for T-cell neoplasms, they may recognize only 60% to 70% of T-cell lymphomas. Other antibodies used to identify

T-cell processes, such as CD43 (L60, Leu-22, MT-1), CD45RA (MT-2), CD45RO (UCHL- 1), and CD5, su er from a lack of specificity.

Primary localized skin lymphomas that have a predominance of anaplastic Reed–Sternberg-like cells and CD30 positivity appear to have a better prognosis than many other large cell cutaneous lymphomas. More than 90% of T-cell lymphomas, MCLs, B-cell small lymphocytic lymphomas, and Burkitt’s lymphomas are positive for CD43.

2.Non-Hodgkin’s T-cell lymphomas can be divided into three groups:

a.Those derived from prethymic and thymic T cells (lymphoblastic lymphoma/leukemia)

Lymphoblastic lymphoma/leukemia (T-cell leukemia/ lymphoma) has an association with a retrovirus, the human T-lymphotropic virus type I (HTLV-I). It has presented with bilateral orbital tumors.

b.Those derived from postthymic or peripheral T cells (called peripheral T-cell lymphomas) and composed of a morphologically and immunologically heterogeneous group of lymphoproliferative disorders (T-cell chronic lymphocytic leukemia, T-prolymphocytic leukemia, monomorphous T-cell lymphoma, immunoblastic T- cell lymphoma)

Immunohistochemistry has shown that the following appear to be abnormal or neoplastic T-cell lymphoproliferative disorders: benign lymphocytic vasculitis, lymphomatoid granulomatosis, midline malignant reticulosis, angiocentric lymphoma, and many cases of angioimmunoblastic lymphadenopathy. NK/T-cell malignancies are uncommon and were previously known as polymorphic reticulosis or angiocentric T- cell lymphomas. The World Health Organization further divides these lesions into NK/T-cell lymphoma (nasal and extranasal) type and aggressive NK-cell leukemia.

c.Mycosis fungoides and Sézary’s syndrome are special forms of cutaneous T-cell lymphomas that have a relatively protracted course (see Fig. 14.46).

1). The neoplastic T cells most typically express a CD3+, CD4+, CD8−, CD7− surface phenotype, although exceptions may occur.

The proliferating small lymphocytes show cerebriform nucleI.