Hereditary Flat Adenoma Syndrome: A Variant of Familial Adenomatous Polyposis? Henry T. Lynch, M.D.* Thomas C. Smyrk, M.D.,-~ Patrice Watson, Ph.D.,* Stephen J. Lanspa, M.D.,~ Patrick M. Lynch,J.D., M.D.,w Joseph X. Jenkins, M.D.,~ Jon Rouse, M.D., ]1Jennifer Cavalieri, R.N.,* Linda Howard, B.S.N.,wJane Lynch, B.S.N.* From the Departments of*Preventive Medicine/Public Health, ~Medicine-Gastroenterology, and ]]Pathology, Creighton University School of Medicine, Omaha, Nebraska, the ~Department of Pathology, Bishop Clarkson Memorial Hospital, Omaha, Nebraska, and the w of Gastrointestinal Oncology, MD Anderson Cancer Center, Houston, Texas We describe the clinical and pathologic features in four extended kindreds that are consistent with the hereditary flat adenoma syndrome (HFAS). This colon cancer susceptibility disorder is believed to be inherited as an autosomal dominant. The principal phenotypic marker is multiple colonic adenomas (usually less than 100), with a tendency for proximal location. The majority of these adenomas are flat or slightly raised and plaquelike, as opposed to polypoid. Colon cancers have typically developed in middle age and show no unusual histologic features. There are a variety of extracolonic manifestations, including adenomas and carcinomas of the small bowel and fundic gland polyps. The HFAS is contrasted with hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis (FAP) and shown to be distinct from both in the numbers and distribution of colonic adenomas and the typical age of cancer diagnosis. The clinical implications of these findings are discussed. Given its linkage to the FAP locus on 5q and the phenotypic parallels between HFAS and FAP, we conclude that HFAS is a variant of FAP. [Key words: Flat adenoma; Heredity; Heterogeneity; Colon cancer; Linkage to chromosome 5q] Lynch HT, Smyrk TC, Watson P, Lanspa SJ, Lynch PM, Jenkins JX, Rouse J, CavalieriJ, Howard L, LynchJ. Hereditary flat adenoma syndrome: a variant of familial adenomatous polyposis? Dis Colon Rectum 1992 ;35:411-42 I.
t h o u g h t to have hereditary n o n p o l y p o s i s colorectal cancer (HNPCC). Further investigation of this and similar kindreds s h o w e d that the fiat a d e n o m a s and colorectal cancer (CRC) had a p r e d i l e c t i o n for the proximal c o l o n and an age of cancer onset later than that s e e n either in HNPCC or familial a d e n o m atous polyposis (FAP). This constellation of findings r e p r e s e n t s a hereditary CRC-prone disorder w h o s e features are closer to FAP than to HNPCC, although not typical of either disorder. We have referred to the condition as hereditary fiat a d e n o m a s y n d r o m e (HFAS) to e m p h a s i z e its m o s t distinctive clinical feature. 3 Our p u r p o s e is to describe colonic and extracolonic clinicopathologic findings in four families with the HFAS p h e n o t y p e , including u p d a t e d findings in three families d e s c r i b e d in our previous publications. 2,3 MATERIALS AND
METHODS
T h r e e of the four families d e s c r i b e d in this report are f r o m the CRC resource at C r e i g h t o n ' s Hereditary Cancer Institute ( H C I ) (Families 1, 2, and 4), and the o t h e r family (Family 3) is f r o m the Hereditary Colon Cancer Registry, University of Texas MD A n d e r s o n Cancer Center (UT-MDACC). Approvals for these studies w e r e given b y the Institutional Review Boards of the two collaborating institutions. T h e families w e r e evaluated by standardized family study protocols 3-6 in use at the HCI and at the UT-MDACC. A c o m m o n data base, standardized questionnaires, and personal interviews in use at each center facilitated uniformity in the c o m p i l a t i o n and e x c h a n g e of information. Re-
UtO et al. 1 d e s c r i b e d the fiat a d e n o m a as a slightly elevated colonic m u c o s a l lesion in w h i c h a d e n o m a t o u s tubules s e e m to s p r e a d laterally b e t w e e n normal crypts, resulting in fiat rather than p o l y p o i d growth. Subsequently, Lynch et aL 2 r e p o r t e d a hereditary c o l o n c a n c e r - p r o n e family w h o s e affected m e m b e r s s h o w e d multiple colonic fiat a d e n o m a s . This family was initially M
support for this effort was provided by a grant from the National Cancer Institute, #1 RO1 CA42705, and by Nebraska Cancer & Smoking Disease Research Fund #92-27. No reprints are available. 411
412
LYNCH E T AL
trieval of primary medical and pathology documents enabled verification of historic material. Archival pathology material and prospectively obtained tissues were available for pathology review by our two collaborating pathologists (T.S.
Dis Colon Rectum, May 1992
and J.R.), Colonoscopic evaluations (S.L., J.J., and P.L.) were performed, whenever possible, on atrisk persons over age 20. Upper endoscopic examinations were later added to the patient evaluation protocol.
Table 1. Tumor Registry for Family 1
Pedigree Number
Sex
Age at Diagnosis
Basis of Diagnosis
Diagnosis*
I-1
M
74
DC
Carcinoma of stomach
I1-1
M
72 77 77
MR PR PR
AC, ascending colon AC, rectum 5 adenomas and flat adenomas
II1-1
F
52 65 65
PR PR PR
AC, transverse colon AC, ascending colon 8 adenomas and flat adenomas
111-2
F
67 67 67 65-71
PR PR PR PR
AC, cecum AC, ascending colon AC, ileocecal valve Multiplet adenomas and flat adenomas
111-4
F
63 64 59-64
PR PR PR
AC, rectum AC, ampulla of Vater 128 adenomas and flat adenomas
111-5
F
45 45 45
PR PR PR
AC, sigmoid colon AC, sigmoid colon >100 adenomas throughout colon
111-6
M
48 48 48
PR PR PR
AC, sigmoid colon AC, rectum Multiplex sigmoid adenomas
IV-1
M
48-55
PR
30 adenomas and flat adenomas
IV-2
M
34 34
PR PR
AC, ascending colon MultipleX adenomas
IV-3
F
44
PR
AC, breast
IV-4
F
44
PR
>50 fundic gland polyps
IV-6
M
PR
Hepatoblastoma
IV-7
F
36 36 42
PR PR PR
AC, cecum MultipleX adenomas 25 fundic gland polyps
IV-8
F
IV-9
F
32 37 39 30-32
PR PR MR PR
Carcinoma of cervix 45 adenomas Multiple1 adenomas, multiplet fundic gland polyps 22 adenomas and flat adenomas, >100 fundic gland polyps
V-2 V-3
F F
25 28-30
PR PR
27 adenomas and flat adenomas 6 adenomas and flat adenomas, >100 fundic gland polyps
V-4
F
27
PR
37 adenomas and flat adenomas
V-7
F
22
PR
Multiplet fundic gland polyps, 1 adenoma
V-9
F
18
PR
25 fundic gland polyps
9.5 mo
AC = adenocarcinoma; DC = death certificate; MR = medical report; PR = pathology report. * Adenomas were colorectal unless otherwise noted. Multiple numbers or sites not specified by pathology report.
