Lynch syndrome C18.9

As early as the 19th century, the physician Aldred Warthin first described HNPCC (Schaffner 2004), describing a family with numerous digestive tract and gynecological carcinomas (Pellat 2018).

In 1962, H. T. Lynch described the Lynch syndrome named after him in more detail (Pellat 2018) and identified two different types of HNPCC:

- Type I: This manifests exclusively as a colorectal carcinoma with a preferred location in the proximal colon. It can occur syn- and metachronously.

- Type II: In addition to colorectal carcinomas, malignancies of the stomach, liver, pancreas, larynx, endometrium and urothelium also occur (Schaffner 2004).

Lynch syndrome (LS) is a hereditary disease in which colorectal carcinomas occur at a median age (Herold 2020).

In addition to the frequent occurrence of colorectal carcinomas, carcinomas of the stomach, small intestine, urinary tract and endometrial carcinomas can also occur (Ganten 2022).

Lynch syndrome is the most common form of hereditary colorectal cancer (Ghadimi 2022).

It was previously assumed that around 5% of all colorectal cancers were caused by Lynch syndrome. However, improvements in diagnostics, particularly panel diagnostics, have shown that the figure is actually around 10 % (Ghadimi 2022).

In patients with endometrial cancer, 2 % of those affected have Lynch syndrome (Pellat 2018).

Lynch syndrome is associated with germline mutations of an MMR gene (MisMatch Repair) [Pellat 2018] and high penetrance (Kasper 2015) in several DNA repair genes (Ganten 2002). It is inherited in an autosomal dominant manner (Herold 2020) and is therefore passed on to 50 % of the offspring (Steinke-Lange 2024).

Carriers of a pathogenic constitutional variant have a significantly increased risk of cancer, but the penetrance of the phenotype is not 100% (Pältomöki 2023).

Typical for a carcinoma associated with Lynch syndrome is the significantly earlier onset of the disease than correspondingly unassociated malignant diseases (Emons 2021).

Most of those affected fall ill before the age of 50, with the main age of manifestation being between 30 and 50. Men and women are affected equally often. Around 70 % of patients are initially diagnosed with colorectal carcinoma (Schaffner 2004).

- Colorectal carcinomas (CRC):

More than 50 % of colorectal carcinomas of Lynch syndrome are localized in the right colon section (Herold 2020).

- Endometrial carcinomas (EC):

Endometrial carcinoma is also referred to as "sentinel carcinoma" (Emons 2021). The risk of developing endometrial cancer is up to 50% on average (Herold 2020). In women affected by Lynch syndrome, EC manifests itself as the first carcinoma in > 50 % of cases (Emons 2021). The median age of onset is between 46 and 48 years (Guideline Program Oncology 2019).

- Ovarian, gastric and urothelial carcinoma:

The probability of developing the disease is < 10% in each case.

- Carcinoma of the small intestine, bile duct and pancreas:

These carcinomas only occur very rarely as part of Lynch syndrome

- Muir-Torre syndrome:

This occurs in combination with sebaceous gland tumors.

- Turcot syndrome:

In Turcot syndrome, there is a combination with brain tumors (Herold 2020).

The first screening method for detecting Lynch syndrome is the presence of MSI tumor cells, also known as microsatellite instability (Emons 2021). It is currently recommended to test all CRC biopsies for MSI-H / MMR-D in order to obtain early indications of Lynch syndrome (Biller 2019). At the same time, the detection of MSI is considered an indication for the use of checkpoint inhibitors (see also under "Internal therapy") (Emons 2021).

Prediction models such as the REMM (see http://premm.dfci.harvard.edu/) are available for families in whom Lynch syndrome is clinically suspected but who are not yet affected (Biller 2019).

The Amsterdam criteria defined by an international study group in 1990 play a particularly important role in the diagnosis of Lynch syndrome. Amsterdam Criteria 1 refer exclusively to colorectal carcinomas, while Amsterdam Criteria 2 also include extracolonic manifestations.

- Amsterdam criteria:

1. the patient has at least three relatives with histologically confirmed HNPCC-associated carcinomas.

2. one affected person is younger than 50 years old.

3. at least one of the two relatives with colon carcinoma is first-degree related to the other two.

4. colorectal carcinomas occur in at least two generations

5. exclusion of familial adenomatous polyposis (2019 oncology guideline program)

All criteria must be met in order to make a diagnosis of HNPCC (Schaffner 2004).

