Familial Gastric Polyposis Revisited Autosomal Dominant Inheritance Confirmed Raquel Seruca, Ffitima Carneiro, S6rgio Castedo, Leonor David, Carlos Lopes, and Manuel Sobrinho-Sim6es
ABSTRACT: We update and review a large pedigree originally described by Santos and Magalhgles with familial gastric polyposis and a high incidence of gastric cancer. The present observation oJ male-to-male transmission of the disease clearly demonstrates the autosomal dominant pattern of inheritance. The histologic review of the polyps present in several members of the family allowed the diagnosis of hyperplastic polyposis. Eight members of the family (two with concomitant gastric pathology) have severe cutaneous psoriasis. This finding may represent the existence of two different disorders segregating in the family or, alternatively, pleiotropic manifestations of the same gene. INTRODUCTION Familial gastric polyposis (FGP} was first described as a separate entity by Santos and Magalh~es [1], based on the observation of a large kindred with several individuals with polyps confined to the stomach and several cases of gastric cancer. A s s u m i n g that both gastric polyps and gastric cancer were the expression of the same genetic disturbance, the aforementioned authors suggested a Men d el i an inheritance of the disease, possibly autosomal dominant [1]. However, no m al e4 o - m al e transmission of the disease was observed. The study of n e w elements of this family led us to reevaluate the type of inheritance and review all gastric biopsies and surgical specimens obtained through the years from the affected relatives.
MATERIALS A N D METHODS The pedigree of the family is s h o w n in Fig. 1. Twenty-three members of the family were submitted to gastrointestinal X-ray ex am i n at i o n and/or endoscopy. Pathologic specimens were available for review from ten members of the pedigree. The s p eci m en s (gastric biopsies and surgical specimens) were processed in a conventional m a n n e r with fixation in an unbuffered solution of formaldehyde and em b ed d i n g in paraffin. Sections were stained with hematoxylin and eosin (H&E) and were classiFrom the Departments of Pathology (R. S., F. C,, L. D., M. S.-S.] and Genetics (S. C.) of the Medical Faculty of Porto, Portugal, and the Departments of Pathology (C. L.) and Genetics (S. C.) of the Portuguese Institute for Oncology, Porto, Portugal. Address reprint requests to: Dr. S6rgio Castedo, Department of Medical Genetics, Medical Faculty of Porto, Hospital de S. Jo(lo, 4200 Porto, Portugal. Received May 9, 1990; accepted September 24, 1990. 97 © 1991 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cytogenet 53:97 100 (1991) 0165-4608/91/$03.50
98
R. Seruca et al.
I1' ~ ~ 3
~1~!415~2 ~2J~1~2~2~2~3 24 -
229-303 32-3435 3637 38 39 404~-43.... 5 46
Figure 1 @ Psoriasis, @ Hyperplastic polyps. • Gastric: carcinoma (GC), ~ Psoriasis + GC, Psoriasis + hypert)lastic: polyps, /" Pmband, *Examined by endoscopy and/or gastrointestinal X-rays,
fled i n d e p e n d e n t l y by two pathologists according to the World Health Organization (WHO) [2] for gastric cancer and following the classification suggested by Whitehead [3, 41 for non-neoplastic lesions of gastric nmcosa. RESULTS
Six members of the family (five dead and one alive) suffered from gastric cancer (Fig. 1). All of them were submitted to laparoscopy. Four cases were considered inoperable because of hepatic metastases or peritoneal carcinomatosis. The remaining two patients (one alive and one dead) were submitted to total gastrectomy. The surgical specimens were reviewed and, in both cases, the gastric neoplasms were classified as signet ring cell type carcinoma (Fig. 2). The endoscopic study disclosed the presence of multiple polyps dispersed in the body and antrum of the stomach in five members.
Figure 2
Signet ring (:ell carcinoma, HE × 160.
?
4,,~ ~ ~ , , . . . . .
