Familial aggregation of nasopharyngeal carcinoma and other malignancies. A clinicopathologic description

Familial Aggregation of Nasopharyngeal Carcinoma and Other Malignancies A Clinicopathologic Description

Cheryl M. Coffin, MD,* Steven S. Rich, PhD,? and Louis P. Dehner, MD*

Nasopharyngeal carcinoma (NPC) occurred in five members in three generations of a white American family of Scandinavian descent. Six other family members had malignancies including malignant melanoma, malignant lymphoma, squamous cell carcinoma of the tongue, adenocarcinoma of the colon, and asynchronous bilateral in situ and invasive ductal carcinomas of the breast. There was also a history of autoimmune disorders and exposure to smoke, fumes, and chemicals in some family members. Regression analysis revealed a significant covariate risk for exposure to smoking, alcohol ingestion, dust, salted or spicy foods, and poorly ventilated conditions. According to segregation analysis, the susceptibility to nasopharyngeal carcinoma and other malignancies in this family was transmitted as an autosomal codominant characteristic. A specific histocompatibility antigen (HLA) haplotype of Al-B37-DR6 was associated with a predisposition for NPC, but no linkage was identified. Laboratory studies in selected family members did not reveal significantly elevated levels of Epstein-Barr virus antibodies or serum carcinoembryonic antigen. No specific karyotypic abnormalities were identified with peripheral blood chromosome analysis. This family was an example of apparent autosomal codominant susceptibility to NPC and other malignancies. The relationship of malignancy to the HLA haplotype of Al-B37-DR6, autoimmune disorders, and cytogenetic abnormalities was intriguing but not defined clearly. Cancer 68:1323-1328.1991.

HE CONCEPT OF CANCER as a genetic disease achieved T increasingly widespread acceptance as more examples of familial malignancies were documented. '3' Naso- pharyngeal carcinoma (NPC) is uncommon in the United States, with an estimated incidence of 0.4 to 2 per 1000,000 in whites3 Although NPC was not included in recent tabulations of recognized cancer-family syndromes, several kindreds were reported with up to four members affected with NPC, sometimes in association with other types of neopla~ia .~- '~ We report the clinicopathologic

From the tDepartment of Laboratory Medicine and Pathology, Di- visions of Surgical Pathology and Health Computer Science, University of Minnesota Hospital and Clinic, Minneapolis, Minnesota: and the *Department of Pathology, The Lauren V. Ackerrnan Laboratory of Surgcal Pathology. Washington University School of Medicine, St. Louis, Missouri.

Supported in part by a grant from the Saint Paul-Ramsey Medical Education and Research Foundation, St. Paul, Minnesota.

Address for reprints: Cheryl M. Coffin, MD, Division of Anatomic Pathology. Barnes Hospital, 1 Barnes Hospital Plaza. St. Louis, MO 631 10.

Accepted for publication March 2 1, 199 1.

findings in a family with five cases of NPC and six other malignancies.

Materials and Methods

The subjects of our study consisted of all family members. The basic pedigree structure was obtained by inter- viewing a series of family members. A detailed form out- lining medical, social, and occupational history and informed consent forms were sent to all living adult members of the kmdred and their spouses. Medical, social, and occupational information about all deceased family members was obtained from interviews and correspon- dence with spouses, parents, children, or other close relatives. Specific information was sought regarding a history of ear, nose, and throat problems; lower respiratory problems; autoimmune disorders; and exposure to smoke, alcohol, dust, salted or spicy foods, and poorly ventilated conditions. The research protocol was approved by the Institutional Review Board, St. Paul-Ramsey Medical Center (St. Paul, MN).

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Pathologic diagnoses were confirmed by review of all available histologic materials by a pathologist and by medical record review. Interviews, medical record reviews, and laboratory testing were done on selected family members and spouses of individuals with malignancies. Blood samples were collected at the time of personal interview.

Laboratory tests included Epstein-Ban- virus (EBV) serology, serum carcinoembryonic antigen (CEA), serum fluorescent antinuclear antibody (FANA) levels, peripheral blood chromosome analysis, and histocompatibility antigen (HLA) typing. The EBV serology was done by Viromed (Minnetonka, MN). Immunoglobulin (Ig) G antibody to viral capsid antigen (VCA) was measured by indirect immunofluorescence.'7 Antibodies to EBV-associated nuclear antigen (EBNA) were measured by an- ticomplement immunofluorescence.'* The IgG antibodies to the diffuse (EA-D) and restricted (EA-R) components of the early antigen complex were measured by an enzyme-linked immunosorbent assay.'' An assay for IgA antibody to VCA was not available at the time testing was done. Roche Biomedical (Wichita, KS) did the enzyme immunoassays for serum CEA levels. Serum FANA were measured by indirect immunofluorescence using the

r Key

0 Male 0 Fsmale 0 Cancer 0 Other risk factor 0 Stillbirth

Kallestad Quantafluor fluorescent autoantibody test (Austin, TX). Peripheral blood chromosome analysis was done on heparinized blood according to standard techniques.20-22 An average of 20 metaphases per specimen was examined. In addition, HLA-A, -B, and -DR typing on heparinized blood was done by the University of Min- nesota Histocompatibility Laboratory by standard meth-

