Familial Juvenile Polyposis Coli

Transcription

1 GASTROENTEROLOGY 982 ;82 : Familial Juvenile Polyposis Coli A Clinical and Pathologic Study of a Large Kindred HAROLD W. GROTSKY, ROBERT R. RICKERT, WILLARD D. SMITH, and JAMES F. NEWSOME The Departments of Pediatrics, Pathology, and Surgery of the Saint Barnabas Medical Center, Livingston, New Jersey A kindred with familial juvenile polyposis coli is described. Of 92 family members, 26 have had symptoms consistent with polyposis, and a definite diagnosis of polyposis has been made in 9. Two family members have developed colorectal carcinoma before age 40 yr. The lesion of juvenile polyposis is a characteristic nonneoplastic polyp that is distinct from the neoplastic lesion of adenomatous polyposis. Patients with this disorder develop symptoms at an earlier age than those with adenomatous polyposis. Both variants of polyposis appear to have a dominant pattern of inheritance. Patients with juvenile polyposis who present in infancy are likely to have severe symptoms and complications. Although the premalignant potential of the juvenile polyp remains in doubt, there may be an increased risk of gastrointestinal cancer in these patients and their families. Multiple polyps of the gastrointestinal tract have been classified as several different entities depending upon the histology, location, and clinical manifestations of the polyps, and upon the associated abnormalities present. Familial polyposis, an autosomal, dominantly inherited condition of diffuse polyps in the large bowel, has recently been separated into two major categories on the basis of polyp histology, clinical manifestations, and premalignant potential (,2). These two entities are familial adenomatous polyposis coli and familial juvenile polyposis coli. Received December 0, 980. Accepted November 5, 98. Address requests for reprints to: Harold W. Grotsky, M.D., Department of Pediatrics, Saint Barnabas Medical Center, Old Short Hills Road, Livingston, New Jersey The authors thank Drs. Alexander Campbell, Charles Carney, and Anthony Giardina for providing pathologic material, and Ms. Dolores Breen for preparing the illustrations. 982 by the American Gastroenterological Association /82/ $02.50 The morphologic differences between these two types of polypoid lesions are well defined (2-5). The lesion of adenomatous polyposis is a benign neoplasm (adenoma) usually of the simple tubular type (adenomatous polyp). In contrast the juvenile polyp is considered to be nonneoplastic. Its histogenesis is uncertain; some believe it results from inflammation. and mucus retention after mucosal injury (5), while others classify the lesion as a hamartoma (2,4). No premalignant potential has been assigned to the juvenile polyp itself. However, several reports have suggested a possible increase in gastrointestinal cancer in juvenile polyposis patients and their families (2,6-8,). This report describes a kindred with familial juvenile polyposis coli. The family consists of nearly 00 members, many of whom have developed polyposis. History of the Pedigree Many members of the family are well known to us. Information concerning other members was obtained from living family members, physicians who cared for them, hospital charts, pathology slides, and x-ray reports. The pedigree consists of 92 individuals and is shown in Figure. The family is black and originated from Green County, North Carolina. The family has since spread with many members now living in New Jersey. Of the 92 family members, 26 have had clinical manifestations of polyposis coli, and another 2 have had carcinoma of the large bowel. The diagnoses in most cases have been confirmed by review of radiologic and pathological material obtained from these patients throughout the period of follow-up. A brief description of some of the individuals in the family defined in Figure follows; a more detailed history of F -V 8 is presented because of his history of severe complications arising at a young age. No polyps in other parts of the gastrointestinal tract or associated malformations were present in this pedigree.

2 March 982 FAMILIAL JUVENILE POLYPOSIS COLI 495 II / I-IS 6 + r , ", '\,,,, 7 8 : 9 +. J l IV v II 2 I.l Figure. Five-generation pedigree of kindred with familial juvenile polyposis coli. Definite Polyposis [) Symptoms of Polyposis ~ Carcinoma of Colon or Rectum + Deceased F-II 7. Represents the first member of this family suspected of having the disease. fie was known to pass blood from the rectum. F-III. Died of a gunshot wound at age 36 yr, 6 mo after undergoing an abdominal perineal resection for adenocarcinoma of the rectum. 3. At age 33 yr was found to have four colonic polyps. 5. Died at age 4 yr of unknown cause. Reported to have passed blood and "meat" from the rectum. 6. Found at age 29 yr to have one polyp in the colon by radiologic and sigmoidoscopic examination. He is asymptomatic. 7. Underwent total abdominal colectomy and ileoproctostomy with the finding of 8 "adenomatous" colonic polyps. Figure 2. Photograph of patient F-V 8 showing prolapsed rectal mucosa with numerous polyps. Figure 3. Barium enema of patient F-V 8 showing polypoid filling defects.

