Neoplastic lymphoproliferation in autoimmune disease: an updated review

CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY

Vol. 63, No. 3, June, pp. 205-213, 1992

SHORT ANALYTICAL REVIEW

Neoplastic Lymphoproliferation in Autoimmune Disease: An Updated Review

VKMA SANTANA,’ AND NOEL R. ROSE

Department of Immunology and Infectious Diseases, The Johns Hopkins University, School of Hygiene and Public Health, 615 North Wolfe

Street, Baltimore, Maryland 21205

INTRODUCTION

At the present time, autoimmune diseases (AD) represent a vast group of immunoregulatory disorders af- fecting almost any organ or system in the body. Re- markably, the list is still growing, as better knowledge of the intricacies of the immune functions is acquired with the help of molecular immunology techniques.

A growing awareness that malfunction of the immune system in AD may prepare the scene for lymphoid malignancies has led to an increasing number of reports documenting that association since we last reviewed this topic (1). Of all the AD studied so far, the two outstanding examples of the intimate relationship with malignant lymphoproliferative disease (MLPD) are autoimmune thyroiditis and Sjogren’s syndrome (SS). Other, less prominent, associations will be dis- cussed later.

Autoimmune Diseases Associated with Lymphoid Malignancy

Hashimoto thyroiditis. Chronic lymphocytic thyroiditis, autoimmune thyroiditis, and Hashimoto thyroiditis (HT) are synonyms for an AD-induced hypo- thyroidism and goiter. Infiltrating small lymphocytes have been observed to display reactivity against various components of the thyroid gland, translated into the production of autoantibodies against thyroglobulin and thyroid peroxidase (2). A close relationship has been described between HT and other AD such as myasthenia gravis (MG), insulin-dependent diabetes, SS, Graves’ disease (GD), and pernicious anemia, suggesting that in all of these conditions there is an underlying disruption of immunoregulation.

Equally intriguing is the well-documented fact that there is an increased (up to 75fold) risk of MLPD, es- pecially malignant lymphoma, in HT (3-5). The tumors described are of the B-cell type non-Hodgkin’s lymphoma (NHL), with histology ranging from follic-

1 To whom correspondence should be addressed at P.O. Box 121, Augusta, Georgia 30903.

ular lymphomas to diffuse lymphomas (6). Conversely, 80% or more of the patients diagnosed as having primary lymphoma of the thyroid had, on closer examination, histologic evidence of an underlying HT (6-8). In one series of patients, preexisting identifiable HT was a favorable prognostic factor (9). The two diseases seem to be so intermingled that it is often quite difficult, if not impossible, to distinguish between them on a histologic basis alone. Immunohistochemistry and flow-cytometric analysis have been used to help in ar- riving at the correct diagnosis. Light-chain Ig restriction was found in some cases of histologically established HT. While some investigators think that such a finding is enough to change the diagnosis from HT to low-grade lymphoma (lo), others believe that clonal restriction does not necessarily indicate malignancy. The latter investigators use the term “prelymphoma” only when monoclonal cytoplasmic Ig and atypical cells are present in an otherwise characteristic HT histology (11). Monoclonal antithyroglobulin autoantibodies have been found in the sera of several patients (12). In one instance, monoclonal antibody was appar- ently produced within the thyroid itself and disap- peared after thyroidectomy (13).

In order to investigate further the extent of the association, genotypic analysis using Southern blot and DNA hybridization has recently been carried out in a series of patients with HT and B-cell lymphoma. Re- stricted immunoglobulin (Ig) gene rearrangements were found only in the histologically diagnosed lymphoma cases. However, uncomplicated cases of HT showed limited T-cell receptor usage, suggesting, among other possibilities, that the immune response of T cells can sometimes be clonally restricted (14). Yet, primary T-cell lymphomas of the thyroid are extremely rare.

Since HT is a chronic disease and malignancy of low- grade type may also run a slow course, perhaps it is not surprising to find discrepancies between the presence of monoclonality and typical HT histology. Needle biopsies or frozen tissue specimens, obtained during sur-

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206 SANTANA AND ROSE

gery, may not reflect the entire picture of the alter- ations taking place in the gland. Sometimes a biopsy of one lobe shows malignant lymphoma, whereas biopsy of the other shows a classic histologic picture of HT (3). Computerized tomography (CT) scanning of the gland can be helpful both in the diagnosis and in the orien- tation for the needle biopsy. One report describes that CT scanning of the gland in 15 patients with thyroid lymphoma demonstrated that 80% had an isolated nod- ule; the remainder had either several nodules or diffuse goitre aspect. On histologic examination, all of them showed underlying HT (5).

