Lynch syndrome

Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Diagnosis is made by genetic testing of the index patient and their family members. Management consists of an earlier screening of individuals with defective MMR genes, as well as total colectomy if colorectal neoplasia is discovered. Prophylactic hysterectomy plus salpingo-oophorectomy are recommended for women beyond reproductive age.

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Epidemiology

  • Prevalence: 1 in 279 people carry defective mismatch repair (MMR) genes.
    • The most common inherited colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix cancer syndrome 
    • Accounts for 2%–4% of colorectal cancers
    • Increased risk for endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer and many other cancers
  • Malignancies occur earlier than in general population (5th decade).
  • General lifetime cancer risks in Lynch syndrome (LS) (approximate midpoints of broad ranges):
    • Colorectal cancer: 50% (right colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix > left colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix)
    • Endometrial cancer: 38% 
    • Ovarian cancer Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer: 19% 
    • Stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach cancer: 7% 
  • Sex ratio: women = men
Lynch syndrome cancer risk comparison

For people with Lynch syndrome, the lifetime cancer risk is also increased to a lesser extent for other cancers, including: renal pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis, ureters, bladder, brain, small bowel, hepatobiliary tract, pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas, prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands, and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin. In the figure, the upper ranges of the individual risks are given.

Image by Lecturio.

Etiology

Lynch syndrome patients inherit one or more mutant MMR genes and the respective normal allele/alleles; the 2nd allele then becomes mutated or loses function by epigenetic silencing so often that the inheritance pattern is effectively autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance.

  • MMR genes that can become mutated: MLH1, MSH2 (an EpCAM (epithelial cell adhesion molecule) gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations can also cause loss), MSH6, and PMS2 
  • Mutations then occur at rates up to 1,000 times higher than normal, mostly in regions of repetitive sequences called microsatellites. 
  • The protein products of mismatch repair (MMR) genes are important in “spell-checking” DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure during duplication by detecting and repairing DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure defects.
  • Loss of MMR activity causes an accumulation of DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication errors, particularly in repetitive sequences (“tandem repeats”).
    • Microsatellite testing that shows mutations in 30% or more microsatellites is called microsatellite instability-high (MSI-H) and is the hallmark of defective MMRs.
    • A cancer-driver mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations is eventually created by one of the uncorrected errors made during DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication.
  • MMR mutations can also occur as sporadic somatic mutations.

Pathogenesis and Pathology

Pathogenis

  • Some mutated microsatellite sequences are associated with cell growth genes, leading to a benign then malignant neoplastic polyp/carcinoma.
  • The MMR pathway of colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix carcinogenesis Carcinogenesis Carcinogenesis is the development of cancer by transforming healthy cells into cancer cells. This complex process occurs because of mutations in DNA that prevent the normal process of cell division. Normal cells have programmed cell death, but cancer cells proliferate without regulation. Carcinogenesis is the 2nd-most common pathway of colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer (CRC), after the adenoma-carcinoma pathway of colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix carcinogenesis Carcinogenesis Carcinogenesis is the development of cancer by transforming healthy cells into cancer cells. This complex process occurs because of mutations in DNA that prevent the normal process of cell division. Normal cells have programmed cell death, but cancer cells proliferate without regulation. Carcinogenesis.

Pathology

  • Characteristics of CRCs arising via the MMR (MSI-H) pathway: tend to show more mucinous features and reactive tumor-infiltrating lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes
  • Characteristics of endometrial carcinomas in LS: increased frequency of non-endometrioid carcinoma histologies
  • Slightly higher number of adenomatous polyps than the general population, but a higher rate of progression to CRC than typical polyps.