3 496 GROTSKY ET AL. GASTROENTEROLOGY Vol. 82, No Had a history of intermittent abdominal pain; two colonic polyps were seen on sigmoidoscopic and radiologic examination. 0. Died at age 3 mo of "colitis." Was noted to have passed bloody stools.. Reported to have passed bloody stools. This was not documented. F-N 6. Underwent total colectomy and ileoproctostomy, with the finding of numerous "adenomatous" polyps of the colon. 8. Found by radiologic and sigmoidoscopic examination to have multiple colonic polyps. 9. Found at 2 yr to have multiple colonic polyps on radiologic and sigmoidoscopic examination. 2. Died at age 8 yr of carcinoma with metastases. 3. Had history of rectal bleeding. Sigmoidoscopic and radiologic examination done at age yr showed no evidence of polyps. 4. Had passed blood per rectum and has had intermittent abdominal pain. 5. At age 5 yr he underwent a subtotal colectomy and ileocolostomy. Pathological examination of the specimen demonstrated the presence of "adenomatous" polyps. 8. At age 0 yr, because of persistent bleeding due to polyps for.5 yr, he had a subtotal colectomy and ileocolostomy. 9. Examined at age 6 yr because of rectal bleeding, he was found on radiologic examination to have multiple polyps of the colon. 20. At age 4 yr he underwent polypectomy because of bleeding colonic polyps. Numerous polyps were removed which were initially interpreted as "adenomatous." Histologic review reveals that the lesions are juvenile polyps. 2. Multiple colonic polyps have been demonstrated on radiologic and sigmoidoscopic examination. Biopsies have demonstrated polyps with histologic features intermediate between that of juvenile polyps and adenomas (see Pathology). 32. At age 2 yr was found on sigmoidoscopic and radiologic examination to have multiple colonic polyps. Although these polyps were originally interpreted as "adenomatous," our histologic review of numerous sections reveals typical juvenile polyps. 40. At age 8 yr, because of bloody stools, was found to have multiple colonic polyps on radiologic examination. 4. At age 9 yr had bloody diarrhea and abdominal pain. On radiologic examination there was no evidence of polyps. F-V 8. Now age 6 yr, he was completely well until approximately age yr when rectal bleeding was noted. Subsequently, he had frequent episodes of bloody diarrhea. Each bowel movement was accompanied hy rectal prolapse that he learned to manually reduce. He also had frequent periumbilical abdominal pain. At age 9.5 yr his height and weight were far below the 3rd percentile for age and were 50th percentile for a 5 yr old. His serum albumin was approximately 2.5 g. His hemoglobin was approximately 7.5 g. The rectal mucosa, seen at the time of prolapse, was studded with polyps (Figure 2). Barium enema (Figure 3) demonstrated multiple nodular filling defects involving the entire colon. Biopsy of a polyp was performed. Subsequently a colectomy with preservation of the lower segment was performed (Figure 4). At age 0 yr he was seen at another institution. Because of multiple polyps in the retained segment, an ileocolostomy and removal of the segment was performed. He experienced some "catch-up growth" and at age 6 yr he is a healthy, asymptomatic fellow. 9. Now age 5 yr, he has a history of bloody bowel movements dating from early childhood. At age 8 yr polyps were first seen at the time of prolapse. Height and weight were below the third percentile. At age 0 yr a colectomy with preservation of the rectal segment was performed. He now has frequent rectal bleeding, and the retained segment is carpeted with polyps. Biopsy has demonstrated typical juvenile polyps. One Figure 4. Resected portion of colon from patient F-V 8 showing numerous sessile and pedunculated polyps.

