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Gynecologic cancer clues to Lynch syndrome II diagnosis: A family report
GYNECOLOCIC
ONCOLOGY
44,
198-203 (1992)
CASE REPORT Gynecologic Cancer Clues to Lynch Syndrome II Diagnosis: A Family Report’ HENRY T. LYNCH, M.D.,*,2 *Depurtment
of Preventive
Medicine/Public
R. JENNIFER CAVALIERI, R. N.,* AND MURRAY JOSEPH CASEY, M.D.t
Health
and tDepartment Omaha,
JANE F. LYNCH,
of Obstetrics and Gynecology, Nebraska 68178
Creighton
B.S.N.,*
University
School
of Medicine,
Received June 27, 1991
Lynch syndromeII wasdiagnosedwhen two sisters manifested early-onset synchronouscarcinomasof the ovary and endometrium and a third sisterwasfound to have Duke’s A carcinoma of the cecum.A detailedcancerfamily history indicatedpaternal transmissionof the deleteriousgenotype. The pattern of carcinoma of the wlorectum and extracolonic sitesthroughout the extended family was then found to be consonantwith this hereditary cancer-pronedisorder. Lynch syndromeII may be exceedinglydifficult to diagnosedue to an absenceof premonitory clinical signsor biomarkersof genotypic susceptibility. Its recognition isthereforedependenton a detailedcancerfamily history (all anatomicsites),coupledwith knowledgeof the pattern of the cancerspectrum,distribution, and natural history, as manifested in this hereditary disorder. We describethe decisionlogic that wasinvolved in the diagnosisof Lynch syndromeII in this family and indicatethe important role of the gynecologistin this process. 0 1992 Academic Press, Inc. INTRODUCTION
Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for approximately 4-6% of the total colorectal cancer (CRC) burden [1,2]. It is much more common than its hereditary counterpart, familial adenomatous polyposis (FAP), which accounts for less than 1% of the total CRC diagnoses [l]. HNPCC has two major subdivisions: (1) Lynch syndrome I, which is characterized by an autosomal dominantly inherited proclivity to earlyonset CRC, with predominance proximal to the splenic ’ Support for this effort was provided by NC1 Grant 5 ROl CA 42705 and the Council for Tobacco Research USA, Inc., Grant 1297D. We also acknowledge the dedicated technical expertise provided by Diane Stanley. ’ To whom correspondence and reprint requests should be addressed. 198 0090-8258/92$1.50 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction
in any form reserved.
flexure [3], an excess of synchronous (at same time as initial cancer) and metachronous (more than 6 months from initial cancer) CRC [4], and the absence of florid colonic polyps, and (2) Lynch syndrome II, which shows all of these clinical features, but in addition, there is an excess of extracolonic cancer, particularly of the endometrium and ovary [l,S]. Other integral cancers have been more recently identified, involving the ureter and kidney [6], pancreas [7,8], small bowel [9], and stomach [lo]. Although the first manifestation of cancer in these patients involves the colorectum, this occasionally may be antedated by cancer of the endometrium or ovary Ill]. Since we are dealing with an autosomal dominantly inherited predisposition to cancer, the cancer family history may aid significantly in the diagnosis of HNPCC, thereby providing one of the most powerful cost-beneficial approaches to cancer family management and control [12]. However, diagnosis of HNPCC may be difficult in that there is an absence of premonitory clinical signs or biomarkers of genotypic susceptibility. Therefore, the diagnostician is wholly dependent on a detailed family history and knowledge of the clinical and natural history facets of cancer in HNPCC. Factors that may obfuscate its diagnosis include inadequate medical and pathology documentation of cancer, small family size, limited knowledge of family history, premature death in key informative relatives from noncancer etiologies, false paternity, patient mobility, and, on occasion, outright rejection of cooperation by family members. However, despite these limitations, the pattern of cancer occurrences within the nuclear family may be so striking as to signify the HNPCC diagnosis. Our purpose is to trace the decision logic that led to
199
CASE REPORT
FamiLy
3208
V
Cancer Individual Unaffected Current Cancer age at Current
by Pathology, diagnosis age
Cancer age at
by Family death
Multiple
Primary
Multiple Medical
Primary Records
Multiple
Prlnary
Number (Both
Ce co En Ki ov Pan Pro Psu Sk Ur ut
age
Cancer Medlca(
q L
Sites
number
History, Cancers
Unverified
Cancers or Death
by
Cancers
by
by Death Records of Unaffected Sexes)
Cecun Colon Endonetrium Kidney Ovary Pancreas Prostate Primary Skin Ureter Uterus
Site
Unknown
Certificates
Certificate
Pathology or
Progeny
Proband
FIG. 1. Family 3208, showing early-onset synchronous carcinoma of the endometrium and ovary in two sisters, early-onset carcinoma of the cecum in the proband, and a pattern of cancer distribution in the paternal lineage consonant with Lynch syndrome II.
the unraveling of a Lynch syndrome II diagnosis in a relatively small cancer-prone kindred that presented as a familial aggregation of gynecologic cancer. FAMILY
STUDY
The protocol for this study was approved by the Creighton University Institutional Review Board. The proband (IV-6; Fig. 1, Table 1) contacted us in 1990 because of her concern about her family history of cancer. We interviewed her in detail and received written permission
to contact her relatives. Questionnaires were then circulated to these individuals. Signed permission forms enabled us to secure primary medical and pathology documents. This allowed us to cross-reference all historical comments about genealogy, medical, and pathology findings for accuracy. The completed pedigree (Fig. 1) and tumor registry (Table 1) clearly showed the significant paternal involvement, comprising a pattern of cancer types consonant with Lynch syndrome II. The proband’s mother (111-6; Fig. 1, Table 1) had manifested ovarian carcinoma in the 1970s at age 54 years.