After so much accumulated evidence, there is little doubt that thyroid lymphoma may represent the end result of HT. Difficulty remains in making the appropriate diagnosis as early as possible in order to improve prognosis. Open-needle biopsies or CT scan-oriented biopsies carried out at reasonable intervals during the clinical follow-up seem essential. Since restricted Ig light chain is a strong indicator of clonal predomi- nance-a hallmark of B-cell malignancy-HT patients in this group deserve genotypic analysis and closer ob- servation. More important, HT represents fertile ground from which to learn where autoimmunity ends and lymphoid malignancy begins.

Sjiigren’s syndrome. Sjogren’s syndrome (SS) is an autoimmune exocrinopathy manifested by a local infiltration and proliferation of lymphocytes in the salivary and lacrimal glands, with consequent mucosal and con- junctival dryness (keratoconjunctivitis sicca or sicca syndrome) (15). The disease can also be generalized, with systemic polyclonal B-cell infiltration of many or- gans, both lymphoid (lymph nodes, bone marrow, spleen) and nonlymphoid (16-18). Other autoimmune syndromes or fully developed AD have been associated with SS, particularly rheumatoid arthritis (RA). Mixed connective tissue disease, with a variety of autoantibodies and elevated serum Ig, may complicate the clinical picture (16).

The incidence of malignant lymphoproliferations in SS is the highest among all AD. Waldenstrom macro- globulinemia, chronic lymphocytic leukemia (CLL), light-chain myelomas and other IgG and IgA monoclonal gammopathies have been reported to be associated with SS, but malignant lymphoma of the NHL variety is by far the predominant tumor (19-22). The risk of occurrence of B-cell NHL in SS was estimated to be almost 50 times greater than in age-matched control subjects (20). Quite a wide spectrum of lymphoid proliferations occurs in the parotid gland. The clinical and histological pictures in SS are even more varied than in HT. All grades of cellular atypia can happen in the tissues involved. For this reason, SS has been referred to as “cross-roads disease” (23). The histologic picture goes from “reactive” adenitis to “atypical cellularity,” followed by “pseudolymphoma,” low-grade and high-

grade malignant lymphomas (24). The term pseudolymphoma has been used to describe extra-glandular tumor-like aggregates of lymphoid tissue that do not meet the histologic criteria for malignancy. Some believe that pseudolymphoma is already a form of low- grade malignant lymphoma.

The lymphoid infiltrate, both in the exocrine glands or elsewhere, may remain in its reactive form of benign hyperplasia for a long time. It is not known why or when the purely autoimmune histological picture starts to change. Yet it does change quite frequently and repeated investigations may reveal the presence of a pseudolymphoma or even of a high-grade lymphoma, with poor prognosis. Pulmonary complications are common in SS, as the lymphocytic infiltration can produce diffuse interstitial lung disease. About one-fifth of the patients with SS and NHL have lung involvement (25, 26).

The low-grade lymphocytic lymphomas run an indolent course, whereas the more frequently found lymphoblastic sarcomas are very aggressive (17,27,28). A less common type of tumor has also been described- the lymphoplasmacytoid lymphoma, in which amyloid deposition is found in various tissues (29, 301. In one such case, in which HT was also present, the tumor cells evolved from the production of a single monoclonal protein (IgM-K) to three monoclonal proteins (IgG- K, IgA-K, and IgM-K), suggesting that the lymphoplasmacytic cells, within the same clone, had under- gone distinct stages of differentiation (30). A recently reported case of mixed connective tissue disease de- serves mention. The pathologic condition spanned 20 years, during which idiopathic thrombocytopenia (ITP), SS, HT, and MG were diagnosed in succession. The clinical picture culminated in a lymphoplasmacytoid lymphoma, with amyloid deposition (containing A light chains) in the parotid glands, muscles, and gums (31). In addition, the recently described rare form of low-grade B-cell lymphoma, called monocytoid B-cell lymphoma, shows a remarkable association with SS (32).

Although the overwhelming majority of NHL in SS are B-cell lymphomas, an increasing number of T-cell malignancies have been reported recently (28, 33-37 ). The available methodology to identify T-cell receptor gene rearrangements, together with phenotyping re- agents, are necessary tools to correctly identify T-ceil lymphomas.

