Document 2Raa4E1MJEQ7kEQ741aQrgOmL

CHAPTER FORTY-THREE Non-Hodgkin's Lymphoma and Mycosis Fungoides Mark H. Greene INTRODUCTION Billroth (1871) originally proposed the term "malignant lymphoma" to describe neoplasms of the lymphoreticular system. With the recognition of the Reed-Sternberg cell, Hodgkin's disease was identified as a unique clinicopathologic process that differed from other lymphoreticular malignancies. Plasma cell neoplasms and, more recently, Burkitt's tumor likewise were regarded as distinct diseases. The remain- ing lymphoreticular cancers have come to be known, albeit clumsily, as the non-Hodgkin's lymphomas (NHL). This heterogeneousgroup of tumors is reviewed in this chapter, along with a cutaneous variant, mycosis fungoides. 6 NON-HODGKIN'S LYMPHOMA Pathology The classification of NHL has been a source of great confusion over the years. Until rec ntly, there were three major categories: lymphosarcoma (LSA), reticulum cell sarcoma (RCS), and giant follicular lymphoma (GFL). Although pathologists debated the cellular characteristics that defined each entity, this terminology gained general clinical acceptance, and even today i s the usual basis for NHL morbidity and mortality statistics. For clarification, various new systems were proposed, with that of Rap- paport ( 1966) gaining widespread acceptance among pathologists, because it is practical and reproducible, and among clinicians, because of its prognostic implications. Rappaport separates NHL into two groups: the nodular lymphomas, in which the normal follicular pattern of the lymph node is relatively presetved, and the diffuse lymphomas, in which the normal architecture is effaced. Cytologi- cally, each category i s further divided into lymphocytic (if the malignant cells are small and resemble normal lymphocytes), histiocytic (if the malignant cells are larger, resembling normal histiocytes), and mixed subsets. Lym- phocytic lymphomas are further characterized as poorly differentiated or well differentiated. Lymphomas cytologically similar to Burkitt's tumor that fail to meet its strict diagnostic criteria are classified as undifferentiated, pleo- morphic NHL. In the naturdl history of NHL, the tumors tend to evolve from a nodular to a diffuse pattern and froM a well differentiated to a poorly differentiated cytology (Berard et al, 1976). The relationship between the historical nomenclature and the Rappaport classification is summarized in Table 1, as are the frequencies of the Rappaport subtypes and representative survival data. Nodular and diffuse lymphomas occur in equal proportions, with nodular, poor- ly differentiated lymphocytic lymphoma (NPDL)and diffuse histiocytic lymphoma (DHL) the most common subtypes. When a complete 754 1! 'S LYMPHOMA A UNGOIDES-755 I 756 -CANCER BY TISSUE OF ORIGIN remission follows initial therapy, the prognosis T-lymphocyte origin (see below) (Jaffe and is improved for patients with either nodular or Berard, 1978) and (b) immunoblastic sarcoma, diffuse morphology. Among pa!ients .who a variety of DHL, which is frequently associated achieve a complete remission, those with DHL with prior immune dysfunction in the host are more likely to remain disease-free than are (Lichtenstein et al, 1979). Third, it has become patients with NPDL (Anderson et al, 1977). apparent that the malignant cell in the histiocy- However, nodular lymphomas have a more tic lymphomas is derived from lymphocyte pre- favorable survival overall due to the indolent cursors, and that NHL of truly histiocytic origin course of many patients who fail to achieve a is quite uncommon (Mann et al, 1979). A complete remission. possible exception may be found in gastrointes- Typically, NHL originates in lymph node tinal NHL, in which one-third of a recent series tissue. However, in 15 to 20 per cent of pa- appeared to be malignancies of histiocytes tients, the tumor develops in an extranodal site (Isaacson et at, 1979). (Hande et al, 19771, such as bone (Boston et al, Finally, and most important, the Rappaport 19741, stomach (Stobbe et al, 19661, thyroid classification scheme does not take into ac- (Burke et al, 19771, small or large intestine count the immunologic advances that now per- (Henry, 1977), breast (Wiseman and Liao, mit finer classification of lymphoid cells accord- 19721, or brain (Henry et al, 1974). By defini- ing to their origin and function. As summarized tion, primary extranodal NHL develops in the by Jaffe in a recent symposium (Berard et al, absence of systemic lymphoma and i s associ- 1976) and discussed in detail by Mann et a l ated with a more favorable prognosis than nodal (19791, there are three classes of immunocom- NHL, which tends to be widespread at the time petent cells identifiable by characteristic surface of diagnosis (Hande et at, 1977). membrane markers: T-lymphocytes (of thymic As experience with NHL has accumulated, origin), responsible primarily for cellular immu- deficiencies in the Rappaport classification nity; B-lymphocytes(of "bursal-equivalent"ori- have become apparent. First, its utility is limited gin), which differentiate into antibody- in childhood when nodular lymphomas are producing plasma cells, effectors of humoral extremely uncommon and both h e l l - immunity; and mononuclear phagocytic cells, differentiated lymphocytic and mixed lympho- which have many immunoregulatory func- mas are virtually unknown (Murphy, 1978). tions. Second, it does not provide for several recently These three classes of cells have specific recognized clinicopathologic subtypes, such as anatomic locations within the normal lymph (a) lymphoblastic lymphoma, a variety of NPDL node and provide a conceptual framework for that is cytologically identical to acute lympho- understanding the distribution and origin of blastic leukemia, predominantly affects adoles- various types of NHL (see Fig. 1). Thus, nodular cent males, has a high rate of leukemic transfor- lymphomas represent the neoplastic counter- mation, and (unlike most NHL) seems to be of part of the normal lymphoid follicle; well- Figure 1. Schematic diagram of a lymph node, Illustrating ana- tomic and functional compartments. The malignancies of the lymphoreticular system are conceptually and functionally related to the above compartments.S. sinuses; F , folllcles; PC, paracor- tex; MC, medullary cords. (From Mann et el, 1979.) -NON-HODGKIN'S LYMPHOMA AND MYCOSIS FUNGOIDES 757 i differentiated lymphocytic lymphomas, the counterpart of the medullary cord Blymphocyte; malignant histiocytosis, the true lymphoma of histiocytes, and so on. Most forms of NHL are B-cell neoplasms (see Table 1). In a recent review of 425 NHL cases, 68 per cent were of B-cell origin, and 19 per cent of T-cell origin; 13 per cent had no surface markers; and 1 case was a true histiocytic lymphoma (Lukes et al, 1978).These observations have led to new classifications (for a summary, see Dorfman et al, 1981),which have not yet gained widespread popularity but which will undoubtedly lead to modification, if not replacement, of the Rappaport system. It should be noted that all lymphadenopathy i s not malignant lymphoma. The differential diagnosis of enlarged lymph nodes is extensive, including nonspecific reactive and inflammatory processes, viral and other infections, drug reactions, and rheumatoid disease (Carr et al, 1978). Even under the microscope, some of these processes can be difficult to distinguish from true neoplasia, as evidenced by the socalled "pseudolymphomas" seen in various organs, particularly the lung (Saltzstein, 1963) and stomach (Faris and Saltzstein, 1964). Thus, histologic verification of NHL by experienced pathologists would add credibiI ity to epidemio- logic research into these