American Journal of Hematology 37:69-74 (1991)

Non-Hodgkin Lymphoma in Common Variable lmmunodeficiency C. Cunningham-Rundles, P. Lieberman, G. Hellman, and R.S.K. Chaganti Department of Medicine, Mount Sinai Medical Center (C.C.-R., G.H.), and Department of Pathology, Memorial Sloan-Kettering Cancer Center (P.L., R.S.K.C.), New York, New York

The association between cancer and immunodeficiency is well established. In common variable immunodeficiency(CVI), a primary immunodeficiency disease characterized by low serum immunoglobulinsand poor antibody production, we previously reported a total of 13 cancers in 11 individuals arising in continuously observed group of patients. Of the 13,7 were NHL and 1 was a myeloma which progressed to lymphoma. We report here the histologic, immunologic, cytogenetic, and clinical features of these 8 NHL along with 3 new lymphomas which have appeared in this group (now 117 patients). From our studies, the lymphomas which have arisen in CVI share certain features with the lymphomas which appear in the childhood immunodeficient syndromes, Wiskott Aldrich Syndrome, Ataxia Telangiectasia, or severe combined immunodeficiency: they are similar in overall frequency (13%), are often B-cell in origin, and extranodal in location. However, unlike the lymphomas of the immunodeficient child, lymphomas in CVI may be more differentiated and secrete immunoglobulin. For CVI patients with stage I or II disease, as for nonHodgkin lymphomas in general, the prognosis is good. In our group, NHL in CVI have appeared most often in females of the 5th to 7th decade and not in childhood. Cytogenetic studies in lymphomas show that cytogenic abnormalities, including chromosomal translocation, can be found in this group, but more studies will be needed to assess the frequency of these events. Key words: CVI, cytogenetics, gene rearrangements

INTRODUCTION

of age is not surprising. Moreover, the reported male predominance of tumors in these studies is at least partly The association between cancer and immunodefidue to the X-linked nature of WAS and SCID [3]. ciency is well established. The first examples of this Unlike WAS, AT, and SCID, patients with CVI are connection were reported for Wiskott-Aldrich Syndrome more likely to be diagnosed as adults. In 1 series, the (WAS) with a cancer incidence of 12% [l] and ataxiaaverage age of patients at diagnosis was reported to be 43 telangiectasia (AT), with an incidence of 11.7% [2]. As [4] while in a more recent study, it was noted to be 27 [ 5 ] . of 1986, for the nearly 500 case records tabulated in the No sex predominance has been observed in this immuImmunodeficiency Cancer Register, there has been an nodeficiency. Previously, we reported the clinical and excess of non-Hodgkin (NHL) lymphomas, comprising 50% of the listings for cancer [3]. The largest numbers of immunologic features of a large series of 98 consecutive patients with CVI, many of whom were adult. In this these have been for AT (67 cases), WAS (59 cases), group of patients, 1 1 individuals developed a total of 13 severe combined immunodeficiency (SCID) (3 1 cases), cancers [6j. Of the 13, 7 were NHL and one was a and common variable immunodeficiency (CVI) (54 myeloma which progressed to lymphoma. We report here cases). The lymphomas in these primary immunodeficiency disorders as a whole are often described as extranodal, more common in males, tend to be poorly differentiated, and associated with poor prognosis. How- Received for publication June 29, 1990; accepted December 20, 1990. ever, 3 of these disorders, (WAS, AT, SCID) are almost Address reprint requests to Dr. Charlotte Cunningham-Rundles, Anexclusively limited to childhood; thus the fact that half of nenberg Building, Box 1089, Mount Sinai Medical Center, One these lymphomas appeared in children less than 10 years Gustave Levy Place, New York, NY 10029. 0 1991 Wiley-Liss, Inc.

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Cunningham-Rundles et al.

