Critical Reviews in Oncology/Hematology 93 (2015) 170–179

Mismatch repair gone awry: Management of Lynch syndrome Tian Zhang a,∗ , Elizabeth L. Boswell b , Shannon J. McCall c , David S. Hsu d a

d

Hematology and Medical Oncology, Duke Cancer Institute, Department of Medicine, Duke University Medical Center, DUMC 3841, Durham, NC 27710, United States b Pathology and Laboratory Medicine Service, Durham VA Medical Center, 508 Fulton St., Durham, NC 27705, United States c Duke Cancer Institute, Department of Pathology, Duke University Medical Center, DUMC 3712, Durham, NC 27710, United States Duke Cancer Institute, Department of Medicine, Division of Medical Oncology, Duke University Medical Center, DUMC 3233, Durham, NC 27710, United States Accepted 1 October 2014

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Background of Lynch syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. DNA mismatch repair: Biology of Lynch tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Clinical presentation of colorectal cancers in Lynch syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Clinical diagnosis of Lynch syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Evidence in prevention of malignancies in Lynch syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Treatment of colorectal cancer in Lynch syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

170 171 171 173 174 175 175 176 177 177 177 177 177 179

Abstract The hallmark of Lynch syndrome involves germline mutations of genes important in DNA mismatch repair. Affected family kindreds will have multiple associated malignancies, the most common of which is colorectal adenocarcinoma. Recently, evidence has shown that clinical diagnostic criteria provided by the Amsterdam Criteria and the Bethesda Guidelines must be linked with microsatellite instability testing to correctly diagnose Lynch syndrome. We present a case of metachronous colorectal adenocarcinomas in a patient less than 50 years of age, followed by a discussion of Lynch syndrome, with an emphasis on surveillance and prevention of malignancies. © 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Lynch syndrome; Mismatch repair; Microsatellite instability; Colorectal cancer; Hereditary gastrointestinal malignancies

1. Introduction ∗

Corresponding author. Tel.: +1 919 684 2287; fax: +1 919 684 3309. E-mail addresses: [email protected], [email protected] (T. Zhang), [email protected] (E.L. Boswell), [email protected] (S.J. McCall), [email protected] (D.S. Hsu). http://dx.doi.org/10.1016/j.critrevonc.2014.10.005 1040-8428/© 2014 Elsevier Ireland Ltd. All rights reserved.

A 47-year-old Caucasian man, self employed mason and former marine with otherwise no significant past medical history, initially presented in October 2002, when he developed acute right lower quadrant abdominal pain. He had

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Fig. 1. Timeline in case presentation.

bright red blood per rectum (BRBPR) for months initially attributed to hemorrhoids. He was taken to the operating room for an exploratory laparotomy and appendectomy, but intraoperative findings of a right-sided colon mass changed the procedure to a right hemicolectomy. He was surgically staged as Stage IIA (pT3N0, with no metastatic disease on subsequent computed tomography (CT) imaging). His tumor showed a microsatellite instability (MSI)-high phenotype, with MSI in 9 of 10 markers tested. The immunohistochemistry (IHC) report at the time further detected a “deficiency of PMS2 and/or MSH6, with normal expression of MSH2 and MLH1.” He received a course of adjuvant chemotherapy with 5-fluorouracil, which was complete in July 2003. His family history was significant for various malignancies. His mother had developed colon cancer in her 30s, with recurrences and eventually had a total colectomy. She subsequently also had breast cancer at age 68. His paternal grandfather also had colon cancer in his 70s. One of his three sisters developed colon cancer aged mid-40s, and another sister developed a possible brain tumor. He had 3 brothers, one of whom had died of liver cancer. In the intervening years, he underwent routine surveillance follow up with no evidence of disease on annual CT scans until 2006, and subsequently had clean colonoscopies every 2 years, including one in August 2011 (Fig. 1). In July 2013, he again presented with abdominal pain for 1 month, straining with bowel movements, stool incontinence with flatus, and hematochezia. On exam, he had a tender abdomen in the left lower quadrant, without rebound or guarding. His rectal exam demonstrated a firm mass palpable with tenderness to palpation and gross blood on inspection. Labs were significant for a normal CEA of 0.7, anemia with hemoglobin 10.7 g/dL, with MCV 82, normal WBC count of 5.5 mL−1 , and normal platelet count of 291,000 mL−1 . He underwent a CT of the abdomen and pelvis that showed new irregular circumferential soft tissue around the rectum with surrounding

lymphadenopathy, with no clear fat plane between rectum and prostate. Positron-emission tomography (PET) scanning showed the same findings, with FDG avidity in the wall thickening, as well as multiple FDG-avid retroperitoneal and pelvic lymph nodes. He subsequently underwent colonoscopy, demonstrating a rectal mass 15 cm from the anal verge, occupying 50–74% of the circumference. The tumor was friable and bled on contact. Biopsy of this lesion showed high grade, poorly differentiated adenocarcinoma (Fig. 2).