4 March 982 FAMILIAL JUVENILE POLYPOSIS COLI 497 Figure 5. Low-power photomicrograph of 2.2 cm pedunculated juvenile polyp from patient F-V 8. Note numerous dilated and irregular gland tubules in abundant edematous stroma. Portion of stalk is at left. large polyp from the most recent polypectomy has a few microscopic foci with gland tubules that are adenomatous in appearance.. Is now age 2 yr. He has had prolapse and rectal bleeding since age 5 yr. Sigmoidoscopy reveals multiple polyps and biopsy has demonstrated the typical appearance of juvenile polyps. 3. Has a history of rectal bleeding and prolapse since early childhood. At age g yr his height and weight are now at the third percentile for age. Sigmoidoscopy reveals multiple polyps that microscopically are juvenile type. 4. At age 7 yr he is asymptomatic. Growth is 0th percentile for age. Sigmoidoscopy reveals multiple polyps which microscopically are juvenile type. Pathology The morphologic features that characterize the juvenile polyp are well demonstrated in the patients from this family. The spectrum of lesions is most dramatic in patient F-V 8 (Figures 2, 3, and 4). The mucosa was studded with numerous polyps measuring from several millimeters to 2.8 cm in diameter. The smaller lesions were mostly sessile while the larger tended to be at least partially pedunculated. Macroscopically, the juvenile polyp has a smoother, more rounded contour than the adenoma, which usually has a distinctly lobulated surface. Microscopically, the typical juvenile polyp is composed of abundant stroma containing irregular but benign gland tubules (Figures 5 and 6). The stroma resembles normal lamina propria, and the tubules are frequently dilated and cystic (Figure 7). The stroma is often edematous and may be markedly vascular. Superficial ulceration is very common, and beneath the ulcerated surface there is a layer of cellular granulation tissue. This typical appearance was seen in the polyps from all of the 5 affected members of the F-V generation (F-V 8, g,, 3, 4) and in 2 of 3 affected members of the F-IV generation whose polyps have been reviewed (F-IV 20, 32). One of the more than 20 polyps from F-V 8, which were examined histologically, also contained microscopic foci with a more crowded glandular pattern and less abundant stroma. The small tubular glands in these foci were composed of hyperchromatic cells with an appearance more typical of adenoma than juvenile polyp (Figure 8). A similar focal change was present in the polyp most recently removed from patient F-IV 9. The father (F-IV 2) of these 5 affected sons has had several polyps examined histologically. These have had microscopic features intermediate between juvenile polyps and adenomas (Figure g). Figure 6. Low-power photomicrograph of 0.75 cm juvenile polyp from patient F-V 8. Note smooth round contour of ulcerated surface. Stromal vessels are dilated and congested. Discussion We have presented five generations of a large family in which the diagnosis of polyposis has definitely been made in 9 members, and is strongly

5 498 GROTSKY ET AL. GASTROENTEROLOGY Vol. 82, No. 3 Figure 7. Medium-power photomicrograph of juvenile polyp from patient F-V 9. Surface is partially ulcerated. Irregular, dilated tubules lined by benign columnar epithelium are surrounded by inflamed stroma. suspected in another 7 members. This family is illustrative of the various problems presented by familial juvenile polyposis coli. In addition, patient F-V 8 demonstrates the complications that arise when the symptoms of familial juvenile polyposis coli develop in infancy. Both adenomas and juvenile polyps usually present as solitary lesions. Although typically the juvenile polyps are seen during the first decade of life, they also occur in adults. The occurrence of multiple adenomatous polyps (polyposis) has been recognized for many years, and the familial occurrence and inheritance pattern of ademomatous polyposis coli are well known (9). McColl et al. are generally credited with the first description of multiple juvenile polyps in a group of children (). They designated the condition as juvenile polyposis coli. Earlier, however, Coleman and Eckert had recognized two cases of multiple juvenile colonic polyps and noted their distinction from adenomatous polyps (0). Although McColl et al. allude to a possible familial pattern, documented familial juvenile polyposis coli was not reported until 2 yr later by Veale et al. (2) and Smilow et al. (6). Veale et al..described the family histories of patients from eight families with juvenile polyposis coli (2). In two of the families more than one person was affected with juvenile polyposis coli, and in three families a number of relatives were known to have died from cancer of the colon or rectum. Of additional interest was the observation that the father of the propositus of one family suffered from adenomatous polyposis coli and died of rectal cancer. No history of bowel disease was obtained in any members of the other four families. It is of interest that until the histology of the polyps was reviewed for the study, these families were thought to have adenomatous polyposis. The report of Smilow et al. described 3 patients in three generations of one family (6). Of significance was the observation that the oldest patient also had carcinoma of the colon. These authors suggested a familial tendency to develop juvenile polyposis coli, but they did not feel that sufficient evidence existed to establish a relationship between familial juvenile polyposis coli and carcinoma. More recently Haggitt and Pitcock documented 2 cases of juvenile polyposis coli occurring in two generations of a family having a high rate of colonic carcinoma (). They noted that a few of the polyps in these patients had histologic features of both juvenile and adenomatous polyps, and patient had an adenomatous polyp of the jejunum. Several other reports of juvenile polyposis have appeared (7,2,3). These differ somewhat from the previously described cases of familial juvenile polyposis coli in that the polyps were generalized. occurring in stomach, small bowel, colon, and rectum. Sachetello et al. regarded this hereditary syndrome of generalized juvenile gastrointestinal polyposis as distinct from juvenile polyposis coli (2). Stemper et al. described a kindred of at least 0 members with single or multiple juvenile polyps of the stomach and large intestine (7). Some lesions had