200
LYNCH ET AL.
TABLE 1 Tumor Registry for Family 3208 Patient No.
Sex
Age at death or diagnosis
Basis for Dx
I-l II-2 II-3
F M F
37 33 57
DC DC DC
Tumor, primary site unknown Carcinoma of the cecum Carcinoma of body of uterus with extensive metastasis
III-1 III-2 III-3
M F M
III-4
M
III-5
M
III-6 III-7 IV-4
F F F
IV-6 IV-8
F F
77 32 45 45 45 53 68 68 ? 71 72 54 66 47 52 40 42
FR DC MR MR MR MR FR FR FR PR PR PR FR PR PR PR PR
IV-9
F
42 38 38 38
PR PR
Prostate carcinoma Carcinoma of the ovary Colon carcinoma Colon carcinoma Skin carcinoma Carcinoma of the head of pancreas Carcinoma of the prostate Carcinoma of the ureter Skin carcinoma Stage D adenocarcinoma of the prostate Grade II Stage 0 carcinoma of the left ureter Grade III adenocarcinoma of both ovaries Kidney carcinoma Endometrial adenocarcinoma of the endometrioid type, Grade I/III Carcinoid islet cell tumor of the pancreas Grade II Dukes A adenocarcinoma of the cecum Well-differentiated endometrial carcinoma with clear cell features, admixed with adenomatous hyperplasia Grade III ovarian carcinoma Infiltrating adenosquamous carcinoma of the endometrium (Grade II) Metastatic adenocarcinoma to one of three lymph nodes Mixed serous and clear cell carcinoma of low malignant potential, with foci of invasion
PR
Diagnosis
Note. DC, death certificate; FR, family report; MR, medical records; PR, pathology report.
At that time, the proband (IV-6; Fig. 1) and her three sisters (IV-7, IV-8, IV-9; Fig. 1) believed that their lifetime risk for cancer of the ovary might be increased. However, they felt that this was a matter that should not concern them until they reached the age of 50 or 60. In 1989, one of the sisters (N-9; Fig. 1, Table 1) at age 38 years, experienced abdominal pain and noted very light, midcycle vaginal spotting that was presumed to be due to an ovarian cyst. However, ultrasound revealed a solid mass in her left ovary. Since she was recently married and wanted to have children, she requested that the surgical approach be as conservative as possible. The initial surgery therefore consisted of a dilation and curettage and excision of a left ovarian tumor. Frozen sections were done on the ovarian mass and the endometrial curettings. The pathology findings revealed a borderline malignancy in the left ovarian tumor and a markedly abnormal endometrium, “. . . probably well-differentiated endometrial adenocarcinoma.” The left ovary and tube were removed and a second opinion on the pathology, which confirmed well-differentiated endometrial carcinoma and mixed serous and clear cell carcinoma of low potential malignancy but with a focus of invasion in the ovarian surface, was obtained. These findings led to transabdom-
inal hysterectomy, right salpingo-oophorectomy, selective pelvic and para-aortic node excisions, and multiple pelvic and peritoneal biopsies. Infiltrating, Grade II, adenosquamous carcinoma of the endometrium was found and one of three pelvic nodes was positive for metastatic carcinoma, There was no residual carcinoma in the uterus, right tube, and ovary, or in other multiple biopsies that were taken. The sisters then sought consultation from a gynecological oncologist, during which time a detailed family history was taken. This consultant told them that there were “two” hereditary syndromes that involve the colon, breast, uterus, and ovary and stressed the need for them to have appropriate screening. They obtained additional consultation from several other oncologists and a medical geneticist. All consultants recommended prophylactic transabdominal hysterectomy-bilateral salpingo oophorectomy (TAH-BSG) on the basis of their estimated 50% risk for ovarian cancer. Patient IV-8 subsequently reported midcycle vaginal spotting without pain. Her physician performed an endometrial biopsy. Atypical hyperplasia of the endometrium was diagnosed. She was told that this was a precancerous lesion and given her family history, a TAH-
CASE REPORT
BSO was recommended. She underwent a normal colonoscopy, and at age 42 years, a prophylactic TAH-BSO was performed. Well-differentiated endometrial carcinoma with clear cell features was found admixed with adenomatous hyperplasia. The ovaries appeared normal on gross inspection, but histopathologic evaluation showed a focus of ovarian carcinoma, Grade III. Peritoneal washings were cytologically negative for malignant cells, and selectively excised pelvic lymph nodes and multiple biopsies from pelvic and abdominal peritoneum and omentum were negative for cancer. However, the recovery of adenocarcinoma cells on cul-de-sac aspiration 7 months later has led to the diagnosis of recurrent, metastatic adenocarcinoma in the upper abdomen and omentum. Patient IV-7 underwent colonoscopy, folllowed by TAH-BSO, at age 46 years. Clinical and pathology findings from these procedures were within normal limits. Finally, the proband (IV-6; Fig. 1, Table 1) became extremely apprehensive as these cancer findings evolved in her sisters. At age 40 years, she underwent colonoscopy and sought prophylactic TAH-BSO. A Duke’s A adenocarcinoma of the cecum was diagnosed (Table 1). She underwent a hemicoloectomy and TAH-BSO. The gynecologic pathology findings were within normal limits.