the histologic, immunologic, cytogenetic, and clinical features of these 8 NHL along with 3 new lymphomas which have appeared in this group of patients since 1986. Striking for this patient group is the generally welldifferentiated nature of the B-cell lymphomas and the especially high prevalence in hypogammaglobulinemic women in the fifth decade or older. MATERIALS AND METHODS Patients Patients with CVI were diagnosed by standard criteria [7]; accordingly, serum immunoglobulin levels of IgG and IgA (and in many cases IgM) were depressed from the normal range by at least 2 standard deviations. The subjects reported here were part of a large series of now 117 patients with this diagnosis who have been followed since 1973 [5]. In order to preserve a numerically defined population for study, this report is restricted to patients with CVI who were registered and attended the Immunodeficiency Clinic at Memorial Hospital from 1973 to September 1986, or after its relocation, the Immunodeficiency Clinic at Mount Sinai Hospital from September 1986 until the present time. In order to exclude patients who were hypogammaglobulinemic due to the presence of unsuspected lymphoma, patients who were diagnosed as having lymphoma either before, or up two years after the diagnosis of CVI was made, were excluded. Immunologic Testing Serum immunoglobulins were quantitated by radial immunodiffusion and were examined for monoclonal proteins by immunoelectrophoresis. Enumeration of Tand B-cells [8] was performed on the first clinic visit for the majority of patients. For patients who had their original diagnosis made at Memorial Hospital after 1980 (4 cases), fluorescence microscopy was also performed on bone marrow samples or tumor cells, in order to determine the percentages of cells bearing various immunoglobulin isotypes [9]. (The diagnosis of lymphoma and the evaluation undertaken to determine stage was not always performed at Memorial Hospital due to the wide geographic referral area of the Immunodeficiency Clinic; thus the same tests were not performed on all patients.) Studies of Lymphomas and Staging All lymphomas identified were reviewed and classified by the Working Formulation “01. Clinical data (age at diagnosis of lymphoma, initial site of presentation, initial Ann Arbor stage, treatment and response, and date of expiration or last follow-up) were obtained from hospital charts and physicians’ records. Clinical evaluation and tumor staging included a physical examination with determination of hepatosplenomegaly and/or lymphadenopathy, chest radiograph,

bone marrow aspiration and biopsy, lymphangiogram and/or computerized tomography of the chest, abdomen and pelvis. Radionucleotide liver/spleen scan, contrast gastrointestinal series, were performed when the clinical presentation suggested involvement of extranodal sites. Laparotomy was not performed for staging. Cytogenetic Analysis Cytogenetic studies were performed on all specimens obtained after 1986, and chromosome preparations were obtained following previously described methods [ 1 11. Air-dried chromosome preparations were stained to reveal Q- and/or G-banding patterns. The karyotypes were described according to the International System for Human Cytogenetic Nomenclature (ISCN, 1985). Chromosome abnormalities were designated as clonal if at least 2 cells had the same structural abnormality or the same non-random gain of a chromosome or 3 cells had the same non-random loss of a chromosome. Gene Rearrangement Studies DNA was extracted from snap-frozen tissue stored at -70°C following previously described methods [ 121. High molecular weight DNA was digested with Hind 111 and EcoRl restriction enzymes following manufacturer’s recommended protocols. Electrophoresis and transfer to nylon membranes were performed using a semi-automated Southern blotting machine (Oncor Probe Tech I). The hybridization probes comprised a genomic 5.6 kb Hind 111-Bam HI fragment of the immunoglobulin heavy chain (IgH) gene which spans the entire J region and a 0.6 kb EcoRl fragment of the constant region of the beta T-cell antigen receptor (P-TCR) gene. The probes were labeled to high specific activity with 32P following the random hexamer priming method described by Feinberg and Vogelstein [13]. Hybridizations were carried out at 42°C for 16 to 18 hours. The filters were washed twice (15 minutes each) at room temperature and once (1 hour) at 52°C in 0.1% SSC and 0.1% SDS. RESULTS

Eleven lymphomas were studied from a total of 10 patients; of these patients, one was a male, the remaining 9 patients were female (Table I). The average age at the time of diagnosis was 54.7 years and the average length of time which had elapsed since the diagnosis of immunodeficiency was 8.6 years (range from 2 to 15 years). All but one patient in this group, who was a child, had been diagnosed as immunodeficient as an adult. Figure 1 illustrates the marked tendency for lymphomas to appear in the older age groups; here, the sex and age of all patients in the entire cohort at the present time, or the age at the time of death from other causes, is given. Included in the figure is the age of the patients discussed here at the