The data were analyzed with the computer programs LIPED,25 PAP,26 and SAGE2' for linkage and segregation analysis.

o d ~ . ~ ~ , ~ ~

Results

The family studied is depicted in the pedigree in Figure 1. Most family members reside in rural eastern Minnesota and western Wisconsin. Eighty-seven family members and spouses returned the informed consent and historic information forms. Thirty-nine individuals, including 3 1 family members and eight spouses, were selected for personal interviews and laboratory evaluation. Eleven family members with cancer, including five cases of NPC, were identified, and pathologic diagnoses and methods of verification are summarized in Table 1. Clinicopathologic

FIG. 1. Pedigree of NPC family.

No. 6 FAMILIAL AGGREGATION OF NASOPHARYNGEAL CA - Cojin el al. 1325

TABLE 1 . Types and Number of Malignancies in Affected Family Members

No. Diagnosis affected Pedigree no. Cancer verification

Nasopharyngeal ca 5 4, 42. 51. 53, 61 Histology-3

Squamous cell ca, tongue 2 3, 17 Histology-I

Adenocarcinoma. rectum I 29 Histology- I Invasive ductal ca, breast 1 62 Histology- I Malignant melanoma 1 I I4 Histology- 1 Malignant lymphoma, non-Hodgkin’s

(poorly differentiated lymphocytic, diffuse) 1 92 Histology- 1

Medical records-2

History- 1

information about the five people with NPC is given in Table 2. All of the NPC specimens available for review were similar histologically in appearance and composed of solid nonkeratinizing neoplastic nests in a lymphoid background (Fig. 2). Ten of the affected individuals had died before initiation of the study. The one living patient (Pedigree Number 62) with cancer was among those selected for interview and laboratory evaluation; she had invasive and in situ ductal carcinoma of the right breast diagnosed several months after initiation of the study, and a second primary ductal carcinoma of the left breast developed 30 months later (Fig. 3).

Initial segregation analysis of NPC resulted in failure to reject the hypothesis of “no polygenes” (chi-square, 0.01). The hypothesis of “no single major locus” was strongly rejected (chi-square, 37.0; P < 0.0 1). In the single major locus category, the autosomal dominant model fit the data significantly worse than either the recessive or intermediate (codominant) model (chi-square, 22.0; P < 0.01 and chi-square, 22.01; P < 0.01, respectively). The best-fit model was intermediate (codominant) in mode of transmission, with increasing penetrance after 40 years of age. Regressive analysis revealed a significant covariate risk only for social and occupational risk factors but none for a positive history of ear, nose, and throat problems; autoimmune disorders; or exposure to smoke and fumes.

All 31 of the family members tested had EBV VCA IgC titers between 1: 10 and 1 : 160. The VCA IgG titers in this range were compatible with immunity to EBV but not diagnostic of current infection. The EBNA results were

available for 30 of these 31 family members and were greater than 2 in all cases. This finding was compatible with past EBV infection, at least 2 months before the time of phlebotomy. The IgG anti-EA-D was negative (titer less than 1:20) in 24 (77%) of 3 1 family members. Seven individuals (23%) had mildly elevated titers ranging from 1 :20 to 1 : 160. The IgG anti-EA-R was negative (titer less than 1 :20) in 22 (7 1 %) of 3 1 family members. Nine individuals (29%) had mildly elevated titers ranging from 1:20 to 1:160. These results indicated that all 31 family members tested had evidence of immunity to EBV but no evidence of acute EBV infection. Based on the combination of serologic results, four individuals may have had a relatively recent infection, at least 2 months before phlebotomy. Unfortunately, VCA-IgA titers were not available.

Serum CEA levels were within normal limits in 29 and minimally elevated in two of 31 family members. Both were men who smoked cigarettes. These levels of CEA were not sufficiently high to raise the suspicion of malignancy.

The FANA levels were negative in 17 (55%) and positive in 14 (45%) family members. Eleven otherwise healthy adults had low titers of 1 :20 to 1 : 160 with a speckled pattern. Two, a healthy 87-year-old woman and a 62-year- old man with an aortic aneurysm, had FANA titers of 1: 320 and 1 :80, respectively, with a homogeneous pattern. A 36-year-old woman with a history of patchy skin lesions and back and shoulder pain had a titer of 1:320 with a nucleolar pattern.