HFAS: A VARIANT OF FAP
Vol. 35, No. 5
413
RESULTS
with 14 male and 14 female patients. The mean
Tables 1 through 4 list the tumor registries and Figures 1 through 4 the pedigrees of the four families. In total, 38 colon cancers have been diagnosed in 28 persons. Sex distribution was equal,
age at diagnosis was 57 years (range, 32-85 years). Six cancers occurred in the cecum, 13 in the ascending colon, 2 in the transverse colon, 1 in the descending colon, 7 in the sigmoid, and 9 in the
Table 2, Tumor Registry for Family 2
Pedigree Number
Sex
Age at Diagnosis
Basis of Diagnosis
Diagnosis*
11-3
F
59
DC
Carcinoma of uterus
111-3
M
79
PR
AC, sigmoid
111-4
F
54 65
DC DC
Carcinoma of breast Leukemia
111-5
M
62
MR
Carcinoma Of gallbladder
111-9
F
67
DC
Nasopharyngeal cancer
111-10
M
79 82
MR DC
AC, cecum AC, rectum
II1-11
F
74
PR
Carcinoma, ascending colon, multiplet adenomas
111-12
M
69
DC
Carcinoma, ascending colon
111-13
M
60
MR
Carcinoma, primary site unknown
IV-5
F
54
PR
AC, ascending colon, 5 adenomas and flat adenomas
IV-11
M
58
DC
Leukemia
IV-13
M
54
PR
AC, sigmoid colon, sessile polyps~ in sigmoid
IV-14
F
65-70
PR
13 adenomas and flat adenomas
IV-15
F
65
PR
65 adenomas and flat adenomas
IV-17
F
56
PR
11 adenomas
IV-20
M
57 57 57
MR PR PR
AC, ascending colon AC, cecum Multiplet adenomas
IV-21
M
73
PR
3 adenomas and flat adenomas
IV-22
M
62
PR
5 adenomas and flat adenomas
IV-23
M
62
PR
AC, ascending colon; 20 adenomas
IV-24
F
39
PR
AC, transverse colon
IV-25
F
32
PR
AC, sigmoid colon; 4 adenomas
V-4
M
2
DC
Leukemia
V-7
F
27
PR
Squamous-cell carcinoma, cervix
V-11
F
29
PR
Squamous-cell carcinoma, cervix
V-20
F
36 52
PR PR
Carcinoma in situ of cecum 4 adenomas 1 flat adenoma
V-21
F
54
PR
Multiplet adenomas and flat adenomas
V-22
M
39
PR
11 adenomas and flat adenomas
V-24
M
32
PR
3 adenomas
VI-1
M
30
PR
6 flat adenomas
Vl-2
F
32
PR
2 flat adenomas
AC = adenocarcinoma; DC = death certificate; MR = medical report; PR = pathology report. * Adenomas were colorectal unless otherwise noted. t Multiple numbers or sites not specified by pathology report. 1: Polyps not otherwise specified in pathology report.
414
LYNCH E T AL
Dis Colon Rectum, May 1992
Table 3. Tumor Registry for Family 3
Pedigree Number
Sex
Age at Diagnosis
Basis of Diagnosis
Diagnosis*
I1-1
F
34
DC
Myelogenous leukemia
11-3
F
85 85 85
PR PR PR
AC, sigmoid colon AC, ascending colon Multiple? adenomas and flat adenomas
II1-1
M
51
PR
AC, prostate
111-3
M
50
PR
AC, rectum
111-4
M
61 61 68
PR PR PR
AC, ascending colon Multiple? adenomas and flat adenomas Carcinoma, prostate
111-5
M
48 48 48
MR PR PR
Carcinoma, cecum Carcinoma, rectum "Innumerable" adenomas and flat adenomas
111-7
M
57 57
PR PR
AC, rectum 2 adenomas
111-8
F
74
MR
Multiplet adenomas
111-9
F
70 70
PR PR
69
PR
AC, descending colon AC, descending/sigmoid colon, cancer in situ within transverse colon Multiplet adenomas and flat adenomas
111-10
F
70
PR
6 adenomas
II1-11
F
65 68
PR PR
AC, ascending colon, multiplet adenomas Villous adenoma, rectum
111-12
F
53
PR
AC, rectum
111-15
F
56 53
PR PR
AC, duodenum/ampulla of Vater Multiple? adenomas and flat adenomas
IV-3 IV-4
M M
39 40
PR PR
44
PR
Malignant melanoma Carcinoma in situ, splenic flexure; multiple? adenomas and flat adenomas 2 duodenal adenomas; >100 fundic gland polyps
IV-11
F
30 46 46
SR PR PR
Thyroid carcinoma AC, rectum >10 adenomas
IV-18
F
30
PR
Multiple? adenomas and flat adenomas
IV-21
M
33
PR
7 fundic gland polyps; 1 adenoma
IV-22
F
34
PR
Multiple? adenomas and flat adenomas
V-3
M
14
PR
5 adenomas
AC = adenocarcinoma; DC = death certificate; MR = medical report; PR = pathology report; SR = self-report. * Adenomas were colorectal unless otherwise noted. ? Multiple numbers or sites not specified by pathology report.
rectum. The carcinomas from nine patients arose without accompanying adenomas, according to the pathology reports which described the colonic mucosa as unremarkable. Seven patients had cancers accompanied by 1 to 10 adenomas, two patients had 11 to 20 adenomas, and the remaining 11 patients had "multiple" adenomas. It appears that,
in some cases, multiple implies dozens but, in other reports, multiple is qualified by descriptors such as "hundreds" and "myriad." The 21 tumors from 19 patients showed no unusual histologic features. There were 6 well-differentiated, 13 moderately differentiated, and 2 poorly differentiated adenocarcinomas. Two tumors were
HFAS: A VARIANT OF FAP
Vol. 35, No. 5
415
Table 4. Tumor Registry for Family 4
Pedigree Number
Sex
Age at Diagnosis
Basis of Diagnosis
I1-1
F
63
DC
Carcinoma, gallbladder
11-3
M
36
DC
Carcinoma, colon
II1-1
M
49 68
PR PR
49 68 64
MR PR PR
49
PR
Intra-abdominal desmoid Adenoma with high-grade dysplasia in sigmoid colon Multiplei- adenomas Duodenal adenoma Papillary transitional-cell carcinoma, urinary bladder Multiple1" adenomas; tubular adenoma with high-grade dysplasia in cecum
111-2
M
Diagnosis*
111-4
M
57 57
PR PR
AC, mucinous, hepatic flexure Multiplet adenomas
IV-2
F
34
PR
2 adenomas
IV-5
M
25 25
PR PR
Multiplei- adenomas and flat adenomas >100 fundic gland polyps
AC = adenocarcinoma; DC = death certificate; MR = medical report; PR = pathology report.
Family 1 1
2
~ d~t4 2 d.40
~5~6 III
oo00 Co52
Co67
d.50
g
~F
20-31
28
Co34 Br44 d.41 50
IF
30
Co45 C048 61
IN6 ,y,
IV 55
co6a PA~p64
44
35-46
gh Co36 9.5 rno 42
Cx32 37
32
36-45 38-42
6,0 72
65
d.9
d.lnf
d.51
41-45
~W
30
20-22
25
7-19
06/19/1991 2764BAWl
Figure 1. Pedigree of family with fiat adenomas and three generations with upper GI pathology. See Figure 4 for key to symbols and abbreviations.
m u c i n o u s (Le., more than 50 percent of the t u m o r c o m p o s e d of extracellular mucin). No squamous or n e u r o e n d o c r i n e areas were present. Five tumors w e r e confined to the bowel wall, and 16 were through the wall; 12 patients had metastatic carcin o m a in regional lymph nodes. Fifty-two patients have had at least o n e colonic adenoma. Because our study is partly retrospective, it is s o m e t i m e s impossible to k n o w the exact number of adenomas discovered in a given patient, but
the range appears to be quite broad, from one to hundreds. The distinctive distribution and appearance of a d e n o m a s may be best illustrated by quoting directly from original pathology reports. Reports came from a variety of institutions and cover a long time span; they w e r e p r e p a r e d by pathologists generally unaware of any familial predisposition to cancer. One report described "multiple tan-brown slightly raised lesions in the c e c u m and proximal
416
LYNCH E T AL
Dis Colon Rectum, May 1992
Family 2 1
z
r 'm'
[I
d~
4.log ~z d.lnf / d 12 ~ d.eB
6'
l
I,,0
uus~
d.~
d.Ts d6&
C~79 ~ ~t*sa 1.4~ dt,K~, ,t.e
N,~7 d.TO 0
l
13
14
Iv 4S-57
d.33
T0
50
d,a9 ?0-SJ
e~
9
7
v
beu5~ 70
Co54
33-At
~0
1~
I
t4
17
T Y-T
7O
~1o
8
L~u2 42-4~ 4~-~7 CX2~ ~
a4-a~ l~-a4
&so
COS2 d.,~ 12
tt
12
t3
18 0I
Ig ~
15
1.