6 March 982 FAMILIAL JUVENILE POLYPOSIS COLI 499 Figure 8. Medium-power photomicrograph of "adenomatous" focus in otherwise typical juvenile polyp from patient F-V 8. Glands are more crowded and composed of columnar cells with hyperchromatic nuclei. features of both adenomatous and juvenile polyps. The family was especially interesting in that members had developed carcinomas of stomach, duodenum, pancreas, or proximal colon. In some instances gastrointestinal carcinoma developed in patients without polyps. Some members of the family had generalized polyposis while others had lesions limited to the colon. For this reason, these authors concluded that these patterns of distribution represented different expressions of the same disorder rather than distinct syndromes. The pattern of inheritance suggested either a single or two closely linked autosomal determinants for gastrointestinal carcinoma and polyposis. Sachetello et al. have also described juvenile gastrointestinal polyposis in a female infant (3). On the basis of this case and a review of other infants with juvenile polyposis, these authors concluded that this infantile form of juvenile polyposis was yet another distinct entity. They emphasized the frequent presentation of these infants with gastrointestinal bleeding, diarrhea, rectal prolapse, and intussusception, and they noted that 6 of 7 infants with this syndrome died before age 2 yr. Sachetello et al. classified juvenile polyposis into three subgroups: (a) juvenile polyposis of infancy, (b) juvenile polyposis coli, and (c) generalized juvenile gastrointestinal polyposis (2,3). We have classified the cases in our kindred as familial juvenile polyposis coli. Like other examples of this disorder, affected members in the early generations of our family were initially thought to have adenomatous polyposis. This probably reflects the rather recent recognition of polyposis of the juvenile type. As expected, in those cases in which material has been available for review, the nature of the polyps has been established as juvenile and not adenomatous. The sporadic juvenile adenoma is usually histologically typical. However, occasional patients with multiple juvenile polyps, especially the familial form of the disorder, may have both juvenile polyps and adenomas, or they may even have polyps with both juvenile and adenomatous features. This "hybrid" situation was noted in 3 of our patients (F-IV 2, F-V 8, and F-V 9). In the latter 2, these changes were limited to minute microscopic foci in otherwise typical juvenile polyps. It seems likely that these hybrid or intermediate forms represent juvenile polyps in which foci of epithelial dysplasia have developed. It is perhaps this adenomatous transformation in some polyps from patients with juvenile polyposis which accounts for the predisposition to cancer in occasional patients. Our kindred also contains 2 members with carci -noma of the large bowel (F-III and F-IV 2.) This apparent increased occurrence of gastrointestinal cancer has been noted by others and in several has been apparently unrelated to the presence of polyps (2,6-8,). Goodman et al. (8) have recently described a patient with nonfamilial juvenile polyposis coli who developed carcinoma of the rectum at age 23 yr. The lesions in this patient had a variety of appearances, including hyperplastic polyps, typical juvenile polyps, juvenile polyps with focal adenomatous epithelium, adenomas, and adenocarcinoma. They suggested that this histologic spectrum may represent a pathogenetic sequence. The authors noted that, although juvenile polyps are not generally regarded as premalignant, neoplastic changes may occur in the polyps of some individuals. These adenomatous foci in turn occasionally give rise to cancer. The clinical manifestations of familial juvenile polyposis coli and of generalized juvenile polyposis are indistinguishable. The mode of inheritance of generalized juvenile polyposis is unclear. Stemper et al. (7) favored a dominant mode of inheritance while

7 500 GROTSKY ET AL. GASTROENTEROLOGY Vol. 82, No. 3 Figure 9. A. Portion of polyp from patient F-IV 2 showing cystically dilated glands and congested and edematous stroma. Appearance is intermediate between juvenile polyp and adenoma. B. Portion of same polyp as in A. Photomicrograph at same power shows features of adenoma with crowding of glands and cells with hyperchromatic nuclei. Sachetello et al. (3) believed that in infants the disorder was transmitted as a non-sex-linked recessive. As our pedigree amply demonstrates, juvenile polyposis coli is inherited as an autosomal dominant. Our pedigree also suggests that juvenile polyposis of infancy and familial juvenile polyposis coli are probably variants of one syndrome. The poorer prognosis noted by Sachetello et al. (3) in infants with polyposis may reflect the more widespread distribution of lesions and more frequent complications rather than representing a different disease. The clinical distinctions between adenomatous and juvenile polyposis are several. The first symptom of familial adenomatous polyposis coli is usually diarrhea; however, patients may present with abdominal pain, anemia, melana, or intussusception. The age of onset of symptoms is variable, but is usually by age 30 yr (2,4,5). Onset of symptoms