Non-Hodgkin Lymphoma in Common Variable Immunodeficiency

71

TABLE 1. Lymphomas in CVI

Pt. Sex

Age at diagnosis of immunodeficiency

Age at diagnosis of lymphoma

Histology of lymphoma

Initial location

Initial clinical stage

Treatment

1 2

F F

I 35

12 54

Diffuse, large cell Diffuse, mixed smalland-large cell

Liver, spleen Right inquinal node

IV I

CHOP CHOP

3

F

35

50

CHOP

F

44

48

Pelvis, recurrence buccal mucosa Proximal jejunem

111

4

Diffuse, mixed smalland-large cell Diffuse large-cell

I

Surgery

5

F

44

(a)54

Follicular, mixed small-and-large cell Same

1. Parotid

Surgery

2. Axilla

I or I1 I1

M-BACOD, CHOP, RT, CP Plasmapheresis, CHOP, M-BACOD C-MOPP

(b)55

6

F

54

56

Diffuse, smallcleaved cell

Pelvic nodes

IV

I

M

51

63

Bone marrow

IV

8

F

51

67

Plasma-cell infiltrate, undifferentiated lymphoma later Diffuse, large-cell

IV

9 10

F F

65 70

71 72

Diffuse, large-cell Diffuse, large-cell

Supraclavicular area, abdomen Lymph nodes, lungs Cervical lymph nodes

IV IV

Surgery

C-MOPP AlphaInterferon

Outcome Died 1983, age 13 Died other causes 15 years later, age 69 Died 1980, age 56 Alive, no cancer, after 8 years Alive, no cancer, after 3 years Alive, no cancer, after 2 years Alive

Died 1981, age 65

Died 1980, age 68 Died 1980, age 72 Alive

Abbreviations: CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; M-BACOD, methotrexate, doxorubicin, cyclosphosphamide, vincristine, dexamethasone; M2, vincristine, cyclosphosphamide; RT, radiation therapy; CP, cisplatinum; C-MOPP, cyclosphosphamide, oncovin, procarbazine, prednisone.

v)

t-

z

Ea

n LL

0 U

14

LYMPHOMA MALES FEMALES

12 10

W

8

z 3 z

6

m

!

4 2

0 0-10

11-20

21-30

31-40

41-50

51-60

61-70

71-80

AGE IN YEARS Fig. 1. In a large group of 117 patients with hypogammaglobulinemia,10 lymphomas (black filled areas) appeared. The age of these patients (within a decade) is shown. For the group of CVI patients as a whole, the age and sex of each patient either at the present time or the age at which that patient died of another cause, is given.

72

Cunningham-Rundles et al.

time lymphoma was diagnosed. As is apparent, the older the patient, the more likely it is that an individual patient will develop lymphoma. However, the males with CVI in this group are younger overall than females (average age 32 for males, as opposed to average age 5 1 for females). Thus in this group, there are fewer males in the latter 4 decades. In 7 of 1 I cases, the lymphoma was extranodal at the time of diagnosis. For patients with stage IV NHL, 516 died of this disease within a span of 1 to 3 years; an additional patient presenting with stage 111 disease died 6 years after diagnosis. Three patients had stage I disease, 2 of whom are alive and a third of whom died of unrelated (cardiovascular) causes, 15 years later. For Patients 3 and 7 elevated levels of monoclonal serum IgM were noted (Table 11). The peripheral B-cells of 2 patients [6 and lo], had an excess of surface IgM kappa at the time of diagnosis of NHL (Table 11). For 4 patients [5, 7, 9, and 101 fluorescence analysis of tumor cells in bone marrow or lymph node also showed evidence of IgM clonal excess.

Gene Rearrangements Evidence for clonal rearrangements in the IgH and P-TCR genes was sought in all specimens on which karyotype analysis was obtained. Clonal rearrangements of IgH were identified in all specimens except the initial specimen (1/21/87) from Patient 5 , which showed only the germ line configuration of this gene. This may have been due to a low representation of tumor cells in the specimen saved for DNA analysis. Figure 2 shows Southern blot analysis of immunoglobulin J region of lymphoma cells of Patient 5 (her second study) and Patient 10; germ line and rearranged bands are indicated. All specimens showed only germ line configuration of the P-TCR gene. DISCUSSION