2. Discussion 2.1. Background of Lynch syndrome Up to 30% of colorectal cancers (CRC) are inherited, and known syndromes account for only 2-5% of all cases (Table 1). The two most common syndromes are Lynch syndrome and familial adenomatous polyposis (FAP), with

Table 1 Mutations affected in hereditary colorectal cancer syndromes. Cancer Syndrome

Mutation

Lynch syndrome Familial adenomatous polyposis Mixed polyposis syndrome Ashkenazi colorectal polyposis Hereditary breast & colorectal cancer MUTYH-associated polyposis

MLH1, MLH2, MSH6, PMS2, EpCAM APC GREM1 APC I1307K CHEK2 MUTYH

Syndromes with hamartomatous lesions Peutz-Jeghers Familial Juvenile polyposis Cowden disease Bannayan–Ruvalcaba–Riley

Mutation STK11 SMAD44, BMPR1A PTEN PTEN

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Fig. 2. Histopathology of patient’s recurrent rectal cancer. Poorly differentiated carcinoma cells with significant nuclear pleomorphism and mitotic figures underlie and invade muscularis mucosa, at 100× (A) and 400× (B). Immunohistochemistry was patchy positive for pan-cytokeratin at 100× (2C) and 400× (D), strongly positive for Ber-EP4 at 400× (E), and occasionally positive for CDX2 (F). Immunohistochemistry was positive for CEA, CK20, CK7, and negative for S100, MART1, PSA, p63, and CD45 (not shown).

Lynch syndrome being unique in having multiple culprit gene mutations, all affecting DNA mismatch repair. Lynch syndrome is named after Henry T. Lynch. He trained in the 1950s at University of Texas—Galveston and completed coursework for a Ph.D. in Human Genetics at Austin. He then became an internal medicine resident at the University of Nebraska and met many cancer patients who had relatives with cancers similar to their own diagnoses. He thus postulated that cancer was hereditary and genetic

during a time when cancer was thought to be largely environmental. He started tracking family kindreds and in 1966 published his findings in Archives of internal Medicine which tracked two families [1]. One family was based in Nebraska and had 51 malignancies in the four generations, with multiple affected family members dying in their 30s and 40s. The other family was based in Michigan, and 27 malignancies were described in 18 people over three generations. This family also had early mortality in affected family members

T. Zhang et al. / Critical Reviews in Oncology/Hematology 93 (2015) 170–179 Table 2 Malignancies observed in Lynch syndrome and lifetime risks of occurrence. Cancer

Lifetime cancer risks (%)

Colon Endometrium Ovary Stomach Hepatobiliary tract Upper urinary tract Pancreatic Small bowel CNS

50–80 40–60 9–12 11–19 2–7 4–5 3–4 1–4 1–3

from colon, uterine, upper GI, breast and ovarian tumors. This was the first description of what we know now to be Lynch syndrome. The term Lynch syndrome was coined in 1984 by others, with Lynch syndrome I indicating familial colon cancer and Lynch syndrome II indicating extracolonic features of Lynch syndrome. Dr. Lynch himself started using the term hereditary non-polyposis colorectal cancer (HNPCC) in 1985 to distinguish it from FAP. Lynch syndrome and hereditary nonpolyposis colorectal cancer (HNPCC) were interchangeable for some time. However, now that the genetic mutations have been better characterized, Lynch syndrome is more specific for patients with known defects in DNA mismatch repair. Lynch syndrome comprises about 2–4% of all colorectal cancers, approximately 2700–5400 cases out of more than 136,000 new cases expected in the US in 2014 [2]. Of affected patients, lifetime colorectal cancer risk ranges between 50% and 80%. Extracolonic malignancies are common, including endometrial, which is most common, but also tumors of the upper GI tract, urinary tract, ovarian, hepatobiliary tract, pancreas, and brain (Table 2) [3]. Patients who develop extracolonic sebaceous tumors can have an overlapping Muir-Torre Syndrome, which also affects MLH1 and MSH2 genes [4] and can occur in about 9% of patients with Lynch syndrome [5]. Intracranial tumors that develop as part of genetic mutations in mismatch repair often result from mutations in PMS2, and can overlap with Turcot syndrome [6]. 2.2. DNA mismatch repair: Biology of Lynch tumors DNA mismatch repair (MMR) is a process by which errors in DNA replication (so-called mismatches) are corrected during the process of cellular division. The mismatch repair process is a multi-step process, which relies on multiple proteins to recognize erroneous nucleotide insertions or deletions in DNA before cleaving and inserting the correct nucleotide into the DNA code. Defective mismatch repair and the inability to correct DNA mismatches lead to unstable DNA. Microsatellites, noncoding sites in DNA with repetitive sequences of 2 to 5 base pairs, are especially sensitive