8 March 982 FAMILIAL JUVENILE POLYPOSIS COLI 50 before age 5 yr is uncommon. Failure to thrive and rectal prolapse are unusual manifestations of the disease. The clinical manifestations of familial adenomatous polyposis coli are variable. Indeed, some individuals whose colons are literally carpeted with polyps may remain asymptomatic. In as many a& one-third of the individuals with adenomatous polyposis coli, the disease appears to be sporadic (9). In the remaining two-thirds of the patients, the autosomal dominant mode of inheritance is apparent. The average age of onset of symptoms in the nonfamilial cases is said to be 23 yr, whereas the average age for onset of symptoms in the familial cases is said to be 29 yr (2,4). The onset of symptoms in familial juvenile polyposis coli is usually earlier than that in adenomatous polyposis coli and generally occurs before adolescence. This is demonstrated by our pedigree, and it has been noted previously (2). In patients with no family history, the age of onset of symptoms is 4.5 yr whereas in familial cases it is 9.5 yr (2). Failure to thrive and rectal prolapse occur more frequently than in adenomatous disease. Malignant potential is another important distinction between adenomatous and juvenile polyposis coli. The malignant potential in familial adenomatous polyposis is well recognized, and it generally occurs about 5 yr after the onset of symptoms. Consequently, most individuals with this disorder develop large bowel cancer at about age 40 yr (6). Because of the ominous prognosis due to malignant transformation, colectomy aimed at the prevention of cancer is usually recommended. The malignant potential of juvenile polyposis coli is much less well documented, and colectomy is usually not recommended. The. management of patients with juvenile polyposis is further complicated by the observation that the possible increased cancer risk in these patients and their families may be independent of the polyps. Surgical intervention, therefore, is more likely to be aimed at nonneoplastic complications such as severe failure to thrive and persistent blood loss. References. McColl I, Bussey RJR, Veale AMO, Morson BC. Juvenile polyposis coli. Proc Roy Soc Med 964;57: Veale AMO, McColl I, Bussey RJR, Morson BC. Juvenile polyposis coli. J Med Genet 966;3: Horrilleno FG, Eckert C, Ackerman LV. Polyps of the rectum and colon in children. Cancer 957;0: Morson BC. Some peculiarities in the histology of intestinal polyps. Dis Colon Rectum 962;5: Roth SI, Helwig, EB. Juvenile polyps of the colon and rectum. Cancer 963;6: Smilow PC, Pryor CA, Jr, Swinton NW. Juvenile polyposis coli: a report of three patients in three generations of one family. Dis Colon Rectum 966;9: Stemper TJ, Kent TH, Summers NW. Juvenile polyposis and gastrointestinal carcinoma: a study of a kindred. Ann Intern Med 975;83: Goodman ZD, Yardley ]H, Milligan FD. Pathogenesis of colonic polyps in multiple juvenile polyposis: report of a case associated with gastric polyps and carcinoma of the rectum. Cancer 979;43: Bussey, HJR. Familial polyposis coli. Baltimore: Johns Hopkins University Press, Coleman ST, Eckert C. Preservation of rectum in familial polyposis of the colon and rectum. Arch Surg 956;73: Haggitt RC, Pitcock JA. Familial juvenile polyposis of the colon. Cancer 970;26: Sachetello CR, Pickren IW, Grance JT, Jr. Generalized juvenile gastrointestinal polyposis. Gastroenterology 970;58: Sachetello CR, Hahn IS, Carrington CB. Juvenile gastrointestinal polyposis in a female infant: report of a case and review of the literature of a recently recognized syndrome. Surgery 974;75: Veale AMO. Familial intestinal polyposis. Ph.D. thesis. University of London, Veale AMO. Intestinal polyposis. Eugenics Laboratory, Memoir Series 40. London: Cambridge University Press, Lockhart-Mummery]p, Dukes CEo Familial adenomatous polyposis of colon and rectum: its relationship to cancer. Lancet 939;2:586-9.