Lymphomas appear with an increased incidence in CVI. In many cases, these have been B-cell in origin [14,15], although cases of T-cell suppressor [I61 or helper type [ 171 have been reported. To our knowledge, Cytogenetics no cytogenetic or gene rearrangement studies so far have Cytogenetic studies were performed twice on Patient 5 been described in these lymphomas. This report concerns 11 cases of NHL appearing in 10 who had 2 lymphoid nodules excised a year apart. By staging, she was thought to be Stage 1 on the first hypogammaglobulinemic patients. The majority of the occasion, but because of the later appearance of histo- lymphomas (9/10) were diffuse in morphology; 5 were logically similar lymphoma in a separate site she was large cell, four were mixed small and large cell and one reclassified as a Stage 11. The first study, the biopsy of the was small cell type. In 2 cases, monoclonal IgM proteins parotid tumor of 1/21/87, histologically a nodular mixed were present in the blood, and in 4 other cases (2 of them lymphoma, yielded 23 analyzable cells of which 4 were from Patient S ) , tumor cells, bone marrow and/or periphnormal (46,XX) and 19 were clonally abnormal with the eral blood B-cells bore an IgM clonal excess. Thus, in 7 chromosomal complement, 4743,XX, +5, + 11,t(X;9) of these NHL’s, well-differentiated cells of B-cell origin (p22;p13),dup( l)(q23;q24). The second study, per- were detected. While B-cell NHL’s in general are more formed on a lymph node specimen of 5/6/88, histologi- common in congenital immunodeficiency disease [ I ,2, lo], cally the same as the first lymphoma, yielded 17 analyz- in the pediatric immunodeficiency disorders NHL have able cells of which one was normal (46,XX) and 16 were most often been poorly differentiated, and not productive clonally abnormal with the karyotype 46,XX,t(X;9) of secreted immunoglobulin [3]. Nonrandom chromosomal abnormalities have previ(p22;p13),dup(1)(q23;24). Thus, the 2 tumors were clonally related and showed clonal evolution. Cytogenetic ously been correlated with histologic subtypes and clinstudies were performed on PHA-stimulated peripheral ical behavior of NHL [ 11,18-211. The most frequent of blood cells and on bone marrow cells from specimens these are t( 14;18)(q32;q21) seen in up to 90% of low from Patient 10 obtained on 8/3/89. The peripheral blood grade follicular lymphomas and t(8;14)(q24;q32), or its yielded 26 analyzable cells of which 22 were normal variants t(2;8)(p13;q32), and t(8;22)(ql l;q32), seen in (46,XX) and 4 were clonally abnormal with the karyo- almost all cases of small-cleaved cell, Burkitt’s type type 4 1-46,X, - X, + 15,t( 1;2)(ql1 ;p 13),der(4)t( 4;?) lesions. Although Patient 5 had a follicular lymphoma, (pl6;?),t(9; 14)(pl3;q32),del( 13)(ql3;q3 1), + random the absence of the t(14;18) translocation indicates that it losses. Although 23 metaphases were encountered in the belongs to the minority subset of these tumors. In the bone marrow preparation, the poor quality of metaphase t(14;18) carrying low grade lymphomas, the bcl-2 gene spreads precluded complete analysis. However, the located at the translocation breakpoint on chromosome clonal markers der(4) and der(l4) derived from the 18, 18q21, undergoes deregulation as a consequence of t(9; 14) translocation observed in the peripheral blood rearrangement with the IgH locus [22]. The status of specimen also were observed in these bone marrow cells, bcl-2 gene in tumors without the translocation is unestablishing that the tumor in the blood and the bone known. Patient 10, with a diffuse large cell lymphoma, marrow were the same. presented with a 14q+ marker chromosome deriving

Non-Hodgkin Lymphoma in Common Variable Immunodeficiency

73

TABLE II. Immunologic Studies

Serum immunoglobulinsa (rngldl) Patient

Date

IgCb IgA

2 3 4 5

5/81 4/78 1/78 4/78 4/85

162 479 289 105 276

2 0 8 34 0

6 7 8 9 10

10/84 3/78 2/79 1I79 8/89

380 276 200 354 425

66 95 20 20 7

1

IgM 26 702 (polyclonal) 992 (IgMK) 5 160 35 3,420 (IgMK) 11 116 140

Peripheral mononuclear cells

(a)

T-cells

B-cells

51 82 89 ND 87

16 5 16 ND 15; no clonality

66 70 97 82 80

29; 90% IgMK 8 0.5 12 37; 90% IgMK

Tumor cell staining ND ND ND I . IgM, IgD, K (node) 2. IgMK, (bone marrow) IgMK, (bone marrow) ND ND IgMK (node) and IgMK bone marrow

"Normal ranges: IgG, 800-1 800 mgldl; IgA, 90-420 mgidl; IgM, 90-300 mgldl. bBefore 198I , all patients were receiving intramuscular immunoglobulin (50 mglkgi2 wks); after 1981 all patients received intravenous immunoglobulin (300 mg/kg/3 wks). ND = not done.

v) c,

r

Q

. I

0

d Y

C

Q . I

Y

G-

R-

Hind ~ / J H Fig. 2. Southern blot analysis of immunoglobulin J region of lymphoma cells of Patients 5 and 10. Hind Ill-digested DNA was hybridized with a JH probe as described. Germ line (G) and rearranged (R) bands are indicated.