0
21
C057 7~
6
2 44
co~
lg
7
CX~ 41-4"/ 34-48 ~8-3~ ~.4 30-34
Co39
Cc~a
2~-40
d.42
4~
e9
Zl C~34~
l
SS
II
24 43
12
~-40
t3
4l
14,
5
~n~v
Figure 2. Pedigree of family with flat adenomas. See Figure 4 for key to symbols and abbreviations.
Family 3
.
1
2
d'
d•IO ~ap
E5
Leu34 d.38
d.SO
Co85 Co85 d.86
I m
I
qu ProSl d.52
74 ~2
Co$0 d.53
CoBl P r6o968
qu rJ]8 ql C048 Co4fi
d.5
Co57 d,59
~,
~aJ ~/,
74 ~/____
Co70 Co70
Co85
72
CO53
13
15
18
86
81
PAz~p$3
17
54
19
22
24
IV 40-56
g
51
Mme139 Co40
2~ 17 20
41
DN 2 15
31
26-43
d.30
28-40
d . l n f Thy30
50
d.lnf
45 47
42 45
27
21-26
34-48
34
29 35
38 40
39
38
24-42 /
d.lnf
6
3 II
44
3-9
9-22
23
20 22
06/19/i99i 3101BAW
Fi9ure 3. Pedigree of family with flat adenomas. See Figure 4 for key to symbols and abbreviations.
5 cm of the ascending colon." Another mentioned "small fiat-like mucosal polyps along the ascending colon." One colon was described as "speckled with adenomatous plaques"; another had "literally hundreds of small fleshy mucosal excrescences concentrated in the ascending and transverse colon." Several reports ventured the opinion that the polyps were hyperplastic, as in "the cecum contains closely packed mucosal irregularities consistent with hyperplastic polyps." We have been able to review polyps from 40
patients. Nearly all polyps were tubular adenomas; there are a few tubulovillous adenomas. Most were small (
]
qw 41-51
ii~i ~
BI64 66-68 Co57
C ~O68 ~ IV
&t~
rlrl
I'-II~
~2 ~3 I~4
III m,m
CancerSiteAbbreviation5
Co36
d,64 ~Z]1
Female
26
07/03/1991 3167BAW
Figure 4. Pedigree of family with flat adenomas. Number of Adenomas 32 2 2 1 1 1
Cecum
Ascending I
Transverse
Flat Adenomas
~
Sigmoid Descending O r d i n a r y Adenomas
Rectum
Area of Colon
Figure 6. Comparison between numbers of flat adenomas and of ordinary adenomas that have occurred in the segments of the colorectum.
Figure 5. A. A flat adenoma on a mucosal fold. The center of the lesion is slightly depressed (x33). B. Adenomatous tubules are concentrated in the upper half of the mucosa. Occasional non-neoplastic crypts are interspersed among the tubules (x165). bution of fiat a d e n o m a s and "typical" a d e n o m a s of the c o l o n o b s e r v e d in cases with n o history of CRC. Nearly 80 percent of the fiat a d e n o m a s w e r e located proximal to the splenic flexure. It is our i m p r e s s i o n that fiat a d e n o m a s , w h e n present, o o
curred 4 or 5 times as frequently as ordinary adenomas in any given patient. Upper gastrointestinal pathology also appeared to be a feature of the syndrome. Information is available from upper GI examinations on 17 patients, 10 of whom are members of Family 1. Two patients with colonic adenomas (Family 3, III-8 and Family 2, V-21) had normal upper endoscopy. Two patients without colon adenomas also had normal upper GI endoscopies (Family 1, III-7 and Family 1, V-5). One patient (Family 1, IV-4) with three normal colonoscopic exams over the course of five years was found to have >50 fundic gland polyps in her stomach (Fig. 7). A woman (Family 1, V-9) was examined by flexible sigmoidoscopy and barium enema and was found to be clear of polyps; her upper intestinal endoscopy showed 25 fundic gland polyps. The remaining 11 patients
LYNCH E T
418
Figure 7. Fundic gland polyp with elongated and dilated glands in an edematous lamina propria (x66).
had both colon adenomas and upper GI pathology: 7 had fundic gland polyps only, 1 had fundic gland polyps and duodenal adenomas, 1 had only a duodenal adenoma, 1 had fundic gland polyps, a gastric adenoma, and a periampullary carcinoma, and 1 had only a periampullary carcinoma. Other pertinent extraintestinal manifestations included hepatoblastoma (Family 1, IV-6) and intra-abdominal desmoid tumor (Family 4, III 1). DISCUSSION The cardinal features of HFAS are: 1) multiple colonic adenomas (usually less than 100) with a tendency for proximal distribution and fiat rather than polypoid growth; 2) colon cancer typically developing in middle age; and 3) a variety of extracolonic manifestations, including adenomas and carcinomas of the small bowel and fundic gland polyps of the stomach. Similarities between HFAS and FAP are clear from our findings; both syndromes feature multiple colonic adenomas, high risk for colon cancer, small bowel tumors,
AL
Dis Colon Rectum, May 1992
and fundic gland polyps. The principal dissimilarity is that HFAS tends not to carpet the colon with adenomas as does the typical case of FAP. Many affected patients with HFAS have less than 20 adenomas, and the adenomas are frequently localized to the proximal colon. Even when hundreds of adenomas are present, the distribution is usually the reverse of that seen in the typical FAP case, with many adenomas in the cecum and ascending colon, fewer in the transverse colon, and fewer still in the distal colon. Among the adenomas observed, the distinctive morphology of the fiat adenoma predominates. Flat adenomas are not unique to HFAS. Similar lesions occur quite commonly in FAP colons and may be seen in the general population as well. Muto and colleagues '1 original article did not discuss the family history of affected patients. A subsequent article by Wolber and Owen 7 found a family history of colon cancer in only 3 of 18 fiat adenoma patients; in their large series of colonic adenomas, 8.5 percent were reported to be flat adenomas. In our own prospective study, 12 percent of patients undergoing colonoscopy, who were not members of FAP or HNPCC families, had polyps endoscopically and histologically consistent with flat adenoma. s However, no patient in this series had more than one or two. In the article by Muto e t al. ~ and that by Wolber and Owen 7 flat adenomas had a greater incidence of high-grade dysplasia than did "ordinary" tubular adenomas of similar size, leading to speculation that the fiat adenoma may be a higher-risk precursor than the ordinary small adenoma. Our experience with fiat adenomas in the familial setting has been different; high-grade dysplasia appears to us to be no more common in flat adenomas than in ordinary adenomas. Significant problems regarding the fiat adenoma remain: is the fiat adenoma really distinct from the small tubular adenoma, and can the distinction be reproducibly made by endoscopic and/or pathologic findings? Certainly, there is a characteristic endoscopic and histologic appearance to the fiat adenoma, but perhaps all small adenomas look this way early in development. Indeed, Chang and Whitener 9 have shown that the adenomas in FAP grow horizontally to a diameter of 0.8 cm before beginning vertical growth. To our knowledge, there have been no published studies employing objective pathology parameters (immunohisto-
Vol. 35, No. 5
HFAS: A VARIANT OF FAP
chemical profile, oncogene expression, DNA index) to compare the flat adenoma with ordinary small adenomas. Si-Chun and Pei-Lang ~~have speculated, on the basis of histologic observations, that flat adenomas are polyclonal in origin although ordinary adenomas are monoclonal), but they offer no supporting experimental evidence. The uniqueness of HFAS does not depend on the uniqueness of fiat adenomas. The fiat adenoma need not be considered a novel, high-risk cancer precursor to justify special emphasis as a syndrome component. Because these small lesions, so important to syndrome recognition, are subtle and easily missed at endoscopy, they should be carefully sought. Even if one considers a flat adenoma to represent nothing more than a small tubular adenoma, the overall syndrome remains distinctive. This distinctiveness is best appreciated when the overall pattern of the phenotype (morphology, number, and anatomic location of adenomas, age of CRC) is examined. Although the pattern we have observed may be seen in occasional members of classical FAP families, its consistency in the families reported here is the basis for our hypothesis that HFAS is a variant of FAP. Fundic gland polyps were found in three of our families (Families 1, 3, and 4). Fundic gland polyps are common, though not pathologically worrisome, features of FAP, but they also occur in the nonhereditary setting and, in fact, may be quite common, having been reported in as many as 1.4 percent of gastroscopic examinations. 11 In their review of the pathology of fundic gland polyps, Lee and Burt 12 found no difference in the pathologic features of polyps occurring with or without FAP. Domizio e t a l . 13 found fundic gland polyps in 44 of 102 patients with FAP in a prospective screening program at St. Mark's Hospital. Fundic gland polyps are classified as hamartomas by most authors, but, as Domizio points out, they are composed of epithelial elements rather than connective tissue and may disappear in some patients; both of these features argue against hamartomatous origin. The presence of fundic gland polyps in our HFAS families provides one more indication that HFAS may be a variant of FAP. In any event, upper gastrointestinal endoscopy should be performed on colon adenomas or cancer-affected patients and repeated periodically. The role, if any, for asymptomatic surveillance requires further study. Recognition of families affected with highly pen-