tumors. Unfortunately, nearly all epidemiologic stud- ies of NHL to date have used the historic nomenclature. In addition, they have included varying combinations of tumors, not only LSA, RCS, and GFL, but also leukemia, Hodgkin's disease, multiple myeloma, and other lymphoproliferative malignancies. Wherever possible in this review, the specific entities included in each study will be identified. When using the International Classificationof Diseases, the term NHL refers to those entities now classified under codes 2 0 0 'and 202 of the 8th revision. "Histiocytic" lymphoma is shown with quotation marks as a reminder that the cell of origin is lymphoid, rather than truly histiocytic; "lymphoma" i s used when multiple lymphoproliferative tumor types are combined. Demography International Patterns' In view of variations in diagnostic practices, international comparisons should be interpreted with caution. LSA is generally more common than RCS, with males having higher rates than Q females for both types. The reported agestandardized (world population) incidence rates for RCS in males range from 0.1 per 100,000 in India to 5.9 in New York State, while thecrates for LSA in females range from 0 . 3 per 100,000 in Germany to 5.5 in Nigeria (Waterhouse et al, 1976). There has been an upward trend in incidence since 1960, especially in Western countries (Stukonis, 1978).The increase ranged from one- to twofold in most countries, and primarily affected older age groups. A surprising increase of 250 per cent was noted for Singa- pore Chinese. A few registries, such as japan and Cali, Colombia, reported decreases in incidence during this time period. United States Incidence N H l is relatively uncommon in the United States, with about 15,000 new cases estimated each year (2 per cent of all cancers) (Anonymous, 1979). Based on the Third National Cancer Survey (1969-1 971), the average annual age-adjusted incidence rates were 5.8 per 100,000for white males, 4.1 for white females and black males, and 2.6 for black females. Overall, the male to female ratio i s 1.4:1 (Cutler and Young, 1975). Age-specific incidence rates for United States whites reveal a pre-adolescent peak followed by a late teenage nadir; rates then rise logarithmically with increasing age (Fig. 2). Between 1960 and 1972, incidence rates in various United States registries also show an upward trend, with residents of Connecticut (107 per cent increase) and native Hawaiians (1 20 per cent increase) having the largest increments (Stukonis, 1978). United States Mortality Based on United States mortality data (1 95019691, the average annual age-adjusted rates were 4.9 per ~00,000for white males, 3.2 for white females, 3.3 for nonwhite males, and 1.9 for nonwhite females (Mason and McKay, 1974).The rates in all groups increased progres- sively with age, though a slight decline was seen in the last age group (Fig. 3). In general, the rates for white males were highest at all ages, followed by rates for nonwhite males before age 65 and white females after age 65. Mortality from NHL in childhood differs by cell type. The rates for LSA rise rapidly between ages 0 and 4 years and reach a plateau from 5 to 18 years, while the rates for RCS rise gradually over childhood. LSA occurs three times more frequently than does RCS prior to age 15 (Grundy et al, 1973). -. - ,B 8 L 1 i 2"4 ,4 5 8* Flgure 2. Average annual agespeciflc incidence rates for NHL per 100,OOO population among white males (closed circles) and white females (open circles) in the United States. (From the Third National Cancer Survey [Cutler and Young, 19751.) Figure 8. Average annual age-specific mortality rates for NHL per 1OO.OOO populatlon among white males (WM, closed circles), white females (WF, open circles), nonwhite males (NM, closed squares), and nodwhite females (NF, open squares) In the United States: 1950-1975. (From Mason and McKay. 1974.) TABLE 2. Average Annual Age-Adjusted Mortality Rates for NHL Per 100,000 Population by Age Group, Race, Sex, and Time, for the United States Age 0-19 20-54 RaceISexA WM WF NM NF WM WF NM NF 1950-7954 8.2 4.6 5.3 3.2 2.6 1.6 2.3 1.3 7955-1059 9.4 4.4 0.2 3.7 2.9 1.e 2.8 1.5 1960-1964 9.4 4.0 6.7 3.8 3.1 2.0 2.8 1.5 1965-1969 8.1 3.6 5.4 3.4 3.3 2.1 2.6 1.7 7970-1975" 6.6 2.6 4.9 2.6 3.0 1.9 2.6 1.5 55+ All ages WM WF NM NF WM WF NM NF 13.7 18.7 18.8 21.0 23.2 9.4 11.5 13.3 15.1 16.3 7.1 10.8 11.3 13.6 14.8 4.1 5.9 6.4 7.4 8.6 3.9 4.6 5.1 5.6 5.7 2.6 3.0 3.4 3.8 3.8 .e2.5 3.9 3.5 3.8 4.0 1.4 i 2.0 2.2 2.3 'WM: white male; WF: white female; NM: nonwhite male; NF: nonwhlte female. bExcludlng 1972(data not avallable). - _. ily ile en nd ed .. - 75" I I -I .% NON-HODGKIN'S LYMPHOMA ' AND MYCOSIS FUNGOIDES -759 Mortality trends in the United States (1950- cases per family. Nearly 80 per cent were sib 1975) are shown in Table 2. Among persons pairs, either sibs alone (63 per cent), including under 20 years of age, mortality peaked in all one pair of monozygous twins (Zachau- groups except white females during 1960- Christiansen and Rasmussen, 19631, G: sibs plus 1964, and then declined 2 per cent per year other relatives (13 per cent). The nialdfemale through 1975 (Mason, unpubiished data). In ratio for familial cases was 1.8 (versus 1.4 in the contrast, mortality among older adults in- general population), while the average age at creased by 2 per cent per year over this 25-year diagnosis was 23.5 years (versus 42.3 in the period, with rates rising somewhat faster in general population). About one-half of the fa- nonwhites than whites. The rate of increase in milial cases with specified origins were extra- NHL mortality in white females is second only nodal (44 cases), primarily involving the gastro- to lung cancer, and in white males it is third, intestinal tract (26 cases). The distal small bowel following lung and pancreatic cancers (Cantor and cecum were most often affected. Cell types and Fraumeni, 1980). Most of the increase were difficult to evaluate owing to varying seems due to RCS rather than LSA (Burbank, diagnostic criteria. One study of several NHL- 1971). Similar increases in NHL mortality have prone families classified all cases using the been reported in Europe (Stalsberg, 1973), Israel Rappaport system (Greene and Miller, 19781, (Abramson and Avitzour, 19751, and the United but found no histologic subtype predominating Kingdom (Smith, 1978a), although the declining overall or within particular families. In the 38 rates in young people have not been seen. The high-risk families, 11 were found after testing to upward trend may be partly related to improve- have evidence of heritable immune dysfunc- ments in diagnosis and classification, but paral- tion, but only 5 could be classified as having a lel increases in incidence data suggest the primary immunodeficiency syndrome (ataxia operation of environmental factors that remain telangiectasia in 2, common variable immuno- to be identified. The declining mortality among deficiency in 2, and Bruton type in 1). young people in the United States can be traced Two general types of high-risk families were in part to substantial improvements in therapy seen. One group consisted of pre-adolescent and survival for childhood NHL (Murphy, male sibships with extra-nodal NHL, primarily 1978). of the gastrointestinal tract. These occurrences Mortality from NHL shows a positive gradient may be related to the rare X-linked recessive with socioeconomic status and urban residence lymphoproliferative syndrome described by (Registrar General, 1958; Curalnick, 1963; Purtilo and coworkers (1975, 1977, 1978). .Hoover et al, 1975). A county by county survey These tumors cover a st>ectrum of B- in the United States revealed elevated mortality lymphocyte