Clinical Presentation and Diagnosis

Clinical Presentation

  • Patients are asymptomatic until they develop malignancy.
  • Colorectal adenocarcinomas:
    • LS manifests with only a low or slightly higher-than-usual number of polyps.
    • Right-side carcinomas (more common): iron deficiency anemia Iron Deficiency Anemia Iron deficiency anemia is the most common type of anemia worldwide. This form of anemia is caused by insufficient iron due to a decreased supply, an increased loss, or an increased demand. Iron deficiency anemia is seen across all ages, sexes, and socioeconomic strata; however, children, women of childbearing age, and patients from lower socioeconomic strata are at higher risk. Iron Deficiency Anemia due to bleeding
    • Left-sided carcinomas: changes in bowel habits or stool caliber
  • Endometrial carcinomas: abnormal endometrial bleeding

Diagnosis

  • 1 or more germline mutations in the mismatch repair (MMR) genes or EPCAM gene are needed for a definitive diagnosis of Lynch syndrome.
  • 2 pathways are used to establish the diagnosis: Test the tumor first, or base testing on family history.
  • Suspect Lynch syndrome in any patient who has:
    • CRC prior to 50 years of age, or if more than 1 CRC
    • Endometrial carcinoma < 60 years of age
    • A 1st-degree relative with known LS 
    • Fulfilled accepted criteria for LS (Amsterdam criteria or Bethesda guidelines)
  • Amsterdam II criteria (poor sensitivity, suspect LS if the following criteria are met):
    • 3 or more relatives (at least 1 first-degree) have LS–associated cancers; familial adenomatous polyposis Familial Adenomatous Polyposis Familial adenomatous polyposis (FAP) is an autosomal dominant inherited genetic disorder that presents with numerous adenomatous polyps in the colon. Familial adenomatous polyposis is the most common of the polyposis syndromes, which is a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract, associated with other extracolonic features. Familial Adenomatous Polyposis ( FAP FAP Familial adenomatous polyposis (FAP) is an autosomal dominant inherited genetic disorder that presents with numerous adenomatous polyps in the colon. Familial adenomatous polyposis is the most common of the polyposis syndromes, which is a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract, associated with other extracolonic features. Familial Adenomatous Polyposis) excluded.
    • LS–associated cancers involving at least 2 generations
    • 1 or more cancers diagnosed before the age of 50 years
  • Bethesda guidelines, revised (better sensitivity and specificity than Amsterdam criteria):
    • CRC diagnosed < 50 years of age
    • 2 or more LS-associated cancers
    • CRC with MSI-H–like histology in patient < 60 years of age
    • CRC in patient with a 1st-degree relative with LS–associated cancer < 50 years
    • CRC in patient with 2 1st-degree relatives with LS–associated cancer, any age

Management

Surveillance and screening tests

  • For CRC: annual colonoscopy starting at 20–25 years of age, or 2–5 years prior to the earliest age of CRC diagnosis in the family
  • For endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer: annual endometrial biopsy, starting at 30 years of age
  • Annual skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin examinations to detect: sebaceous tumors (benign and malignant) and cutaneous keratoacanthomas associated with Muir-Torre syndrome (a variant of LS)
  • Reproductive counseling: LS patients of reproductive age should be offered carrier testing.

Surgical management

For CRC:

  • Total abdominal colectomy instead of segmental resection for CRC
  • If rectal cancer: total proctocolectomy

For endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer

  • Total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAHBSO) if cancer diagnosed
  • Prophylactic TAHBSO when childbearing is complete

Medical management

Chemoprevention:

  • Estrogen-progestin contraceptives reduce risk of endometrial and ovarian cancers
  • Aspirin: may reduce the risk of CRC 

Immunotherapy:

  • Pembrolizumab or nivolumab 
  • Used in MSI-H–/MMR–deficient tumors

Differential Diagnosis

  • FAP FAP Familial adenomatous polyposis (FAP) is an autosomal dominant inherited genetic disorder that presents with numerous adenomatous polyps in the colon. Familial adenomatous polyposis is the most common of the polyposis syndromes, which is a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract, associated with other extracolonic features. Familial Adenomatous Polyposis: presents with hundreds of adenomatous polyps and typically results in CRC in the distal colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix. Lynch syndrome typically manifests with CRC in the proximal colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix and only a low number of polyps. Genetic testing can distinguish between the 2 conditions.
  • Familial colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer type X (FCCTX): Amsterdam I criteria are met but the tumors lack the MSI seen in LS. No increased risk of other LS–associated cancers.