Autoimmune hemolytic anemia. Many studies have shown that erythrocytes are indeed targets for autoantibodies, either before or after the onset of a lymphoid malignancy (38). Sometimes, overt hemolysis is not present and patients are clinically free of symptoms, but strong hemolysis is not uncommon (39-42). The “cold’‘-reacting variety of antibodies secondary to MLPD is typically monoclonal in nature and produces

LYMPHOID MALIGNANCY AND AUTOIMMUNITY 207

severe hemolysis (42-45). Generally, a relationship of cause and effect between the lymphoproliferation and the autoimmune hemolytic anemia (AHA) is difficult to prove. This link was found in a well-documented case of cold agglutinin disease associated to a B-cell lymphoma; the pathologic cells secreted a monoclonal IgM- K, with antibody specificity directed to the Pr antigen on the patient’s erythrocytes (46). The “warm” variety of antibodies to erythrocytes is more frequently associated with MLPD. It has been reported in Hodgkin’s disease (42, 47, 481, NHL (42) and, quite frequently, with CLL (39, 42, 49-51). They are mostly of the IgG class and can produce severe AHA. A rare case of warm-reacting IgM autoantibody has been described recently in a patient with AHA (52).

Antibodies to other blood cells such as platelets have also been found in association with MLPD. As described for AHA, autoimmune thrombocytopenia (AT) may coincide with the diagnosis of the malignancy or appear before or long after the MLPD has been suc- cessfully treated (48, 53). AT can occur concomitantly with AHA (Evans’ syndrome) in association with the MLPD (54). In acute lymphocytic leukemia (ALL), for example, it can occur with anti-lymphocyte and anti- neutrophil antibodies (55, 56).

Antibodies against granulocytes (agranulocytosis) are less commonly observed in relation to AD or MLPD. Because drugs are frequently involved as part of the treatment of the underlying disease, a firm connection cannot be ascertained (57). In one case, antibodies against autologous ALL leukemia cells were demonstrated at diagnosis in one case, and did not alter with chemotherapy (58). In another reported series of investigations, all patients with adult T-cell leukemia (ATL) had high titers of antibodies against O- phosphotyrosine, a protein detected in the patient’s lymphocytes (59).

Rheumatoid arthritis. Rheumatoid arthritis (RA) is an AD that typically strikes young women, produc- ing severe deformities of the joints. A similar disease in rats, called adjuvant arthritis, implicates a protein of Mycobacterium tuberculosis, that shares antigenic se- quences or shapes with proteoglycans, in the cartilage wall of the joints. Thus, the disease in rats seems to be linked with this organism through “antigen mimicry” (60). Most of the manifestations of RA appear to be due to the products of T cells. Examination of the inflamed joints shows the presence of several cytokines (61).

An increased incidence of MLPD has been described in patients with RA (62). Most of the tumors are of B-cell origin such as NHL, multiple myeloma (MM), and CLL. The relative risk of developing these malignancies in RA has been reported from 2.7 to 15, com- pared to the general population (63, 641, even before any treatment with immunosuppressive drugs. In im- munosuppressed patients, the incidence of NHL is in-

creased lo- to 13-fold (65). Severe deficiency of NK cells and of T cells seems to be a primary feature of non- treated RA and may play an important role in the induction of oncogenesis (66, 67).

Systemic lupus erythematosus. Unlike RA, association of systemic lupus erythematosus (SLE) with MLPD has not been strong, probably because only a few well-controlled studies have been carried out. An- imal models of SLE-the (NZB/NZW)Fl hybrids and MRLlZpr inbred mice-that spontaneously develop lymphoma show strong evidence of an association. However, reports are now growing in number and Hodgkin’s disease and NHL seem to be the major malignancies involved (68, 69). Although the majority of the malignant proliferations reported to be associated with SLE are of B-cell origin, two intriguing cases involving T-cell malignancies have been published recently. One concerned a patient with a 12-year history of SLE who received no previous immunosuppressive treatment. She developed a rare primary T-cell lymphoma of the liver, with CD4+ cells (70). The other case described the discovery of nephritic lupus in a patient with ATL (71). It is possible that a better follow-up of patients with biopsy of enlarged lymph nodes performed at regular intervals may show the real incidence of the association SLE-MLPD.