419
etrant, autosomal, dominantly inherited CRC syndromes allows implementation of appropriate treatment, including targeted preventive and early detection strategies. 5 In the case of FAP, recognition is based on the presence of colonic adenomatosis in a family member. In HNPCC, the absence of morphologic abnormality places the family history of cancer in a pivotal role. HFAS falls somewhere in between: adenomas occur, but frequently they are few in number. Rarely do family members exhibit the florid polyposis readily associated with hereditary CRC. The phenotype of HFAS will also complicate the process of screening family members once the disorder has been recognized. The adenomas are generally small, fiat, and right-sided, mandating colonoscopy rather than sigmoidoscopy. The diagnostic difficulty is further compounded by variability in phenotypic expression. Some affected patients may have hundreds of adenomas, although others may have only one or two. Some patients with upper gastrointestinal tract pathology have no colonic lesions; others have pathology confined to the colon. Parallel problems in FAP have led to the application of linked genetic markers to refine risk assessments for family members whose colonic screening resuits are ambiguous. ~4 Recognition of HFAS will depend on a combination of family history and endoscopic findings as well as a clinician who is aware of the syndrome; screening in HFAS families will require adjustment of screening guidelines developed for FAP. Additional clinical issues are raised by the phenotypic description of HFAS. Because we observed later ages at CRC diagnosis and relatively small numbers of adenomas, we believe that the best management for HFAS cases will not always involve subtotal colectomy at diagnosis of polyposis (as in FAP). It is also unclear whether examination for adenomas will be sufficient to identify gene carriers. We have reports of colon cancer without accompanying adenomas in HFAS, although the adenomas are often so subtle that they may be missed by both endoscopist and pathologist. ~5 We also have reports of patients with normal colonic mucosa and gastric polyps. More information is required on these clinically important questions. The data we have provided on the number and distribution of adenomas in the colon, the frequency of finding upper gastrointestinal tract abnormalities, and the typical age at diagnosis of
420
LYNCH E T AL
colorectal cancer must be interpreted cautiously in light of the relatively small n u m b e r of cases inc l u d e d in the study. Studies of additional families will be n e e d e d to provide better estimates of these clinically important parameters. Studies that are m o r e systematic as well as larger will be r e q u i r e d to find the age distribution for first onset of each aspect of the p h e n o t y p e , to accurately estimate the age-specific risk for cancer d e v e l o p m e n t , and to evaluate the impact of alternative m a n a g e m e n t strategies. To test the hypothesis that the inherited predisposition to colon cancer and a d e n o m a t o u s polyps is the result of an inherited mutation at the FAP locus on c h r o m o s o m e 5, a genetic linkage study was performed. Using a series of markers flanking the FAP locus, 16 significant multipoint linkage (lod score >3) to the FAP locus was d e m o n s t r a t e d in two of the families in this study, namely, Families 1 and 3 (L. Spirio e t al., manuscript in preparation). These results are consistent with those r e p o r t e d in a phenotypically similar family 17 and suggest that variants in the expression of familial polyposis occur in certain families. These linkage families indicate that it may b e c o m e possible to identify HFAS g e n e carriers through DNA-polymorphism analysis, as is already used in FAP. ~4 It is possible that a series of mutations within the FAP locus has occurred. HFAS may represent o n e part of a c o n t i n u u m of progressively more severe mutations, culminating in FAP variants with early onset of florid polyps and CRC. These mutations might differ in the propensity to give rise to desmoids, osteomas, congenital h y p e r t r o p h y of the retinal pigment epithelium, c h i l d h o o d hepatoblastomas, brain tumors, adrenal cortical carcinomas, and papillary carcinoma of the thyroid. An alternative possibility is that other genes closely linked to the FAP locus are involved in these disorders, influencing the spectrum of p h e n o t y p i c features that characterize and differentiate these disorders. A third possibility is based on the observation that within classical FAP families there is variability in the p h e n o t y p e . Occasionally, patients are observed with relatively few adenomas a n d / o r with later ages o f onset of CRC. The families we have described may be chance aggregations of cases with relatively mild manifestations. Discovery and s e q u e n c i n g of the g e n e ( s ) for FAP and its variants and studies of
Dis Colon Rectum, May 1992
associations b e t w e e n p h e n o t y p e and specific mutations will eventually d e c i d e the issue.
REFERENCES 1. Muto T, Kamiya J, Sawada T, e t al. Small "flat adenoma" of the large bowel with special reference to its clinicopathologic features. Dis Colon Rectum 1985;28:847-51. 2. Lynch HT, Smyrk T, Lanspa SJ, e t al. Flat adenomas in a colon cancer-prone kindred. J Natl Cancer Inst 1988;80:278-82. 3. Lynch HT, Smyrk TC, Lanspa SJ, e t al. Phenotypic variation in colorectal adenoma/cancer expression in two families--the hereditary flat adenoma syndrome. Cancer 1990;66:909-15. 4. Lynch HT, Lanspa SJ, Boman BM, e t al. Hereditary nonpolyposis colorectal cancer--Lynch syndromes I and II. Gastroenterol Clin North Am 1988;17: 679-712. 5. Lynch PM, Lynch HT, eds. Colon cancer genetics. New York: VN Reinhold, 1985. 6. Lynch P, Winn WJ. Clinical management of hereditary nonpolyposis colon cancer: high risk clinics and registries. Hematol Oncol Clin North Am 1989;3: 75-86. 7. Wolber RA, Owen DA. Flat adenomas of the colon. Hum Pathol 1991;22:70-4. 8. Lanspa SJ, Rouse J, Smyrk T, Watson P, Jenkins JX, Lynch HT. Epidemiologic characteristics of the flat adenoma of Muto: a prospective study (abstr). Gastroenterology 1991;100:A378. 9. Chang WW, Whitener CJ. Histogenesis of tubular adenomas in hereditary colonic adenomatous polyposis. Arch Pathol Lab Med 1989;113:1042-9. 10. Si-Chun M, Pei-Liang Y. Histogenesis of experimental colonic carcinomas. In: Rozen P, Reich CB, Winawer SJ, eds. Large bowel cancer: policy, prevention, research, and treatment. Front GI Res 1991;18: 200-24. 11. Snover DC. Benign epithelial polyps of the stomach. Pathol Annu 1985;29:303-29. 12. Lee RG, Burt RW. The histopathologyof fundic gland polyps of the stomach. Am J Clin Pathol 1986;86: 498-503. 13. Domizio P, Talbert K, Spigelman AD, Williams CB, Phillips RN. Upper gastrointestinal pathology in familial adenomatous polyposis: results from a prospective study of 102 patients. J Clin Pathol 1990; 43:738-43. 14. Petersen GM, Slack J, Nakamura Y. Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology 1991;
Vol. 35, No. 5
HFAS: A VARIANT OF FAP
100:1658-64. 15. Adachi M, Muto T, Morioka Y, Ikenaga T, Hara M. Flat adenoma and fiat mucosal carcinoma (IIb type)--a new precursor of colorectal carcinoma? Report of two cases. Dis Colon Rectum 1988;31: 236-43. 16. Nakamura Y, Lathrop M, Leppert M, et al. Localiza-
421
tion of the genetic defect in familial adenomatous polyposis within a small region of chromosome 5. Am J Hum Genet 1988;43:638-44. 17. Leppert M, Butt R, Hughes JP, et al. Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. N Engl J Med 1990;322:904-8.
