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Cancer family syndrome of Lynch
Cancer Family Syndrome of Lynch
HANI
ABUSAMRA,
SONJA
MAXIMOVA,
SIMON
BAR-MEIR,
MAYER
KRISPIN,
HESCHI
H.
M.D. M.D. M.D. M.D.,
ROTMENSCH,
F.A.C.S. M.D.,
F.A.C.P.
Ho/on, Israel
This report describes a family in whom eight cancers (six coionic and two endometriai) occurred in seven relatives. The coionic cancer was diagnosed in five of the six affected patients at an unusually young age, had a predilection for the proximal colon, and was of the mutinous type in four patients. Poiyposis was not found in any colon. The occurrence of cancer in this kindred is characteristic of the “cancer family syndrome” of Lynch. A subset of patients with colorectai cancer has an increased susceptibility on a familial basis. Persons at increased risk may be divided into those with one of the well-defined syndromes of inherited colon carcinoma, such as Gardner’s syndrome or colonic familial polyposis, and those with one of the non-polypotic entities, such as familial colonic cancer [l] and the cancer family syndrome [2]. This report describes a kindred with multiple neoplastic lesions characteristic of the “cancer family syndrome” of Lynch.
CASEREPORT
From the Departments of Medicine “E” and Surgery “A,” and the Division of Gastroenterology, Edith Wolfson Medical Center, Holon, Israel. Requests for reprints should be addressed to Dr. H. H. Rotmensch, Edith Wolfson Medical Center, P.O. Box 5, Holon 58100, Israel. Manuscript submitted Feburary 24, 1987, and accepted May 8, 1987.
A 41-year-old man (Ill-A, Figure 1) was admitted to the Edith Wolfson Medical Center for evaluation of iron-deficiency anemia. He had a radiographically documented duodenal ulcer and was treated periodically with cimetidine. On physical examination, the patient was pale and had guaiacpositive stools without abnormal abdominal or rectal findings. The barium enema showed a large annular constrictive lesion at the hepatic flexure that was deemed to be a carcinoma by colonoscopy. The patient underwent extended right hemicolectomy of a Duke’s B lesion and had an uneventful recovery. The patient had a remarkable family history (Figure 1). His grandmother had undergone surgery for endometrial adenocarcinoma at the age of 62 years; 21 years later, she underwent anterior resection for two independent primary colonic cancers located in the sigma and rectum. The patient’s 70year-old mother, is healthy and recently had normal findings on colonoscopit examination. Four of her siblings, however, had undergone surgery for cancer, three colonic and one endometrial (well-differentiated papillary adenocarcinoma). One of the patient’s sisters (Ill-D, Figure 1) underwent anterior resection of an adenocarcinoma of the rectum at the age of 24 years. Two siblings had an unremarkable colonoscopic examination, while the remainder of the family members refused to have diagnostic examinations. Members of the fourth generation are less than 25 years old. In four of the six affected family members, the colon tumors were mutinous adenocarcinoma; two were in the ascending colon and two occurred distal to the splenic flexure. Polyposis was not found in any colon. Pathologic reports were not available in two patients. All affected family members are alive and free of disease three to 16 years post-surgery.
November 1987
The American Journal of Medicine
Volume
83
981
CANCER
FAMILY
SYNDROME
OF LYNCH-ABUSAMRA
ET AL
A I
II
A m
m
o-
@-ColonCa. 1
Female
rJvMalr g3y-. oUnaffOCld Progeny
I
COMMENTS
acterized by all of the features of Lynch syndrome I with the additional risks for development of cancer in the female genital tract and other sites [ 1,8]. Remarkably, all seven affected members in this family are alive and free of disease three to 18 years postsurgery, raising the question of whether this phenomenon may be characteristic of the familial cancer syndrome. Little is known regarding the pathogenesis of the familial colonic cancer syndromes without polyposis. Preliminary work has shown chromosomal abnormalities with excess tetraplokly in cultured fibroblasts and dermal epithelial cells in five affected patients and in 42 percent of the unaffected family members [9]. Other investigators have reported a dysfunction of the immune system, expressed as a decrease in the responsiveness of lymphocytes to allogenic stimuli in mixed leukocyte cultures, in three of five patients with familial colonic cancer and in eight of their 18 healthy first-degree relatives [IO]. Cancer family syndrome has been reported in only a dozen well-defined kindreds; however, with a careful family history taking, this entity might be diagnosed more commonly. The recognition of a cancer family has serious implications for the affected, as well as the unaffected, relatives. All members need to be advised to check for occult blood in the stool and undergo periodic examination beginning at age 25. Women, in addition, will require repeated gynecologic examinations and periodic aspiration cytologic study of the uterus. Close medical surveillance and early recognition of malignancy will significantly reduce mortality.