There are further criteria such as:

- Copenhagen criteria

These were developed in Copenhagen in 1993. These criteria are based on the above-mentioned Amsterdam criteria. In addition, these were expanded as follows:

1. endometrial carcinomas

2. carcinomas of the small intestine

3. ovarian carcinomas before the age of 50

4. gastric carcinomas before the age of 50

5. hepatobiliary carcinomas

6. urothelial carcinomas (Schaffner 2004)

In 1996, an international HNPCC workshop in Bethesda established screening criteria for the identification of patients with HNPCC, the so-called Bethesda criteria:

- Bethesda criteria

They state that the following patients should be tested:

1. patients with a family history of cancer who fulfill the Amsterdam criteria

2. patients with two HNPCC-associated carcinomas (syn- or metachronous) or associated carcinomas outside the colon

3. patients with colorectal carcinoma and a relative 1° with colorectal carcinoma

and / or

HNPCC- typical extracolonic carcinoma

and / or

colorectal adenoma. One of the carcinomas must have been diagnosed at the age of ≤ 45 years, the adenoma at the age of ≤ 40 years

4. patients with colorectal carcinoma or endometrial carcinoma. Age at diagnosis ≤ 45 years

5. patients with right-sided colorectal carcinoma of undifferentiated histology (solid / cririform). Age at diagnosis ≤ 45 years (Siegenthaler 2006)

The Bethesda criteria were subsequently revised as follows:

1. diagnosis of colorectal carcinoma before the age of 50.

2. regardless of age, diagnosis of syn- or metachromic colorectal carcinoma or other HNPCC-associated tumors such as colon, rectum, endometrium, stomach, renal pelvis, ureter, ovary, biliary syndrome, brain, skin, pancreas.

3. diagnosis of colorectal carcinoma before the age of 60 with tumors with typical MSI-H tumor histology, e.g. Crohn's-like lesions, tumor-infiltrating lymphocytes, medullary carcinoma, mucinous or signet ring cell differentiation.

4. patients with colorectal carcinoma in whom at least one relative also developed colorectal carcinoma or an HNPCC-associated tumor before the age of 50.

5. patient with colorectal carcinoma, regardless of age, in whom at least two 1st or 2nd degree relatives have also developed colorectal carcinoma or HNPCC-associated tumors regardless of age (Oncology Guideline Program 2019).

If one of the criteria described is met, the patient should be examined for microsatellite instability (Siegenthaler 2006).

Lynch syndrome is characterized by histological Crohn's-like lesions, tumor-infiltrating lymphocytes, medullary carcinomas, mucinous or signet-ring cell-like differentiation (2019 oncology guidelines).

- Type I: mucinous adenocarcinoma (Schaffner 2004)

- Brain tumors: Histologically predominantly as astrocytomas and glioblastomas (Guideline Program Oncology 2019).

- Lynch-like syndrome (LLS)

In this tumor, screening tests reveal an MSI or an absence of MMR gene products, but there is no germline mutation in the MMR genes (Emons 2021).

In approx. 60 % of mismatch repair-deficient colorectal carcinomas, no germline mutation is detected (Ghadimi 2022).

- Checkpoint inhibitors

The detection of MSI is considered an indication for the use of checkpoint inhibitors (Emons 2021).

Checkpoint inhibitors belong to the class of antibodies (Aktorius 2022)

Since Lynch syndrome-associated carcinoma diseases almost always contain MSI-H / MMR- D, the tumors are particularly responsive to immune-based therapies such as immune checkpoint inhibitors. Corresponding randomized studies are currently underway (Biller 2019).

If colorectal carcinoma is detected, extended resection of the affected section of bowel is recommended (Ghadimi 2022).

All major Lynch syndrome-associated carcinomas are associated with very good survival rates. The 10-year survival rate for:

- Colon carcinoma 88 %

- Rectal carcinoma 70 %

- Endometrial carcinoma 89 %

- Ovarian cancer 84 % (Pältomäki 2023)

To date, there are no generally recognized measures for the early detection of Lynch syndrome (Schaffner 2004).

Members of families affected by Lynch syndrome should undergo a colonoscopy annually or every two years from the age of 25, and women should also undergo a pelvic ultrasound examination and biopsies of the endometrium (Kasper 2015).