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to DNA mismatch during cell replication. Thus, defective mismatch repair leads to MSI and can be easily tested from biopsy specimens [7]. In genetic linkage analysis of families with Lynch syndrome, patients were found to have defects in chromosomes 2, 3 and 7. In the early 1990s, these genes were cloned and sequenced and found to contain the MSH2 and MSH6 genes on the short arm of chromosome 2, the PSM1 gene on the long arm of chromosome 2, the MLH1 gene on the short arm of chromosome 3, and the PMS2 gene on chromosome the short arm of chromosome 7 [8]. 70% of the mutations were found to be truncating and 30% were missense. Of these, MLH1 and MSH2 mutations account for 90% of Lynch syndrome cases, MSH6 account for 10%, and PMS2 mutations are rare [3]. The specific gene mutation has been found to correspond to varying risks of cancer development; when compared to carriers of MLH1 or MSH2 mutations, for example, carriers of the MSH6 mutations have about one third less risk of developing colorectal cancer [9], but the same risk (40–60%) of developing endometrial cancer [10,11]. DNA MMR has been found to be a highly conserved process in evolution. MutS, MutH, and MutL are all parts of the mechanism of DNA MMR in Escherichia coli [12]. MutS has been found to recognize and bind mismatches, and has homologue genes in humans, MSH2 through MSH6. MutL is the scaffold protein that coordinates the multiple steps in MMR and its homologues in the human genome include MLH1, MLH2, MLH3 as well as PMS2. In humans, MLH1/PMS2 and MSH2/MSH6 form heterodimers to accomplish the task of repairing mismatches in the genome. For patients with Lynch syndrome, mutations in mismatch repair proteins result in higher rates of mutations in the genome including tumor suppressor genes or in oncogenes that lead to tumor development. Recently, germline EPCAM deletions have been shown to lead to hypermethylation of promoter sequences of MLH1 and MSH2 [13], and carriers of the EPCAM deletion have been shown to have a 75% risk of colorectal cancer in a retrospective cohort [14]. In addition, epigenetic silencing of MLH1 can sporadically occur through methylation of its promoter sequence, not necessarily linked to EPCAM deletions. These patients often demonstrate a mutation in BRAF (V600E) [7]. Therefore, not all MSI-high tumors can be attributable to Lynch syndrome. As a distinctly separate mechanism from microsatellite instability, chromosomal instability (CIN), resulting in aneuploidy and loss of heterozygosity, can also accumulate genomic aberrations to cause colorectal tumorigenesis [15]. CIN from germline mutations of APC is the hallmark of familial adenomatous polyposis (FAP) and will not be covered in this review. Focal CIN (such as deletion and amplification of focal genes) was recently found to be associated more often with sporadic V600E BRAF mutations, with wholearm chromosomal loss occurring more often in BRAF wild type patients [16].

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Fig. 3. Histologic features of colon cancer associated with Lynch syndrome. Mucinous pattern with malignant cells in pools of mucin at magnification of 200× (A). Signet ring cell histology at magnification 200× alone (B) and in combination with mucinous histology (C). Medullary histology demonstrating abundant tumor infiltrating lymphocytes shown at 200× magnification (D). Crohn’s-like lymphocytic response with lymphoid aggregates and follicles surrounding tumor and muscularis propria, 40× (E and F).

