Obstetrics & Gynecology:
Gynecologic Cancer as a “Sentinel Cancer” for Women With Hereditary Nonpolyposis Colorectal Cancer Syndrome
Lu, Karen H. MD*; Dinh, Mai MS*; Kohlmann, Wendy MS∥; Watson, Patrice PhD†; Green, Jane MD‡; Syngal, Sapna MD§; Bandipalliam, Prathap MD§; Chen, Lee-May MD¶; Allen, Brian MS¶; Conrad, Peggy MS¶; Terdiman, Jonathan MD¶; Sun, Charlotte PhD*; Daniels, Molly MS*; Burke, Thomas MD*; Gershenson, David M. MD*; Lynch, Henry MD†; Lynch, Patrick MD*; Broaddus, Russell R. MD, PhD*
From the *University of Texas M. D. Anderson Cancer Center, Houston, Texas; †Creighton University, Omaha, Nebraska; ‡Memorial University of Newfoundland, Canada; §Dana Farber Cancer Institute, Boston, Massachusetts; ¶University of California, San Francisco, California; and ∥University of Michigan, Ann Arbor, Michigan.
This study was supported by the National Cancer Institute (N01-CN-05127).
Presented at the 2004 Society of Gynecologic Oncologists Annual Meeting on Women's Cancer, February 7–11, 2004, San Diego, California.
Address reprint requests to: Karen H. Lu, MD, Department of Gynecologic Oncology, Division of Surgery, UT M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 440, Houston, TX 77030–4009; e-mail: email@example.com.
Received June 2, 2004. Received in revised form October 26, 2004. Accepted December 2, 2004.
OBJECTIVE: Women with hereditary nonpolyposis colorectal cancer syndrome have a 40–60% lifetime risk for colon cancer, a 40–60% lifetime risk for endometrial cancer, and a 12% lifetime risk for ovarian cancer. A number of women with hereditary nonpolyposis colorectal cancer syndrome will have more than one cancer in their lifetime. The purpose of this study was to estimate whether women with hereditary nonpolyposis colorectal cancer syndrome who develop 2 primary cancers present with gynecologic or colon cancer as their “sentinel cancer.”
METHODS: Women whose families fulfilled Amsterdam criteria for hereditary nonpolyposis colorectal cancer syndrome and who developed 2 primary colorectal/gynecologic cancers in their lifetime were identified from 5 large hereditary nonpolyposis colorectal cancer syndrome registries. Information on age at cancer diagnoses and which cancer (colon cancer or endometrial cancer/ovarian cancer) developed first was obtained.
RESULTS: A total of 117 women with dual primary cancers from 223 Amsterdam families were identified. In 16 women, colon cancer and endometrial cancer/ovarian cancer were diagnosed simultaneously. Of the remaining 101 women, 52 (51%) women had an endometrial or ovarian cancer diagnosed first. Forty-nine (49%) women had a colon cancer diagnosed first. For women who developed endometrial cancer/ovarian cancer first, mean age at diagnosis of endometrial cancer/ovarian cancer was 44. For women who developed colon cancer first, the mean age at diagnosis of colon cancer was 40.
CONCLUSION: In this large series of women with hereditary nonpolyposis colorectal cancer syndrome who developed 2 primary colorectal/gynecologic cancers, endometrial cancer/ovarian cancer was the “sentinel cancer,” preceding the development of colon cancer, in half of the cases. Therefore, gynecologists and gynecologic oncologists play a pivotal role in the identification of women with hereditary nonpolyposis colorectal cancer syndrome.