Vusculitis. The cutaneous vasculitides are a broad, heterogeneous group of diseases which are usually related to a systemic disorder. The most significant ones associated with lymphoid malignancies are the necrotizing vasculitis and the cutaneous granulomatous vasculitis. Most patients have RA and, in the case of cutaneous granulomatous vasculitis, about one-third of them have an association with an MLPD (72, 73). A recent publication describes the connection between necrotizing vasculitis in adult celiac disease and T-cell lymphoma (74).

Immunoproliferative Diseases with High Risk of Lymphoid Malignancy

Autoimmune disease-associated lymphoadenopathy. Several diseases responsible for lymphadenopathies and autoimmune features have been identified and are called collectively autoimmune disease-associated lymphoadenopathy, because they all share similarities in their clinical manifestations and nodal histology. The first one to be recognized was the immunoblastic lymphadenopathy (IBL) or angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) (75, 76). Later, other diseases were identified that are similar, but do not quite meet the criteria for the diagnosis of IBL. The general clinical picture includes fever, weight loss, generalized lymphadenopathy, and hepa- tosplenomegaly. The basic histological findings are a florid lymphoplasmacytic and immunoblastic prolifer-


ation, with a few variations in pattern (77-79). The most common and characteristic laboratory findings are polyclonal hypergammaglobulinemia, with circu- lating immune complexes and cryoglobulinemis. It is important to note that in almost all cases there is evidence of an immune disturbance (indicated by autoantibodies or immune complexes), or of a well- defined AD (SLE, SS, RA, polyarteritis nodosa, or Schonlein-Henoch purpura) (78). They all seem to have in common a basic immunologic deficiency, probably a defective suppressor T-cell function. The most frequently found cause of death is infection, but in many cases there is an elevated incidence of malignant lymphoma, often immunoblastic sarcoma.

Immunoproliferative small intestinal disease or a-chain disease. Of all the heavy-chain Ig diseases described in humans (CX, k, and y), the o-chain disease is the most common. The biochemical defect present in the cx heavy chain is the deletion of part, or all, of the variable region, and of one or two constant region do- mains, usually Cnl. Thus, the heavy chains synthe- sized are abnormally short, the form in which they appear in the serum, urine, or digestive secretions. In some patients these abnormal chains are found only in the cytoplasm of plasma cells (nonsecretory type) (80). Initially described as Mediterranean lymphoma, this a-chain abnormality is now called immunoproliferative small intestinal disease (IPSID), since it is neither confined to the Mediterranean region nor is the lymphoma always present. When the lymphoma- tous process does appear, it is almost exclusively local- ized in the small intestine (81).

The reason why this pathologic entity has been ex- tensively studied in recent years is threefold: (a) the high incidence in patients of the lesser developed coun- tries, with high morbidity and mortality; (b) the spectrum of infection-immunity-lymphoid malignancy that has emerged, with a high incidence of primary lymphomas of the gastrointestinal tract; (c) the evidence, from clinical and epidemiological studies, that this fatal disease can be prevented with appropriate early detection and treatment of malnutrition and infections.

IPSID is prevalent in underprivileged populations in the Mediterranean basin, who live in substandard so- cioeconomic and hygienic conditions. Other affected areas are the Middle East, the Far East, and Africa. Spo- radic cases have been found in South and Central America, Europe and the U.S.A., often among Third World immigrants (reviewed in Ref. (82)). The disease affects chiefly the enteromesenteric system, causing di- arrhea, pain, weight loss, and growth retardation. En- vironmental factors represented by infections and par- asitic infestations seem to be unusually important, possibly representing the precipitating agents in an individual with a predisposed genetic background (83, 84).

The striking feature of this disease is its strong association with MLPD. Early pathological findings in the small intestine show only a benign-looking lymphoid proliferation. The nonmalignant nature of this prelymphomatous stage is supported by reports of cure with treatment of the concurrent infection or, in some cases, spontaneous regression (85). There is only a dense mucosal infiltration by lymphoplasmacytic cells, without atypia. However, monoclonality of this initial infiltrate has recently been demonstrated by Ig gene rearrangements, which implies the malignant potential of those cells (86). As the disease progresses, the plasmacytic cells start to exhibit marked nuclear atypia, and the infiltrate, initially only mucosal, reaches all layers of the small intestine. Later, florid lymphoma supervenes, which typically seldom exceeds abdominal boundaries. The most prevalent type of lymphoma is the immunoblastic sarcoma (Lukes-Collins classifica- tion), which appears to originate in the very cells pro- ducing the abnormal a-chain (87, 88).