• '~ ~ 4
Autosomal Dominant Inheritance in Familial Gastric Polyposis
99
Figure 3 Hyperplastic polyp, HE x 4. Inset: Papillary/villous configuration of foveolar epithelium, HE x 64.
The p o l y p o i d lesions were available for review and all of them were classified as hyperptastic polyps (Fig. 3). In some polyps the foveolar e p i t h e l i u m assumed a papillary, ahnost villous, configuration, with atypia. No adenomatous dysplasia could be recognized in any of them. No colorectal lesions were found in any member studied. Moreover, after thorough investigations no cancers other than gastric cancer could be found. Eight members of the family {two with concomitant gastric lesions) had severe cutaneous psoriasis.
DISCUSSION
The analysis of the pedigree shown in Fig. 1 strongly suggests a d o m i n a n t pattern of inheritance. The fact that II-3 transmitted the condition to his son (III-21) excludes an X-linked disorder, thus allowing the conclusion of an autosomal d o m i n a n t transmission. Although i n d i v i d u a l I-1 was never subjected to gastroscopy, her age at death (87 years) suggests that she might not have been affected. However, the demonstration of FGP among her offspring and in her sister {I-3) indicates that she was most likely a {healthy/carrier of the gene, possibly because of non-penetrance. The existence of several members of the family who refused gastroscopy obviously hampers an accurate estimate of the penetrance rate of the responsible gene. Santos and Magalhfies [1] suggested that there was a possible sex-influenced inheritance in view of the "greater male incidence." However, the greater number of affected males is probably due to a deviated sex ratio favoring males in the second generation rather than to real differences in incidence. Contrary to the initial description [1], the histology of the gastric polyps present in the affected members revealed hyperplastic features and no adenomatous changes. Together with the confinement of the lesions to the stomach, these histologic charac-
100
R. Seruca et al.
teristics represent f u n d a m e n t a l differences from Familial Adenomatous Polyposis of the Colon [5]. It is interesting to note that eight members of the family (two with concomitant gastric pathology) have cutaneous psoriasis (Fig. 1). Psoriasis is a frequent disease, with a strong genetic c o m p o n e n t (see [6] for review). Despite the high concordance in monozygotic twins and the n u m b e r of published pedigrees suggesting an autosomal d o m i n a n t inheritance (see [6] for review), it remains to be determined whether psoriasis is a multifactorial disorder [7] or a monogenic disease with incomplete penetrance
[8]. It is presently unclear whether there are two different disorders segregating in this family or pleiotropic manifestations of a single gene. In the latter hypothesis, it would be tempting to speculate that a deregulation in epithelial growth might be the c o m m o n pathogenetic pathway to both psoriasis and gastric pathology.
REFERENCES
1. Santos JG, Magalhfies J (1980): Familial gastric polyposis. A new entity. J G6n6t Hum 28(3):293-297. 2. Oota K, Sobin J (1977): Histological typing of gastric and esophageal tumors. World Health Organization, Geneva. 3. Whitehead R (1985): Gastritis. In: Mucosal biopsy of the gastrointestinal tract, Bennington JL, ed. 3rd edition, W. B. Saunders Co., Philadelphia, pp. 41 58. 4. Whitehead R (1985): Early gastric carcinoma, gastric epithelial dysplasia, polyps, polyposis, and malignant lymphoma. In: Mucosal biopsy of the gastrointestinal tract. Bennington JL. ed. 3rd edition, W. B. Saunders Co., Philadelphia, pp. 65 99. 5. Morson BC, Dawson IMP (1979): Gastrointestinal Pathology. Blackwell, Oxford, pp. 615 647. 6. Goldsmith LA (1983): Other genetic disorders of the skin. In: Principles and Practice of Medical Genetics, Emery AEH, Rimoin DL, eds. Churchill Livingstone, Edinburgh, pp. 689. 7. Watson W, Cann HW, Farber EM, Nail ML (1972): The genetics of psoriasis. Arch Derm 195:197-207. 8. Abele DC, Dobson RL, Graham JB (1963): Heredity and psoriasis. Study of a large family. Arch Derm 88:38-47.