disorders, including NHL of the rates in coastal California and the Midwest and immunoblastic sarcoma type and Burkitt's Iym- lower than average rates in the Southeast (Can- phoma, and mononucleosis-likestates. Because tor and Fraumeni, 1980). This pattern may of an inborn immunodeficiency state, the affect- reflect socioeconomic factors, particularly so- ed individuals are unable to regulate lymphoid cia1 class, urbanization, and ethnicity, with responses to Epstein-Barr virus (EBV) infection. higher rates seen in counties with many res- The second group of families consisted of adult idents of Russian (mainly Jewish) or Greek sibs, mainly females, with nodal NHL. The ancestry (Cantor and Fraumeni, 1980). It i s susceptibility of women may be related to noteworthy that the risk of NHL is greater changes in hormonal modulation of lymphoid among Israelis of Jewish background than other function with increasing age, which has been groups in Israel (Waterhouse et al, 1976). observed in some animal systems (Raveche et ai, 1976). Host Factors Primary lmmunodeficiency Syndromes Familial Aggregation Although empirical risk studies have not been done, a literature review uncovered 38 mul- tiple-case families with NHL, excluding lymphohistiocytosis (Ladish et al, 1978) ahd its variants (Table 3). There was a total of 111 family members with NHL, an average of 3 Gatti and Good (1971) surveyed the literature on primary immunodeficiency disorders and estimated that these patients were 10,000 times more likely to develop cancer, especially of the lymphoreticular system, than persons of similar age in the general population. Although reliable risk estimates for lymphoma or other cancers are not available, associations have been clari- Text continued on page 764 I ! NON-HODGKIN'S t YMPHOMA AND MYCOSIS FUNGOIDES -761 5 a3 G L 0 C i .Em .Bm2 E E 8 -cm0 f n0 -m c 760-CANCER BY TISSUE OF ORIGIN z .m- .- cm d -> 0 .- (I, 5 o -c .mm E VI E 5 n Z I If U L I 1 u 11 IUI - m b, 8v) 'XE 2 aI C n 3 -C 0" P .>Q- aQ ! .C- Y 0, '0 0 5 t z0 U UUlAUIUUZ NrD NI. m - 01 8 8 mI(C0 U m ;; UI -- L a, I 4 c # b. L uai % U m U -a L ? 0 t n; NON-HODGKIN'S LYMPHOMA AND MYCOSIS FUNGOIDES-763 E 0mc 0) E c al 0 0 " C c al .m- U -5m5 c c0 x ::m 0 .A mr cmu It. . mm 8 m .I E %w tm . mm NON-HODGKIN'S LYMPHOMA AND MYCOSIS FUNGOIDES - 765 miinized populations. For example, an excess of NHL has been reported in some but not all surveys of persons immunized agairist tuberculosis with BCG vaccine (Skegg, 1978). BCG is considered an "immunostimu1ant, " but its specific effects on various lymphocyte populations in man have not been evaluated. Such data would be useful in understandiqip: po7;iLle mechanisms of lymphomagenesis. Acquired Disorders of Immunity A variety of autoimmune or rheumatoid diseases associated wit h defective imniunity have been related to NHL, although the associations range from controversial to well-established. These diseases are generally characterized by persistent antigenic stimulation and defective regulation of lymphocyte proliferation (Steinberg and Klassen, 1977). In 1967, Oleinick found no increased risk of NHL in patients with rheumatoid arthritis (RA) or systeniic lupus erythematosus (SLE), but a more recent review of the literature suggested that untreated patients are prone to N H L (Louie and Schwartz, 1978). A population-based Finnish study indicated a 2.7-fold risk of NHL in patients with rheumatoid arthritis (Isoniaki et al, 1978), but the possible effects of immunosuppressive therapy were not considered. It has been suggested that acute nonlymphocytic leukemia (rather than NHL) is the major cancer observed in RA patients treated with immunosuppressive/cytotoxic medications (Louie and Schwartz, 1978). Over 100 patients with SLE and lymphoma have been reported (Wyburn- Mason, 1979), but this relationship has not been quantitatively evaluated. Another literature review suggested a relative excess of NHL among cancer patients with dermatomyositis (Barnes, 1976), but this particular disease may be a complication rather than a precursor of NHL. A model study of the type required to evaluate these relationships recently quantified the long-standing suspicion of an NHL excess (relative risk = 44) in patients with Sjogren`s syndrome (Kassan et al, 1978). The risk was great- est in patients with an unusual degree of lymphoid reactivity, manifested by splenome- galy, lymphadenopathy, and parotid enlargement, suggesting that the NHL is a complication of the autoimmune process rather than of treatment. Immunologic mechanisms also appear responsible for the development of extranodal NHL in the thyroid of patients with 1-lashitnoto's thyroiditis (Burke et al, 1977) and in the stom- ach of patients with autoimmune gastritis(Dutz, 1978). Sarcoidosis, a granulomatous disease of unknown etiology, is associated with lymphoid hyper-reactivity, defective celIular i m m mity, and suppressor cell dysfunction (Goodwin et al, 1979). In a Danish follow-up study, six cases developed lymphoma: two with LSA and four with Hodgkin's disease (Brincker and Wilbek, 1974). More striking i s the 100-fold excess o f NHL in patients with celiac disease or glutensensitive enteropathy (Holmes et al, 1976). Gluten sensitivity may provide chronic antigenic stimulation as a stimulus to the DHL that typically develops in the gastrointestinal tract. A variant of celiac disease is dermatitis herpetifor- mis, which appears to share the increased risk of NHL, although based on smaller nunihers (Connon et al, 1975). A number of patients presenting with primary intestinal lyniphonia have underlying celiac disease or derrnatitic herpetiformis, but the manifestations are subtle and easily overlooked (Freeman et al, 1977). This suggests that celiac diseaseldermatitis herpetiformis may underlie a significant fraction of the so-called "Western" variant of primary intestinal lymphoma, a disease of middle-aged males, with tumors arising in the distal s m a l l bowel or proximal large intestine (Lewin et al, 1976). The "Mediterranean" variant of primary in- testinal lymphoma is characterized by an earlier age dt onset (20to 40 years), equal sex risk, inverse correlation with social status, origin in the proximal small intestine, and a pleomorphic cellular pattern, along with diffuse plasma cell infiltration of the bowel wall and often a preneoplastic syndrome known as alpha heavy chain disease (AHCD) (WHO, 1976). In AHCD, the heavy chain proteins normally part of IgA antibody molecules are found free in the serum. The circulating alpha chains are themselves abnormal, while IgA light chains are not synthesized at all, a puzzling observation in view of the independent genetic control of these two proteins (Seligmann, 1975). The socioeconomic patterns and geographic distribution of AHCD in the Mediterranean region and in southwest Asia have implicated environmental factors, particularly enteric path- ogens, and although no one agent has been isolated consistently from these patients, complete remission of AHCD may follow antibiotic therapy (WHO, 1976). When lymphoma complicates AHCD, heavy chains are found on the surface of tumor cells, suggesting a common clonal origin for both diseases (Brouet et al, t 764- CANCER B Y TISSUE OF ORIGIN TABLE 4. Immunodeficiency Cancer Registry Data: Cancer Cases by Disease Category' lmrnunodeticiency Disease ?eta/ Cancer Cases Hodgkin's LymphomaiB Disease Other Cancer Ataxia telangiectasia Variable Immunodeficiency Wiskott-Aldrich syndrome IgA deficiency X-linked hypogamrnaglobulinemia Severe combined immunodeficiency IgM deficiency Immunodeficiency/thymoma Immunodeficiency with normal or elevated gammaglobulins X-linked hyper-IgM Episodic lymphopenia Thymic hypoplasia Transient