The following intervals are now recommended for examinations of Lynch patients:

- Physical examination once a year

- Presence of colorectal cancer: colonoscopy every 12 - 24 months from the age of 25 or 5 years before the earliest age of onset of the disease

- Presence of gastric or small intestine carcinoma: oesophagogastroduodenotomy every 12 - 36 months from the age of 25 or 5 years before the earliest age of onset of the disease

- Presence of ovarian cancer: none

- Presence of endometrial cancer: Optional examination by transvaginal sonography and endometrial biopsy from 30 - 35 years of age (Ghadimi 2022).

There is no recommendation for prophylactic colectomy, as carcinomas are usually detected at an early stage through appropriate screening (Ghadimi 2022).

Prophylactic hysterectomies and salpingoophorectomies effectively prevent Lynch-associated EC and ovarian cancer. High-dose aspirin therapy (≥ 2 years of 600 mg aspirin per day) can also reduce the incidence of Lynch-associated carcinomas (Biller 2019). Burn et al. published a study in the Lancet in 2020, according to which the preventive administration of 600 mg acetylsalicylate per day for 2-4 years reduced the incidence of CRC by almost half over a 10-year follow-up period (Burn 2020).

Recently, increasing evidence has emerged suggesting that the clinical phenotype and cancer risk vary depending on the mismatch repair mutation (Biller 2019).

1. Aktories K, Flockerzi V, Förstermann U, Hofmann F B (2022) General and special pharmacology and toxicology. Elsevier Urban and Fischer Publishers 16.5.4
2. Biller L H, Syngai S, Yurgelun M B (2019) Recent advances in Lynch syndrome. Fam Cancer 18 (2) 211 - 219
3. Burn J, Sheth H, Elliott F, Reed L, Macrae F, Mecklin J P, Möslein G, McRonald F E, Bertario L, Evans D G, Gerdes A M, Ho J W C, Lindblom A, Morrison P J, Rashbass J, Ramesar R, Seppälä T, Thomas H J W, Pylvänäinen K, Borthwick G M, Mathers J C, Bishop D T (2020) Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomized, placebo-controlled trial. Randomized Controls Trial. Lancet 395 (10240) 1855 - 1863
4. Emons G (2021) Focus on hereditary tumors: Lynch syndrome is an important hereditary tumor syndrome. Tumor, Diagnostics and Therapy 42 (10) 716 - 724
5. Ganten D, Ruckpaul K, Hahn S A, Schmiegel W (2002) Molecular medical principles of non-hereditary tumor diseases. Springer Verlag Berlin / Heidelberg / New York 176
6. Ghadimi M, Kalff J C (2022) General and Visceral Surgery II: Special Surgical Techniques. Elsevier Urban and Fischer Publishers Germany 298 - 302
7. Herold G et al (2020) Internal medicine. Herold publishing house 491
8. Kasper D L, Fauci A S, Hauser S L, Longo D L, Jameson J L, Loscalzo J et al. (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education 446, 540
9. Oncology guideline program (German Cancer Society, German Cancer Aid, AWMF): S3 guideline Colorectal carcinoma, long version 2.1 (2019) AWMF registration number: 021/007OL, http://www.leitlinienprogrammonkologie.de/leitlinien/kolorektales-karzinom/ [accessed on: 22.08.2024]
10. Pellat A, Netter J, Perkins G, Cohen R, Coulet F, Parc Y, Svrcek M, Duval A, Andre T (2018) Lynch syndrome: What is new? Bull Cancer (7 - 8) 647 - 655
11. Pältomäki P, Nyström M, Mecklin J P, Seppälä T T (2023) Lynch Syndrome Genetics and Clinical Implications. Gastroenterology 164 (5) 783 - 799
12. Schaffner M (2004) Studies on the incidence and identification of patients with hereditary non-polyposis colorectal carcinoma (HNPCC) in a university hospital and in academic teaching hospitals. Inaugural dissertation for the degree of Doctor of Medicine of the Faculty of Medicine of the Johann Wolfgang Goethe University in Frankfurt am Main.
13. Siegenthaler W, Blum H E (2006) Clinical Pathophysiology. Georg Thieme Verlag Stuttgart / New York 853
14. Steinke- Lange V, Holinsky- Feder E (2024) Lynch syndrome. Best Practice Oncology (19) 270 - 279