References

  1. Win, A.K. (2019). Lynch syndrome (hereditary nonpolyposis colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer): Clinical manifestations and diagnosis. UpToDate. Retrieved November 10, 2020, from https://www.uptodate.com/contents/lynch-syndrome-hereditary-nonpolyposis-colorectal-cancer-clinical-manifestations-and-diagnosis
  2. Kumar, V., Abbas, A. K., Aster, J.C., (Eds.). (2020). Small Intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine and Colon. Robbins & Cotran Pathologic Basis of Disease. (10th ed. pp. 814-816). Elsevier, Inc.
  3. Lynch syndrome. (2020). Cancer.Net. https://www.cancer.net/cancer-types/lynch-syndrome
  4. Li, K., Luo, H., Huang, L., Luo, H., & Zhu, X. (2020). Microsatellite instability: A review of what the oncologist should know. Cancer Cell International, 20(1), 16. https://doi.org/10.1186/s12935-019-1091-8
  5. Checkpoint inhibitor immunotherapy delays colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer progression. (n.d.). News.Cancerconnect.Com. Retrieved November 11, 2020, from https://news.cancerconnect.com/colon-cancer/checkpoint-inhibitor-immunotherapy-delays-colorectal-cancer-progression-cKTur5yY-k-yUY3aHZCjEw
  6. Oiseth, S. J., & Aziz, M. S. (2017). Cancer immunotherapy: A brief review of the history, possibilities, and challenges ahead. Journal of Cancer Metastasis and Treatment, 3, 250–261. https://doi.org/10.20517/2394-4722.2017.41
  7. Mardis, E. R. (2019). Neoantigens and genome instability: Impact on immunogenomic phenotypes and immunotherapy response. Genome Medicine, 11(1), 71. https://doi.org/10.1186/s13073-019-0684-0
  8. Therkildsen, C., Ladelund, S., Smith-Hansen, L. et al. (2017). Towards gene- and gender-based risk estimates in Lynch syndrome; age-specific incidences for 13 extra- colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer types. Br J Cancer, 117, 1702–1710. https://doi.org/10.1038/bjc.2017.348 
  9. Kalady, M. F., Kravochuck, S. E., Heald, B., Burke, C. A., & Church, J. M. (2015). Defining the adenoma burden in lynch syndrome. Diseases of the colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix and rectum Rectum The rectum and anal canal are the most terminal parts of the lower GI tract/large intestine that form a functional unit and control defecation. Fecal continence is maintained by several important anatomic structures including rectal folds, anal valves, the sling-like puborectalis muscle, and internal and external anal sphincters. Rectum and Anal Canal, 58(4), 388–392. https://doi.org/10.1097/DCR.0000000000000333
  10. Burn J, Sheth H, Elliott F, et al (Eds.) (2020). Cancer prevention with aspirin in hereditary colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial. Lancet (London, England), 395(10240), 1855–1863. https://doi.org/10.1016/S0140-6736(20)30366-4
  11. Peltomäki, P., Olkinuora, A., & Nieminen, T. T. (2020). Updates in the field of hereditary nonpolyposis colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer. Expert Review of Gastroenterology & Hepatology, 14(8), 707–720. https://doi.org/10.1080/17474124.2020.1782187
  12. Møller, P. (2020). The Prospective Lynch Syndrome Database reports enable evidence-based personal precision health care. Hereditary Cancer in Clinical Practice, 18. https://doi.org/10.1186/s13053-020-0138-0

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