COMMENT Lack of therapeutic progress in CRC during the past several decades has fostered increasing interest in its genetic epidemiology, early detection, and prevention. Several well-defined hereditary CRC-prone disorders have been identified, including HNPCC [1,5,13,14]. Strategies for HNPCC’s diagnosis that focus heavily on the cancer family history and the natural history features, in the face of the lack of premonitory clinical signs or biomarkers of genotypic susceptibility have evolved [ 1,5,11,14]. In certain circumstances, such as those in this family report, findings in the nuclear portion of the kindred may enable the diagnostician to focus almost immediately on the differential diagnosis of hereditary cancer. In this kindred, a familial cluster of gynecologic cancer prompted extension of the pedigree, with development of a hereditary cancer differential diagnosis, ultimately leading to the recognition of Lynch syndrome II [15-171. Success in this venture was based on the consulting physician’s knowledge of the natural history, pathology, and cancer’s pattern of distribution within the kindred, coupled with an understanding of how these factors associate with an increasingly important variety of extracolonic forms of cancer that may be integral to the Lynch syndrome II diagnosis [6,9,14,18,19]. In this case, the diagnosis of Lynch syndrome II was given high priority on the basis
201
of the presence of early-onset synchronous carcinoma of the endometrium and ovary in two sisters (IV-8, IV-9; Fig. 1, Table 1). This impression was further elucidated when the proband (IV-6; Fig. 1, Table 1) was found to manifest Duke’s A adenocarcinoma of her cecum. When the pedigree was extended to include second- and thirddegree relatives (Fig. 1, Table l), the most likely explanation for the mode of genetic transmission was through the paternal lineage. However, the possibility of transmission of a deleterious gene predisposing to ovarian cancer through the proband’s mother cannot be excluded. Given the common occurrence of cancer, one will frequently encounter familial clustering of cancer that may be attributable to chance alone. In the clinical practice setting, physicians are not usually in a position to perform extended research-type cancer family investigations on all of their patients who may appear to be cancer-prone. However, when certain of the cardinal features of cancer genetics appear in a proband’s first-degree relatives, such as early age of onset and specific patterns of multiple primary tumor combinations, this should alert one to the possibility of a hereditary syndrome diagnosis. Cancer history should then be extended to include the proband’s maternal and paternal second-degree relatives. This limited pedigree study takes advantage of the fact that it includes relatives who are older than the proband’s siblings and progeny and thereby will likely have passed through the cancer risk age. The occurrence of ovarian carcinoma in the mother (111-6; Fig. 1, Table 1) of this informative sibship was given primary etiologic consideration by several consultants during the evaluation of this family. The mother’s family was small and she did not have any siblings. Her mother’s (11-3; Fig. 1) history of uterine cancer could not be histologically verified. There was no other evidence of cancer in her lineage. There was a history of unverified kidney cancer in this mother’s paternal half-sister (111-7; Fig. 1). However, while we cannot exclude a contributory host susceptibility role relevant to the proband’s mother, we believe that the major genotypic influence contributing to Lynch syndrome II in this kindred was paternally transmitted. This decision logic was only possible when the family history was sufficiently extended to include details of the paternal lineage. Herein, we identified a pattern of cancer occurrences consonant with that of Lynch syndrome II. Specifically, the proband’s father (111-5; Fig. 1, Table l), his siblings (111-2, 111-3, 111-4;Fig. 1, Table 1) his father (11-2; Fig. 1, Table l), and his niece (IV-4; Fig. 1, Table 1) all manifested cancers of the type that have been described in Lynch syndrome II. For example, carcinoma of the ureter, as found in the proband’s father (111-S;Fig. 1, Table 1) has been described as an integral lesion in certain Lynch syndrome II kindreds [6]. Note that his brother (111-3) had early-onset colon cancer and
202
LYNCH ET AL.
carcinoma of the pancreas. His sister (111-2) had earlyonset ovarian carcinoma, while his father (B-2) had earlyonset carcinoma of the cecum, and his niece (IV-4) had endometrial carcinoma at age 47 and pancreatic cancer at age 52. When considering any hereditary cancer syndrome diagnosis, one must be cognizant of the fact that variable expressivity and reduced penetrance of the gene may occur. This is particularly the case in autosomal dominantly inherited disorders [12]. In the case of HNPCC, the gene penetrance, namely, whether the cancer will occur, is about 80% [20], while the expressivity of the cancer phenotype may be extremely variable, particularly with respect to tumor variation within and between families [ml.