2.3. Clinical presentation of colorectal cancers in Lynch syndrome Approximately 70–85% of the time, colorectal tumors in Lynch syndrome are predominantly found in the right colon [17,18]. The median age of onset of colorectal cancer in patients with Lynch syndrome is earlier than the general population (45 years compared to 63 years) [19]. They also demonstrate accelerated carcinogenesis, as adenomas can develop into carcinomas within 2–3 years [19]. On histology,

they are poorly differentiated, with mucinous or signet ring cell features [3]. In addition, these tumors often have tumorinfiltrating lymphocytes, can display a medullary growth pattern, and can display a lymphocytic reaction with nodules surrounding germinal centers at the periphery of tumors, which is a pattern reminiscent of Crohn’s disease [18] (Fig. 3). In addition, there is a high risk of a metachronous primary malignancy within the colon; one series of Lynch syndrome patients had 10% metachronous cancers within 5 years of colonoscopy or subtotal colectomy [20]. Therefore,

T. Zhang et al. / Critical Reviews in Oncology/Hematology 93 (2015) 170–179 Table 3 Amsterdam criteria and Bethesda guidelines for the diagnosis of Lynch syndrome. Amsterdam Criteria II At least 3 relatives with associated cancer (colorectal, endometrial, small intestine, ureter, or renal pelvis), One should be first-degree relative of the other two Exclusion of FAP At least 1 of the tumors diagnosed before age 50 At least 2 successive generations involved Tumors verified by pathologic examination Bethesda Guidelines Colorectal cancer diagnosed in patient before age 50 Presence of synchronous or metachronous colorectal or other Lynch syndrome tumors, regardless of age Colorectal cancer with MSI-H diagnosed in patient before age 60 Colorectal cancer diagnosed in patient with one or more first-degree relatives with an HNPCC-related tumor, with one diagnosed before age 50 Colorectal cancer diagnosed in patient with two or more first-degree relatives with HNPCC-related tumors, regardless of age

it is necessary to accurately diagnose Lynch syndrome, appropriately treat, and continue interval surveillance, as will be discussed in the next few sections. 2.4. Clinical diagnosis of Lynch syndrome The Amsterdam criteria are a set of diagnostic criteria developed in 1990 to identify patients with Lynch syndrome [21] (Table 3). For the diagnosis of Lynch syndrome, three relatives must have a Lynch syndrome malignancy, with one patient being a first-degree relative of the other two, with at least two affected generations, at least one affected patient before age 50, verified by pathologic examination, and at the exclusion of FAP. However, about half of all patients who met these criteria did not qualify as having Lynch syndrome based on their pathology and were designated as familial colorectal cancer type X [22]. In 2004, the Bethesda Guidelines were released to diagnose Lynch syndrome [23]. These criteria encompass the following: (1) colorectal CA in a patient younger than 50; (2) presence of synchronous or metachronous colon cancers, or other tumors associated with the syndrome; (3) colorectal cancer with the MSI-high histology in a patient younger than 60; (4) CRC or Lynch tumor diagnosed before 50 in 1 firstdegree relative; and (5) CRC or tumor associated with Lynch in two first or second-degree relatives (Table 3). However, the Amsterdam and Bethesda guidelines are not as sensitive and specific as universal screening of testing for MMR mutations in tumor pathology [24]. In 2005, a large screening study of 1066 patients analyzed their MSI and germ-line mutations in the four mismatch repair genes using polymerase chain reaction (PCR). 208 patients had MSI-high and 23 of those had a mutation causing Lynch syndrome, 2.2%. 25% of the patients identified did not meet either the Amsterdam criteria or the Bethesda guidelines [25].