ABSTRACT: We update and review a large pedigree originally described by Santos and Magalhgles with familial gastric polyposis and a high incidence of gastric cancer. The present observation oJ male-to-male transmission of the disease clearly demonstrates the autosomal dominant pattern of inheritance. The histologic review of the polyps present in several members of the family allowed the diagnosis of hyperplastic polyposis. Eight members of the family (two with concomitant gastric pathology) have severe cutaneous psoriasis. This finding may represent the existence of two different disorders segregating in the family or, alternatively, pleiotropic manifestations of the same gene. INTRODUCTION Familial gastric polyposis (FGP} was first described as a separate entity by Santos and Magalh~es [1], based on the observation of a large kindred with several individuals with polyps confined to the stomach and several cases of gastric cancer. A s s u m i n g that both gastric polyps and gastric cancer were the expression of the same genetic disturbance, the aforementioned authors suggested a Men d el i an inheritance of the disease, possibly autosomal dominant [1]. However, no m al e4 o - m al e transmission of the disease was observed. The study of n e w elements of this family led us to reevaluate the type of inheritance and review all gastric biopsies and surgical specimens obtained through the years from the affected relatives.
MATERIALS A N D METHODS The pedigree of the family is s h o w n in Fig. 1. Twenty-three members of the family were submitted to gastrointestinal X-ray ex am i n at i o n and/or endoscopy. Pathologic specimens were available for review from ten members of the pedigree. The s p eci m en s (gastric biopsies and surgical specimens) were processed in a conventional m a n n e r with fixation in an unbuffered solution of formaldehyde and em b ed d i n g in paraffin. Sections were stained with hematoxylin and eosin (H&E) and were classiFrom the Departments of Pathology (R. S., F. C,, L. D., M. S.-S.] and Genetics (S. C.) of the Medical Faculty of Porto, Portugal, and the Departments of Pathology (C. L.) and Genetics (S. C.) of the Portuguese Institute for Oncology, Porto, Portugal. Address reprint requests to: Dr. S6rgio Castedo, Department of Medical Genetics, Medical Faculty of Porto, Hospital de S. Jo(lo, 4200 Porto, Portugal. Received May 9, 1990; accepted September 24, 1990. 97 © 1991 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cytogenet 53:97 100 (1991) 0165-4608/91/$03.50
98
R. Seruca et al.
I1' ~ ~ 3
~1~!415~2 ~2J~1~2~2~2~3 24 -
229-303 32-3435 3637 38 39 404~-43.... 5 46
Figure 1 @ Psoriasis, @ Hyperplastic polyps. • Gastric: carcinoma (GC), ~ Psoriasis + GC, Psoriasis + hypert)lastic: polyps, /" Pmband, *Examined by endoscopy and/or gastrointestinal X-rays,
fled i n d e p e n d e n t l y by two pathologists according to the World Health Organization (WHO) [2] for gastric cancer and following the classification suggested by Whitehead [3, 41 for non-neoplastic lesions of gastric nmcosa. RESULTS
Six members of the family (five dead and one alive) suffered from gastric cancer (Fig. 1). All of them were submitted to laparoscopy. Four cases were considered inoperable because of hepatic metastases or peritoneal carcinomatosis. The remaining two patients (one alive and one dead) were submitted to total gastrectomy. The surgical specimens were reviewed and, in both cases, the gastric neoplasms were classified as signet ring cell type carcinoma (Fig. 2). The endoscopic study disclosed the presence of multiple polyps dispersed in the body and antrum of the stomach in five members.
Figure 2
Signet ring (:ell carcinoma, HE × 160.
?
4,,~ ~ ~ , , . . . . .
• '~ ~ 4
Autosomal Dominant Inheritance in Familial Gastric Polyposis
99
Figure 3 Hyperplastic polyp, HE x 4. Inset: Papillary/villous configuration of foveolar epithelium, HE x 64.