In evaluating this family, it is important that the diagnostician took into consideration cancer findings in both the paternal and the maternal lineages. Clearly, the more detailed the family history, coupled with the clinician’s knowledge of hereditary CRC’s natural history and differential diagnosis, the more likely that an accurate diagnosis will be obtained. In the case of Lynch syndrome II, one must carefully consider the variable tumor spectrum aspect of the cancer phenotype. The cardinal components of this tumor spectrum include carcinoma of the colon and endometrium and, to a lesser extent, carcinoma of the ovary [5,7,11]. However, the extracolonic cancer spectrum in Lynch syndrome II also includes several more rarely occurring cancers, such as carcinoma of the ureter, which was a feature in this family [6]. Surveillance and management therefore must be focused appropriately on these aspects of cancer’s natural history in Lynch syndrome II. For example, there is substantial evidence of an excess of synchronous and metachronous colorectal carcinoma in the Lynch syndromes, thereby mandating subtotal colectomy as opposed to a more limited resection [4]. Note, however, that the proband received a hemicolectomy for her adenocarcinoma of the cecum. Clearly, a subtotal colectomy would have been the preferred operation. It will now be necessary to meticulously monitor her remaining colonic segment since her lifetime risk for metachronous colonic cancer may approach 100% [1,4]. The proband’s sisters (IV-g, IV-9; Fig. 1, Table 1) will require lifetime surveillance (annual colonoscopy) since they are considered to be obligate carriers of the Lynch syndrome II genotype in light of the fact that they have manifested synchronous carcinomas of the ovary and endometrium. Women at 50% genetic risk for Lynch syndrome II who present with CRC should be considered strong candidates for prophylactic TAH-BSO. The cancer control strategies in this family will now apply to all first-degree relatives of Lynch syndrome II cancer affecteds in this kindred. In order to ensure full
compliance with our surveillance recommendations, we initiate genetic counselling during the late teens. We believe it important that the physician devote sufficient time to explain in as great a detail as possible the significance of the genetic risk and the natural history of the cancer phenotype, so that the patient can more fully appreciate why the indicated surveillance measures are so much more rigorous than what would be expected for individuals in the general population. We then initiate colonoscopy at age 25. If polyps are lacking, we recommend that this be repeated every other year through age 35 and annually thereafter. For women, we recommend endometrial screening by cytologic and histologic techniques, vaginal probe ultrasound screening of the ovaries, and serum determinations of CA-125, to be performed at the same time that we initiate colonoscopy. Thereafter, we recommend annual repetition of this evaluation. We explain the limitations of surveillance for ovarian cancer. It is also essential that those women who undergo prophylatic TAH-BSO understand fully that there remains a risk for extraovarian peritoneal carcinomatosis [22-241. In conclusion, the clinical/genetic cancer nuances in this family were very striking and prompted concern about the likelihood of primary genetic factors being of etiologic importance. The differential diagnosis included a variety of familial ovarian cancer syndromes [11,25]. Consideration must also be given to familial aggregation of endometrial carcinoma [11,26]. However, with the exception of its occurrence in Lynch syndrome II, the evidence for its host factor susceptibility is limited [11,26]. One must even consider familial adenomatous polyposis (FAP) [l] since this disorder is exceedingly heterogeneous and may involve marked variation in the colonic polyp phenotype [l]. However, given the extremely early age of onset of synchronous endometrial and ovarian carcinoma in two of the proband’s sisters (IV-g, IV-9; Fig. 1, Table 1) and the finding of early-onset carcinoma of the cecum in the proband herself (IV-6; Fig. 1, Table l), the diagnosis of Lynch syndrome II emerged as the most secure diagnostic candidate. Undoubtedly, however, anticipated future advances in molecular genetics and gene linkage studies will enable greater ease and security in establishing hereditary cancer syndrome diagnoses. This should abet more costeffective management of these high-risk cancer-prone families.
REFERENCES 1. Lynch, P. M., and Lynch, H. T. Colon cancer genetics, Reinhold, New York (1985). 2. Mecklin, J. P. Frequency of hereditary colorectal carcinoma, Gustroenterology 83, 1021-1025 (1987).
CASE
3. Lynch, H. T., and Lynch, P. M. Tumor variation in the Cancer Family Syndrome: Ovarian cancer, Am. J. Surg. 138, 439-442 (1979). 4. Fitzgibbons, R. J., Jr., Lynch, H. T., Stanislav, G. V., et al. Recognition and treatment of patients with hereditary nonpolyposis colon cancer (Lynch syndromes I and II), Ann. Surg. 2@6,289-295 (1987). 5. Lynch, H. T., Kimberling, W., Albano, W., et al. Hereditary nonpolyposis colorectal cancer: Parts I and II, Cancer 56, 934-951 (1985). 6. Lynch, H. T., Ens, J. A., and Lynch, J. F. The Lynch syndrome II and urological malignancies, J. Ural. 143, 24-28 (1990). 7. Lynch, H. T., Voorhees, G. J., Lanspa, S. J., McGreevy, P. S., and Lynch, J. F. Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: A Family study, Br. J. Cancer 52,271-273 (1985). 8. Lynch, H. T., Fitzsimmons, M. L., Smyrk, T. C., et al. Familial pancreatic cancer: Clinicopathologic study of 18 nuclear families, Am. J. Gastroenterol. 85, 54-60 (1990). 9. Lynch, H. T., Smyrk, T. C., Lynch, P. M., et al., Adenocarcinoma of the small bowel in Lynch syndrome II, Cancer 64, 2178-2183 (1989). 10. Cristofaro, G., Lynch, H. T., Caruso, M. L., et al. New phenotypic aspects in a family with Lynch syndrome II, Cancer 60, 51-58 (1987). 11. Lynch, H. T., and Kullander, S. Cancer genetics in women, CRC Press, Boca Raton, FL (1987). 12. Lynch, H. T. Cancer genetics. Thomas, Springfield, IL (1976). 13. Lynch, H. T., Shaw, M. W., Magnuson, C. W., Larsen, A. L., and Krush, A. J. Hereditary factors in cancer: Study of two large midwestem kindreds, Arch. Intern. Med. 117, 206-212 (1966). 14. Lynch, H. T., Lanspa, S. J., Boman, B. M., et al. Hereditary nonpolyposis colorectal cancer-Lynch syndromes I and II, Gustroint. Clin. N. Am. 17, 679-712 (1988). 15. Lynch, H. T., and Lynch, J. F. Genetic predictability and minimal
REPORT
16.
17.
18. 19.
20.
21.
22. 23. 24.
25.
26.