IPSID, in summary, represents another of those diseases with a strong inflammatory autoimmune background, where the evolution to malignancy seems to take a progressive, histologically documented course, In addition, because it is possible to prevent it with early diagnosis and treatment, this model to study the infection-autoimmunity-cancer pathway is not only scientifically rich, but clinically rewarding.

DISCUSSION

The mechanisms involved in the “transformation” of a histologically benign lymphoproliferative lesion into a malignant one are intricate because they involve various cells of the immune system able to perform a complex array of different functions. To begin with, suppressor T cells seem to be few in number and defective in function in several AD (89), thus allowing B cells to escape their regulatory control and indulge in unlim- ited proliferation. Suppressor T cells can also be present in higher numbers, as in CLL, a leukemia frequently associated with AD involving blood cells (901. In this context, they are thought to be a hindrance to the helper T cells’ defense against malignancy. In either case, B lymphocytes tend to go into a state of chronic proliferation that is sustained by their auton- omous capacity to secrete B-cell growth factors. Spon- taneous B-cell lines have been obtained from such B cells in SS, for example, without the help of added stim- ulators (91). Uncontrolled expanded B-cell populations seem to be at risk of later developing lymphoid malignancy, even if their “benign” phase can last as long as many years (92).

The link between a reactive immunologic lymphoproliferation and an MLPD is still elusive. Two obser- vations made in the past few years deserve special at- tention because they may be closely related to that association. One was made at a cellular level and deals


with the special characteristics of the CD5 + B cell; the other, at a molecular level, focuses on the presence of monoclonality in AD.

Possible Cellular and Biochemical Links between Autoimmune and Malignant Lymphoid Proliferation

The CD5+ B cell. It is now well established that B-cell oncogenesis has a strong relationship with autoimmunity. In mice genetically predisposed to autoimmune syndrome, a special lineage of B lymphocytes was found that displays strong self-reactivity and secretes numerous autoantibodies. Besides carrying typical B-cell antigens, such cells are characterized by the coexpression of Ly-1 or pan-T cell antigen (93,94), suggesting that they may have progenitors distinct from those of other B cells (95). In humans, the Ly-1 antigen, recently termed CD5, is expressed normally only on 20% of B cells in adult blood and spleen, on 10% of B cells in tonsil, and on more than half of fetal spleen and cord blood B cells (96, 97).

Surprisingly, in more than 90% of the cases, CD5+ B cells were found to be predominant in expanded populations of CLL B cells (96-100). Thus, CLL may represent a monoclonal expansion of self-reactive B lymphocytes-which is not surprising, due to the high frequency of autoantibodies and AD found associated with this LPD. Most of the CLL autoantibodies are directed to mature hematopoietic cells, such as erythrocytes, platelets, and granulocytes (101). Less frequently, AD such as hyperthyroidism, polymyositis, pernicious anemia, RA, chronic active hepatitis, immune complex nephritis and autoimmune neuropathy have been associated with CLL (102-108).

CD5 + B cells are also expanded in 60% of the small lymphocytic lymphomas (SLL) and in 25% of the fol- licular lymphomas (99). Both CLL and SLL cells have been cultured in vitro and their products analyzed for autoantibody activity. The monoclonal obtained had a light chain identical to that of the surface Ig on the original cells. Such Ig, clearly the product of CD5+ B cells, was shown to react with IgG, ssDNA, and ds- DNA, antigen targets often seen in the serum of AD patients (109). Malignant CD5+ B cells from CLL and SLL were also examined with a special panel of monoclonal antibodies specific for cross-reacting idiotypes present in human IgM autoantibodies and in several rheumatoid-factor paraproteins. It was found that those cells expressed a high frequency of cross-reacting idiotypes, suggesting that they carry a restricted set of IgV genes that have not substantially changed from the germline DNA (104, 110).

In conclusion, CD5+ B cells are unique in that the simultaneous expression of B- and T-cell differentiation antigens on their surface is corroborated at the DNA level. Simultaneous clonal rearrangements of

both Ig and T-cell receptors (Y, p, and y genes have been demonstrated by Southern blot analysis.

Evidence points to the likelihood that this special subset of B cells may represent a strong link between an autoimmune state and B-cell malignancies. If true, they should be seriously considered in the pathogene- sis, and possibly immunotherapy, of both .diseases (111).