hypogammaglobulinemiaof infancy 90 71 45 16 14 12 8 4 3 1 1 1 1 65 34 39 6 11 11 5 2 3 0 1 0 1 Total - ~~ 267 178 'Modified from Spector et a1 (1978) all lymphomas other than Hodgkin's disease, including unspecified lymphomas 9 5 3 1 1 1 1 0 0 1 0 0 0 22 16 32 3 9 2 0 2 2 0 0 0 1 0 67 fied by the Immunodeficiency Cancer Registry, as summarized in Table 4 (Spector et ai, 1978). Overall, there was a disproportionate number of lymphoid tumors, including NHL, acute lymphocytic leukemia, and Hodgkin's disease. Two-thirds of these NHL cases were male, 60 per cent were below age 15, and DHL was the most frequent form. NHL also has developed in 3 of the 50 known patients with intestinal lymphangiectasia, in which a lymphatic developmental anomaly results in hypogammaglobu- linemia from severe enteric protein loss (Waldmann et al, 1972). The susceptibility to lymphoma appears related in some way to defective immunoregulatory processes (Wald- mann et al, 19721, although patients with these diseases are prone to recurrent infections, and repeated antigenic challenge may play an etiologic role as well. Therapeufic Immunosuppression In two large series of renal transplant recipients, NHL developed 40 to 100 times more often than expected (Fraumeni and Hoover, 1977; Kinlen et al, 1979). These tumors, predominantly RCS, are characterized by a predi- lection for the central nervous syslerri and an explosive onset following transplantation, with the lymphoma excess clearly evident within the first post-transplant year. This short latent period suggests the involvement of oncogenic viruses, particularly since transplant patients are prone to herpesvirus and other infections. Virus- induced lymphoproliferation may be activated and promoted through graft-versus-host allogeneic stimulation and immunosuppressive agents (Schwartz, 1972;Matas et al, 1975). The role of viruses is also suggested by the polyclona1 proliferations of 6-lymphocytes in NHL fol- lowing transplantation, rather than the monoclonal pattern usually seen in lymphoma (Hertel et al, 19771, and by a recent case report of a transplant patient developing a fatal Iymphoproliferative disorder following an EBV in- fection (Holahan et ai, 1979). An increased risk of NHL has also been reported following cardiac transplantation, with tumors occurring in 6 of 95 long-term survivors. The excess was confined to patients under 40 years of age with idiopathic cardiomyopathy (Anderson et al, 1978). The risk of NHL was even higher than in renal transplant recipients, perhaps because primary cardiomyopathy i s associated with a defect in mononuclear suppressor cell activity. Suppressor cells play an important role in regulating the proliferation of lymphocytes and may be central to the development of NHL, both in animal models and man (Steinberg and Klassen, 1977). Kinlen et al (1979) described an excess of NHL in patients receiving immunosuppressive therapy for nonmalignant diseases other than transplantation. The risk observed was substan- tially below that of transplant recipients, sug- gesting that allogeneic stimulation from the graft plays a promoting role. Clarification of mechan- isms may come from surveys of specially im- . 766 - CANCER BY TISSUE OF ORIGIN 1977). Possible environmental factors include quite common, these double primary neoplasms gastrointestinal injury induced by enterotoxins may represent fortuitous associations. _I (e.g.,Vibrio cholerae, which has the same geo- A leukemic phase has long been recognized graphic distribution as AHCD) (Al-Saleem, in some NHL cases, occurring in over 7 per cent 1978) and persistent thymus-dependent im- of one large series (Rosenberg, 1961); leukemic mune dysfunction following early infantile en- transformation is more common in children [ m i t i s (Dutz, 1978). Whatever the environmen- than adults, and more typical of LSA (12.6 per tal stimulus, Mediterranean lymphoma appears cent) than RCS (2.4 per cent). This phenomenon to evolve from the apparently benign, reversible was seen in 14 per cent of 214 consecutive hyperplastic infiltrate of AHCD (Seligmann, patients, with 12 per cent nodular and 7 per 1977). cent diffuse NHL so affected (Come et al, 1980). linniunoblastic lymphadenopathy (IL) is Leukemic transformation of lymphoid cells i s another apparently benign lymphoproliferative considered a part of the natural history of NHL disorder that often progresses to NHL (Frizzera ither than a true second malignancy. et al, 1974). In the largest series of patients In contrast, a 37-fold excess risk of acute reported, 48 had only immunoblastic lymph- nonlymphocytic leukemia (ANLL) has been re- adenopathy at initial biopsy; 13 patients had ported for NHL (Zarrabi et al, 1979). Most such follow-up biopsies, of whom 6 developed frank ANLL cases seem to result from alkylating immunoblastic sarcoma (IS) (Nathwani et al, agents or radiation therapy (Casciato and Scott, 1978b). Another 36 patients had focal changes 19791, despite some case reports of ANLL in of IS in their initial biopsies, with 10 sub- untreated patients with NHL (Lonnqvist and seqrieritly evolving into frank IS. A disorder of Lockner, 1979). An association once reported B-lymphocytes, IL is frequently associated with between NHL and chronic myelogenous leuke- a hktory of drug allergy, autoimmune disease, mia now seems to be spurious, since the "lym- and/or dysproteinemia, and seems to occupy an phomas" were actually an extramedullary blast intermediate position between the benign phase of the leukemia (Josephet al, 1968). ("reactive") lymphoid hyperplasias and true immunoblastic sarcoma. It shares many features Genetic Markers with graft-versus-host disease (Frizzera et al, 19741, which in animals predisposes to NHL, In contrast to Hodgkin's disease and acute and niay represent yet another disorder in leukemia, there have been limited studies of the which suppressor cell regulation of B-cell prolif- HLA phenotype in NHL. Reports based on small wation is defective (Kosniidis et al, 1978). An numbers of cases have implicated various B- Cxcess of NHL has been suggested in other locus antigens, including B5, 67, B12, and 313 I)t.nign lymphoproliferative conditions, which (Morris and Forbes, 1971; Jeannetand Magnin, ate not well characterized, including nontropi- 1972; Rege et al, 1972; Miller, 1974). An c-a1 splenomegaly (Dacie et al, 1978) and lym- excess of the haplotype ,49435 has also been phomatoid granulomatosis (Katzenstein et al, suggested (Terasaki and Mickey, 1975). Given 1979). the evidence for immunologic determinants in NHL, and the possible association of immun- Associaled Neoplasms oregulatory genes with the major histocompa- tibility complex in man, this would seem a An excess risk of skin cancer has been r e p r t - fruitful area for additional study, particularly if cd in patients with NHL (Berg, 1967). Immun- Dr-locus and B-cell alloantigens are deter- ologic factors may be involved, since melano- mined. ma and squamous cell cancers of skin occur NHL has a diploid modal chromosome excessively, along with NHL, in renal transplant number, in contrast to HD, which usually recipients (Hoover and Fraumeni, 1973; Kinlen shows hyperploidy (Rowley, 1978). Following et al, 1979). An excess of lung cancer was the introduction of banding techniques and the described recently in NHL (Libshitzet al, 1978) discovery that Burkitt's lymphoma involves a and in chronic lymphocytic leukemia (Greene specific translocation of a segment from the et ai, 1978). Case reports have suggested an long arm of chromosome 8 to the long arm of association with colorectal cancer (Cornes, chromosome 14, it was soon recognized that at 1960; Barron and Localio, 19761, particularly in least half of the patients with NHL also have the context of familial aggregation (Law et al, abnormalities of chromosome 14 (Fukuhara and 1977; Mulvihill and McKeen, 1977; Cheng et Rowley, 1978; Mark et al, 1978). Unlike Bur- al, 1979), but risks have not been increased in kitt's lymphoma, in NHL no single chromosome follow-up studies. Since colorectal cancer i s has been regularly implicated as the donor of . , .