203 cancer clues in Lynch syndrome II, DI. Colon. Rectum 30, 243246 (1987). Lynch, H. T., Watson, P. Kriegler, M., et al. Differential diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II), Dis. Colon. Rectum 31, 372-377 (1988). Lynch, H. T., Watson, P., Lanspa, S. J., et al. Natural history of colorectal cancer in hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II), Dis. Colon. Rectum, 31, 439-444 (1988). Lynch, H. T., Ens, J., Lynch, J. F., and Watson, P. Tumor variation in three extended Lynch syndrome II kindreds, Am. J. Gastroenterol. 83, 741-747 (1988). Lynch, H. T., Kriegler, M., Christiansen, T. A., Smyrk, T., Lynch, J. F., and Watson, P. Laryngeal carcinoma in a Lynch syndrome II kindred, Cancer 62, 1007-1013 (1988). Bailey-Wilson, J. E., Elston, R. C., Schuelke, G. S., et al. Segregation analysis of hereditary nonpolyposis colorectal cancer, Genet. Epidemiol. 3, 27-38 (1986). Vasen, H. F. A.,, Offerhaus, G. J. A., den Hartog Jager, F. C. A., et al. The tumor spectrum in HNPCC: A study of 24 kindreds in the Netherlands, ht. J. Cancer 46, 31-34 (1990). Dalrymple, J. C., Bannatyne, P., Russell, P., et al. Extraovarian peritoneal serous papillary carcinoma: A clinicopathologic study of 31 cases, Cancer 64, 110-115 (1989). Lynch, H. T., Bewtra, C., and Lynch, J. F. Familial ovarian carcinoma: Clinical nuances, Am. J. Med. 81, 1073-1076 (1986). Tobacman, J. K., Greene, Tucker, M. A., Costa, J., Kase, R., and Fraumeni, J. F. Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian cancer-prone families, Lancet ii, 795-797 (1982). Lynch, H. T., Fitzsimmons, M. L., Conway, T. A., Bewtra, C., and Lynch, J. Hereditary carcinoma of the ovary and associated cancers: A study of two families, Gynecol. Oncol. 36,48-55 (1990). Boltenberg, A., Furgyik, S., and Kullander, S. Familial cancer aggregations in cases of adenocarcinoma of the corpus uteri, Acta Obstet. Gynecol. Stand. 69, 249-258 (1990).
ONCOLOGY
44,
198-203 (1992)
CASE REPORT Gynecologic Cancer Clues to Lynch Syndrome II Diagnosis: A Family Report’ HENRY T. LYNCH, M.D.,*,2 *Depurtment
of Preventive
Medicine/Public
R. JENNIFER CAVALIERI, R. N.,* AND MURRAY JOSEPH CASEY, M.D.t
Health
and tDepartment Omaha,
JANE F. LYNCH,
of Obstetrics and Gynecology, Nebraska 68178
Creighton
B.S.N.,*
University
School
of Medicine,
Received June 27, 1991
Lynch syndromeII wasdiagnosedwhen two sisters manifested early-onset synchronouscarcinomasof the ovary and endometrium and a third sisterwasfound to have Duke’s A carcinoma of the cecum.A detailedcancerfamily history indicatedpaternal transmissionof the deleteriousgenotype. The pattern of carcinoma of the wlorectum and extracolonic sitesthroughout the extended family was then found to be consonantwith this hereditary cancer-pronedisorder. Lynch syndromeII may be exceedinglydifficult to diagnosedue to an absenceof premonitory clinical signsor biomarkersof genotypic susceptibility. Its recognition isthereforedependenton a detailedcancerfamily history (all anatomicsites),coupledwith knowledgeof the pattern of the cancerspectrum,distribution, and natural history, as manifested in this hereditary disorder. We describethe decisionlogic that wasinvolved in the diagnosisof Lynch syndromeII in this family and indicatethe important role of the gynecologistin this process. 0 1992 Academic Press, Inc. INTRODUCTION
Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for approximately 4-6% of the total colorectal cancer (CRC) burden [1,2]. It is much more common than its hereditary counterpart, familial adenomatous polyposis (FAP), which accounts for less than 1% of the total CRC diagnoses [l]. HNPCC has two major subdivisions: (1) Lynch syndrome I, which is characterized by an autosomal dominantly inherited proclivity to earlyonset CRC, with predominance proximal to the splenic ’ Support for this effort was provided by NC1 Grant 5 ROl CA 42705 and the Council for Tobacco Research USA, Inc., Grant 1297D. We also acknowledge the dedicated technical expertise provided by Diane Stanley. ’ To whom correspondence and reprint requests should be addressed. 198 0090-8258/92$1.50 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction
in any form reserved.
flexure [3], an excess of synchronous (at same time as initial cancer) and metachronous (more than 6 months from initial cancer) CRC [4], and the absence of florid colonic polyps, and (2) Lynch syndrome II, which shows all of these clinical features, but in addition, there is an excess of extracolonic cancer, particularly of the endometrium and ovary [l,S]. Other integral cancers have been more recently identified, involving the ureter and kidney [6], pancreas [7,8], small bowel [9], and stomach [lo]. Although the first manifestation of cancer in these patients involves the colorectum, this occasionally may be antedated by cancer of the endometrium or ovary Ill]. Since we are dealing with an autosomal dominantly inherited predisposition to cancer, the cancer family history may aid significantly in the diagnosis of HNPCC, thereby providing one of the most powerful cost-beneficial approaches to cancer family management and control [12]. However, diagnosis of HNPCC may be difficult in that there is an absence of premonitory clinical signs or biomarkers of genotypic susceptibility. Therefore, the diagnostician is wholly dependent on a detailed family history and knowledge of the clinical and natural history facets of cancer in HNPCC. Factors that may obfuscate its diagnosis include inadequate medical and pathology documentation of cancer, small family size, limited knowledge of family history, premature death in key informative relatives from noncancer etiologies, false paternity, patient mobility, and, on occasion, outright rejection of cooperation by family members. However, despite these limitations, the pattern of cancer occurrences within the nuclear family may be so striking as to signify the HNPCC diagnosis. Our purpose is to trace the decision logic that led to
199
CASE REPORT
FamiLy
3208
V
Cancer Individual Unaffected Current Cancer age at Current
by Pathology, diagnosis age
Cancer age at
by Family death
Multiple
Primary
Multiple Medical
Primary Records
Multiple
Prlnary
Number (Both
Ce co En Ki ov Pan Pro Psu Sk Ur ut
age
Cancer Medlca(
q L
Sites
number
History, Cancers
Unverified
Cancers or Death
by
Cancers
by
by Death Records of Unaffected Sexes)
Cecun Colon Endonetrium Kidney Ovary Pancreas Prostate Primary Skin Ureter Uterus
Site
Unknown
Certificates
Certificate
Pathology or
Progeny
Proband
FIG. 1. Family 3208, showing early-onset synchronous carcinoma of the endometrium and ovary in two sisters, early-onset carcinoma of the cecum in the proband, and a pattern of cancer distribution in the paternal lineage consonant with Lynch syndrome II.