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Different modalities of testing can provide complementary information regarding MSI. PCR identifies the MSI-high phenotype, but does not provide information regarding which mismatch repair enzyme is mutated. Immunohistochemistry (IHC), on the other hand, can detect the specific mismatch repair protein(s) affected and can therefore suggest etiology [7]. Tumors deficient in the MSH2/MSH6 heterodimer are more likely to present from Lynch syndrome, whereas tumors deficient in the MSH1/PMS2 heterodimer are more commonly associated with the sporadic MSI-high tumors with BRAF V600E mutation [7,26]. Regardless of the test of choice, testing for MSI with either PCR or IHC (or both) has been shown to be sensitive, specific, and cost effective, now with widespread clinical use [27]. 2.5. Evidence in prevention of malignancies in Lynch syndrome The evidence in preventing malignancies in Lynch syndrome is sparse. Chemoprevention of colorectal cancer has been investigated the most using aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) [28]. Aspirin inhibits both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), enzymes necessary to make prostaglandin in cellular pathways for inflammation. COX-2 specifically has been found to be elevated in 90% of colon cancers and 40% of colonic adenomas [29]. To investigate whether aspirin prevents colorectal cancer in Lynch syndrome, the CAPP2 prevention trial enrolled 746 patients with Lynch syndrome between 1999 and 2005 and randomized them to aspirin 600 mg daily versus placebo [30]. The primary outcome was colorectal cancer development, and secondary outcomes included the development of colorectal adenoma and development of other Lynch syndrome cancers. They found that at a mean follow up of 55 months, the hazard ratio of developing CRC for those completing 2 years of aspirin therapy compared to those in the placebo arm was 0.41, with 95% CI 0.19–0.86. This led the authors to conclude that aspirin was protective against CRC in Lynch syndrome patients. Given the findings of aspirin protection in other CRCs [31], these results have been largely attributed to anti-inflammation effects of aspirin. Surveillance colonoscopies have been a key modality toward preventing or catching colorectal malignancies at early stages. A prospective cohort in South Africa studied 178 patients with the MLH1 mutation [32]. These patients were offered surveillance colonoscopy and about 2/3 agreed to surveillance. These patients had a lower risk of outcomes second CRC (2% in surveillance compared to 11% in non-surveillance group, p = 0.019) as well as death (12% in surveillance group compared to 27% in non-surveillance group, p = 0.032) [32]. In addition, the frequency of surveillance colonoscopies has been an important clinical question. Another prospective cohort in Finland identified Lynch families and offered surveillance or not with colonoscopies every 3 years [33].

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133 patients accepted and 119 patients declined surveillance colonoscopies. 18% of patients who had mutations in DNA mismatch repair and who underwent surveillance colonoscopies developed colorectal cancer, compared to 41% of patients with mutations who did not undergo surveillance [33]. The authors also showed an improvement in overall survival with colonoscopies every 3 years, with a 15-year survival rate of 92% in patients with mutations undergoing surveillance vs. 74% in those who did not receive surveillance (p = 0.05) [33]. A separate study analyzed 745 patients with gene mutations in MLH1, MSH2, and MSH6 in 205 families, and compared them against 344 patients in 46 families without Lynch syndrome, with surveillance colonoscopies every 1 to 2 years. Their endpoint was development of colorectal cancer or date of last colonoscopy. Comparing those with or without Lynch syndrome, 4.4% of patients with Lynch syndrome developed colorectal cancer under surveillance, compared to 1.7% of those without Lynch syndrome [34]. These rates were much lower than the cumulative risk over 10 years of 18% in 3-year surveillance that had been seen in previous studies [33]. Of the 3 mutations that were studied, the authors showed that MLH1 and MSH2 mutation carriers had higher risk of developing colorectal cancer [34]. Patients who have a first colon cancer are also at higher risk for a second primary. In a retrospective analysis of an international cohort of Lynch syndrome patients, Parry and colleagues compared patients with segmental colectomy with those that had a more extensive colectomy. Patients who had segmental colectomy without a more extensive colectomy had a risk of a second primary colorectal malignancy of 16% at 10 years, 41% at 20 years, and more than 60% at 30 years [35]. They commented that risk for a second primary colorectal cancer decreased by about one-third for every 10 cm more of bowel removed. Therefore, while prophylactic colectomy is not recommended before the diagnosis of colon cancer, after the appearance of colon cancer, a subtotal colectomy with ileorectal anastomosis may be considered to prevent the appearance of a second primary [11]. However, given limitations of bowel function after colonic removal, the decision to undertake a subtotal colectomy is certainly part of a complicated decision-making process, which clinicians and patients should undertake together. In addition to colorectal cancer, patients with Lynch syndrome have an increased risk of extracolonic tumors such those of the endometrium, ovaries, upper urinary tract, stomach, small bowel, hepatobiliary system, and pancreas (Table 2). These extracolonic malignancies were documented in the first two kindreds described in the 1960s [1]. Of the extracolonic tumors, endometrial and ovarian cancer are the second and third most commonly found in women with Lynch syndrome [18]. The current screening recommendations for patients in Lynch family cohorts are outlined in Table 4 [11]. These include a screening colonoscopy every 1–2 years starting at age 20–25. Due to the high risks of endometrial and ovarian

Table 4 Screening recommendations for Lynch syndrome families. Cancer

Recommendations

Age

Colon

Colonoscopy every 1–2 years Prophylactic colectomy generally not recommended Consider prophylactic TAH/BSO