\, 1 is-" .#-*.&I*-<- NON-HODGKIN'S LYMPHOMA AND MYCOSIS FUNGOIDES -767 the material found on chromosome 14. The consistent with preliminary reports of Ntil- 14qt abnormality is more common in PDL among uranium millers (Archer el al, 19731, (poorly differentiated lymphocytic lymphoma) among patients therapeutically irradiated for than in DHL, and i s found in NHL of T-cell ovarian cancer (Reimer et at, 19781, ant1 per- origin as well (Rowley, 1980). It i s noteworthy haps among children given thymic irradiation in that a report of familial NHL showed a marker childhood (Bisbee and Thoeny, 1975). O n the chromosome in Group C during the pre-banding other hand, several irradiated group have PX- era (Kajii et al, 1968) and that chromosome 14 perienced no lymphoma excess (BEIK, 1979). abnormalities have been described in ataxia Thus, it would seem that radiation can indw e telangiectasia (AT), which predisposes to NHL NHL only after relatively heavy exposurt's, i e., (McCaw et al, 1975). The role of viruses was over 100 rads. Immunologic me(-hanisms niay ,suggested by a recent study of AT lymphoid be involved, in view of the radiation sensitivity cells that developed an 8;14 translocation iden- of suppressor T-cells (Broder et al, 1978), clcple- tical to that seen in Burkitt's lymphoma follow- tion of which could permit unregulated lyrn- ing in vitro infection with EBV (Jeanet al, 1979), phocyte proliferation to evolve into lymphoma. a phenomenon not observed foilowing EBV It is also possible that radiation may activate infection of lymphocytes from normal persons. endogenous oncogenic viruses (Upton, 1976). It i s clear that there are nonrandom abnormali- lies of chromosome 14 in various lymphoma- Drugs t o u s disorders, including NHL, perhaps due to instability in the distal segment of this chromo- A variety of medications may produc P a some. 1hese cytogenetic abnormalities may lymphadenopathy that histologic ally rcwviihlr~s confer a proliferative advantage on the altered but fails to meet the diagnostic criteria for lyniphocytes, thus increasing the likelihood of lyniphoma (Schen, 1964). Best studied is [tic developing lymphoma (McCaw et al, 1975). so-called "pseudolymphoma" seen in patient\ taking the anticonvulsant agent phenytoin ([li- lantin) (Gams et ai, 1968). In the form o f a hypersensitivity reaction, the lyniphatienopattiy Environmental Factors typically resolves when the drug is tiiscoritin- ued. This syndrome has some features of itn- Radiation rnunoblastic lymphadenopathy (Matmcr and Polliack, 1978) and sometimes progresscs to Although ionizing radiation can induce lyrn- malignant lymphoma (Harrington ct al, 1062). phomas in various animal systems (Loutit and A small excess of phenytoin usage h,is I)ccvi Ckrr, 19781, the evidence in man i s less persua- reported in surveys of NHL, in which there was sive. A proportionate mortality surve*jof radiol- no evidence of an intermediate stage (Iiymarl ogists in the United States indicated a nonsig- and Sommers, 1966; L i et at, 1975). However, nificant excess of lymphoma (Lewis,l963), follow-up of a large Danish series o f epilcpsy while similar surveys in the United Kingdom patients indicated no lymphoma excess (Clem- were entirely negative (Court-Brown and Doll, rnesen, 1974). Although phenytoin is carcin- 1958). Recent follow-up studies of radiologists ogenic in animals (IARC, 1977) and immuno- in North America revealed a "lymphoma" ex- suppressive in man (Charlesworth, 1977), the cess that was due to multiple myeloma (Matan- available evidence suggests that the risk of oski et al, 1975). However, NHL was among the lymphoma i s increased only slightly, ifat all. cancers occurring excessively in patients ir- Another agent that can produce lyrnphade- radiated for ankylosing spondylitis (Court- nopathy and a hypersensitivity syndrotne is Brown and Doli, 1965). dapsone (DeGowin, 1967), a sulfone uscd in Best documented i s the small but significant the treatment of leprosy and malaria, and re- excess of NHL among Japanesesurvivors of the cently found to cause lymphomas a n d olher atoniic bomb (Nishiyama et al, 1973; Beebe et cancers in latmratory animals (NCI, 1977). Most al, 1978). The elevated risk was found in both reports of NHL with the predisposing syndrome sexes and was most pronounced in Hiroshima dermatitis herpetiformis have been in paticnts survivors, persons under 25 years of age at receiving dapsone (Freeman et al, 1977). Fur- exposure, and persons exposed to more than ther studies are needed, particularly since the 100 rads. The excess risk from NHL did not drug has been widely used by the military for e appear until 14 to 16 years after exposure, and malaria prophylaxis. was calculated as 0.18 deaths per million per- An excess of NHL was recently reported in a lf son-year-rads of observation. These findings are series of Hodgkin's disease patients, perhaps 768- CANCER BY TISSUE OF ORIGIN NON-HODGKIN'S LYMPHOMA AND MYCOSIS -FUNGOIDES 769 VIlnVI VImmmVIm ooocncnmoooooo OOOZtZOOOOOO vvv vvvvvv bin o0 o0mz mz YB2 000 Z0Z0SZ0c0ncZnzcnacnz v v v v v "VVVV mzczncznmz I, c- I 770 -CANCER BY TISSUE OF ORIGIN -- 1cst r It ing from the immunosi tppressive proper- mias or sarcomas in laboratory animals (Hehl- tics o f combination cheniot herapy and radio- mann et al, 1973). Seroepideniiologic studies in tlwrnpy (Krikorian et al, 1979). The diagnostic man have shown no evidence of infection by rliffic ulties inherent in such a study make this a feline and bovine leukemia viruses (Donham et c oritroversial observation, but one that merits al, 1977; Krakower and Aaronson, 19781, and ftrrtiicr investigat'1011. there is no convincing evidence relating human lymphoma or other canters to pets or clomcstic OccupaI ional Exposures animals (Essex and Franc is, 1976). tiowever, a It i s rliffic tilt to evaluate occupational factors tw ause in most studies NHL has been comIjiriccl with other lymphatic and hematopoietic ncoolasms. Nevertheless, six surveys of oc cupatioii and cancer were reviewed for clues (Table 5).An excess o f lyniphomawas reported among snlw a n t i clerical personnel, postal workers, iriwranc e and real estate brokers, engineers, staticinary engineers, several types of electrical \vorkerc, niechanics, machinists, primary metal \\oikers, and farmers. Some of these groups niay reflect socioeconomic or general environiiiciital fat tors, while others may involve chemic a l or physical exposures in the work place. The a s o c iation with electrical occupations may be tclcvarit t o the t e c ent report that childhood lyini)liotiia arid other ( ancers rnay occur excesqively w a r high-current flow electrical fields (Wtvtlirimer and Leper, 1979). The findings for several occupational groups have h e n inconsistent. An excess of lymphoriins has been reported for anesthesiologists in sonic, but not all studies (Vessey, 1978). A small PXC e55 of lymphomas has been observed among vinyl chloride workers in the United States, but not in the United Kingdom (Chiazzeet al, 1977; f o x and Collier, 1977). Mortality from lymphoma i s excessive in chemists from three countries (Li et al, 1969; O h , 1980; Searle, 1978), although specific exposures have not been itlwitified. Rubber workers are prone to lymphoma, particularly in the tire building proce,ssPS (Monson and Nakano, 1976). An excess has