from a t(9;14) translocation. This finding is consistent with published data on the cytogenetics of large cell lymphomas. The genetic abnormalities which underlie CVI, a disorder in which B-cell development appears incomplete

and immunoglobulin secretion is absent or subnormal, are still unknown. No characteristic abnormalities of immunoglobulin genes have been described, although unusual patterns of immunoglobulin gene rearrangements, and/or restricted use of V gene segments have been demonstrated in a few recent studies [23,24]. It was thus of interest to determine whether the B-cell lymphomas which arise in hypogammaglobulinemic individuals would have different cytogenetic abnormalities than individuals with no immunodeficiency disease. The reason patients with CVI have a tendency to develop NHL, specifically of B-cell type, is also unknown. Various theories have been proposed, including absence of immune surveillance [25], continuous exposure to environmental antigens [ 141, intrinsic chromosomal susceptability to mutagens [26], and uncontrolled blastogenesis of B lymphocytes due to impaired T-cell regulation [15,27]. Some aspects of the latter reason appear to be involved in the development of B-cell malignancies in patients who have undergone bone marrow transplantation for congenital immune deficiency. In these cases, 25% of recipients of T-depleted and mismatched marrow, as opposed to none of a group of recipients of matched, T-depleted transplants and only 1 of 500 matched, non-T-depleted, transplants, developed lymphoma [27]. Thus, reconstitution of B-cells with incomplete reconstitution of T-cell immunity in these cases was linked to the development of B-cell lymphomas. Since the lymphomas in the transplant setting contain multiple copies of Epstein-Barr virus genomic DNA, this virus has been implicated as an important etiologic agent. For patients with CVI, no evidence for a viral agent in NHL has yet been presented. Thus, the lymphomas which arise in CVI share certain

74

Cunningharn-Rundles et al.

features with the lymphomas which appear in WAS, AT, or SCID: they are similar in overall frequency (13%), are often B-cell in origin, and extranodal in location. However, unlike the lymphomas of the immunodeficient child, lymphomas in CVI may be more differentiated and secrete immunoglobulin. For CVI patients with stage I or I1 disease, as for NHLs in general, the prognosis is good. In our group, NHL in CVI have appeared most often in females of the 5th to 7th decade and not in childhood. Cytogenetic studies in lymphomas show that cytogenetic abnormalities, including chromosomal translocations, can be found in this group, but more studies will be needed to assess the frequency of these events. ACKNOWLEDGMENTS This work was supported in part by the NIH grant AI-24839, CA-34775, and CA-20196. REFERENCES 1. Perry GS, Spector B, Shuman LM, Mandel JS, Anderson VE, McHugh RB, Hanson MR, Fahlstrom SM. Krivit W, Kersey JH: The Wiscott-Aldrich syndrome in the United States and Canada (18921979). J Pediatr 97:72-78, 1980. 2. Spector BD, Filipovich AH, Perry GS, Kersey JH: Epidemiology of cancer in ataxia-telangiectasia. In Bridges BA, Hamden DG (eds): “Ataxia- Telangiectasia-A Cellular and Molecular Link Between Cancer, Neuropathology, and Immune Deficiency.” New York: John Wiley and Sons, 1982, pp 103-138. 3. Filipovich AH, Heintiz KJ, Robinson LL, Frizzera G: The Immunodeficiency Cancer Registry. Am J Pediatr HematoliOncol 9: 183, 1987. 4. Hermans PE, Diax-Buxo JA, Stobo JD: Idiopathic late onset immunoglobulin deficiency: Clinical observations in SO patients. Am J Med 61:221, 1976. 5 . Cunningham-Rundles C: Clinical and immunologic analyses of 103 patients with common variable immunodeficiency. J Clin Lab Immuno1 9:22-33, 1989. 6. Cunningham-Rundles C, Siegal FP, Cunningham-Rundles S, Lieberman P: Incidence of cancer in 98 patients with common varied immunodeficiency. J Clin Lab Immunol 7:294, 1987. 7. March of Dimes Birth Defects Foundation: “Birth Defects: Original Article Series,” Vol. 19, No. 3. New York: Alan R. Liss, Inc., 1983, pp 345-360. 8. Hoffman RA, Kung PC, Hansen WP, Goldstein G: Simple and rapid measurement of human T lymphocytes and their subclasses in peripheral blood. Proc Natl Acad Sci USA 77:491, 1982. 9. Koziner B, Kempin S, Passe S, Gee TS, Good RS, Clarkson BD: Characterization of B-cell neoplasms in leukemic phase. A tentative immunomorphological classification. Blood 56:8IS-820, 1980. 10. Non-Hodgkin’s lymphoma pathologic classification project: National Cancer Institute-sponsored study of classifications of non-Hodgkin’s lymphoma: Summary and description of a working formulation for clinical usage. Cancer 49:2112, 1982.