t h o u g h t to have hereditary n o n p o l y p o s i s colorectal cancer (HNPCC). Further investigation of this and similar kindreds s h o w e d that the fiat a d e n o m a s and colorectal cancer (CRC) had a p r e d i l e c t i o n for the proximal c o l o n and an age of cancer onset later than that s e e n either in HNPCC or familial a d e n o m atous polyposis (FAP). This constellation of findings r e p r e s e n t s a hereditary CRC-prone disorder w h o s e features are closer to FAP than to HNPCC, although not typical of either disorder. We have referred to the condition as hereditary fiat a d e n o m a s y n d r o m e (HFAS) to e m p h a s i z e its m o s t distinctive clinical feature. 3 Our p u r p o s e is to describe colonic and extracolonic clinicopathologic findings in four families with the HFAS p h e n o t y p e , including u p d a t e d findings in three families d e s c r i b e d in our previous publications. 2,3 MATERIALS AND
METHODS
T h r e e of the four families d e s c r i b e d in this report are f r o m the CRC resource at C r e i g h t o n ' s Hereditary Cancer Institute ( H C I ) (Families 1, 2, and 4), and the o t h e r family (Family 3) is f r o m the Hereditary Colon Cancer Registry, University of Texas MD A n d e r s o n Cancer Center (UT-MDACC). Approvals for these studies w e r e given b y the Institutional Review Boards of the two collaborating institutions. T h e families w e r e evaluated by standardized family study protocols 3-6 in use at the HCI and at the UT-MDACC. A c o m m o n data base, standardized questionnaires, and personal interviews in use at each center facilitated uniformity in the c o m p i l a t i o n and e x c h a n g e of information. Re-
UtO et al. 1 d e s c r i b e d the fiat a d e n o m a as a slightly elevated colonic m u c o s a l lesion in w h i c h a d e n o m a t o u s tubules s e e m to s p r e a d laterally b e t w e e n normal crypts, resulting in fiat rather than p o l y p o i d growth. Subsequently, Lynch et aL 2 r e p o r t e d a hereditary c o l o n c a n c e r - p r o n e family w h o s e affected m e m b e r s s h o w e d multiple colonic fiat a d e n o m a s . This family was initially M
support for this effort was provided by a grant from the National Cancer Institute, #1 RO1 CA42705, and by Nebraska Cancer & Smoking Disease Research Fund #92-27. No reprints are available. 411
412
LYNCH E T AL
trieval of primary medical and pathology documents enabled verification of historic material. Archival pathology material and prospectively obtained tissues were available for pathology review by our two collaborating pathologists (T.S.
Dis Colon Rectum, May 1992
and J.R.), Colonoscopic evaluations (S.L., J.J., and P.L.) were performed, whenever possible, on atrisk persons over age 20. Upper endoscopic examinations were later added to the patient evaluation protocol.
Table 1. Tumor Registry for Family 1
Pedigree Number
Sex
Age at Diagnosis
Basis of Diagnosis
Diagnosis*
I-1
M
74
DC
Carcinoma of stomach
I1-1
M
72 77 77
MR PR PR
AC, ascending colon AC, rectum 5 adenomas and flat adenomas
II1-1
F
52 65 65
PR PR PR
AC, transverse colon AC, ascending colon 8 adenomas and flat adenomas
111-2
F
67 67 67 65-71
PR PR PR PR
AC, cecum AC, ascending colon AC, ileocecal valve Multiplet adenomas and flat adenomas
111-4
F
63 64 59-64
PR PR PR
AC, rectum AC, ampulla of Vater 128 adenomas and flat adenomas
111-5
F
45 45 45
PR PR PR
AC, sigmoid colon AC, sigmoid colon >100 adenomas throughout colon
111-6
M
48 48 48
PR PR PR
AC, sigmoid colon AC, rectum Multiplex sigmoid adenomas
IV-1
M
48-55
PR
30 adenomas and flat adenomas
IV-2
M
34 34
PR PR
AC, ascending colon MultipleX adenomas
IV-3
F
44
PR
AC, breast
IV-4
F
44
PR
>50 fundic gland polyps
IV-6
M
PR
Hepatoblastoma
IV-7
F
36 36 42
PR PR PR
AC, cecum MultipleX adenomas 25 fundic gland polyps
IV-8
F
IV-9
F
32 37 39 30-32
PR PR MR PR
Carcinoma of cervix 45 adenomas Multiple1 adenomas, multiplet fundic gland polyps 22 adenomas and flat adenomas, >100 fundic gland polyps
V-2 V-3
F F
25 28-30
PR PR
27 adenomas and flat adenomas 6 adenomas and flat adenomas, >100 fundic gland polyps
V-4
F
27
PR
37 adenomas and flat adenomas
V-7
F
22
PR
Multiplet fundic gland polyps, 1 adenoma
V-9
F
18
PR
25 fundic gland polyps
9.5 mo
AC = adenocarcinoma; DC = death certificate; MR = medical report; PR = pathology report. * Adenomas were colorectal unless otherwise noted. Multiple numbers or sites not specified by pathology report.
HFAS: A VARIANT OF FAP
Vol. 35, No. 5
413
RESULTS
with 14 male and 14 female patients. The mean
Tables 1 through 4 list the tumor registries and Figures 1 through 4 the pedigrees of the four families. In total, 38 colon cancers have been diagnosed in 28 persons. Sex distribution was equal,
age at diagnosis was 57 years (range, 32-85 years). Six cancers occurred in the cecum, 13 in the ascending colon, 2 in the transverse colon, 1 in the descending colon, 7 in the sigmoid, and 9 in the
Table 2, Tumor Registry for Family 2
Pedigree Number
Sex
Age at Diagnosis
Basis of Diagnosis
Diagnosis*
11-3
F
59
DC
Carcinoma of uterus
111-3
M
79
PR
AC, sigmoid
111-4
F
54 65
DC DC
Carcinoma of breast Leukemia
111-5
M
62
MR
Carcinoma Of gallbladder
111-9
F
67
DC
Nasopharyngeal cancer
111-10
M
79 82
MR DC
AC, cecum AC, rectum
II1-11
F
74
PR
Carcinoma, ascending colon, multiplet adenomas
111-12
M
69
DC
Carcinoma, ascending colon
111-13
M
60
MR
Carcinoma, primary site unknown
IV-5
F
54
PR
AC, ascending colon, 5 adenomas and flat adenomas
IV-11
M
58
DC
Leukemia
IV-13
M
54
PR
AC, sigmoid colon, sessile polyps~ in sigmoid
IV-14
F
65-70
PR
13 adenomas and flat adenomas
IV-15
F
65
PR
65 adenomas and flat adenomas
IV-17
F
56
PR
11 adenomas
IV-20
M
57 57 57
MR PR PR
AC, ascending colon AC, cecum Multiplet adenomas
IV-21
M
73
PR
3 adenomas and flat adenomas
IV-22
M
62
PR
5 adenomas and flat adenomas
IV-23
M
62
PR
AC, ascending colon; 20 adenomas
IV-24
F
39
PR
AC, transverse colon
IV-25
F
32
PR
AC, sigmoid colon; 4 adenomas
V-4
M
2
DC
Leukemia
V-7
F
27
PR
Squamous-cell carcinoma, cervix
V-11
F
29
PR
Squamous-cell carcinoma, cervix
V-20
F
36 52
PR PR
Carcinoma in situ of cecum 4 adenomas 1 flat adenoma
V-21
F
54
PR
Multiplet adenomas and flat adenomas
V-22
M
39
PR
11 adenomas and flat adenomas
V-24
M
32
PR
3 adenomas
VI-1
M
30
PR
6 flat adenomas
Vl-2
F
32
PR
2 flat adenomas
AC = adenocarcinoma; DC = death certificate; MR = medical report; PR = pathology report. * Adenomas were colorectal unless otherwise noted. t Multiple numbers or sites not specified by pathology report. 1: Polyps not otherwise specified in pathology report.