20–25

Endometrium/ovary

Upper urinary tract Upper GI tract Other

Annual urinalysis Consider EGD q1–2 years Annual physical exam, ROS for related cancers, skin exam

After childbearing complete 30–35 30–35 21

cancers, female patients are recommended to start surveillance with transvaginal ultrasound for both endometrial and ovarian masses, endometrial aspiration, and CA-125 levels at age 30, repeated annually [18]. There is the caveat, however, that lesions on ultrasound are often premalignant on pathology [36], and surveillance is not as useful as heightened awareness and clinical symptoms such as vaginal bleeding and pain [36,37]. Moreover, women with Lynch syndrome should consider prophylactic hysterectomy and oophorectomy after childbearing is complete. After age 30–35, all patients should undergo annual urinalysis and consider EGD every 1-2 years. Finally, they should have an annual physical exam with particular attention to related cancers and a thorough skin exam after age 21. Most of these recommendations are based on expert recommendations and do not have grade 1 evidence to support the interventions [3,11,19]. 2.6. Treatment of colorectal cancer in Lynch syndrome There are currently no specific guidelines on the treatment of CRC in Lynch syndrome, and adjuvant treatment with 5fluorouracil, the typical backbone of treatment in CRC, is controversial. One of the first studies to address this issue was performed by Ribic et al., where they collected 570 tumor specimens from patients with stage II or stage III CRC in five randomized trials of 5-FU treatment and assessed the tumor specimens for MSI. Upon retrospectively analyzing outcomes, the investigators found that MSI-high tumors (compared to MSI-low or microsatellite stable) were associated with a benefit in overall survival in patients who did not receive adjuvant chemotherapy (HR 0.31, p = 0.004). In addition, adjuvant chemotherapy with 5-FU did not improve 5-year survival rates in patients who had MSI-high disease (HR 2.17, p = 0.10) [38]. In a subsequent study by Sargent et al., 457 tumor specimens from patients with Stage II or Stage III CRC across multiple trials were assessed for MSI status [39]. Similar to the Ribic study, patient with MSI receiving adjuvant 5-FU therapy showed no improvement in DFS (HR 1.10, p = 0.85) [39].

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However, as the primary endpoint of these two trials for DFS or OS defined as the time from randomization to death or recurrence or disease, a study by Sinicrope et al., asked a more specific question on the association between MSI and adjuvant treatment on site of tumor recurrence. In this study of 2141 stage II and III CRC patients in randomized trials of 5-FU-based adjuvant therapy, it was found that patients with stage III CRCs with MSI-high receiving adjuvant therapy with 5-FU had lower rates of distant recurrence (11% vs. 29%, p = 0.011) [40]. This analysis further showed that the subset of patients who benefited from adjuvant 5-FU based treatment were those with suspected germline mutations in MMR genes and therefore, in selected Stage III CRC patients with Lynch syndrome, adjuvant treatment based on 5-FU may be beneficial to reduce the distant recurrence risk. This raises an interesting question on whether or not the biology of patients with germline mutations in MMR genes versus sporadic MSI tumors is different. The latter is associated with epigenetic silencing of the promoter region of MMR genes by CpG island hypermethylation [41]. Only epigenetic silencing has been associated with the BRAF V600E mutation, which confers a poorer prognosis and potentially decreases response to chemotherapy in Stage III colorectal cancer [42]. In addition, the resistance to 5FU-based therapy in MSI tumors defined by epigenetic changes has been linked to preferential incorporation of fluorouracil metabolites into DNA, resulting in decreased inhibition of its target, thymidylate synthase [43]. Therefore, this suggests that patients with Lynch syndrome and germline mutations in MMR genes may be more sensitive to 5FU therapy than patients with epigenetic silencing MSI tumors. However, the trials to date have all been retrospective analysis and it remains unclear especially in Stage III disease how MSI status should impact clinical decision-making. The largest retrospective review of Stage III MSI patients was presented by Sargent, where 7803 stage II/III CRC across 17 trials were tested for MSI [44]. Of the 5533 Stage III tumor tested, 823 (14.9%) were found to be MSI-high and appeared to be prognostic in Stage III MSI tumors treated with 5-FU (time to recurrence HR = 0.8, p = 0.02 and overall survival HR = 0.79, p = 0.02), but as stated by the author, MSI appears to impact outcomes in Stage III patients, but does not currently alter patient management. Therefore, because of the limited data available for Stage III patients, the findings in Stage II patients should not be extrapolated to the Stage III setting. Finally, as all of these analyses were retrospective in nature, prospective trials testing the efficacy of adjuvant 5-FU based chemotherapy may be necessary to decipher the true value of adjuvant chemotherapy for patients with Lynch syndrome.