TABLE 2. Features of the Five Family Members With Nasopharyngeal Carcinoma

Risk factors Age at Age at

Pedigree diagnosis death HLA haplotype Medical no. (yr) Sex (Yd Al-B37-DR6 Social/occupational history Smoke/fumes

4 43 F 44 + 42 56 M 58 ? 51 52 M 52 + 53 61 M 62 + 61 36 F 40 ?

+ + + + + + + + +

-

1326 CANCER September 15 199 1 Vol. 68

FIG. 2. Nasopharyngeal carcinoma showing a cohesive nest of non keratinizing tumor cells with a prominent nucleolus and vesicular nucleus (H & E, original magnification X600).

Peripheral blood chromosome analysis was completed in 28 family members, 16 male and 12 female members, including the woman with breast cancer. There was no growth in specimens from three other relatives. Overall, 14 of 28 (50%) had minor abnormalities in structure and/ or number of chromosomes. Three of these also had a HLA haplotype of A 1-B37-DR6. The chromosomal abnormalities are summarized in Table 3. The abnormalities involved one or two of 20 metaphases examined per specimen; 2 1 % were structural, and 43% were numeric. Al- though age and sex-matched controls were not available for comparison, this frequency of abnormalities was much higher than observed in genetic amniocentesis specimens (most of the samples examined by the laboratory). No marker chromosome or consistent pattern of cytogenetic abnormalities was evident.

The HLA typing was completed in 39 individuals, including 3 1 family members and eight spouses. The HLA haplotypes of deceased family members were determined

FIG. 3. Intraductal carcinoma of the breast with a cribriform pattern (H & E, original magnification X600).

TABLE 3.

Pedigree Age

Cytogenetic Abnormalities in 14 Family Members

no. (Yr) Sex Karyotm

46,XX/47,XXX 15* 86 F 45,XY,-19/46,XY 24 43 M 45,XY,-3,-3,-6,+2 markersl46,XY 25 34 M 45,X/46,XX/47,XXX 44 58 F 45,XY,-14/45,XY,-17/46, XY 55 40 M 45,XX,- 15/45,XY,XX-22/46,XX 56 43 F 46,XX/47,XX,+3, broken 9 62t 63 F 46,XX/47,XXX 68 46 F 45,X/+fra/46,XX 94 37 F 45,X/46,XX

105 26 F 45,X/46,XX 1 I8 27 F 46,X,t(X;13)(q22:q36)/46,XX 137 33 F 45,XY,-9,brokenX/46,XX

143* 31 M 46.XY I40* 29 M 46,XY,-14,+14p,t(7:14)(q36;qI I ) /

* HLA AI-B37-DR6. t Breast cancer patient.

by inference. In this family, the haplotype of Al-B37- DR6 was associated with both NPC, in particular, and cancer susceptibility, in general. The relative risk of NPC for family members with this haplotype was 13.67 (P < 0.01). The relative risk of malignancy in general was 5.40 ( P = 0.05). Linkage to the HLA region under the genetic model of an autosomal codominant gene with reduced penetrance for NPC was not confirmed, with a Lod score of 0.10 at 0 = 0.48.

Discussion Our study of a large white kindred with NPC and other

malignancies showed a pedigree in which transmission of NPC was consistent with the action of a single autosomal codominant (intermediate) gene providing increased susceptibility for NPC with increasing age. The incidence of NPC exceeded the expected rate for whites of one to two per 100,000 for men and 0.04 per 100,000 for women.3 The male to female ratio of 1.5 was lower than the ratio of 2.4 described in epidemiologic studiesz8 The mean age of 50 years at diagnosis of NPC in this family was lower than the peak age incidence for whites in general of 65 to 75 years.29 Other examples of familial NPC were reported with as many as four members affected with NPC; some occurred at an earlier age than e~pected.~- '~ Some families had other malignancies in association with NPC, such as Burkitt's lymphoma, gastric adenocarcinoma, colonic adenocarcinoma, brain tumors, and leukemia.' ' 9 ' 3 - ' 5 , 2 9

Other factors appeared to influence the risk of malignancy in this family. Segregation analysis revealed a significant covariate risk for social and occupational risk factors, such as smoking, alcohol ingestion, dust exposure, salted or spicy food ingestion, and poorly ventilated working conditions. There was no increased risk with a positive history of ear, nose, throat, or autoimmune dis-

No. 6 FAMILIAL AGGREGATION OF NASOPHARYNGEAL CA . Cojin er af. 1327

orders or exposure to smoke and fumes. However, the broad characterization of risk factors in our analysis mil- itates in favor of a cautious interpretation of these findings. A history of nonneoplastic conditions of the ears, nose, and throat and occupational exposure to fumes, smoke, and chemicals were reported to increase the relative risk for NPC.30.” In Chinese patients with NPC, occupational exposure in combination with specific HLA haplotypes increased the relative risk.30