LEVEL OF EVIDENCE: II-3
Hereditary nonpolyposis colorectal cancer syndrome, or Lynch syndrome, is an autosomal-dominant inherited cancer susceptibility syndrome. Hereditary nonpolyposis colorectal cancer syndrome accounts for approximately 3% of all colon cancers and may account for a similar number of endometrial cancers.1,2 Hereditary nonpolyposis colorectal cancer syndrome is the result of a germline mutation in one of the genes in the DNA mismatch repair gene family, which includes MSH2, MLH1, and MSH6 and, less commonly, PMS1 and PMS2.3,4 As the name implies, hereditary nonpolyposis colorectal cancer syndrome primarily has been regarded as a colorectal cancer-dominated syndrome. However, recent studies have highlighted that for women, the risk of endometrial cancer may equal or exceed the risk for colon cancer. In studies that included individuals who were known to carry a germline mutation in MLH1 or MSH2, Aarnio et al5 reported a 60% lifetime risk of endometrial cancer in women with hereditary nonpolyposis colorectal cancer syndrome and a 54% lifetime risk of colon cancer, whereas Dunlop et al6 reported a 60% lifetime risk of endometrial cancer and a 39% lifetime risk of colon cancer. Lifetime risk of ovarian cancer was estimated to be 12%. In men, these same studies estimated a 74–83% risk of colon cancer.5,6
Traditionally, most hereditary nonpolyposis colorectal cancer syndrome registries have been established and maintained by gastroenterologists, colorectal surgeons, and gastrointestinal medical oncologists who have identified colon cancer patients with strong family histories and young age of onset as probands. Before the determination of DNA mismatch repair gene mutations as the germline genetic defect in families with hereditary nonpolyposis colorectal cancer syndrome, clinical criteria, called Amsterdam criteria, defined individuals with hereditary nonpolyposis colorectal cancer syndrome.7 The recognition of extracolonic cancers, including endometrial, ovary, small bowel, and ureteral/renal pelvis cancers, as part of the cancer spectrum of hereditary nonpolyposis colorectal cancer syndrome resulted in a revision to the Amsterdam criteria in 1999 (Appendix A).8 Although the revised Amsterdam criteria demonstrate excellent specificity for hereditary nonpolyposis colorectal cancer syndrome, it lacks sensitivity as a screening tool for clinicians to identify individuals who may benefit from further genetic evaluation. Therefore, the Bethesda Guidelines were developed in 1997 and revised in 2004 (Appendix B).9 The criteria focus primarily on patients with colon cancer and recommend further evaluation depending on certain tumor histology and age of onset. Individuals with 2 synchronous or metachronous hereditary nonpolyposis colorectal cancer syndrome-associated cancers also are included in the Bethesda criteria.
The risk of developing a second, metachronous cancer in individuals with hereditary nonpolyposis colorectal cancer syndrome is striking: 25% in the 10 years after diagnosis of a first cancer and 50% by 15 years after an initial cancer diagnosis.10,11 Therefore, the identification of an individual with hereditary nonpolyposis colorectal cancer syndrome at the time of diagnosis of a first cancer can have significant health ramifications. A woman with hereditary nonpolyposis colorectal cancer syndrome who survives a colon cancer has a high likelihood of developing an endometrial cancer. Similarly, a woman with hereditary nonpolyposis colorectal cancer syndrome who survives an endometrial cancer has a high likelihood of developing a colon cancer. Therefore, the recognition of the possibility of a hereditary cancer syndrome by a clinician caring for an individual with cancer has critical health implications both for the patient and for their siblings, children, and extended family.
Although recent studies have reported that women with hereditary nonpolyposis colorectal cancer syndrome have slightly higher risks of endometrial cancer than colon cancer,5,6 it is unclear which malignancy presents first. If women with hereditary nonpolyposis colorectal cancer syndrome all present with a colorectal cancer as their first cancer, gastroenterologists, gastrointestinal (GI) surgeons, and GI medical oncologists have a responsibility to identify these women and inform them of their risk for endometrial cancer. However, if women with hereditary nonpolyposis colorectal cancer syndrome present with endometrial cancer as their first cancer, gynecologists have a responsibility to identify these women and inform them of their risk for colon cancer. For hereditary nonpolyposis colorectal cancer syndrome, the mean age of onset for colon cancer has been reported as 41–44 years11–13 whereas the mean age of onset for endometrial cancer has been reported as 48–50 years.14–17 As a way of determining which cancer, colon or endometrial, presented first in women with hereditary nonpolyposis colorectal cancer syndrome who developed more than one primary cancer, we examined the records from 5 large hereditary nonpolyposis colorectal cancer syndrome registries and identified women who had multiple primary cancers, including a colorectal cancer and a gynecologic cancer. We hypothesized that, in a proportion of women with hereditary nonpolyposis colorectal cancer syndrome, gynecologic cancers are the “sentinel cancers.”