The proband is a member of a large family in whom eight cancers (six colonic and two endometrial) occurred in seven relatives. The colonic cancer was diagnosed in five of the six affected patients at a median age that was about 20 years younger than that in the general population [3]. In one patient (Ill-D, Figure l), the tumor was diagnosed when she was 24 years old. Two members of the family (I-A and II-E, Figure 1) had endometrial carcinoma at a relatively young age; in one (I-A), this occurred 21 years prior to the development of multiple primary colonic malignancies. The occurrence of cancer in this kindred is characteristic of the family cancer syndrome of Lynch rather than cases clustering by chance [2,4]. Lynch and co-workers [l] have defined two forms of familial non-polypotic coIonic cancer syndromes. Lynch syndrome I (“site-specific familial colonic cancer”) is typified by the appearance of colonic malignancies at unusually early ages. Multiple primary carcinomas may be found at the time of initial diagnosis (synchronous), and if part of the colon is not removed initially there is a high likelihood that cancer will recur (metachronous). In contrast to the common variety of colorectal cancer in the general population that occurs predominantly (65 to 85 percent) in the distal colon and rectum [3,5], this syndrome, inherited in an autosomal dominant fashion, has a predilection for the proximal colon (65 to 88 percent) and is frequently of the mutinous or colloid type [1,6,7]. Lynch syndrome II (“cancer family syndrome”) is char-
982
November
1987
The American
Journal
of Medicine
Figure 1. Pedigree of proband (Ill-A). Age at diagnosis is indicated by sub script. Diamonds indicate unaffected progeny.
Volume
83
CANCER
FAMILY
SYNDROME
OF LYNCH-ABUSAMRA
ET AL
REFERENCES 1. 2.
3.
4.
5.
Lynch PM, Lyncfi HT, Harris RE: Hereditary proximal colonic cancer. Dis Colon Rectum 1977; 20: 661-668. Lynch HT, Lyncl-i PM, Harris RE: Minimal genetic findings and their cancer control implications: a family with the cancer family syndrome. JAMA 1978; 140: 535-538. Copeland EM, Miller LD, Jones RS: Prognostic factors in carcinoma of the colon and rectum. Am J Surg 1968; 116: 875-881. Boland CR: Cancer family syndrome: a case report and literature review. A’m J Dig Dis 1978; 23(suppl): 25S275. Eisenberg B, Decosse JJ, Harford F, et al: Carcinoma of the colon and rectum: the natural history reviewed in 1704 patients. Cancer 1982; 49: 1131-I 134.
November
6.
7.
8. 9.
10.
1987
Budd DC, Fink DL: Mucoid colonic carcinoma as an autpsomal-dominant inherited syndrome. Arch Surg 1981; 116: 901-905. Boland CR, Troncale FJ: Familial colonic cancer without antecedent polyposis. Ann intern Med 1984; 100: 700701. Lynch HT, Krush AJ: Cancer family ‘G’ revisited: 1895 1970. Cancer 1971; 27: 1505-1511. Danes BS: Occurrence of in vitro tetraploidy in the hereditable colon cancer syndromes. Cancer 1981; 48: 15961601. Berlinger NT, Lopez C, Lipkin M, et al: Defective recognitive immunity in family aggregates of colon carcinoma. J Clin invest 1977; 59: 761-769.