also been suggested in workers involved in pcitrolrum refining (Tabershaw and Cooper, 1974), in the processing of arsenic-containing ore (Axelson et al, 19781, and in herbicide cxposure to phenoxyacetic acid or chlorophenol (1 tardell, 1979). Thus, there are preliminary i r i d i c ations that various occupational chemical t'xlwsures may induce NHL, but more definitive analytic studies are needed. suggestive excess of lymphomas has liceti reported in mortality surveys of veterinarians (Matanoski and Lilienfeld, 1976; Blair and Hayes, 1980). The association between EBV and Burkitt's lymphoma has stimulated efforts t o link this virus with other lymphoproliferative nialignanties. w i t h the exception of the X-linked lymphoproliferative syndrome (Purtilo et al, 1978), there has been no Convincing evidence that EBV induces NHL (Carter et al, 1977) A recent report suggesting that persons who have had childhood varicella are at incrcased NHL risk ns aclul~s remains unconfirmed (Paffenhargcr, 1978). The role of RNA viruses was suggestt~i hy the finding that in tumor tissue 7 0 p t r cent o f human Nt l L cases had RNA sequent tli,it were honiologous t o the R,iusc hcr Irukrniia virus (Hehlmann et al, 1973). In atlditton, h o f 1 3 permanent human NHL cell lintxs showctl spontaneous C-virus particle production; one cell line contained a reverse transcriptase apparently related to those seen in viruses frotii subhuman prifhate and feline hosts (Kaplan et al, 1979). In some instances, parasites may be a risk factor. Among 863 patients in Brazil undergoing splenectomy because of infestation with Sthistosoma rnansoni, 8 were found to have giant follicular lymphoma of the spleen (Andrade and Abreu, 1971). In an autopsy study from Africa, NHL was found in 6 per cent of patients with schistosomiasis, compared to 1 per cent of controls (Edington et al, 1970). As with the relationship between malaria and Burkitt's lymphoma, it has been claimed that the chronic lymphoid stimulation from Schistosoma mansoni may predispose to NHL. This mechanism may also apply to the excess risk of NHL reported in patients with leprosy (Rodrigue7 et al, 19681, although this association has not heen confirmed (Kolonel and Hirohata, 1977). The case clustering found in some studies of Infectious Agents Hodgkin's disease and Burkitt's lymphoma has prompted similar investigations of NHL, but the In various mammalian and avian species, evidence is insufficient to implicate person-to- lymphomas have been induced by C-type RNA person transmission (Smith, 1978b). The risk of viruses or by DNA viruses of the herpes class NHL in spouse pairs does not appear to exceed (Kaplan, 1974). Similar viruses can cause leuke- the limits of chance (Stephens et al, 19771, and 1 NON-HODGKIN'S LYMPHOMA AND MYCOSIS FUNGOIDES -- 771 no lyniptionias were identified in a follow-up of persons receiving blood transfusions from tionors who later developed NHL (Grwrwald, 1976) Diet which normally regulate the proliferation of helper T-cells (Kerrnani-Arab et al, 1978), and that both MF and SS represent neoplastic proliferations of helper T-cells (Broder et al, 1976; Berger at al, 1979). Evitknct for dietary variables i s sc arc e, a!tliough tht. positive gradient of Nt 1L mortality 1)y soc iocw)nomic class suggests the influcnce of over-nutrition. An excess of lymphoma was r r p o r t d in rats fed sodium nitrite (Newberne, 1979) or a diet rich in protein (Roc< and Bras, 1965), and international surveys have shown a correlation between NHL mortalitv and per capita animal (bovine) protein consumption (['unningharn, 1976). It was proposed that c tironic antigenic stimulation from ingested forrtgn protein might explain t h i s latter retation\hip [hinking water contaminated by organic haloriit~thaneconipounds has been linked with N t 1L mortality, particularly in males, in several ( o r t ( ~ l c i t t o tsi tutlies (Cantor et al, 1978). A positi\,(> (orrt>lation tias been reported with the c o n ( entration of lead and cadmium in drinking w,itcr (Ocrg and Burhank, 1972) and a negative (orrclation with the selcnium content of forage crops (Shmiherger et dl, 1976). A role for niagnesiuni deiiciency in NHL has been suggt'strd in 1al)oratory studies (Bois et al, 1969). MYCOSIS FUNGOIDES Pathology Mycosis fungoides (MF) is a primary rutaneo u s lymphoma with unique clinical and histologic features. Its onset i s heralded by a nonslwec ific scaling dermatitis lasting months to years, which evolves into plaques and ulcerated trrniors. These patients frequently dwelop diffuse lymphadenopathy and visceral lymphoma, with 50 per cent dying within four years of initial diagnosis (Lutzner et al, 1975). The medim survival is 2.5 years from ori;et of skin titmors or adenopathy, and 1.5 to 2.0 years from onsct of visceral disease (Safai, 1977). A leuktviic variant i s called Sezary's syndrome (SS), arid i t is accompanied by an acute erythroderma. The malignant cells in the peripheral l h d have a characteristic lobular, cerebriform morphology that resembles MF tumor cells (Mann et al, 1979). These neoplasms appear to be of T-cell origin, involving the thymus-dependent portions of the spleen and lymph nodes (see Fig. 1). Recent studies suggest that patients with MF atid S S lack a population of suppressor T-cells, Demography International incidence statistics for M i are unavailable because t h i s neoplasm is gcrierally combined with other lymphoproliferative tumors. Unpublished data from the 1 1 SEFR cancer registries (1973-1976) in tht3 United States reveal the following average annual ageadjusted incidence rates: white males, 0 2 x 10'; white females, 0 1 x 10;; black males, 0 3 x 105;and black females, 0.1 x 10' In gcnwal, MF rarely occurs before age 40, but the incidence then rises with age to reach a plateau of 0.7 cases per 100,000 in white males above age 60. During the 25-year period 1950-1975 (excluding 1972), there were 1,948 deaths attributed to MF in the United States - 1,034 in white males, 631 in white females, 162 in nonwhite males, and 121 in nonwhite females. The rates were generally higher among males than females and among nonwhites than whites (Fig 4). Mortality rose sharply with age, peaking at ages 65 to 69 for nonwhite males and at ages 75 to 84 for white males. The average annual age-adjusted mortality rates for the total United States population during this 25-year period were as follows: white males, 0.53 x 10";white females, 0.28 x 10"; nonwhite males, 0.84 X 10"; and nonwhite females, 0.54 x 10"(Greene et al, 1979). Mortality rates showed an upward trend over time. For whites of both sexes and nonwhite females, the rates rose 10 to 20 per cent between 1950-1954 and 1970-1975, while fot nonwhite males the rate doubled. The rates in white males were highest in the Northeast (0 61 x lo"), in association with a strong urban gradient but no socioeconomic differential (Greene et al, 1979). Geographic clustering of MF has also been reported in Swedish men (Gip and Nilsson, 19771, a finding of uncertain significance given that multiple comparisons were made in a small number of patients. Host Factors Familial Tendency Five multiple-case families with MF have been reported (Greene et al, 1979), but etiolog- 772- CANCER BY TISSUE OF ORIGIN -_ Whites Nonwhites lid 19; (1.0 tFC kyl An alsc inc rad cat AGE AT DEATH -.1-,0 ' 0 10 20 30 40 50 60 70 80 90 100 AGEATDEATH rlgure 4. Average annual age-specific mortality rates for mycosis fungoides per 100,000 population by race and sex, United States, 1950-1975. ic dctails are sparse. Of the four instances in that described for other lymphoproliferative which the relationship was specified, two viere !mors (Rowley, 1978). <it> pairs and two involved a parent