MATERIALS AND METHODS
Five large hereditary nonpolyposis colorectal cancer syndrome registries participated in this study: the University of Texas M. D. Anderson Cancer Center; Creighton University; University of California, San Francisco; Memorial University of Newfoundland; and Dana-Farber Cancer Institute. Three registries (M. D. Anderson Cancer Center; University of California, San Francisco; and Dana-Farber Cancer Institute) are predominantly colon-based, ie, probands are ascertained primarily through a GI clinic. Institutional Review Board approval was obtained for this study. Families that were included fulfilled revised Amsterdam criteria. All women who had a gynecologic (endometrial or ovarian) cancer and a colorectal cancer, whether synchronous or metachronous, were identified from the 5 participating registries. The total number of women identified was 126, of which 9 were excluded because the order of cancers was unknown, resulting in 117 women for the final study group. Age at diagnosis for each cancer was obtained, as well as site of cancers. For one patient, order of cancers was known but age at diagnosis for the cancers was not.
Data were analyzed using SPSS 11.5.1 (SPSS Inc, Chicago, IL). Descriptive statistics were used to summarize the clinical and demographic patient data. The Mann–Whitney U test was used to compare median age differences between those women who had a gynecologic cancer first compared with those who had a GI cancer first. P values of less than .05 were considered significant.
A total of 117 women with dual primary cancers from 223 families who fulfilled Amsterdam criteria were identified (Table 1). The overall median age of the cohort was 43 years (range 21–66 years). The interquartile range was 38–48 years. Sixteen of 117 women (13.7%) in this series had synchronous cancers at initial diagnosis. Of the 16 women with synchronous cancers, 11 patients had dual primary colon and endometrial cancers, 4 women had dual primary colon and ovarian cancers, and 1 woman had synchronous colon, endometrial, and ovarian cancers. Women with synchronous, dual primary colon and endometrial cancers had a median age of 50 years (range 42–56 years). Women with synchronous dual primary colon and ovarian cancers were considerably younger, with a median age of 42 years (P = .05).
Excluding the aforementioned 16 women with synchronous first primaries, 52 of 101 (51%) women presented with a gynecologic cancer first (n = 46 with endometrial cancer and n = 6 with ovarian cancer). The remainder (49%) women presented with a colon cancer first.
In the cohort of women with hereditary nonpolyposis colorectal cancer syndrome who had an endometrial cancer as their first cancer (n = 46), the median age was 45 years (range 27–62 years; Table 1). The median age of diagnosis of the second cancer was 50 years (range 32–72 years). Most of these women (44/46) had colon cancer as a second primary cancer, whereas 1 patient was diagnosed with an ovarian cancer as second primary and a colon cancer as a third primary, and 1 patient had a duodenal cancer as a second primary and a colon cancer as a third primary.
In the cohort of women with hereditary nonpolyposis colorectal cancer syndrome who had an ovarian cancer as their first cancer (n = 6), the median age at diagnosis was 39.5 years (range 29–65 years; Table 1). All of these women had colon cancer as their second diagnosis.
In the cohort of women with hereditary nonpolyposis colorectal cancer syndrome who had a colon cancer as their first cancer (n = 49), the median age at diagnosis was 40 years (range 21–66 years; Table 1). A statistically significant difference was found between the median ages of diagnosis in this cohort as compared with the cohort of women who had endometrial cancer as their first cancer (P = .002). Most of the women with colon cancer as their first cancer (41/49) had endometrial cancer as a second primary cancer, and 7 of 49 had an ovarian cancer as a second primary cancer.