414
LYNCH E T AL
Dis Colon Rectum, May 1992
Table 3. Tumor Registry for Family 3
Pedigree Number
Sex
Age at Diagnosis
Basis of Diagnosis
Diagnosis*
I1-1
F
34
DC
Myelogenous leukemia
11-3
F
85 85 85
PR PR PR
AC, sigmoid colon AC, ascending colon Multiple? adenomas and flat adenomas
II1-1
M
51
PR
AC, prostate
111-3
M
50
PR
AC, rectum
111-4
M
61 61 68
PR PR PR
AC, ascending colon Multiple? adenomas and flat adenomas Carcinoma, prostate
111-5
M
48 48 48
MR PR PR
Carcinoma, cecum Carcinoma, rectum "Innumerable" adenomas and flat adenomas
111-7
M
57 57
PR PR
AC, rectum 2 adenomas
111-8
F
74
MR
Multiplet adenomas
111-9
F
70 70
PR PR
69
PR
AC, descending colon AC, descending/sigmoid colon, cancer in situ within transverse colon Multiplet adenomas and flat adenomas
111-10
F
70
PR
6 adenomas
II1-11
F
65 68
PR PR
AC, ascending colon, multiplet adenomas Villous adenoma, rectum
111-12
F
53
PR
AC, rectum
111-15
F
56 53
PR PR
AC, duodenum/ampulla of Vater Multiple? adenomas and flat adenomas
IV-3 IV-4
M M
39 40
PR PR
44
PR
Malignant melanoma Carcinoma in situ, splenic flexure; multiple? adenomas and flat adenomas 2 duodenal adenomas; >100 fundic gland polyps
IV-11
F
30 46 46
SR PR PR
Thyroid carcinoma AC, rectum >10 adenomas
IV-18
F
30
PR
Multiple? adenomas and flat adenomas
IV-21
M
33
PR
7 fundic gland polyps; 1 adenoma
IV-22
F
34
PR
Multiple? adenomas and flat adenomas
V-3
M
14
PR
5 adenomas
AC = adenocarcinoma; DC = death certificate; MR = medical report; PR = pathology report; SR = self-report. * Adenomas were colorectal unless otherwise noted. ? Multiple numbers or sites not specified by pathology report.
rectum. The carcinomas from nine patients arose without accompanying adenomas, according to the pathology reports which described the colonic mucosa as unremarkable. Seven patients had cancers accompanied by 1 to 10 adenomas, two patients had 11 to 20 adenomas, and the remaining 11 patients had "multiple" adenomas. It appears that,
in some cases, multiple implies dozens but, in other reports, multiple is qualified by descriptors such as "hundreds" and "myriad." The 21 tumors from 19 patients showed no unusual histologic features. There were 6 well-differentiated, 13 moderately differentiated, and 2 poorly differentiated adenocarcinomas. Two tumors were
HFAS: A VARIANT OF FAP
Vol. 35, No. 5
415
Table 4. Tumor Registry for Family 4
Pedigree Number
Sex
Age at Diagnosis
Basis of Diagnosis
I1-1
F
63
DC
Carcinoma, gallbladder
11-3
M
36
DC
Carcinoma, colon
II1-1
M
49 68
PR PR
49 68 64
MR PR PR
49
PR
Intra-abdominal desmoid Adenoma with high-grade dysplasia in sigmoid colon Multiplei- adenomas Duodenal adenoma Papillary transitional-cell carcinoma, urinary bladder Multiple1" adenomas; tubular adenoma with high-grade dysplasia in cecum
111-2
M
Diagnosis*
111-4
M
57 57
PR PR
AC, mucinous, hepatic flexure Multiplet adenomas
IV-2
F
34
PR
2 adenomas
IV-5
M
25 25
PR PR
Multiplei- adenomas and flat adenomas >100 fundic gland polyps
AC = adenocarcinoma; DC = death certificate; MR = medical report; PR = pathology report.
Family 1 1
2
~ d~t4 2 d.40
~5~6 III
oo00 Co52
Co67
d.50
g
~F
20-31
28
Co34 Br44 d.41 50
IF
30
Co45 C048 61
IN6 ,y,
IV 55
co6a PA~p64
44
35-46
gh Co36 9.5 rno 42
Cx32 37
32
36-45 38-42
6,0 72
65
d.9
d.lnf
d.51
41-45
~W
30
20-22
25
7-19
06/19/1991 2764BAWl
Figure 1. Pedigree of family with fiat adenomas and three generations with upper GI pathology. See Figure 4 for key to symbols and abbreviations.
m u c i n o u s (Le., more than 50 percent of the t u m o r c o m p o s e d of extracellular mucin). No squamous or n e u r o e n d o c r i n e areas were present. Five tumors w e r e confined to the bowel wall, and 16 were through the wall; 12 patients had metastatic carcin o m a in regional lymph nodes. Fifty-two patients have had at least o n e colonic adenoma. Because our study is partly retrospective, it is s o m e t i m e s impossible to k n o w the exact number of adenomas discovered in a given patient, but
the range appears to be quite broad, from one to hundreds. The distinctive distribution and appearance of a d e n o m a s may be best illustrated by quoting directly from original pathology reports. Reports came from a variety of institutions and cover a long time span; they w e r e p r e p a r e d by pathologists generally unaware of any familial predisposition to cancer. One report described "multiple tan-brown slightly raised lesions in the c e c u m and proximal
416
LYNCH E T AL
Dis Colon Rectum, May 1992
Family 2 1
z
r 'm'
[I
d~
4.log ~z d.lnf / d 12 ~ d.eB
6'
l
I,,0
uus~
d.~
d.Ts d6&
C~79 ~ ~t*sa 1.4~ dt,K~, ,t.e
N,~7 d.TO 0
l
13
14
Iv 4S-57
d.33
T0
50
d,a9 ?0-SJ
e~
9
7
v
beu5~ 70
Co54
33-At
~0
1~
I
t4
17
T Y-T
7O
~1o
8
L~u2 42-4~ 4~-~7 CX2~ ~
a4-a~ l~-a4
&so
COS2 d.,~ 12
tt
12
t3
18 0I
Ig ~
15
1.
0
21
C057 7~
6
2 44
co~
lg
7
CX~ 41-4"/ 34-48 ~8-3~ ~.4 30-34
Co39
Cc~a
2~-40
d.42
4~
e9
Zl C~34~
l
SS
II
24 43
12
~-40
t3
4l
14,
5
~n~v
Figure 2. Pedigree of family with flat adenomas. See Figure 4 for key to symbols and abbreviations.
Family 3
.