the unraveling of a Lynch syndrome II diagnosis in a relatively small cancer-prone kindred that presented as a familial aggregation of gynecologic cancer. FAMILY
STUDY
The protocol for this study was approved by the Creighton University Institutional Review Board. The proband (IV-6; Fig. 1, Table 1) contacted us in 1990 because of her concern about her family history of cancer. We interviewed her in detail and received written permission
to contact her relatives. Questionnaires were then circulated to these individuals. Signed permission forms enabled us to secure primary medical and pathology documents. This allowed us to cross-reference all historical comments about genealogy, medical, and pathology findings for accuracy. The completed pedigree (Fig. 1) and tumor registry (Table 1) clearly showed the significant paternal involvement, comprising a pattern of cancer types consonant with Lynch syndrome II. The proband’s mother (111-6; Fig. 1, Table 1) had manifested ovarian carcinoma in the 1970s at age 54 years.
200
LYNCH ET AL.
TABLE 1 Tumor Registry for Family 3208 Patient No.
Sex
Age at death or diagnosis
Basis for Dx
I-l II-2 II-3
F M F
37 33 57
DC DC DC
Tumor, primary site unknown Carcinoma of the cecum Carcinoma of body of uterus with extensive metastasis
III-1 III-2 III-3
M F M
III-4
M
III-5
M
III-6 III-7 IV-4
F F F
IV-6 IV-8
F F
77 32 45 45 45 53 68 68 ? 71 72 54 66 47 52 40 42
FR DC MR MR MR MR FR FR FR PR PR PR FR PR PR PR PR
IV-9
F
42 38 38 38
PR PR
Prostate carcinoma Carcinoma of the ovary Colon carcinoma Colon carcinoma Skin carcinoma Carcinoma of the head of pancreas Carcinoma of the prostate Carcinoma of the ureter Skin carcinoma Stage D adenocarcinoma of the prostate Grade II Stage 0 carcinoma of the left ureter Grade III adenocarcinoma of both ovaries Kidney carcinoma Endometrial adenocarcinoma of the endometrioid type, Grade I/III Carcinoid islet cell tumor of the pancreas Grade II Dukes A adenocarcinoma of the cecum Well-differentiated endometrial carcinoma with clear cell features, admixed with adenomatous hyperplasia Grade III ovarian carcinoma Infiltrating adenosquamous carcinoma of the endometrium (Grade II) Metastatic adenocarcinoma to one of three lymph nodes Mixed serous and clear cell carcinoma of low malignant potential, with foci of invasion
PR
Diagnosis
Note. DC, death certificate; FR, family report; MR, medical records; PR, pathology report.
At that time, the proband (IV-6; Fig. 1) and her three sisters (IV-7, IV-8, IV-9; Fig. 1) believed that their lifetime risk for cancer of the ovary might be increased. However, they felt that this was a matter that should not concern them until they reached the age of 50 or 60. In 1989, one of the sisters (N-9; Fig. 1, Table 1) at age 38 years, experienced abdominal pain and noted very light, midcycle vaginal spotting that was presumed to be due to an ovarian cyst. However, ultrasound revealed a solid mass in her left ovary. Since she was recently married and wanted to have children, she requested that the surgical approach be as conservative as possible. The initial surgery therefore consisted of a dilation and curettage and excision of a left ovarian tumor. Frozen sections were done on the ovarian mass and the endometrial curettings. The pathology findings revealed a borderline malignancy in the left ovarian tumor and a markedly abnormal endometrium, “. . . probably well-differentiated endometrial adenocarcinoma.” The left ovary and tube were removed and a second opinion on the pathology, which confirmed well-differentiated endometrial carcinoma and mixed serous and clear cell carcinoma of low potential malignancy but with a focus of invasion in the ovarian surface, was obtained. These findings led to transabdom-
inal hysterectomy, right salpingo-oophorectomy, selective pelvic and para-aortic node excisions, and multiple pelvic and peritoneal biopsies. Infiltrating, Grade II, adenosquamous carcinoma of the endometrium was found and one of three pelvic nodes was positive for metastatic carcinoma, There was no residual carcinoma in the uterus, right tube, and ovary, or in other multiple biopsies that were taken. The sisters then sought consultation from a gynecological oncologist, during which time a detailed family history was taken. This consultant told them that there were “two” hereditary syndromes that involve the colon, breast, uterus, and ovary and stressed the need for them to have appropriate screening. They obtained additional consultation from several other oncologists and a medical geneticist. All consultants recommended prophylactic transabdominal hysterectomy-bilateral salpingo oophorectomy (TAH-BSG) on the basis of their estimated 50% risk for ovarian cancer. Patient IV-8 subsequently reported midcycle vaginal spotting without pain. Her physician performed an endometrial biopsy. Atypical hyperplasia of the endometrium was diagnosed. She was told that this was a precancerous lesion and given her family history, a TAH-
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BSO was recommended. She underwent a normal colonoscopy, and at age 42 years, a prophylactic TAH-BSO was performed. Well-differentiated endometrial carcinoma with clear cell features was found admixed with adenomatous hyperplasia. The ovaries appeared normal on gross inspection, but histopathologic evaluation showed a focus of ovarian carcinoma, Grade III. Peritoneal washings were cytologically negative for malignant cells, and selectively excised pelvic lymph nodes and multiple biopsies from pelvic and abdominal peritoneum and omentum were negative for cancer. However, the recovery of adenocarcinoma cells on cul-de-sac aspiration 7 months later has led to the diagnosis of recurrent, metastatic adenocarcinoma in the upper abdomen and omentum. Patient IV-7 underwent colonoscopy, folllowed by TAH-BSO, at age 46 years. Clinical and pathology findings from these procedures were within normal limits. Finally, the proband (IV-6; Fig. 1, Table 1) became extremely apprehensive as these cancer findings evolved in her sisters. At age 40 years, she underwent colonoscopy and sought prophylactic TAH-BSO. A Duke’s A adenocarcinoma of the cecum was diagnosed (Table 1). She underwent a hemicoloectomy and TAH-BSO. The gynecologic pathology findings were within normal limits.