The significance of monoclonality in AD. In the highly reactive settings where autoimmune phenom- ena are taking place, such as in the parotid gland in SS, the thyroid gland in HT, or the intestinal wall in IPSID, the lymphoid proliferation may proceed at such a tempo that some clones start taking prevalence over others. The initial polyclonal Ig production gradually becomes oligoclonal and eventually monoclonal, i.e., the antibodies are light-chain restricted. This change is very important in the light of our present under- standing of the clonal response to antigen. Normal reaction to antigen involves cells from various clones, with the production of Ig of different heavy and light chains, as the immune response goes on. Therefore, the advent of monoclonality in a hyperactive background should always be the signal that alerts the clinician that a neoplastic insertion or “transformation” is taking place. Recent investigation of focal areas of autoimmune reactivity with classic histology has shown, in some cases, the presence of light chain restriction in both surface and cytoplasmic Ig in B cells and in plasma cells, respectively (112,113). Moreover, analysis of the patients’ serum Ig revealed the same light chain bias (114). The Southern blot analysis with DNA hybridization technique has confirmed monoclonality by the demonstration of Ig rearrangements of either K

or A chains. (Similar monoclonal changes have been described for the T-cell receptor in some clinically “benign” diseases, in which there is polyclonal Ig (Ref. 34, 36).

Because of the above findings, some authors believe that monoclonality can be part of a benign, autoimmune proliferative process, based on the fact that careful analysis of the tissues shows no detectable histologic signs of malignancy. It should be well kept in mind, however, that monoclonality is out of place here. Immune lymphoproliferation in reaction to antigen molecules uses the antibody diversity to their advan- tage and, therefore, are polyclonal. Malignant proliferations are overwhelmingly monoclonal, since an abnormal clone takes over. Monoclonality in seemingly benign lesions might be explained by the fact that some malignant lymphomas have an indolent progres- sion. Indeed, in a few cases that were followed long enough, malignant transformation, with change from the “reactive” to the “atypical” lymphoplasmacytic or lymphoblastic picture, was documented. The distinc- tion between a reactive lesion and an initial neoplastic proliferation may be very difficult to make from the


histological standpoint, mainly because the accepted criteria for diagnosis of NHL do not apply well to lymphomas from mucosal tissues, such as salivary glands (115). In a few reported cases of SS in which Ig gene rearrangements during the benign phase had been found, some of the patients went on to develop a malignant lymphoma, whereas others still remained sta- tus quo at the time of the publication (116). Only a careful follow-up of the patients will clarify the diagnosis.

Other potential factors. Other mechanisms have been cited to explain the correlation of AD and MLPD. One of them is the decrease in immunosurveillance, substantiated by a defective natural immunity. If NK cells are unable to prevent chronic viral infections, these may be the trigger to an autodestructive cycle (117).

There is no doubt that genetics plays a part by pro- viding selected MHC alleles that allow the development of AD or MLPD, as shown for CLL. In fact, recent evidence suggests that oncogene activation and expression may be intimately involved in both pathologies, probably representing the reason for the initial process of malignant transformation (118).

Finally, the effect of prolonged stimulation on the immune system should not be overlooked. An autoimmune response, where the autologous antigenic stim- ulus continues over a long period of time, produces chronic proliferation of both antigen-specific and non- specific lymphocytes. Autoimmunity, in a sense, acts like a classic promoting agent of carcinogenesis which “stimulatelsl an increase in DNA synthesis and/or cell replication. . . .” (119). In this case, the promotor is specific for lymphoid cells.

CONCLUSIONS

The list of AD is long and continues to grow. At the present time, more than 40 diseases have been so described. Even Beethoven’s medical history has been recently reviewed and all his ailments are now considered to be symptoms of a “rheumatic disorder,” maybe an AD (120).

Early reports could not provide the in-depth infor- mation about the underlying cellular and molecular changes taking place in those diseases and their pathway to malignancy. For this reason, in most AD the correlation with MLPD is still a matter of speculation. This is not the case, however, with SS, HT, and IPSID, where the association is not only clear but strong.

We hope that the important progress made in the past decade will stimulate clinicians and pathologists alike to investigate further the ADMLPD association. It will be necessary to maintain a long-term patient follow-up, make regular biopsies to observe the histological and cytological changes, and use the techniques of molecular biology whenever possible to document

the potential clonal restrictions. The next decade will probably bring us fresh insight to grasp the so-far elusive link connecting the reactive and neoplastic lymphoproliferation.

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Received April 2, 1991; accepted with revision September 24, 1991

Neoplastic lymphoproliferation in autoimmune disease: an updated review

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