The American
Journal
of Medicine
Volume
83
993
HANI
ABUSAMRA,
SONJA
MAXIMOVA,
SIMON
BAR-MEIR,
MAYER
KRISPIN,
HESCHI
H.
M.D. M.D. M.D. M.D.,
ROTMENSCH,
F.A.C.S. M.D.,
F.A.C.P.
Ho/on, Israel
This report describes a family in whom eight cancers (six coionic and two endometriai) occurred in seven relatives. The coionic cancer was diagnosed in five of the six affected patients at an unusually young age, had a predilection for the proximal colon, and was of the mutinous type in four patients. Poiyposis was not found in any colon. The occurrence of cancer in this kindred is characteristic of the “cancer family syndrome” of Lynch. A subset of patients with colorectai cancer has an increased susceptibility on a familial basis. Persons at increased risk may be divided into those with one of the well-defined syndromes of inherited colon carcinoma, such as Gardner’s syndrome or colonic familial polyposis, and those with one of the non-polypotic entities, such as familial colonic cancer [l] and the cancer family syndrome [2]. This report describes a kindred with multiple neoplastic lesions characteristic of the “cancer family syndrome” of Lynch.
CASEREPORT
From the Departments of Medicine “E” and Surgery “A,” and the Division of Gastroenterology, Edith Wolfson Medical Center, Holon, Israel. Requests for reprints should be addressed to Dr. H. H. Rotmensch, Edith Wolfson Medical Center, P.O. Box 5, Holon 58100, Israel. Manuscript submitted Feburary 24, 1987, and accepted May 8, 1987.
A 41-year-old man (Ill-A, Figure 1) was admitted to the Edith Wolfson Medical Center for evaluation of iron-deficiency anemia. He had a radiographically documented duodenal ulcer and was treated periodically with cimetidine. On physical examination, the patient was pale and had guaiacpositive stools without abnormal abdominal or rectal findings. The barium enema showed a large annular constrictive lesion at the hepatic flexure that was deemed to be a carcinoma by colonoscopy. The patient underwent extended right hemicolectomy of a Duke’s B lesion and had an uneventful recovery. The patient had a remarkable family history (Figure 1). His grandmother had undergone surgery for endometrial adenocarcinoma at the age of 62 years; 21 years later, she underwent anterior resection for two independent primary colonic cancers located in the sigma and rectum. The patient’s 70year-old mother, is healthy and recently had normal findings on colonoscopit examination. Four of her siblings, however, had undergone surgery for cancer, three colonic and one endometrial (well-differentiated papillary adenocarcinoma). One of the patient’s sisters (Ill-D, Figure 1) underwent anterior resection of an adenocarcinoma of the rectum at the age of 24 years. Two siblings had an unremarkable colonoscopic examination, while the remainder of the family members refused to have diagnostic examinations. Members of the fourth generation are less than 25 years old. In four of the six affected family members, the colon tumors were mutinous adenocarcinoma; two were in the ascending colon and two occurred distal to the splenic flexure. Polyposis was not found in any colon. Pathologic reports were not available in two patients. All affected family members are alive and free of disease three to 16 years post-surgery.
November 1987
The American Journal of Medicine
Volume
83
981
CANCER
FAMILY
SYNDROME
OF LYNCH-ABUSAMRA
ET AL
A I
II
A m
m
o-
@-ColonCa. 1
Female
rJvMalr g3y-. oUnaffOCld Progeny
I
COMMENTS
acterized by all of the features of Lynch syndrome I with the additional risks for development of cancer in the female genital tract and other sites [ 1,8]. Remarkably, all seven affected members in this family are alive and free of disease three to 18 years postsurgery, raising the question of whether this phenomenon may be characteristic of the familial cancer syndrome. Little is known regarding the pathogenesis of the familial colonic cancer syndromes without polyposis. Preliminary work has shown chromosomal abnormalities with excess tetraplokly in cultured fibroblasts and dermal epithelial cells in five affected patients and in 42 percent of the unaffected family members [9]. Other investigators have reported a dysfunction of the immune system, expressed as a decrease in the responsiveness of lymphocytes to allogenic stimuli in mixed leukocyte cultures, in three of five patients with familial colonic cancer and in eight of their 18 healthy first-degree relatives [IO]. Cancer family syndrome has been reported in only a dozen well-defined kindreds; however, with a careful family history taking, this entity might be diagnosed more commonly. The recognition of a cancer family has serious implications for the affected, as well as the unaffected, relatives. All members need to be advised to check for occult blood in the stool and undergo periodic examination beginning at age 25. Women, in addition, will require repeated gynecologic examinations and periodic aspiration cytologic study of the uterus. Close medical surveillance and early recognition of malignancy will significantly reduce mortality.