COMMENT Lack of therapeutic progress in CRC during the past several decades has fostered increasing interest in its genetic epidemiology, early detection, and prevention. Several well-defined hereditary CRC-prone disorders have been identified, including HNPCC [1,5,13,14]. Strategies for HNPCC’s diagnosis that focus heavily on the cancer family history and the natural history features, in the face of the lack of premonitory clinical signs or biomarkers of genotypic susceptibility have evolved [ 1,5,11,14]. In certain circumstances, such as those in this family report, findings in the nuclear portion of the kindred may enable the diagnostician to focus almost immediately on the differential diagnosis of hereditary cancer. In this kindred, a familial cluster of gynecologic cancer prompted extension of the pedigree, with development of a hereditary cancer differential diagnosis, ultimately leading to the recognition of Lynch syndrome II [15-171. Success in this venture was based on the consulting physician’s knowledge of the natural history, pathology, and cancer’s pattern of distribution within the kindred, coupled with an understanding of how these factors associate with an increasingly important variety of extracolonic forms of cancer that may be integral to the Lynch syndrome II diagnosis [6,9,14,18,19]. In this case, the diagnosis of Lynch syndrome II was given high priority on the basis
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of the presence of early-onset synchronous carcinoma of the endometrium and ovary in two sisters (IV-8, IV-9; Fig. 1, Table 1). This impression was further elucidated when the proband (IV-6; Fig. 1, Table 1) was found to manifest Duke’s A adenocarcinoma of her cecum. When the pedigree was extended to include second- and thirddegree relatives (Fig. 1, Table l), the most likely explanation for the mode of genetic transmission was through the paternal lineage. However, the possibility of transmission of a deleterious gene predisposing to ovarian cancer through the proband’s mother cannot be excluded. Given the common occurrence of cancer, one will frequently encounter familial clustering of cancer that may be attributable to chance alone. In the clinical practice setting, physicians are not usually in a position to perform extended research-type cancer family investigations on all of their patients who may appear to be cancer-prone. However, when certain of the cardinal features of cancer genetics appear in a proband’s first-degree relatives, such as early age of onset and specific patterns of multiple primary tumor combinations, this should alert one to the possibility of a hereditary syndrome diagnosis. Cancer history should then be extended to include the proband’s maternal and paternal second-degree relatives. This limited pedigree study takes advantage of the fact that it includes relatives who are older than the proband’s siblings and progeny and thereby will likely have passed through the cancer risk age. The occurrence of ovarian carcinoma in the mother (111-6; Fig. 1, Table 1) of this informative sibship was given primary etiologic consideration by several consultants during the evaluation of this family. The mother’s family was small and she did not have any siblings. Her mother’s (11-3; Fig. 1) history of uterine cancer could not be histologically verified. There was no other evidence of cancer in her lineage. There was a history of unverified kidney cancer in this mother’s paternal half-sister (111-7; Fig. 1). However, while we cannot exclude a contributory host susceptibility role relevant to the proband’s mother, we believe that the major genotypic influence contributing to Lynch syndrome II in this kindred was paternally transmitted. This decision logic was only possible when the family history was sufficiently extended to include details of the paternal lineage. Herein, we identified a pattern of cancer occurrences consonant with that of Lynch syndrome II. Specifically, the proband’s father (111-5; Fig. 1, Table l), his siblings (111-2, 111-3, 111-4;Fig. 1, Table 1) his father (11-2; Fig. 1, Table l), and his niece (IV-4; Fig. 1, Table 1) all manifested cancers of the type that have been described in Lynch syndrome II. For example, carcinoma of the ureter, as found in the proband’s father (111-S;Fig. 1, Table 1) has been described as an integral lesion in certain Lynch syndrome II kindreds [6]. Note that his brother (111-3) had early-onset colon cancer and
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carcinoma of the pancreas. His sister (111-2) had earlyonset ovarian carcinoma, while his father (B-2) had earlyonset carcinoma of the cecum, and his niece (IV-4) had endometrial carcinoma at age 47 and pancreatic cancer at age 52. When considering any hereditary cancer syndrome diagnosis, one must be cognizant of the fact that variable expressivity and reduced penetrance of the gene may occur. This is particularly the case in autosomal dominantly inherited disorders [12]. In the case of HNPCC, the gene penetrance, namely, whether the cancer will occur, is about 80% [20], while the expressivity of the cancer phenotype may be extremely variable, particularly with respect to tumor variation within and between families [ml.