and child. Leukemia or lymphoma was reported in a first- Associated Conditions tlvgrce relative of 9 of 21 1 MF patients (4.3 per (twt) in the MF Cooperative Study Group series In the analysis of the MF Cooperative Study ((ircene et at, 19791, compared to 15 of 315 Group data, a number of antecedent host condi- paticnts (4.8 per cent) from Temple University tions were reported by patients with surprising (F. C. Vonderheid, E. J. VanScott, personal frequency (Greene et al, 1979).These included conimunication) and 3 of 59 patients (5.1 per histories of allergic conditions (56 per cent), cent) from Yale (Cohen et al, 1980). Hodgkin's fungal and viral skin infections (64 per cent), tfiwase seemed to be especially common. These ,sun sensitivity (43 per cent), and possible MF (lata suggest that some cases of MF are part of a precursor states (e.g., parapsoriasis, poikiloder- familiaI predisposition to Iymphoproliferative ma, and alopecia mucinosa) (16 per cent). In tumors. A recent study supports this notion; the the absence of a control group, it i s difficult to o c c-rrrrence of Hodgkin's disease among the interpret these descriptive data other than as rclatives of patients with MF was particularly leads for future studies. striking (Greene et al, 1981). Genetic factors The older literature is replete with reports are suggested also by the excessive frequency of describing the "transformation" of MF into t I I A antigens B8, Aw31 , and Aw32 in MF pa- other malignant lymphomas. The vast majority ticrits (Dick et al, 1976). of such cases now appear to represent the Cytogenetic studies of MF and SS are rare, extracutaneous dissemination of MF, as part of arid most antedate the introduction of chromo- its natural history (Rappaport and Thomas, some banding. One well-studied MF patient 1974). An exception to this general rule is the tiad chromosomally normal bone marrow cells, recent description of three MF patients who hut abnormal lymph node cells, including a developed clear-cut Hodgkin's disease (Chan et trandocation to the long arm of chromosome 14 al, 1979). An association with nonlymphoid (fukuhara et al, 1978). The finding resembles tumors i s limited to case reports, such as those in frt n; CC 5P NON-HODGKIN'S LYMPHOMA AND MYCOSIS FUNGOIDES -773 linking M F to fibrosarcoma (Presbury et al, 1974) and acute myelomonocytic leukemia (Lofgren et al, 1978). The leukemias may have txwi induced by ionizing radiation and/or alkylating agents used to treat the primary disease. An excess of skin carcinomas in MF patients ako seems related to therapeutic measures, i r i c lutling arsenicals (Edgcomb et al, 196.31, radiation (Volrlen and Larsen, 19771, and topical nitrogen mustard (DuVivier et al, 1978). Environmental Factors Some case reports have linked MF with expow e to arsenic, bismuth, and tar ointments, but the evidence i s inconclusive (Bluefarb, 1959). Detailed interviews of the 44 patients in the NCI scries revealed a history of multiple, potentially tovic environmental exposures in 43, the most frcquent exposures being to chemicals (91 per c w t ) and drugs (86 per cent) (Fischmann et al, 1979). Exposure to hazardous chemicals was Icported by 30 per cent of the patients evaluatcd by the MF Cooperative Study Group, with pctrochemicals, metals, and solvents most freqriently cited (Greene et al, 1979). Analysis of the occupational histories of these patient<, and a correlation study of occupation and MF mortality in the United States suggested that the prtrochemical, rubber, metals, machinery, printing, and textile industries might be associated with elevated MF mortality (Greene et al, 1979). Preliminary results from a case-control study of MF indicated a fourfold relative risk for manufacturing and construction workers (Cohen et al, 1980). Ultraviolet radiation i s the major risk factcr for skin cancer, but the absence of a latitudinal gradient in MF suggests that any sunlight effect differs from that observed in skin carcinoma and melanoma (Greene et al, 1979). Of special interest i s the recent isolation of a unique retrovirus from several patients with MF and SS (Poiesz et al, 1980). Further assessment of a viral etiology for t h i s disorder will be needed to clarify this obqervalion. BIOLOGIC MECHANISMS Since lymphomas arise from cells of the immune system, etiologic insights should result from a better understanding of the normal dynamics of the immune response. Like other cornplex biologic systems, the immune response is controlled by a network of delicately balanced positive and negative regulatory'processe~F. or example, cells that aid the convtvsion of 6-lymphocytes into immunoglobulinsecreting plasma cells are classified as help: cells, while those that inhibit this transition are called suppressor cells (Broder and Waldmann, 1978). Special subsets of B-cells, T-cells, and monocyte/macrophages may mediate eittier a helper or a suppressor function for different aspects of the immune response. Lymphocytes seem to be genetically committed to mediating on!\,, one of these two regulatory functions. It is normal for lymphocytes to proliferate in response to various stimuli (e.g., antigen exposure), and suppressor cells play an important role in terminating this normal proliferative response (Steinberg and Klassen, 1977). Im- mune regulation may be impaired by genetic or environmental factors, leading to excessive proliferation of that subset of cells normally controlled by the injured component. A critical role may be played by immunoregulatory genes that are found partly within or near the major histocompatibility complex determining the HLA phenotype. With this background, the various lymphoma-prone states begin to form a pattern. NHL tends to develop after prolonged antigenic stimulus to lymphoproliferation, after loss of normal regulation (inhibition) of lymphocyte proliferation, or especially after both processes. Experimental data in mice support this formulation (Krueger et al, 1971). In theorgan transplant setting, the host is simultaneously subjected to persistent antigenic challenge from the allograft and to therapeutic immunosuppression to prevent graft rejection. In cardiomyopathy patients, who have an antecedent suppressor cell abnormality, the risk of NHL after cardiac transplantation appears to be even greater than in renal transplant recipients, who have no primary immune defect. The presence of a graft is clearly not required for NHL development, since nontransplant patients with connective tissue diseases treated with immunosuppressive drugs are at increased risk, although not nearly as high a risk as in transplant recipients (Kinlen et al, 1979). A source for chronic antigenic stimulation exists in the primary immunodeficiency disorders (e.g., recurrent infection), rheumatoid disease (autoimmunity), celiac disease (gluten sensitivity), immunohlastic lymphadenopathy (drug allergy, autoimmunity), chronic infections (schistosomiasis, leprosy), and possibly certain occupational exposures. Suppressor cell abnormalities have been reported in primary cardiomyopathy, certain rheumatoid diseases, .I : 772 - CANCER BY TISSUE OF ORIGIN Whites Nonwhites 1 .- nwa a 4vr) 1- 00 - 1 + L & _ L _ L I . l L l L I I 1 . L 1.1 .d 20 30 40 50 60 70 80 90 100 AGE AT DEATH '01k%%%40 U.I.LI-I__LI_LLU 50 60 70 80 90 100 AGE AT DEATH Ftgure 4. Average annual age-specific mortality rates for mycosis fungoides per 100,000population by race and sex, United States, 1950-1975. ic details are sparse. Of the four instances in that described for other lymphoproliferative which the relationship was specified, two were tumors (Rowley, 1978). 