upper gastrointestinal, and urinary tract malignancies. The clinical diagnosis of Lynch syndrome is based on MSI testing at the time of tumor biopsy or resection. Patients in Lynch syndrome familial cohorts should undergo preventive colonoscopies every 1 to 2 years, as surveillance colonoscopies are key to diagnosing malignancies early in the disease course and improving rates of overall survival.

2.7. Summary

References

Lynch syndrome families carry mutations in highly conserved genes that regulate DNA mismatch repair, increasing their lifetime risk of colorectal, endometrial,

3. Case conclusion The preservation of MLH1 expression in this patient’s tumor supports the diagnosis of Lynch syndrome, since the vast majority of colorectal cancers with sporadic MSI phenotypes will display loss of MLH1 and PMS2 rather than loss of MSH2, MSH6, or isolated loss of PMS2. Given the current understanding of lack of benefit of chemotherapy for patients with stage II colon cancers that are MSI-high, in retrospect the patient should not have received adjuvant chemotherapy for his initial presentation in 2002. Eleven years after his first primary colorectal cancer, he was diagnosed with a second primary rectal adenocarcinoma, despite every 2-year colonoscopies. He was treated with neoadjuvant chemoradiation and symptoms of pain and hematochezia improved. He then underwent total proctocolectomy and was recommended by our multidisciplinary tumor conference to undergo subsequent adjuvant chemotherapy.

Conflict of interest statement All authors have no conflicts of interest.

Reviewers Hanna Sanoff, MD, MPH, Assistant Professor: University of North Carolina, Division of Hematology/Oncology, 170 Manning Drive, CB 7305, Chapel Hill, NC 27599-7305, United States. Andrew Ko, MD, Associate Professor: Department of Medicine (Hematology/Oncology), University of California, San Francisco, Box 1705, UCSF, San Francisco, CA 941431705, United States. Laura Goff, MD, Assistant Professor of Medicine (Hematology/Oncology), Associate Director: Hematology/Oncology Fellowship Program, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN 37232-6307, United States.

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Biographies Tian Zhang, MD, is a fellow in hematology and medical oncology at Duke University. She graduated from the Health Sciences and Technology program at Harvard Medical School-MIT in 2009 and completed residency training in internal medicine at Duke University Hospital. Her research interest is in the development of novel therapeutics and biomarkers in gastrointestinal and genitourinary malignancies. Elizabeth L. Boswell, MD is the Chief of Pathology and Laboratory Medicine Services at the Durham Veterans Affairs Medical Center in Durham, North Carolina, and Assistant Professor of Pathology at Duke University Medical Center. She received her MD degree from Mercer University in 2007 and completed residency in anatomic and clinical pathology at Duke University Medical Center. She also completed a fellowship in surgical pathology at the University of North Carolina-Chapel Hill. She has broad research interests including surgical pathology, hematopathology and clinical laboratory utilization practices.

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Shannon J. McCall, MD is Assistant Professor and Director of the Biospecimen Repository & Processing Core in the Duke Cancer Institute and the Department of Pathology at Duke University Medical Center. She received her MD from Duke University in 2000 and completed residency in anatomic and clinical pathology at Duke University Medical Center. She also completed a fellowship in gastrointestinal and hepatic pathology at Duke. She studies the pathobiology of gastrointestinal premalignant and malignant phenotypes. She is a member of the Expert Pathology Committee for Esophageal Cancer for The Cancer Genome Atlas Project. David S. Hsu, MD, PhD, is the William Dalton Family Assistant Professor of Cancer Genomics in the Division of Medical Oncology, Department of Medicine, in the Duke Cancer Institute and Duke University Medical Center. He received his PhD in Biochemistry from University of North Carolina–Chapel Hill in 1997 and his MD from University of North Carolina–Chapel Hill in 2001. He completed internal medicine residency training at University of Texas Southwestern Medical Center, and fellowship in hematology and medical oncology at Duke University. His research interest is in the development of genomic strategies improving the treatment of colorectal and other gastrointestinal malignancies.