The proband is a member of a large family in whom eight cancers (six colonic and two endometrial) occurred in seven relatives. The colonic cancer was diagnosed in five of the six affected patients at a median age that was about 20 years younger than that in the general population [3]. In one patient (Ill-D, Figure l), the tumor was diagnosed when she was 24 years old. Two members of the family (I-A and II-E, Figure 1) had endometrial carcinoma at a relatively young age; in one (I-A), this occurred 21 years prior to the development of multiple primary colonic malignancies. The occurrence of cancer in this kindred is characteristic of the family cancer syndrome of Lynch rather than cases clustering by chance [2,4]. Lynch and co-workers [l] have defined two forms of familial non-polypotic coIonic cancer syndromes. Lynch syndrome I (“site-specific familial colonic cancer”) is typified by the appearance of colonic malignancies at unusually early ages. Multiple primary carcinomas may be found at the time of initial diagnosis (synchronous), and if part of the colon is not removed initially there is a high likelihood that cancer will recur (metachronous). In contrast to the common variety of colorectal cancer in the general population that occurs predominantly (65 to 85 percent) in the distal colon and rectum [3,5], this syndrome, inherited in an autosomal dominant fashion, has a predilection for the proximal colon (65 to 88 percent) and is frequently of the mutinous or colloid type [1,6,7]. Lynch syndrome II (“cancer family syndrome”) is char-
982
November
1987
The American
Journal
of Medicine
Figure 1. Pedigree of proband (Ill-A). Age at diagnosis is indicated by sub script. Diamonds indicate unaffected progeny.
Volume
83
CANCER
FAMILY
SYNDROME
OF LYNCH-ABUSAMRA
ET AL
REFERENCES 1. 2.
3.
4.
5.
Lynch PM, Lyncfi HT, Harris RE: Hereditary proximal colonic cancer. Dis Colon Rectum 1977; 20: 661-668. Lynch HT, Lyncl-i PM, Harris RE: Minimal genetic findings and their cancer control implications: a family with the cancer family syndrome. JAMA 1978; 140: 535-538. Copeland EM, Miller LD, Jones RS: Prognostic factors in carcinoma of the colon and rectum. Am J Surg 1968; 116: 875-881. Boland CR: Cancer family syndrome: a case report and literature review. A’m J Dig Dis 1978; 23(suppl): 25S275. Eisenberg B, Decosse JJ, Harford F, et al: Carcinoma of the colon and rectum: the natural history reviewed in 1704 patients. Cancer 1982; 49: 1131-I 134.
November
6.
7.
8. 9.
10.
1987
Budd DC, Fink DL: Mucoid colonic carcinoma as an autpsomal-dominant inherited syndrome. Arch Surg 1981; 116: 901-905. Boland CR, Troncale FJ: Familial colonic cancer without antecedent polyposis. Ann intern Med 1984; 100: 700701. Lynch HT, Krush AJ: Cancer family ‘G’ revisited: 1895 1970. Cancer 1971; 27: 1505-1511. Danes BS: Occurrence of in vitro tetraploidy in the hereditable colon cancer syndromes. Cancer 1981; 48: 15961601. Berlinger NT, Lopez C, Lipkin M, et al: Defective recognitive immunity in family aggregates of colon carcinoma. J Clin invest 1977; 59: 761-769.
The American
Journal
of Medicine
Volume
83
993