The median time to second cancer is shown in Table 2. In the 44 patients with endometrial cancer as the first cancer, the median time to a second cancer was 11 years (range 1–39 years). In the 6 patients with ovarian cancer as the first cancer, the median time to a second cancer was 5.5 years (range 2–17 years). In the 49 patients with colon cancer as the first cancer, the median time to a second cancer was 8 years (range 1–26 years).
In this large study, we found that women with hereditary nonpolyposis colorectal cancer syndrome who had metachronous GI and gynecologic cancers often had an endometrial or ovarian cancer as their first diagnosed cancer, or “sentinel cancer.” Vasen et al14 examined a series of endometrial cancers in hereditary nonpolyposis colorectal cancer syndrome families and similarly found that in women with metachronous primary cancers, the diagnosis of an endometrial cancer as a first cancer was slightly more common than the diagnosis of a colorectal cancer as a first cancer. Recognition by the gynecologist that a patient with endometrial cancer or ovarian cancer may have hereditary nonpolyposis colorectal cancer syndrome is crucial and has profound ramifications for the patient and her family. Patients who are suspected to have hereditary nonpolyposis colorectal cancer syndrome should be referred for genetic counseling, and those at very high risk on the basis of family history or mutation status should undergo screening for colon cancer.
In our study, the median number of years between the diagnosis of a gynecologic cancer and the diagnosis of a colon cancer was 11 years. Patients who survive an initial endometrial or ovarian cancer diagnosis and are not identified by their physicians as having hereditary nonpolyposis colorectal cancer syndrome cannot take advantage of screening and prevention options for colon cancer. Currently, screening colonoscopy either yearly or every 2 years is recommended for individuals with hereditary nonpolyposis colorectal cancer syndrome beginning at age 20–25, and a recent study showed that screening colonoscopy was effective in decreasing mortality in this population of patients.18,19
In our study, the median number of years between the diagnosis of a colon cancer and the diagnosis of a gynecologic cancer was 8 years. Those women who survive an initial colon cancer diagnosis and are not identified as having hereditary nonpolyposis colorectal cancer syndrome cannot take advantage of screening and prophylactic surgery options for endometrial and ovarian cancer. We recommend that prophylactic hysterectomy and salpingo-oophorectomy should be considered when childbearing is complete. In our cohort, 22 women were aged 40 or older at the time of their initial colon cancer diagnosis. It is unclear how many of these patients were offered prophylactic hysterectomy and bilateral salpingo-oophorectomy at the time of their colon cancer surgery or how many subsequently were offered prophylactic surgery. Currently, guidelines for screening of gynecologic cancers in hereditary nonpolyposis colorectal cancer syndrome have been determined on the basis of consensus opinion.20 A pelvic examination, transvaginal ultrasonography, endometrial biopsy, and CA 125 are recommended annually, beginning at ages 25–35.
Finally, 13.7% of patients in our study had a colon cancer and gynecologic cancer diagnosed simultaneously. Gynecologists or gynecologic oncologists who suspect hereditary nonpolyposis colorectal cancer syndrome in a patient with endometrial cancer should consider colonoscopy or imaging of the colon preoperatively to rule out a concurrent colon cancer. Similarly, gastroenterologists and GI surgeons who suspect hereditary nonpolyposis colorectal cancer syndrome in a patient with colon cancer should consider an endometrial biopsy and/or pelvic ultrasonography preoperatively to rule out an endometrial or ovarian cancer. Patients diagnosed with colon cancer who are known mutation carriers or have a high likelihood for hereditary nonpolyposis colorectal cancer syndrome can undergo total abdominal hysterectomy and bilateral salpingo-oophorectomy at the time of surgery for their colon cancer.
Our study included only those individuals with synchronous or metachronous gynecologic (endometrial or ovarian) and colon cancers. Women with hereditary nonpolyposis colorectal cancer syndrome also may have dual primary cancers and also are at increased risk for stomach, small bowel, and ureteral/renal pelvis cancers.