1
2
d'
d•IO ~ap
E5
Leu34 d.38
d.SO
Co85 Co85 d.86
I m
I
qu ProSl d.52
74 ~2
Co$0 d.53
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qu rJ]8 ql C048 Co4fi
d.5
Co57 d,59
~,
~aJ ~/,
74 ~/____
Co70 Co70
Co85
72
CO53
13
15
18
86
81
PAz~p$3
17
54
19
22
24
IV 40-56
g
51
Mme139 Co40
2~ 17 20
41
DN 2 15
31
26-43
d.30
28-40
d . l n f Thy30
50
d.lnf
45 47
42 45
27
21-26
34-48
34
29 35
38 40
39
38
24-42 /
d.lnf
6
3 II
44
3-9
9-22
23
20 22
06/19/i99i 3101BAW
Fi9ure 3. Pedigree of family with flat adenomas. See Figure 4 for key to symbols and abbreviations.
5 cm of the ascending colon." Another mentioned "small fiat-like mucosal polyps along the ascending colon." One colon was described as "speckled with adenomatous plaques"; another had "literally hundreds of small fleshy mucosal excrescences concentrated in the ascending and transverse colon." Several reports ventured the opinion that the polyps were hyperplastic, as in "the cecum contains closely packed mucosal irregularities consistent with hyperplastic polyps." We have been able to review polyps from 40
patients. Nearly all polyps were tubular adenomas; there are a few tubulovillous adenomas. Most were small (
]
qw 41-51
ii~i ~
BI64 66-68 Co57
C ~O68 ~ IV
&t~
rlrl
I'-II~
~2 ~3 I~4
III m,m
CancerSiteAbbreviation5
Co36
d,64 ~Z]1
Female
26
07/03/1991 3167BAW
Figure 4. Pedigree of family with flat adenomas. Number of Adenomas 32 2 2 1 1 1
Cecum
Ascending I
Transverse
Flat Adenomas
~
Sigmoid Descending O r d i n a r y Adenomas
Rectum
Area of Colon
Figure 6. Comparison between numbers of flat adenomas and of ordinary adenomas that have occurred in the segments of the colorectum.
Figure 5. A. A flat adenoma on a mucosal fold. The center of the lesion is slightly depressed (x33). B. Adenomatous tubules are concentrated in the upper half of the mucosa. Occasional non-neoplastic crypts are interspersed among the tubules (x165). bution of fiat a d e n o m a s and "typical" a d e n o m a s of the c o l o n o b s e r v e d in cases with n o history of CRC. Nearly 80 percent of the fiat a d e n o m a s w e r e located proximal to the splenic flexure. It is our i m p r e s s i o n that fiat a d e n o m a s , w h e n present, o o
curred 4 or 5 times as frequently as ordinary adenomas in any given patient. Upper gastrointestinal pathology also appeared to be a feature of the syndrome. Information is available from upper GI examinations on 17 patients, 10 of whom are members of Family 1. Two patients with colonic adenomas (Family 3, III-8 and Family 2, V-21) had normal upper endoscopy. Two patients without colon adenomas also had normal upper GI endoscopies (Family 1, III-7 and Family 1, V-5). One patient (Family 1, IV-4) with three normal colonoscopic exams over the course of five years was found to have >50 fundic gland polyps in her stomach (Fig. 7). A woman (Family 1, V-9) was examined by flexible sigmoidoscopy and barium enema and was found to be clear of polyps; her upper intestinal endoscopy showed 25 fundic gland polyps. The remaining 11 patients
LYNCH E T
418
Figure 7. Fundic gland polyp with elongated and dilated glands in an edematous lamina propria (x66).
had both colon adenomas and upper GI pathology: 7 had fundic gland polyps only, 1 had fundic gland polyps and duodenal adenomas, 1 had only a duodenal adenoma, 1 had fundic gland polyps, a gastric adenoma, and a periampullary carcinoma, and 1 had only a periampullary carcinoma. Other pertinent extraintestinal manifestations included hepatoblastoma (Family 1, IV-6) and intra-abdominal desmoid tumor (Family 4, III 1). DISCUSSION The cardinal features of HFAS are: 1) multiple colonic adenomas (usually less than 100) with a tendency for proximal distribution and fiat rather than polypoid growth; 2) colon cancer typically developing in middle age; and 3) a variety of extracolonic manifestations, including adenomas and carcinomas of the small bowel and fundic gland polyps of the stomach. Similarities between HFAS and FAP are clear from our findings; both syndromes feature multiple colonic adenomas, high risk for colon cancer, small bowel tumors,
AL
Dis Colon Rectum, May 1992
and fundic gland polyps. The principal dissimilarity is that HFAS tends not to carpet the colon with adenomas as does the typical case of FAP. Many affected patients with HFAS have less than 20 adenomas, and the adenomas are frequently localized to the proximal colon. Even when hundreds of adenomas are present, the distribution is usually the reverse of that seen in the typical FAP case, with many adenomas in the cecum and ascending colon, fewer in the transverse colon, and fewer still in the distal colon. Among the adenomas observed, the distinctive morphology of the fiat adenoma predominates. Flat adenomas are not unique to HFAS. Similar lesions occur quite commonly in FAP colons and may be seen in the general population as well. Muto and colleagues '1 original article did not discuss the family history of affected patients. A subsequent article by Wolber and Owen 7 found a family history of colon cancer in only 3 of 18 fiat adenoma patients; in their large series of colonic adenomas, 8.5 percent were reported to be flat adenomas. In our own prospective study, 12 percent of patients undergoing colonoscopy, who were not members of FAP or HNPCC families, had polyps endoscopically and histologically consistent with flat adenoma. s However, no patient in this series had more than one or two. In the article by Muto e t al. ~ and that by Wolber and Owen 7 flat adenomas had a greater incidence of high-grade dysplasia than did "ordinary" tubular adenomas of similar size, leading to speculation that the fiat adenoma may be a higher-risk precursor than the ordinary small adenoma. Our experience with fiat adenomas in the familial setting has been different; high-grade dysplasia appears to us to be no more common in flat adenomas than in ordinary adenomas. Significant problems regarding the fiat adenoma remain: is the fiat adenoma really distinct from the small tubular adenoma, and can the distinction be reproducibly made by endoscopic and/or pathologic findings? Certainly, there is a characteristic endoscopic and histologic appearance to the fiat adenoma, but perhaps all small adenomas look this way early in development. Indeed, Chang and Whitener 9 have shown that the adenomas in FAP grow horizontally to a diameter of 0.8 cm before beginning vertical growth. To our knowledge, there have been no published studies employing objective pathology parameters (immunohisto-
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HFAS: A VARIANT OF FAP
chemical profile, oncogene expression, DNA index) to compare the flat adenoma with ordinary small adenomas. Si-Chun and Pei-Lang ~~have speculated, on the basis of histologic observations, that flat adenomas are polyclonal in origin although ordinary adenomas are monoclonal), but they offer no supporting experimental evidence. The uniqueness of HFAS does not depend on the uniqueness of fiat adenomas. The fiat adenoma need not be considered a novel, high-risk cancer precursor to justify special emphasis as a syndrome component. Because these small lesions, so important to syndrome recognition, are subtle and easily missed at endoscopy, they should be carefully sought. Even if one considers a flat adenoma to represent nothing more than a small tubular adenoma, the overall syndrome remains distinctive. This distinctiveness is best appreciated when the overall pattern of the phenotype (morphology, number, and anatomic location of adenomas, age of CRC) is examined. Although the pattern we have observed may be seen in occasional members of classical FAP families, its consistency in the families reported here is the basis for our hypothesis that HFAS is a variant of FAP. Fundic gland polyps were found in three of our families (Families 1, 3, and 4). Fundic gland polyps are common, though not pathologically worrisome, features of FAP, but they also occur in the nonhereditary setting and, in fact, may be quite common, having been reported in as many as 1.4 percent of gastroscopic examinations. 11 In their review of the pathology of fundic gland polyps, Lee and Burt 12 found no difference in the pathologic features of polyps occurring with or without FAP. Domizio e t a l . 13 found fundic gland polyps in 44 of 102 patients with FAP in a prospective screening program at St. Mark's Hospital. Fundic gland polyps are classified as hamartomas by most authors, but, as Domizio points out, they are composed of epithelial elements rather than connective tissue and may disappear in some patients; both of these features argue against hamartomatous origin. The presence of fundic gland polyps in our HFAS families provides one more indication that HFAS may be a variant of FAP. In any event, upper gastrointestinal endoscopy should be performed on colon adenomas or cancer-affected patients and repeated periodically. The role, if any, for asymptomatic surveillance requires further study. Recognition of families affected with highly pen-