Apart from reports of familial NPC, the first recognized association between an increased risk for NPC and a genetic factor was for a specific HLA haplotype in Chinese patients with HLA A2-B si112.~’ The HLA studies in North American families yielded variable results, but the haplotype A2-B Sin2 described in the Chinese was not detected.33 The A 10-B 1 8 haplotype was identified in two siblings with NPC from a family of German-Mennonite extraction with considerable consanguinity and an apparent autosomal recessive pattern of inheritan~e.’~ In other ethnic groups, NPC was associated with various HLA haplotypes, such as B ~ 4 0 , ~ ~ B18-B 1 7,35 and A29- B ~ 4 2 . ~ ~ In an epidemiologic study of HLA types in North American whites with NPC, none of the HLA alleles associated with NPC in the Chinese were found nor were there any HLA associations detected in comparisons with normal, healthy controls.37

The family we described represents the first report of the HLA haplotype AI-B37-DR6 with an increased relative risk for NPC. None of the other previously described HLA haplotypes associated with NPC were identified in family members. With the haplotype A l-B37-DR6, the relative risk for NPC was 13.67 ( P < 0.01). and the relative risk for cancer in general was 5.40 ( P = 0.05) compared with family members without the haplotype. However, linkage of the codominant susceptibility for NPC and other malignancies to the HLA-region on the short arm of chromosome 6 was not confirmed.

The presence of diabetes mellitus, pernicious anemia, psoriasis, and thyroid disease in this family was intriguing and suggested a possible relationship between the susceptibility to malignancy and autoimmune disorders. Certain HLA haplotypes, HLA-B 15-DR4 and HLA-B8-DR3, were linked to autoimmune disorders but not found with increased frequency in this family. Serum FANA levels were positive in 45% of family members, but in most, the titers were low, and the staining pattern was nonspecific.

Peripheral blood chromosome analysis in the family revealed an unexpectedly high frequency of minor abnormalities; 50% of the family members tested had nonspecific, irreproducible structural or numeric aberrations, including the patient with breast cancer. The three family members with both chromosomal aberrations and the HLA haplotype A 1 -B37-DR6 all had different cytogenetic abnormalities. The significance of these changes in relation

to the familial predisposition to malignancy is unknown. Other familial malignancies with documented cytogenetic abnormalities tend to be associated with reproducible changes involving a specific chromosome or oncogene. A study of peripheral blood cytogenetics in 41 unrelated Chinese NPC patients revealed numeric abnormalities in 12.67%, mainly involving group C chromosomes, with nonspecific structural abnormalities in 5 .0770.~~ An epithelioid cell line established from tumor tissue from a Chinese patient with NPC was near triploid, with a modal number of 67 to 68 and a series of marker chromosomes that included a deletion on the short arm of chromosome 2 and an addition on the long arm of chromosome 14.39 Tissue from tumors in NPC patients in this family was not available for cytogenetic studies because all were deceased at the initiation of the study.

Because of the well-documented association between EBV and NPC, we wanted to investigate whether EBV infection was related to neoplastic transformation in this far nil^.^'-^^ Unfortunately specimens from deceased family members were not available for serologic or DNA hy- bridization studies for EBV. We screened relatives for serologic evidence of EBV infection because antibodies to VCA, EA-D, EA-R, and EBNA are elevated in 73% to 90% of patients with nonkeratinizing and undifferentiated NPC and a smaller proportion of patients with keratinizing NPC.40,4’ All of the 31 family members screened had evidence ofpast infection with and immunity to EBV with IgG anti-VCA levels comparable with or lower than normal subjects or patients with benign head and neck disorders in other studies.40 None had evidence of chronic, persistent EBV infection. At the time of the study, a test for IgA anti-VCA was not available to us. Thus, there was no evidence to support or refute an underlying defect in the immune response to EBV predisposing these family members to the development of NPC. In addition CEA screening did not detect any degree of elevation suggesting potential occult malignancies in family members.44

In summary, our study found an autosomal codominant (intermediate) inherited risk of cancer in this family. The relative risk, especially for NPC, was higher with the HLA haplotype of A 1 -B37-DR6. Other social and occupational risk factors also appeared to influence the development of malignancy. It would be prudent for family members to minimize exposures to substances or behav- iors that increase risks. However, if, when, or in whom a malignancy will occur is unpredictable. The relationship of malignancy to autoimmune disorders and minor cytogenetic abnormalities identified in the family members tested was intriguing but not defined.

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Familial aggregation of nasopharyngeal carcinoma and other malignancies. A clinicopathologic description