In contrast to hereditary breast and ovarian cancer syndromes (BRCA1 and BRCA2), gynecologists and gynecologic oncologists have not played a significant role in identifying hereditary nonpolyposis colorectal cancer syndrome probands. Few studies have been performed to determine what clinical criteria should be applied to identify women with endometrial cancer as possible hereditary nonpolyposis colorectal cancer syndrome germline mutation carriers. Revised Bethesda Guidelines primarily focus on individuals with colon cancer. However, recent studies from our group and others have found that endometrial cancer in women younger than the age of 50, as well as in women younger than the age of 50 who have a first-degree relative with an hereditary nonpolyposis colorectal cancer syndrome-associated cancer, may be more appropriate screening criteria21 Although numerous studies have been conducted to determine the clinical, histologic, and molecular criteria that can be used to identify individuals with colon cancer who may have hereditary nonpolyposis colorectal cancer syndrome, very few large studies of a similar nature have been performed for individuals with endometrial cancer.
For all women with hereditary nonpolyposis colorectal cancer syndrome, early identification of a patient at the time of initial cancer diagnosis is crucial in proactively managing and reducing the patient's risk for subsequent cancers. Clinicians caring for women with endometrial cancer need to be aware that women with hereditary nonpolyposis colorectal cancer syndrome 1) are at equal or higher risk for developing endometrial cancer as colon cancer and 2) can present with endometrial cancer, ovarian cancer, or colon cancer as their initial cancer diagnosis. Recognition that a patient may have hereditary nonpolyposis colorectal cancer syndrome at their initial cancer diagnosis can be crucial to their future medical care. Future studies are necessary to determine what criteria gynecologists and gynecologic oncologists should use to triage patients for genetic counseling and testing.
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13. Lynch HT, Watson P, Lanspa SJ, Marcus J, Smyrk T, Fitzgibbons RJ Jr, et al. Natural history of colorectal cancer in hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). Dis Colon Rectum 1988;31:439–44.
14. Vasen HF, Watson P, Mecklin JP, Jass JR, Green JS, Nomizu T, et al. The epidemiology of endometrial cancer in hereditary nonpolyposis colorectal cancer. Anticancer Res 1994;14:1675–8.
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Amsterdam Criteria II8
Patient must meet ALL of the following criteria:
* Three or more relatives with a histologically verified hereditary nonpolyposis colorectal cancer–associated cancer (colorectal cancer, cancer of the endometrium, ovary, small bowel, ureter, or renal pelvis), one of whom is a first-degree relative of the other two (familial adenomatous polyposis should be excluded); AND
* Cancers involving at least 2 generations; AND
* One or more cancer cases diagnosed before the age of 50.
The Revised Bethesda Criteria for Testing Colorectal Tumors for Microsatellite Instability9
Tumors from individuals should be tested for microsatellite instability in the following situations:
* Colorectal cancer diagnosed in a patient who is less than 50 years of age.
* Presence of synchronous, metachronous colorectal, or other hereditary nonpolyposis colorectal cancer–associated tumors, regardless of age. (Hereditary nonpolyposis colorectal cancer–related tumors include colorectal, endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain [usually glioblastoma as seen in Turcot syndrome] tumors, sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome, and carcinoma of the small bowel.)
* Colorectal cancer with the microsatellite instability-high histology diagnosed in a patient who is less than 60 years of age. (Microsatellite instability-high in tumors refers to changes in 2 or more of the 5 National Cancer Institute–recommended panels of microsatellite markers. Histology indicated by presence of tumor-infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern.)
* Colorectal cancer diagnosed in one or more first-degree relatives with a hereditary nonpolyposis colorectal cancer–related tumor, with one of the cancers being diagnosed under age 50 years.
* Colorectal cancer diagnosed in 2 or more first- or second-degree relatives with hereditary nonpolyposis colorectal cancer–related tumors, regardless of age.
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