The p o l y p o i d lesions were available for review and all of them were classified as hyperptastic polyps (Fig. 3). In some polyps the foveolar e p i t h e l i u m assumed a papillary, ahnost villous, configuration, with atypia. No adenomatous dysplasia could be recognized in any of them. No colorectal lesions were found in any member studied. Moreover, after thorough investigations no cancers other than gastric cancer could be found. Eight members of the family {two with concomitant gastric lesions) had severe cutaneous psoriasis.
DISCUSSION
The analysis of the pedigree shown in Fig. 1 strongly suggests a d o m i n a n t pattern of inheritance. The fact that II-3 transmitted the condition to his son (III-21) excludes an X-linked disorder, thus allowing the conclusion of an autosomal d o m i n a n t transmission. Although i n d i v i d u a l I-1 was never subjected to gastroscopy, her age at death (87 years) suggests that she might not have been affected. However, the demonstration of FGP among her offspring and in her sister {I-3) indicates that she was most likely a {healthy/carrier of the gene, possibly because of non-penetrance. The existence of several members of the family who refused gastroscopy obviously hampers an accurate estimate of the penetrance rate of the responsible gene. Santos and Magalhfies [1] suggested that there was a possible sex-influenced inheritance in view of the "greater male incidence." However, the greater number of affected males is probably due to a deviated sex ratio favoring males in the second generation rather than to real differences in incidence. Contrary to the initial description [1], the histology of the gastric polyps present in the affected members revealed hyperplastic features and no adenomatous changes. Together with the confinement of the lesions to the stomach, these histologic charac-
100
R. Seruca et al.
teristics represent f u n d a m e n t a l differences from Familial Adenomatous Polyposis of the Colon [5]. It is interesting to note that eight members of the family (two with concomitant gastric pathology) have cutaneous psoriasis (Fig. 1). Psoriasis is a frequent disease, with a strong genetic c o m p o n e n t (see [6] for review). Despite the high concordance in monozygotic twins and the n u m b e r of published pedigrees suggesting an autosomal d o m i n a n t inheritance (see [6] for review), it remains to be determined whether psoriasis is a multifactorial disorder [7] or a monogenic disease with incomplete penetrance
[8]. It is presently unclear whether there are two different disorders segregating in this family or pleiotropic manifestations of a single gene. In the latter hypothesis, it would be tempting to speculate that a deregulation in epithelial growth might be the c o m m o n pathogenetic pathway to both psoriasis and gastric pathology.
REFERENCES
1. Santos JG, Magalhfies J (1980): Familial gastric polyposis. A new entity. J G6n6t Hum 28(3):293-297. 2. Oota K, Sobin J (1977): Histological typing of gastric and esophageal tumors. World Health Organization, Geneva. 3. Whitehead R (1985): Gastritis. In: Mucosal biopsy of the gastrointestinal tract, Bennington JL, ed. 3rd edition, W. B. Saunders Co., Philadelphia, pp. 41 58. 4. Whitehead R (1985): Early gastric carcinoma, gastric epithelial dysplasia, polyps, polyposis, and malignant lymphoma. In: Mucosal biopsy of the gastrointestinal tract. Bennington JL. ed. 3rd edition, W. B. Saunders Co., Philadelphia, pp. 65 99. 5. Morson BC, Dawson IMP (1979): Gastrointestinal Pathology. Blackwell, Oxford, pp. 615 647. 6. Goldsmith LA (1983): Other genetic disorders of the skin. In: Principles and Practice of Medical Genetics, Emery AEH, Rimoin DL, eds. Churchill Livingstone, Edinburgh, pp. 689. 7. Watson W, Cann HW, Farber EM, Nail ML (1972): The genetics of psoriasis. Arch Derm 195:197-207. 8. Abele DC, Dobson RL, Graham JB (1963): Heredity and psoriasis. Study of a large family. Arch Derm 88:38-47.