1I . Koduru PRK, Filippa DA, Richardson ME, Jhanwar SC, Chaganti SR, Koziner B, Clarkson BD, Lieberman PH, Chaganti RSK: Cytogenetic and histologic correlations in malignant lymphoma. Blood 69:97, 1987. 12. Maniatis T, Fritsch EE, Sambrook J: “Molecular cloning: A Laboratory Manual.” Cold Spring Harbor, New York: Cold Spring Harbor Laboratory, 1982. 13. Feinberg AP, Vogelstein B: A technique for radiolabeling of DNA restriction endonuclease fragments to high specific activity. Addendum Anal Biochem 137:266267, 1984. 14. Filipovich AH, Zerbe D, Spector BD, Kersey JH: Lymphomas in persons with naturally occurring immunodeficiency disorders. In Magrath IT, O’Connor GT, Ramot B (eds): Pathogenesis of Leukemias and Lymphomas: Environmental Influences, New York: Raven Press, 1984, pp 225-234. I S . Tsuchiya M, Miguchi S, Kuwahara T, Matsuda I, Mitsuya H: Immunologic studies in peripheral blood in a child with hypogammaglobulinemia: Suggested mechanism of the development of malignant B-cell lymphoma. Cancer 53:1492, 1984. 16. Durham JC, Stephens DS, Rimland D, Nassar VH, SpiraTJ: Common variable hypogammaglobulinemia complicated by an unusual Tsuppressoricytoxic cell lymphoma. Cancer 59:27 1-276, 1987. 17. Kim JH, Bedrosian CL, Schlossman DM: Peripheral T-cell lymphoma complicating common variable hypogammaglobulinemia. Am J Med 85: 123-125, 1988. 18. Yunis JJ, Oken MM, Kaplan ME, Ensrud KM, Howe RB, Theologides A (1982): Distinctive chromosomal abnormalities in histologic subtypes of non-Hodgkin lymphoma. N Engl J Med 307:1231, 1982. 19. Bloomfield CD, Arthur DC, Frizzera G, Levine EG, Peterson BA, Gajl-Peczalska K: Non-random chromosome abnormalities in lymphoma. Cancer Res 43:2975, 1983. 20. Kaneko Y , Rowley JD, Variakojis D, Haren JM, Ueshima Y, Daly K, Kluskens LF: Prognostic implications of karotype and morphology in patients with non-Hodgkin lymphoma. Int J Cancer 32:683, 1983. 21. Kristoffersson U, Heim S , Mandahl N , Olson H, Ranstam J, Akerman M, Mitelman F: Prognostic implication of cytogenetic findings in 106 patients with non-Hodgkin lymphoma. Cancer Genet Cytogenet pp 55-64, 1987. 22. Cleary MJ, Sklar J: Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakcluster region near a transcriptionally active focus on chromosone 18. Proc Natl Acad Sci USA 82:7439, 1985. 23. Hauke G , Hadam M, Epplen JT, Gahr M, Hollmann A, Peter HH: Predominant immunoglobulin gene rearrangements in two patients with immunodeficiency: restricted use of V gene segments and DNA hypermethylation. Immunobiology I78:449, 1989. 24. Hauke G, Epplen JT, Gahr M , Hollmann A, Pfister S, Rump JA, Peter HH: Unusual immunoglobulin gene rearrangements in patients with immunodeficiency. Immun Infekt 17:53, 1989. 25. Stutman 0: Immunological surveillance. In Hiatt HH, Watson JD, Winstern JW (eds): Origins of Human Cancer, Cold Springs Harbor, NY: Cold Spring Harbor Laboratories, 1977, p 729. 26. Vorechovsky I, Munzarova M, Lokaj J: Increased bleomycin-induced chromosome damage in lymphocytes of patients with common variable immunodeficiency indicates an involvement of chromosomal instability in their cancer predisposition. Cancer Immunol Immunother 29:303, 1989. 27. Kersey JH, Shapiro RS, Filopovich AM: Relationship of immunodeficiency to lymphoid malignancy. Pediatr Infect Dis J 7510, 1988.