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etrant, autosomal, dominantly inherited CRC syndromes allows implementation of appropriate treatment, including targeted preventive and early detection strategies. 5 In the case of FAP, recognition is based on the presence of colonic adenomatosis in a family member. In HNPCC, the absence of morphologic abnormality places the family history of cancer in a pivotal role. HFAS falls somewhere in between: adenomas occur, but frequently they are few in number. Rarely do family members exhibit the florid polyposis readily associated with hereditary CRC. The phenotype of HFAS will also complicate the process of screening family members once the disorder has been recognized. The adenomas are generally small, fiat, and right-sided, mandating colonoscopy rather than sigmoidoscopy. The diagnostic difficulty is further compounded by variability in phenotypic expression. Some affected patients may have hundreds of adenomas, although others may have only one or two. Some patients with upper gastrointestinal tract pathology have no colonic lesions; others have pathology confined to the colon. Parallel problems in FAP have led to the application of linked genetic markers to refine risk assessments for family members whose colonic screening resuits are ambiguous. ~4 Recognition of HFAS will depend on a combination of family history and endoscopic findings as well as a clinician who is aware of the syndrome; screening in HFAS families will require adjustment of screening guidelines developed for FAP. Additional clinical issues are raised by the phenotypic description of HFAS. Because we observed later ages at CRC diagnosis and relatively small numbers of adenomas, we believe that the best management for HFAS cases will not always involve subtotal colectomy at diagnosis of polyposis (as in FAP). It is also unclear whether examination for adenomas will be sufficient to identify gene carriers. We have reports of colon cancer without accompanying adenomas in HFAS, although the adenomas are often so subtle that they may be missed by both endoscopist and pathologist. ~5 We also have reports of patients with normal colonic mucosa and gastric polyps. More information is required on these clinically important questions. The data we have provided on the number and distribution of adenomas in the colon, the frequency of finding upper gastrointestinal tract abnormalities, and the typical age at diagnosis of
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colorectal cancer must be interpreted cautiously in light of the relatively small n u m b e r of cases inc l u d e d in the study. Studies of additional families will be n e e d e d to provide better estimates of these clinically important parameters. Studies that are m o r e systematic as well as larger will be r e q u i r e d to find the age distribution for first onset of each aspect of the p h e n o t y p e , to accurately estimate the age-specific risk for cancer d e v e l o p m e n t , and to evaluate the impact of alternative m a n a g e m e n t strategies. To test the hypothesis that the inherited predisposition to colon cancer and a d e n o m a t o u s polyps is the result of an inherited mutation at the FAP locus on c h r o m o s o m e 5, a genetic linkage study was performed. Using a series of markers flanking the FAP locus, 16 significant multipoint linkage (lod score >3) to the FAP locus was d e m o n s t r a t e d in two of the families in this study, namely, Families 1 and 3 (L. Spirio e t al., manuscript in preparation). These results are consistent with those r e p o r t e d in a phenotypically similar family 17 and suggest that variants in the expression of familial polyposis occur in certain families. These linkage families indicate that it may b e c o m e possible to identify HFAS g e n e carriers through DNA-polymorphism analysis, as is already used in FAP. ~4 It is possible that a series of mutations within the FAP locus has occurred. HFAS may represent o n e part of a c o n t i n u u m of progressively more severe mutations, culminating in FAP variants with early onset of florid polyps and CRC. These mutations might differ in the propensity to give rise to desmoids, osteomas, congenital h y p e r t r o p h y of the retinal pigment epithelium, c h i l d h o o d hepatoblastomas, brain tumors, adrenal cortical carcinomas, and papillary carcinoma of the thyroid. An alternative possibility is that other genes closely linked to the FAP locus are involved in these disorders, influencing the spectrum of p h e n o t y p i c features that characterize and differentiate these disorders. A third possibility is based on the observation that within classical FAP families there is variability in the p h e n o t y p e . Occasionally, patients are observed with relatively few adenomas a n d / o r with later ages o f onset of CRC. The families we have described may be chance aggregations of cases with relatively mild manifestations. Discovery and s e q u e n c i n g of the g e n e ( s ) for FAP and its variants and studies of
Dis Colon Rectum, May 1992
associations b e t w e e n p h e n o t y p e and specific mutations will eventually d e c i d e the issue.
REFERENCES 1. Muto T, Kamiya J, Sawada T, e t al. Small "flat adenoma" of the large bowel with special reference to its clinicopathologic features. Dis Colon Rectum 1985;28:847-51. 2. Lynch HT, Smyrk T, Lanspa SJ, e t al. Flat adenomas in a colon cancer-prone kindred. J Natl Cancer Inst 1988;80:278-82. 3. Lynch HT, Smyrk TC, Lanspa SJ, e t al. Phenotypic variation in colorectal adenoma/cancer expression in two families--the hereditary flat adenoma syndrome. Cancer 1990;66:909-15. 4. Lynch HT, Lanspa SJ, Boman BM, e t al. Hereditary nonpolyposis colorectal cancer--Lynch syndromes I and II. Gastroenterol Clin North Am 1988;17: 679-712. 5. Lynch PM, Lynch HT, eds. Colon cancer genetics. New York: VN Reinhold, 1985. 6. Lynch P, Winn WJ. Clinical management of hereditary nonpolyposis colon cancer: high risk clinics and registries. Hematol Oncol Clin North Am 1989;3: 75-86. 7. Wolber RA, Owen DA. Flat adenomas of the colon. Hum Pathol 1991;22:70-4. 8. Lanspa SJ, Rouse J, Smyrk T, Watson P, Jenkins JX, Lynch HT. Epidemiologic characteristics of the flat adenoma of Muto: a prospective study (abstr). Gastroenterology 1991;100:A378. 9. Chang WW, Whitener CJ. Histogenesis of tubular adenomas in hereditary colonic adenomatous polyposis. Arch Pathol Lab Med 1989;113:1042-9. 10. Si-Chun M, Pei-Liang Y. Histogenesis of experimental colonic carcinomas. In: Rozen P, Reich CB, Winawer SJ, eds. Large bowel cancer: policy, prevention, research, and treatment. Front GI Res 1991;18: 200-24. 11. Snover DC. Benign epithelial polyps of the stomach. Pathol Annu 1985;29:303-29. 12. Lee RG, Burt RW. The histopathologyof fundic gland polyps of the stomach. Am J Clin Pathol 1986;86: 498-503. 13. Domizio P, Talbert K, Spigelman AD, Williams CB, Phillips RN. Upper gastrointestinal pathology in familial adenomatous polyposis: results from a prospective study of 102 patients. J Clin Pathol 1990; 43:738-43. 14. Petersen GM, Slack J, Nakamura Y. Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology 1991;
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100:1658-64. 15. Adachi M, Muto T, Morioka Y, Ikenaga T, Hara M. Flat adenoma and fiat mucosal carcinoma (IIb type)--a new precursor of colorectal carcinoma? Report of two cases. Dis Colon Rectum 1988;31: 236-43. 16. Nakamura Y, Lathrop M, Leppert M, et al. Localiza-
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tion of the genetic defect in familial adenomatous polyposis within a small region of chromosome 5. Am J Hum Genet 1988;43:638-44. 17. Leppert M, Butt R, Hughes JP, et al. Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. N Engl J Med 1990;322:904-8.