In evaluating this family, it is important that the diagnostician took into consideration cancer findings in both the paternal and the maternal lineages. Clearly, the more detailed the family history, coupled with the clinician’s knowledge of hereditary CRC’s natural history and differential diagnosis, the more likely that an accurate diagnosis will be obtained. In the case of Lynch syndrome II, one must carefully consider the variable tumor spectrum aspect of the cancer phenotype. The cardinal components of this tumor spectrum include carcinoma of the colon and endometrium and, to a lesser extent, carcinoma of the ovary [5,7,11]. However, the extracolonic cancer spectrum in Lynch syndrome II also includes several more rarely occurring cancers, such as carcinoma of the ureter, which was a feature in this family [6]. Surveillance and management therefore must be focused appropriately on these aspects of cancer’s natural history in Lynch syndrome II. For example, there is substantial evidence of an excess of synchronous and metachronous colorectal carcinoma in the Lynch syndromes, thereby mandating subtotal colectomy as opposed to a more limited resection [4]. Note, however, that the proband received a hemicolectomy for her adenocarcinoma of the cecum. Clearly, a subtotal colectomy would have been the preferred operation. It will now be necessary to meticulously monitor her remaining colonic segment since her lifetime risk for metachronous colonic cancer may approach 100% [1,4]. The proband’s sisters (IV-g, IV-9; Fig. 1, Table 1) will require lifetime surveillance (annual colonoscopy) since they are considered to be obligate carriers of the Lynch syndrome II genotype in light of the fact that they have manifested synchronous carcinomas of the ovary and endometrium. Women at 50% genetic risk for Lynch syndrome II who present with CRC should be considered strong candidates for prophylactic TAH-BSO. The cancer control strategies in this family will now apply to all first-degree relatives of Lynch syndrome II cancer affecteds in this kindred. In order to ensure full
compliance with our surveillance recommendations, we initiate genetic counselling during the late teens. We believe it important that the physician devote sufficient time to explain in as great a detail as possible the significance of the genetic risk and the natural history of the cancer phenotype, so that the patient can more fully appreciate why the indicated surveillance measures are so much more rigorous than what would be expected for individuals in the general population. We then initiate colonoscopy at age 25. If polyps are lacking, we recommend that this be repeated every other year through age 35 and annually thereafter. For women, we recommend endometrial screening by cytologic and histologic techniques, vaginal probe ultrasound screening of the ovaries, and serum determinations of CA-125, to be performed at the same time that we initiate colonoscopy. Thereafter, we recommend annual repetition of this evaluation. We explain the limitations of surveillance for ovarian cancer. It is also essential that those women who undergo prophylatic TAH-BSO understand fully that there remains a risk for extraovarian peritoneal carcinomatosis [22-241. In conclusion, the clinical/genetic cancer nuances in this family were very striking and prompted concern about the likelihood of primary genetic factors being of etiologic importance. The differential diagnosis included a variety of familial ovarian cancer syndromes [11,25]. Consideration must also be given to familial aggregation of endometrial carcinoma [11,26]. However, with the exception of its occurrence in Lynch syndrome II, the evidence for its host factor susceptibility is limited [11,26]. One must even consider familial adenomatous polyposis (FAP) [l] since this disorder is exceedingly heterogeneous and may involve marked variation in the colonic polyp phenotype [l]. However, given the extremely early age of onset of synchronous endometrial and ovarian carcinoma in two of the proband’s sisters (IV-g, IV-9; Fig. 1, Table 1) and the finding of early-onset carcinoma of the cecum in the proband herself (IV-6; Fig. 1, Table l), the diagnosis of Lynch syndrome II emerged as the most secure diagnostic candidate. Undoubtedly, however, anticipated future advances in molecular genetics and gene linkage studies will enable greater ease and security in establishing hereditary cancer syndrome diagnoses. This should abet more costeffective management of these high-risk cancer-prone families.
REFERENCES 1. Lynch, P. M., and Lynch, H. T. Colon cancer genetics, Reinhold, New York (1985). 2. Mecklin, J. P. Frequency of hereditary colorectal carcinoma, Gustroenterology 83, 1021-1025 (1987).
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3. Lynch, H. T., and Lynch, P. M. Tumor variation in the Cancer Family Syndrome: Ovarian cancer, Am. J. Surg. 138, 439-442 (1979). 4. Fitzgibbons, R. J., Jr., Lynch, H. T., Stanislav, G. V., et al. Recognition and treatment of patients with hereditary nonpolyposis colon cancer (Lynch syndromes I and II), Ann. Surg. 2@6,289-295 (1987). 5. Lynch, H. T., Kimberling, W., Albano, W., et al. Hereditary nonpolyposis colorectal cancer: Parts I and II, Cancer 56, 934-951 (1985). 6. Lynch, H. T., Ens, J. A., and Lynch, J. F. The Lynch syndrome II and urological malignancies, J. Ural. 143, 24-28 (1990). 7. Lynch, H. T., Voorhees, G. J., Lanspa, S. J., McGreevy, P. S., and Lynch, J. F. Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: A Family study, Br. J. Cancer 52,271-273 (1985). 8. Lynch, H. T., Fitzsimmons, M. L., Smyrk, T. C., et al. Familial pancreatic cancer: Clinicopathologic study of 18 nuclear families, Am. J. Gastroenterol. 85, 54-60 (1990). 9. Lynch, H. T., Smyrk, T. C., Lynch, P. M., et al., Adenocarcinoma of the small bowel in Lynch syndrome II, Cancer 64, 2178-2183 (1989). 10. Cristofaro, G., Lynch, H. T., Caruso, M. L., et al. New phenotypic aspects in a family with Lynch syndrome II, Cancer 60, 51-58 (1987). 11. Lynch, H. T., and Kullander, S. Cancer genetics in women, CRC Press, Boca Raton, FL (1987). 12. Lynch, H. T. Cancer genetics. Thomas, Springfield, IL (1976). 13. Lynch, H. T., Shaw, M. W., Magnuson, C. W., Larsen, A. L., and Krush, A. J. Hereditary factors in cancer: Study of two large midwestem kindreds, Arch. Intern. Med. 117, 206-212 (1966). 14. Lynch, H. T., Lanspa, S. J., Boman, B. M., et al. Hereditary nonpolyposis colorectal cancer-Lynch syndromes I and II, Gustroint. Clin. N. Am. 17, 679-712 (1988). 15. Lynch, H. T., and Lynch, J. F. Genetic predictability and minimal
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