413 pairs and two involved a parent and chilci. Leukemia or lymphoma was reported in a first- * Associated Conditions degree relative of 9 of 21 1 MF patients (4.3 per cent) in the MF Cooperative Study Group series In the analysis of the MF Cooperative Study (Greene et al, 1979), compared to 15 of 315 Group data, a number of antecedent host condi- patients (4.8 per cent) from Temple University tions were reported by patients with surprising (E. C. Vonderheid, E. J. VanScott, personal frequency (Greene et al, 1979). These included communication) and 3 of 59 patients (5.1 per histories of allergic conditions (56 per cent), cent) from Yale (Cohen et al, 1980). Hodgkin's fungal and viral skin infections (64 per cent), disease seemed to be especially common. These ,sun sensitivity (43 per cent), and possible MF data suggest that some cases of MF are part of a precursor states (e.g., parapsoriasis, poikiloder- familial predisposition to lymphoproliferative ma, and alopecia mucinosa) (16 per cent). In tumors. A recent study supports this notion; the the absence of a control group, it is difficult to occurrence of Hodgkin's disease among the interpret these descriptive data other than as relatives of patients with MF was particularly leads for future studies. striking (Greene et al, 1981). Genetic factors The older literature is replete with reports are suggested also by the excessive frequency of describing the "transformation" of MF into t I I A antigens 08, Aw31 , and Aw32 in MF pa- other malignant lymphomas. The vast majority ficrits (Dick et al, 1976). of such cases now appear to represent the Cytogenetic studies of MF and SS are rare, extracutaneous dissemination of MF, as part of and most antedate the introduction of chromo- its natural history (Rappaport and Thomas, some banding. One well-studied MF patient 1974). An exception to this general rule is the had chromosomally normal bone marrow cells, recent description of three MF patients who but abnormal lymph node cells, including a developed clear-cut Hodgkin's disease (Chan et translocation to the long arm of chromosome 74 al, 1979). An association with nonlymphoid (Fukuhara et al, 1978). The finding resembles tumors i s limited to case reports, such as those 774 -CANCER BY TISSUE OF ORIGIN and sarcoidosis and may exist in therapeutic scheme to relate etiologic hypotheses to specif- immunosuppression as well. ic morphologic entities. At a minimum, N t i L Viruses can be incorporated into this model, must be considered separately from the other since latent oncogenic viruses in mammals may lymphoproliferative malignancies. There are be activated by various types of immune dys- now many etiologic leads to NHL that can be function, particularly graft-versus-host disease. tested by analytic studies with sufficient sample Schwartz (1972) suggested that viral informa- size. tion present in lymphocytes, expression of NHL accounts for only a small fraction of a11 which is normally inhibited, may be triggered as cancers, but is important beyond its frequency lymphocytes proliferate in response to an an- as a model for new therapeutic regimens and for tigenic challenge or to a loss of regulatory improved understanding of the immune re- control. Another mechanism for viral induction sponse and carcinogenic mechanisms. Recent is radiation exposure, although more recent advances in immunology should lead to rapid data suggest that the viruses seen in that experi- progress in the delineation of pathogenic mech- mental setting are not of etiologic significance anisms in lymphoma. The immunologist and (Ihle, 1978). Nonetheless, the animal models for epidemiologist should join forces to clarify the viral lymphoma, the various types of viral infor- risk of NHL and other cancers in various dis- mation in human lymphoma tissue, and the orders with defective immunity and to deter- possible role of viruses in transplant-related mine the immunoregulatory abnormalities lymphomas (Holahan et ai, 1979) underscore found in these high-risk states. As specific host the importance of this hypothesis. factors and environmental exposures are linked Immunogenetic factors in NHL are illustrated to NHL, it will be important to study their effects by the primary immunodeficiencydisorders and on the immune response, since the evidence to lymphoma-prone families, including the X- date points to disturbances in immune regu- linked lymphoproliferative syndrome. The ab- lation as precursors to lymphoma. normalities in chromosome 14 that characterize various lymphoproliferative neoplasms may confer a proliferative advantage on affected lymphocytes. Ionizing radiation and chehicals References may produce a selective injury to suppressor Abramson IH. Avitzour PE: Mortality from lymphomas in lw.wl, cells. Thus, the proposed mechanisms for in- 1950-71: The pnssible role of environmental factors. Int I Epitlr- ducing NHL intertwine, and sharp distinctions miol 4321-329,1975. At-Saleem TI: Evidenceof acquirrd imniunedeficiencies in Mediter- -' are difficult to draw. ranean lymphoma: a possible aetiologiral link. Lancet 2:709, Mycosis fungoides may also fit into this model, since its pathogenesis has been linked to 1978. Ammann AI, Good RA, Bier D, et al: Long-term plasma infwiorrc in patients with ataxia telangiectaria and drfirient IgA and IgE. epidermal Langerhans' cells (Rowden and Pediatricf 44:672+7h, 1969. Lewis, 19761, which play a role in the primary ininiune response to external contact allergens Anderson JL, Bieber CP, Fowles RE, et al: ldiopathir c;irrIinmyop athy, age, and suppresu~r-celtllycfunction as risk tlrtrrniinantc of lymphoma after cardiar transplantation. Lancet 2:l 174-1 177, (Silherherg-Sinakin et ai, 1976). Langerhans' cells modulate the response of specific T- lymphocytes to various foreign antigens; perSis- tence of these antigens in the skin may be a source of chronic antigenic stimulation. The influence of environmental agents in MF is supported by the affinity of Langerhans' cells for such contact sensitizers as heavy metals, various aldehydes, and amines (Shelley and Juhlin, 1976). 1978. Anderson 1,Bender RA, Fisher R), et al: Conibinationchemr,thrrapy in non-Hodgkin`s lymphoma: results of long-term follow-up. Cancer Treat Rep 61:1057-1066,1977. Antlrade ZA, Abreu WN: Follicular lyniphonia of the sple~nin patients with hepato5plenic Schismsomiasis mansoni. Am I 1r o p Med Hyg 2O:237-243.1971. Anonymous: Public health wrvice and social security atlniinistration: occupationalcharacteristics of disabled workers by disdlilitv condition (Public HealthServicePublicationNo. 153 1). Washing- ton, D.C., Government PrintingOffice, 1967,p. 307. Anonymous: Cancer statistics, 1979.CA 29:6-21,1979. Archer VE, Wagoner IK, Lvndiii FE lr: Cancer mortality arnnng uranium mill workers. ]OM 15:11-14,1973. Axelson 0,Dahlgren E, JanssonC-13. et al: Arsenic expisure and RECOMMENDATIONS It remains to be seen whether or not the clinical and pathologic diversity of NHL reflects mortality: a case-referent study from a Swedishcopper smeltc-r. Rr J Ind Med 35:&15, 1978. Banihashemi A, Nasr K, tlclayalee H, et al: Familial lymphoma includinga report of milia1primary upper small intestinal lymphoma. Blut 2b363-368, 1973. Barnes BE: Dermatomyositis and malignancy. Ann Intern Mrd 84~68-76,1976. major etiologic heterogeneity. In the meantime, whenever possible, epidemiologic studies should employ a contemporary pathology Barron EA, Localio SA: A statistical note on the association of colorectal cancer and lymphoma. Am J Epidemiol 104:517-522, 1976. Earth RF, Khurana SK, Vergara GG, et al: Rapidly fatal familial I *- I I II '\ J 111 `I' 1 1\ 1 1.1 1 VI 2. dI NON-HODGKIN'S LYMPHOMA AND MYCOSIS FUNGOIDES-775 histiocytosis associated with eosinophilia and primary immunological drficiency. 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